Addressing current challenges in cancer immunotherapy with mathematical and computational modelling.

PubMed

Konstorum, Anna; Vella, Anthony T; Adler, Adam J; Laubenbacher, Reinhard C

2017-06-01

The goal of cancer immunotherapy is to boost a patient's immune response to a tumour. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumour microenvironment, immune-modulating effects of conventional treatments and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modelling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumour classification, optimal treatment scheduling and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modellers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumour-immune biology. We conclude the review with recommendations for modellers both with respect to methodology and biological direction that might help keep modellers at the forefront of cancer immunotherapy development. © 2017 The Author(s).

Allogeneic tumor cell vaccines

PubMed Central

Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N; Imasuen, Imade E; He, Sara; Daniels, Danielle; Selvaraj, Periasamy

2014-01-01

The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies. PMID:24064957

Allogeneic tumor cell vaccines: the promise and limitations in clinical trials.

PubMed

Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N; Imasuen, Imade E; He, Sara; Daniels, Danielle; Selvaraj, Periasamy

2014-01-01

The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies.

Gold Nanoparticle Mediated Cancer Immunotherapy

PubMed Central

Almeida, Joao Paulo Mattos; Figueroa, Elizabeth Raquel; Drezek, Rebekah Anna

2013-01-01

Significant progress has been made in the field of cancer immunotherapy, where the goal is to activate or modulate the body’s immune response against cancer. However, current immunotherapy approaches exhibit limitations of safety and efficacy due to systemic delivery. In this context, the use of nanotechnology for the delivery of cancer vaccines and immune adjuvants presents a number of advantages such as targeted delivery to immune cells, enhanced therapeutic effect, and reduced adverse outcomes. Recently, gold nanoparticles (AuNP) have been explored as immunotherapy carriers, creating new AuNP applications that merit a critical overview. This review highlights recent advances in the development of AuNP mediated immunotherapies that harness AuNP biodistribution, optical properties and their ability to deliver macromolecules such as peptides and oligonucleotides. It has been demonstrated that the use of AuNP carriers can improve the delivery and safety of immunotherapy agents, and that AuNP immunotherapies are well suited for synergistic combination therapy with existing cancer therapies like photothermal ablation. PMID:24103304

Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge". Napoli, December 1st-4th 2015.

PubMed

Ascierto, Paolo A; Agarwala, Sanjiv; Botti, Gerardo; Cesano, Alessandra; Ciliberto, Gennaro; Davies, Michael A; Demaria, Sandra; Dummer, Reinhard; Eggermont, Alexander M; Ferrone, Soldano; Fu, Yang Xin; Gajewski, Thomas F; Garbe, Claus; Huber, Veronica; Khleif, Samir; Krauthammer, Michael; Lo, Roger S; Masucci, Giuseppe; Palmieri, Giuseppe; Postow, Michael; Puzanov, Igor; Silk, Ann; Spranger, Stefani; Stroncek, David F; Tarhini, Ahmad; Taube, Janis M; Testori, Alessandro; Wang, Ena; Wargo, Jennifer A; Yee, Cassian; Zarour, Hassane; Zitvogel, Laurence; Fox, Bernard A; Mozzillo, Nicola; Marincola, Francesco M; Thurin, Magdalena

2016-11-15

The sixth "Melanoma Bridge Meeting" took place in Naples, Italy, December 1st-4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various locoregional interventions that demonstrate promising results in treatment of advanced melanoma are also integrated with immunotherapy agents and the combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for melanoma patients' population. This meeting's specific focus was on advances in immunotherapy and combination therapy for melanoma. The importance of understanding of melanoma genomic background for development of novel therapies and biomarkers for clinical application to predict the treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into personalized-medicine approach for treatment of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. We also discussed the requirements for pre-analytical and analytical as well as clinical validation process as applied to biomarkers for cancer immunotherapy. The concept of the fit-for-purpose marker validation has been introduced to address the challenges and strategies for analytical and clinical validation design for specific assays.

Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy

PubMed Central

Baird, Jason R.; Savage, Talicia; Cottam, Benjamin; Friedman, David; Bambina, Shelly; Messenheimer, David J.; Fox, Bernard; Newell, Pippa; Bahjat, Keith S.; Gough, Michael J.; Crittenden, Marka R.

2016-01-01

The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstrate that the combination of immunotherapy and radiation results in improved therapeutic efficacy, and that the ideal timing of administration with radiation is dependent on the mechanism of action of the immunotherapy utilized. PMID:27281029

Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors.

PubMed

Terranova-Barberio, Manuela; Thomas, Scott; Munster, Pamela N

2016-06-01

Immune surveillance should be directed to suppress tumor development and progression, involving a balance of coinhibitory and costimulatory signals that amplify immune response without overwhelming the host. Immunotherapy confers durable clinical benefit in 'immunogenic tumors', whereas in other tumors the responses are modest. Thus, immune checkpoint inhibitors may need to be combined with strategies to boost immune response or increase the tumor immune profile. Epigenetic aberrations contribute significantly to carcinogenesis. Recent findings suggest that epigenetic drugs prime the immune response by increasing expression of tumor-associated antigens and immune-related genes, as well as modulating chemokines and cytokines involved in immune system activation. This review describes our current understanding regarding epigenetic and immunotherapy combination, focusing on immune response priming to checkpoint blockade.

Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy.

PubMed

Hoos, Axel; Ibrahim, Ramy; Korman, Alan; Abdallah, Kald; Berman, David; Shahabi, Vafa; Chin, Kevin; Canetta, Renzo; Humphrey, Rachel

2010-10-01

Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined ipilimumab pharmacokinetics and possibilities for combinability. Phase II trials of ipilimumab in advanced melanoma showed objective responses, but a greater number of patients had disease stabilization. In a phase III trial, ipilimumab was the first agent to demonstrate an improvement in overall survival in patients with previously treated, advanced melanoma. The adverse event profile associated with ipilimumab was primarily immune-related. Adverse events can be severe and life-threatening, but most were reversible using treatment guidelines. Ipilimumab monotherapy exhibits conventional and new patterns of activity in advanced melanoma, with a delayed separation of Kaplan-Meier survival curves. The observation of some new response patterns with ipilimumab, which are not captured by standard response criteria, led to novel criteria for the evaluation of immunotherapy in solid tumors. Overall, lessons from the development of ipilimumab contributed to a new clinical paradigm for cancer immunotherapy evolved by the Cancer Immunotherapy Consortium. Copyright © 2010 Elsevier Inc. All rights reserved.

Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach?

PubMed

Bernstein, Michael B; Krishnan, Sunil; Hodge, James W; Chang, Joe Y

2016-08-01

Conventional radiotherapy, in addition to its well-established tumoricidal effects, can also activate the host immune system. Radiation therapy modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents, which also promote the host antitumour immune response is, therefore, a logical progression. As the spectrum of clinical use of stereotactic radiotherapy continues to broaden, the question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). In this Perspectives article, we explore the preclinical and clinical evidence supporting activation of the immune system following SABR. We then examine studies that provide data on the effectiveness of combining these two techniques - immunotherapy and SABR - in an approach that we have termed 'ISABR'. Lastly, we provide general guiding principles for the development of future clinical trials to investigate the efficacy of ISABR in the hope of generating further interest in these exciting developments.

The emerging role of exosome and microvesicle- (EMV-) based cancer therapeutics and immunotherapy.

PubMed

Moore, Colin; Kosgodage, Uchini; Lange, Sigrun; Inal, Jameel M

2017-08-01

There is an urgent need to develop new combination therapies beyond existing surgery, radio- and chemo-therapy, perhaps initially combining chemotherapy with the targeting specificities of immunotherapy. For this, strategies to limit inflammation and immunosuppression and evasion in the tumour microenvironment are also needed. To devise effective new immunotherapies we must first understand tumour immunology, including the roles of T cells, macrophages, myeloid suppressor cells and of exosomes and microvesicles (EMVs) in promoting angiogenesis, tumour growth, drug resistance and metastasis. One promising cancer immunotherapy discussed uses cationic liposomes carrying tumour RNA (RNA-lipoplexes) to provoke a strong anti-viral-like (cytotoxic CD8 + ) anti-tumour immune response. Mesenchymal stem cell-derived EMVs, with their capacity to migrate towards inflammatory areas including solid tumours, have also been used. As tumour EMVs clearly exacerbate the tumour microenvironment, another therapy option could involve EMV removal. Affinity-based methods to deplete EMVs, including an immunodepletion, antibody-based affinity substrate, are therefore considered. Finally EMV and exosome-mimetic nanovesicles (NVs) delivery of siRNA or chemotherapeutic drugs that target tumours using peptide ligands for cognate receptors on the tumour cells are discussed. We also touch upon the reversal of drug efflux in EMVs from cancer cells which can sensitize cells to chemotherapy. The use of immunotherapy in combination with the advent of EMVs provides potent therapies to various cancers. © 2017 UICC.

Cancer Immunotherapy and Breaking Immune Tolerance-New Approaches to an Old Challenge

PubMed Central

Makkouk, Amani; Weiner, George

2014-01-01

Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. A growing understanding of immune tolerance has been the foundation for new approaches to cancer immunotherapy. Adoptive transfer of immune effectors such as antitumor monoclonal antibodies and Chimeric Antigen Receptor T cells bypasses many of the mechanisms involved in immune tolerance by allowing for expansion of tumor specific effectors ex vivo. Vaccination with whole tumor cells, protein, peptide, or dendritic cells has proven challenging, yet may be more useful when combined with other cancer immunotherapeutic strategies. Immunomodulatory approaches to cancer immunotherapy include treatment with agents that enhance and maintain T cell activation. Recent advances in the use of checkpoint blockade to block negative signals and so maintain the antitumor response are particularly exciting. With our growing knowledge of immune tolerance and ways to overcome it, combination treatments are being developed, tested and have particular promise. One example is in situ immunization that is designed to break tolerance within the tumor microenvironment. Progress in all these areas is continuing based on clear evidence that cancer immunotherapy designed to overcome immune tolerance can be useful for a growing number of cancer patients. PMID:25524899

Immunotherapy of non-small cell lung cancer: report from an international experts panel meeting of the Italian association of thoracic oncology.

PubMed

Gridelli, Cesare; Ascierto, Paolo A; Barberis, Massimo C P; Felip, Enriqueta; Garon, Edward B; O'brien, Mary; Senan, Suresh; Casaluce, Francesca; Sgambato, Assunta; Papadimitrakopoulou, Vali; De Marinis, Filippo

2016-12-01

The potential long term survival gain, related to immune adaptability and memory, the potential activity across multiple tumour types through targeting the immune system, and the opportunity for combinations offered by the unique mechanism of actions and safety profile of these new agents, all support the role of immunotherapy in the cancer treatment pathway or paradigm. Areas covered: The authors discuss the recent advances in the understanding of immunology and antitumor immune responses that have led to the development of new immunotherapies, including monoclonal antibodies that inhibit immune checkpoint pathways, such as Programmed Death-1 (PD-1) and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4). Currently, two PD-1 inhibitors are available in clinical practice for treatment of advanced non-small cell lung cancer (NSCLC): nivolumab and pembrolizumab. Expert opinion: Ongoing research will dictate future strategies, including the potential incorporation of immunotherapy in stage dependent treatment settings (early stage locally advanced disease and first line therapy for metastatic disease). Immunotherapy combinations are promising avenues, and careful selection of patients, doses of each agent and information supporting strategies (i.e. concomitant or sequential) is still needed.

Using Antigen-Specific B Cells to Combine Antibody and T Cell-Based Cancer Immunotherapy.

PubMed

Wennhold, Kerstin; Thelen, Martin; Schlößer, Hans Anton; Haustein, Natalie; Reuter, Sabrina; Garcia-Marquez, Maria; Lechner, Axel; Kobold, Sebastian; Rataj, Felicitas; Utermöhlen, Olaf; Chakupurakal, Geothy; Theurich, Sebastian; Hallek, Michael; Abken, Hinrich; Shimabukuro-Vornhagen, Alexander; von Bergwelt-Baildon, Michael

2017-09-01

Cancer immunotherapy by therapeutic activation of T cells has demonstrated clinical potential. Approaches include checkpoint inhibitors and chimeric antigen receptor T cells. Here, we report the development of an alternative strategy for cellular immunotherapy that combines induction of a tumor-directed T-cell response and antibody secretion without the need for genetic engineering. CD40 ligand stimulation of murine tumor antigen-specific B cells, isolated by antigen-biotin tetramers, resulted in the development of an antigen-presenting phenotype and the induction of a tumor antigen-specific T-cell response. Differentiation of antigen-specific B cells into antibody-secreting plasma cells was achieved by stimulation with IL21, IL4, anti-CD40, and the specific antigen. Combined treatment of tumor-bearing mice with antigen-specific CD40-activated B cells and antigen-specific plasma cells induced a therapeutic antitumor immune response resulting in remission of established tumors. Human CEA or NY-ESO-1-specific B cells were detected in tumor-draining lymph nodes and were able to induce antigen-specific T-cell responses in vitro, indicating that this approach could be translated into clinical applications. Our results describe a technique for the exploitation of B-cell effector functions and provide the rationale for their use in combinatorial cancer immunotherapy. Cancer Immunol Res; 5(9); 730-43. ©2017 AACR . ©2017 American Association for Cancer Research.

Rationale for combining immunotherapy with chemotherapy.

PubMed

Dalgleish, Angus G

2015-01-01

Immunotherapy has usually been considered as an alternative to more traditional modalities. Moreover, it has previously been felt that chemotherapy is inherently immunosuppressive and not suitable for combining with immunotherapy. In this review, the concept of combining different modalities that result in cell death, such as radiotherapy and chemotherapy, with immunotherapy is explored. Tumors actively cause immune suppression which can be reversed by their removal but when this is not possible, enhancing the immune response with nonspecific immune stimulation can enhance the response to other modalities, such as radiotherapy and chemotherapy. Additionally, several chemotherapy agents at low doses selectively inhibit regulatory and suppressor cells.

Recent progress in GM-CSF-based cancer immunotherapy.

PubMed

Yan, Wan-Lun; Shen, Kuan-Yin; Tien, Chun-Yuan; Chen, Yu-An; Liu, Shih-Jen

2017-03-01

Cancer immunotherapy is a growing field. GM-CSF, a potent cytokine promoting the differentiation of myeloid cells, can also be used as an immunostimulatory adjuvant to elicit antitumor immunity. Additionally, GM-CSF is essential for the differentiation of dendritic cells, which are responsible for processing and presenting tumor antigens for the priming of antitumor cytotoxic T lymphocytes. Some strategies have been developed for GM-CSF-based cancer immunotherapy in clinical practice: GM-CSF monotherapy, GM-CSF-secreting cancer cell vaccines, GM-CSF-fused tumor-associated antigen protein-based vaccines, GM-CSF-based DNA vaccines and GM-CSF combination therapy. GM-CSF also contributes to the regulation of immunosuppression in the tumor microenvironment. This review provides recommendations regarding GM-CSF-based cancer immunotherapy.

Strategies for Increasing Pancreatic Tumor Immunogenicity

PubMed Central

Johnson, Burles A.; Yarchoan, Mark; Lee, Valerie; Laheru, Daniel A.; Jaffee, Elizabeth M.

2017-01-01

Immunotherapy has changed the standard of care for multiple deadly cancers including lung, head and neck, gastric, and some colorectal cancers. However, single agent immunotherapy has had little effect in pancreatic adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single agent immunotherapies. In this review, we discuss differences between immunotherapy sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are drugable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes. PMID:28373364

Long-term intravital imaging of the multicolor-coded tumor microenvironment during combination immunotherapy

PubMed Central

Qi, Shuhong; Li, Hui; Lu, Lisen; Qi, Zhongyang; Liu, Lei; Chen, Lu; Shen, Guanxin; Fu, Ling; Luo, Qingming; Zhang, Zhihong

2016-01-01

The combined-immunotherapy of adoptive cell therapy (ACT) and cyclophosphamide (CTX) is one of the most efficient treatments for melanoma patients. However, no synergistic effects of CTX and ACT on the spatio-temporal dynamics of immunocytes in vivo have been described. Here, we visualized key cell events in immunotherapy-elicited immunoreactions in a multicolor-coded tumor microenvironment, and then established an optimal strategy of metronomic combined-immunotherapy to enhance anti-tumor efficacy. Intravital imaging data indicated that regulatory T cells formed an 'immunosuppressive ring' around a solid tumor. The CTX-ACT combined-treatment elicited synergistic immunoreactions in tumor areas, which included relieving the immune suppression, triggering the transient activation of endogenous tumor-infiltrating immunocytes, increasing the accumulation of adoptive cytotoxic T lymphocytes, and accelerating the infiltration of dendritic cells. These insights into the spatio-temporal dynamics of immunocytes are beneficial for optimizing immunotherapy and provide new approaches for elucidating the mechanisms underlying the involvement of immunocytes in cancer immunotherapy. DOI: http://dx.doi.org/10.7554/eLife.14756.001 PMID:27855783

Synergizing Radiation Therapy and Immunotherapy for Curing Incurable Cancers: Opportunities and Challenges

PubMed Central

Hodge, James W.; Guha, Chandan; Neefjes, Jacques; Gulley, James L.

2012-01-01

The combination of radiation therapy and immunotherapy holds particular promise as a strategy for cancer therapeutics. There is evidence that immunotherapy is most beneficial alone when employed early in the disease process or in combination with standard therapies (e.g., radiation) later in the disease process. Indeed, radiation may act synergistically with immunotherapy to enhance immune responses, inhibit immunosuppression, and/or alter the phenotype of tumor cells, thus rendering them more susceptible to immune-mediated killing. Furthermore, as monotherapies, both immunotherapy and radiation may be insufficient to eliminate tumor masses. However, following immunization with a cancer vaccine, the destruction of even a small percentage of tumor cells by radiation could result in cross-priming and presentation of tumor antigens to the immune system, thereby potentiating antitumor responses. Learning how to exploit radiation-induced changes to tumor-cell antigens, and how to induce effective immune responses to these cumulatively immunogenic stimuli, is an exciting frontier in cancer therapy research. This review examines a) mechanisms by which many forms of radiation therapy can induce or augment antitumor immune responses and b) preclinical systems that demonstrate that immunotherapy can be effectively combined with radiation therapy. Finally, we review current clinical trials where standard-of-care radiation therapy is being combined with immunotherapy. PMID:18777956

[Immune checkpoints inhibitors: Recent data from ASCO's meeting 2017 and perspectives].

PubMed

Kfoury, Maria; Disdero, Valentine; Vicier, Cécilé; Le Saux, Olivia; Gougis, Paul; Sajous, Christophe; Vignot, Stéphane

2018-06-19

Immune checkpoint inhibitors anti-PD-1, anti-PD-L1 and anti-CTLA-4 have been in development in several indications and have changed the face of cancer patients' management. Cancer immunotherapy was central in ASCO's meeting 2017. The identification of patients who could benefit most from immune checkpoint inhibitors is essential. The predictive value of PD-L1 status remains insufficient to select patients who could respond to immunotherapy. An extended search for new biomarkers predictive of response (INF-γ, mutational load) is ongoing, in order to better select responders. Immune checkpoint inhibitors have mainly been developed as monotherapy. However, the low response rate, between 10 and 30%, and the occurrence of resistance, contributes to the increment of new therapeutic strategies. This review summarizes the results of combination trials of two immune checkpoint inhibitors, combination of immunotherapy with conventional chemotherapy, radiotherapy or targeted therapies active on the oncogenic addiction pathway. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Fighting liver cancer with combination immunotherapies | Center for Cancer Research

Cancer.gov

A new clinical trial testing the effectiveness of immunotherapy treatment combinations against liver cancer is enrolling patients at the NIH Clinical Center in Bethesda, Maryland. Individually, immunotherapy drugs harness the power of the human immune system to better identify and kill cancer cells. Now, researchers at the NIH’s Center for Cancer Research have begun to find

The synergy between ionizing radiation and immunotherapy in the treatment of prostate cancer.

PubMed

Sathianathen, Niranjan J; Krishna, Suprita; Konety, Badrinath R; Griffith, Thomas S

2017-09-01

There has been a surge in the use of immunotherapy for genitourinary malignancies. Immunotherapy is an established treatment for metastatic renal cell carcinoma and nonmuscle invasive bladder cancer, but its potential for treating prostate cancer (PCa) remains under investigation. Despite reported survival benefits, no published Phase III PCa trials using immunotherapy only as a treatment has demonstrated direct antitumor effects by reducing prostate-specific antigen levels. Subsequently, the thought of combining immunotherapy with other treatment modalities has gained traction as a way to achieving optimal results. Based on data from other malignancies, it is hypothesized that radiotherapy and immunotherapy can act synergistically to improve outcomes. We will discuss the clinical potential of combining immune-based treatments with radiotherapy as a treatment for advanced PCa.

Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy.

PubMed

Shrimali, Rajeev; Ahmad, Shamim; Berrong, Zuzana; Okoev, Grigori; Matevosyan, Adelaida; Razavi, Ghazaleh Shoja E; Petit, Robert; Gupta, Seema; Mkrtichyan, Mikayel; Khleif, Samir N

2017-08-15

We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4 + and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4 + and CD8 + T cells along with a decrease of inhibitory cells. To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.

Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-14-1-0109 TITLE: Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer PRINCIPAL INVESTIGATOR...Elizabeth A. Mittendorf, MD, PhD CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston, TX 77030 REPORT DATE: October...CONTRACT NUMBER Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0109 5c. PROGRAM

Combinations of Radiotherapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

PubMed Central

Barker, Christopher A.; Postow, Michael A.

2015-01-01

Radiotherapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiotherapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiotherapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiotherapy. The cytokines interferon-alpha and interleukin-2 have been combined with radiotherapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiotherapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested radiotherapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiotherapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study. PMID:24661650

Mechanisms and applications of interleukins in cancer immunotherapy.

PubMed

Anestakis, Doxakis; Petanidis, Savvas; Kalyvas, Spyridon; Nday, Christiane M; Tsave, Olga; Kioseoglou, Efrosini; Salifoglou, Athanasios

2015-01-13

Over the past years, advances in cancer immunotherapy have resulted in innovative and novel approaches in molecular cancer diagnostics and cancer therapeutic procedures. However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted. The goal of this review is to evaluate the major cytokines-interleukins involved in cancer immunotherapy and project their basic biochemical and clinical applications. Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines. Furthermore, current interleukin-based approaches and clinical trial data from combination cancer immunotherapies will also be discussed. It appears that continuously increasing comprehension of cytokine-induced effects, cancer stemness, immunoediting, immune-surveillance as well as understanding of molecular interactions emerging in the tumor microenvironment and involving microRNAs, autophagy, epithelial-mesenchymal transition (EMT), inflammation, and DNA methylation processes may hold much promise in improving anti-tumor immunity. To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents.

Mechanisms and Αpplications of Ιnterleukins in Cancer Immunotherapy

PubMed Central

Anestakis, Doxakis; Petanidis, Savvas; Kalyvas, Spyridon; Nday, Christiane M.; Tsave, Olga; Kioseoglou, Efrosini; Salifoglou, Athanasios

2015-01-01

Over the past years, advances in cancer immunotherapy have resulted in innovative and novel approaches in molecular cancer diagnostics and cancer therapeutic procedures. However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted. The goal of this review is to evaluate the major cytokines-interleukins involved in cancer immunotherapy and project their basic biochemical and clinical applications. Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines. Furthermore, current interleukin-based approaches and clinical trial data from combination cancer immunotherapies will also be discussed. It appears that continuously increasing comprehension of cytokine-induced effects, cancer stemness, immunoediting, immune-surveillance as well as understanding of molecular interactions emerging in the tumor microenvironment and involving microRNAs, autophagy, epithelial-mesenchymal transition (EMT), inflammation, and DNA methylation processes may hold much promise in improving anti-tumor immunity. To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents. PMID:25590298

Combined Treatment Effects of Radiation and Immunotherapy: Studies in an Autochthonous Prostate Cancer Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wada, Satoshi; Harris, Timothy J.; Tryggestad, Erik

2013-11-15

Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evidentmore » with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.« less

Fighting liver cancer with combination immunotherapies | Center for Cancer Research

Cancer.gov

A new clinical trial testing the effectiveness of immunotherapy treatment combinations against liver cancer is enrolling patients at the NIH Clinical Center in Bethesda, Maryland. Individually, immunotherapy drugs harness the power of the human immune system to better identify and kill cancer cells. Now, researchers at the NIH’s Center for Cancer Research have begun to find evidence that the drugs may work far more effectively when taken in combination with other therapies and with each other than when taken alone.

Combining immunotherapies for the treatment of prostate cancer.

PubMed

Redman, Jason M; Gulley, James L; Madan, Ravi A

2017-12-01

Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration-approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel-T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen-targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway. Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction. Copyright © 2017. Published by Elsevier Inc.

Cancer Immunotherapy Utilized Bubble Liposomes and Ultrasound as Antigen Delivery System

NASA Astrophysics Data System (ADS)

Oda, Yusuke; Otake, Shota; Suzuki, Ryo; Otake, Shota; Nishiie, Norihito; Hirata, Keiichi; Taira, Yuichiro; Utoguchi, Naoki; Maruyama, Kazuo

2010-03-01

In dendritic cells (DCs)-based cancer immunotherapy, it is important to present the epitope peptide derived from tumor associated antigens (TAAs) on MHC class I in order to induce tumor specific cytotoxic T lymphocytes (CTLs). However, MHC class I molecules generally present the epitope peptides derived from endogenous antigens for DCs but not exogenous ones such as TAAs. Recently, we developed the novel liposomal bubbles (Bubble liposomes) encapsulating perfluoropropane nanobubbles. In this study, we attempted to establish the novel antigen delivery system to induce MHC class I presentation using the combination of ultrasound and Bubble liposomes. Using ovalbumin (OVA) as model antigen, the combination of Bubble liposomes and ultrasound exposure for the DC could induce MHC class I presentation. In addition, the viability of DCs was more than 80%. These results suggest that Bubble liposomes might be a novel ultrasound enhanced antigen delivery tool in DC-based cancer immunotherapy.

CTLA-4 blockade plus adoptive T cell transfer promotes optimal melanoma immunity in mice

PubMed Central

Mahvi, David A.; Meyers, Justin V.; Tatar, Andrew J.; Contreras, Amanda; Suresh, M.; Leverson, Glen E.; Sen, Siddhartha; Cho, Clifford S.

2014-01-01

Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T cell populations (e.g., CTLA-4 blockade-mediated checkpoint inhibition) or introduce exogenously-prepared tumor-specific T cell populations (e.g., adoptive cell transfer). Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and non-lymphodepletional adoptive cell transfer could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, adoptive cell transfer, or combination immunotherapy of CTLA-4 blockade with adoptive cell transfer. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, as well as a stronger systemic immune responses reflected by more potent tumor antigen-specific T cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with non-lymphodepletional adoptive cell transfer may promote additive endogenous and exogenous T cell activities that enable greater therapeutic efficacy in the treatment of melanoma. PMID:25658614

Advances in urothelial bladder cancer immunotherapy, dawn of a new age of treatment.

PubMed

Aoun, Fouad; Rassy, Elie El; Assi, Tarek; Albisinni, Simone; Katan, Joseph

2017-03-01

Urothelial bladder cancer displays a high number of somatic mutations that render these tumors more responsive to immunotherapy. Several immunotherapeutic agents were examined in patients with advanced stage urothelial bladder cancer and recently atezolizumab - an (PDL-1) immune checkpoint inhibitor antibody - was approved for the treatment of patients with metastatic disease progressing after platinum combination therapy. Despite the great success, there are still some unanswered questions and ongoing trials that are in progress to define the role of combination therapy and sequencing strategies. The objective of our manuscript is to summarize the most recent data on immunotherapy in advanced urothelial cancer. Current challenges and future perspectives of immunotherapy as a monotherapy or in combination strategies will also be analyzed.

Oncolytic Immunotherapy for Treatment of Cancer.

PubMed

Tsun, A; Miao, X N; Wang, C M; Yu, D C

2016-01-01

Immunotherapy entails the treatment of disease by modulation of the immune system. As detailed in the previous chapters, the different modes of achieving immune modulation are many, including the use of small/large molecules, cellular therapy, and radiation. Oncolytic viruses that can specifically attack, replicate within, and destroy tumors represent one of the most promising classes of agents for cancer immunotherapy (recently termed as oncolytic immunotherapy). The notion of oncolytic immunotherapy is considered as the way in which virus-induced tumor cell death (known as immunogenic cancer cell death (ICD)) allows the immune system to recognize tumor cells and provide long-lasting antitumor immunity. Both immune responses toward the virus and ICD together contribute toward successful antitumor efficacy. What is now becoming increasingly clear is that monotherapies, through any of the modalities detailed in this book, are neither sufficient in eradicating tumors nor in providing long-lasting antitumor immune responses and that combination therapies may deliver enhanced efficacy. After the rise of the genetic engineering era, it has been possible to engineer viruses to harbor combination-like characteristics to enhance their potency in cancer immunotherapy. This chapter provides a historical background on oncolytic virotherapy and its future application in cancer immunotherapy, especially as a combination therapy with other treatment modalities.

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma.

PubMed

McNeel, Douglas G; Bander, Neil H; Beer, Tomasz M; Drake, Charles G; Fong, Lawrence; Harrelson, Stacey; Kantoff, Philip W; Madan, Ravi A; Oh, William K; Peace, David J; Petrylak, Daniel P; Porterfield, Hank; Sartor, Oliver; Shore, Neal D; Slovin, Susan F; Stein, Mark N; Vieweg, Johannes; Gulley, James L

2016-01-01

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly.

BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy

PubMed Central

Koya, Richard C.; Mok, Stephen; Otte, Nicholas; Blacketor, Kevin J.; Comin-Anduix, Begonya; Tumeh, Paul C.; Minasyan, Aspram; Graham, Nicholas A.; Graeber, Thomas G.; Chodon, Thinle; Ribas, Antoni

2012-01-01

Combining immunotherapy with targeted therapy blocking oncogenic BRAFV600 may result in improved treatments for advanced melanoma. Here, we developed a BRAFV600E-driven murine model of melanoma, SM1, which is syngeneic to fully immunocompetent mice. SM1 cells exposed to the BRAF inhibitor vemurafenib (PLX4032) showed partial in vitro and in vivo sensitivity resulting from the inhibition of MAPK pathway signaling. Combined treatment of vemurafenib plus adoptive cell transfer (ACT) therapy with lymphocytes genetically modified with a T cell receptor (TCR) recognizing chicken ovalbumin (OVA) expressed by SM1-OVA tumors, or pmel-1 TCR transgenic lymphocytes recognizing gp100 endogenously expressed by SM1, resulted in superior antitumor responses compared with either therapy alone. T cell analysis demonstrated that vemurafenib did not significantly alter the expansion, distribution, or tumor accumulation of the adoptively transferred cells. However, vemurafenib paradoxically increased MAPK signaling, in vivo cytotoxic activity, and intratumoral cytokine secretion by adoptively transferred cells. Together, our findings, derived from two independent models combining BRAF-targeted therapy with immunotherapy, support the testing of this therapeutic combination in patients with BRAFV600 mutant metastatic melanoma. PMID:22693252

Impact of immunotherapy among patients with melanoma brain metastases managed with radiotherapy.

PubMed

Stokes, William A; Binder, David C; Jones, Bernard L; Oweida, Ayman J; Liu, Arthur K; Rusthoven, Chad G; Karam, Sana D

2017-12-15

Patients with melanoma brain metastases (MBM) have been excluded from trials evaluating immunotherapy in melanoma. As such, immunotherapy's role in MBM is poorly understood, particularly in combination with radiotherapy. The National Cancer Database was queried for patients with MBM receiving brain radiotherapy. They were classified according to immunotherapy receipt. Multivariate Cox regression was performed to identify factors associated with survival. Among 1287 patients, 185 received immunotherapy. Factors associated with improved survival included younger age, academic facility, lower extracranial disease burden, stereotactic radiotherapy, chemotherapy, and immunotherapy. Adding immunotherapy to radiotherapy for MBM is associated with improved survival. Copyright © 2017 Elsevier B.V. All rights reserved.

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma.

PubMed

Kamat, Ashish M; Bellmunt, Joaquim; Galsky, Matthew D; Konety, Badrinath R; Lamm, Donald L; Langham, David; Lee, Cheryl T; Milowsky, Matthew I; O'Donnell, Michael A; O'Donnell, Peter H; Petrylak, Daniel P; Sharma, Padmanee; Skinner, Eila C; Sonpavde, Guru; Taylor, John A; Abraham, Prasanth; Rosenberg, Jonathan E

2017-08-15

The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is immunotherapy with intravesical Bacillus Calmette-Guérin (BCG), which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit. Urologic best-practice guidelines and consensus reports have been developed and strengthened based on data on the timing, dose, and duration of therapy from randomized clinical trials, as well as by critical evaluation of criteria for progression. However, these reports have not penetrated the community, and many patients do not receive appropriate therapy. Additionally, several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease. The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of expanded use for both advanced and, potentially, localized disease. To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer, the Society for Immunotherapy of Cancer (SITC) convened a Task Force of experts, including physicians, patient advocates, and nurses, to address issues related to patient selection, toxicity management, clinical endpoints, as well as the combination and sequencing of therapies. Following the standard approach established by the Society for other cancers, a systematic literature review and analysis of data, combined with consensus voting was used to generate guidelines. Here, we provide a consensus statement for the use of immunotherapy in patients with bladder cancer, with plans to update these recommendations as the field progresses.

[Modern Diagnosis and Therapy of the rhinitis allergica].

PubMed

Hauswald, B; Yarin, Y M

2015-05-01

The prevalence of allergic diseases is increasing worldwide. The highest increase rate is observed in rhinitis allergica. Apart from the anamnesis, the diagnosis relies mainly on skin tests, laboratory analyses and if necessary provocation tests. Symptomatic and causal therapy with abstention and specific immunotherapy are available as therapeutic means. Specific immunotherapy should be aspired as the method of choice. It is comprised of subcutane and sublingular immunity therapy. Usually native allergens and allergoids are used as therapeutics. Recombinant allergens are currently under development. Modern therapy procedures involving these drugs consist of year-round or pre- and co-seasonal treatment which spans at least 3-4 years. In cases of polyvalent allergy, different types of drugs and therapy procedures can be combined. The future of rhinitis allergica treatment lies in further development of specific immunotherapy. © Georg Thieme Verlag KG Stuttgart · New York.

A second chance for telomerase reverse transcriptase in anticancer immunotherapy.

PubMed

Zanetti, Maurizio

2017-02-01

Telomerase reverse transcriptase (TERT) is a self-antigen that is expressed constitutively in many tumours, and is, therefore, an important target for anticancer immunotherapy. In the past 10 years, trials of immunotherapy with TERT-based vaccines have demonstrated only modest benefits. In this Perspectives, I discuss the possible immunological reasons for this limited antitumour efficacy, and propose that advances in our understanding of the genetics and biology of the involvement of TERT in cancer provides the basis for renewed interest in TERT- based immunotherapy. Telomerase and TERT are expressed in cancer cells at every stage of tumour evolution, from the cancer stem cell to circulating tumour cells and tumour metastases. Many cancer types also harbour cells with mutations in the TERT promoter region, which increase transcriptional activation of this gene. These new findings should spur new interest in the development of TERT-based immunotherapies that are redesigned in line with established immunological considerations and working principles, and are tailored to patients stratified on the basis of TERT-promoter mutations and other underlying tumour characteristics. Thus, despite the disappointment of previous clinical trials, TERT offers the potential for personalized immunotherapy, perhaps in combination with immune-checkpoint inhibition.

Advances in the understanding of cancer immunotherapy.

PubMed

Shore, Neal D

2015-09-01

The principal role of the immune system is to prevent and eradicate pathogens and infections. The key characteristics or features of an effective immune response include specificity, trafficking, antigen spread and durability (memory). The immune system is recognised to have a critical role in controlling cancer through a dynamic relationship with tumour cells. Normally, at the early stages of tumour development, the immune system is capable of eliminating tumour cells or keeping tumour growth abated; however, tumour cells may evolve multiple pathways over time to evade immune control. Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumour burden, in whom disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve. Because immunotherapies may have a different mechanism of action from traditional cytotoxic or targeted biological agents, immunotherapy techniques have the potential to combine synergistically with traditional therapies. © 2014 The Authors. BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.

Two is better than one: advances in pathogen-boosted immunotherapy and adoptive T-cell therapy.

PubMed

Xin, Gang; Schauder, David M; Zander, Ryan; Cui, Weiguo

2017-09-01

The recent tremendous successes in clinical trials take cancer immunotherapy into a new era and have attracted major attention from both academia and industry. Among the variety of immunotherapy strategies developed to boost patients' own immune systems to fight against malignant cells, the pathogen-based and adoptive cell transfer therapies have shown the most promise for treating multiple types of cancer. Pathogen-based therapies could either break the immune tolerance to enhance the effectiveness of cancer vaccines or directly infect and kill cancer cells. Adoptive cell transfer can induce a strong durable antitumor response, with recent advances including engineering dual specificity into T cells to recognize multiple antigens and improving the metabolic fitness of transferred cells. In this review, we focus on the recent prospects in these two areas and summarize some ongoing studies that represent potential advancements for anticancer immunotherapy, including testing combinations of these two strategies.

Immunotherapy Combination Approved for Advanced Kidney Cancer

Cancer.gov

FDA has approved the combination of the immunotherapy drugs nivolumab (Opdivo) and ipilimumab (Yervoy) as an initial treatment for some patients with advanced kidney cancer. The approval is expected to immediately affect patient care, as this Cancer Currents post explains.

Emerging immunotherapy for the treatment of esophageal cancer.

PubMed

Jackie Oh, SeungJu; Han, Songhee; Lee, Wooin; Lockhart, A Craig

2016-06-01

Esophageal cancer is the third most common cancer of the gastrointestinal tract. Despite new therapies, the prognosis for patients with these cancers remains poor with 5-year survival rates lower than 15%. Recently, immunotherapy has increasingly gained attention as a novel treatment strategy for advanced esophageal cancer. Recent success of immunotherapy in treating other solid tumors has shed light on the utility of these approaches for esophageal cancers. Here, the authors focus on antibody-based, adoptive-cell-therapy-based, and vaccine-based immunotherapies, and briefly address their rationale, clinical data, and implications. Immunotherapy is now established to be a key treatment modality that can improve the outcomes of many cancer patients and appears to be ushering in a new era in cancer treatment. Checkpoint inhibitor drugs have shown preliminary favorable results in esophageal cancer treatment. Adoptive cell therapy and vaccine studies have also shown some promise in various clinical studies. Future endeavors will need to focus on identifying patients who are likely to benefit from immunotherapy, monitoring and managing immune responses and designing optimal combination strategies where immunotherapy agents are combined with other traditional treatment modalities.

An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0.

PubMed

Sullivan, Ryan J; Atkins, Michael B; Kirkwood, John M; Agarwala, Sanjiv S; Clark, Joseph I; Ernstoff, Marc S; Fecher, Leslie; Gajewski, Thomas F; Gastman, Brian; Lawson, David H; Lutzky, Jose; McDermott, David F; Margolin, Kim A; Mehnert, Janice M; Pavlick, Anna C; Richards, Jon M; Rubin, Krista M; Sharfman, William; Silverstein, Steven; Slingluff, Craig L; Sondak, Vernon K; Tarhini, Ahmad A; Thompson, John A; Urba, Walter J; White, Richard L; Whitman, Eric D; Hodi, F Stephen; Kaufman, Howard L

2018-05-30

Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

Nanotechnology Approaches to Improving Cancer Immunotherapy.

PubMed

Hagan, C Tilden; Medik, Yusra B; Wang, Andrew Z

2018-01-01

Cancer immunotherapy is a powerful, growing treatment approach to cancer that can be combined with chemotherapy, radiotherapy, and oncosurgery. Modulating the immune system to enhance anticancer response by several strategies has yielded improved cancer survival. Despite this progress, the success rate for immunotherapy has been below expectations due to unpredictable efficacy and off-target side effects from systemic dosing. Nanotechnology offers numerous different materials and targeting properties to overcome many of these challenges in immunotherapy. In this chapter, we review current immunotherapy and its challenges as well as the latest nanotechnology applications in cancer immunotherapy. © 2018 Elsevier Inc. All rights reserved.

[Immunotherapy: a therapeutic revolution against prostate cancer?].

PubMed

Pracht, Marc; Herrera, Fernanda; Tawadros, Thomas; Berthold, Dominik

2013-05-22

The interaction between the immune system and cancer was an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of sipuleucel-T and ipilimumab stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies under development are therapeutic vaccination strategies, such as sipuleucel-T and PROSTVAC-VF, or immune checkpoint blockade of CTLA-4. Improved understanding of the immune responses generated by the development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide new treatment options in prostate cancer.

TLR7 agonist in combination with Salmonella as an effective antimelanoma immunotherapy.

PubMed

Vola, Magdalena; Mónaco, Amy; Bascuas, Thais; Rimsky, Geraldine; Agorio, Caroline Isabel; Chabalgoity, José Alejandro; Moreno, María

2018-03-22

We evaluated a novel approach combining the use of attenuated Salmonella immunotherapy with a Toll-like receptor agonist, imiquimod, in B16F1 melanoma-bearing mice. B16F1 melanoma-bearing mice were daily treated with topical imiquimod in combination with one intratumoral injection of attenuated Salmonella enterica serovar Typhimurium LVR01. The combined therapy resulted in retarded tumor growth and prolonged survival. Combination treatment led to an enhancement in the expression of pro-inflammatory cytokines and chemokines in the tumor microenvironment, with a Th1-skewed profile, resulting in a broad antitumor response. The induced immunity was effective in controlling the occurrence of metastasis. Salmonella LVR01 immunotherapy in combination with imiquimod is a novel approach that could be considered as an effective antimelanoma therapy.

Novel targets for natural killer/T-cell lymphoma immunotherapy.

PubMed

Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

2016-01-01

Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL.

Mathematical Modelling and Analysis of the Tumor Treatment Regimens with Pulsed Immunotherapy and Chemotherapy

PubMed Central

Pang, Liuyong; Shen, Lin; Zhao, Zhong

2016-01-01

To begin with, in this paper, single immunotherapy, single chemotherapy, and mixed treatment are discussed, and sufficient conditions under which tumor cells will be eliminated ultimately are obtained. We analyze the impacts of the least effective concentration and the half-life of the drug on therapeutic results and then find that increasing the least effective concentration or extending the half-life of the drug can achieve better therapeutic effects. In addition, since most types of tumors are resistant to common chemotherapy drugs, we consider the impact of drug resistance on therapeutic results and propose a new mathematical model to explain the cause of the chemotherapeutic failure using single drug. Based on this, in the end, we explore the therapeutic effects of two-drug combination chemotherapy, as well as mixed immunotherapy with combination chemotherapy. Numerical simulations indicate that combination chemotherapy is very effective in controlling tumor growth. In comparison, mixed immunotherapy with combination chemotherapy can achieve a better treatment effect. PMID:26997972

Mathematical Modelling and Analysis of the Tumor Treatment Regimens with Pulsed Immunotherapy and Chemotherapy.

PubMed

Pang, Liuyong; Shen, Lin; Zhao, Zhong

2016-01-01

To begin with, in this paper, single immunotherapy, single chemotherapy, and mixed treatment are discussed, and sufficient conditions under which tumor cells will be eliminated ultimately are obtained. We analyze the impacts of the least effective concentration and the half-life of the drug on therapeutic results and then find that increasing the least effective concentration or extending the half-life of the drug can achieve better therapeutic effects. In addition, since most types of tumors are resistant to common chemotherapy drugs, we consider the impact of drug resistance on therapeutic results and propose a new mathematical model to explain the cause of the chemotherapeutic failure using single drug. Based on this, in the end, we explore the therapeutic effects of two-drug combination chemotherapy, as well as mixed immunotherapy with combination chemotherapy. Numerical simulations indicate that combination chemotherapy is very effective in controlling tumor growth. In comparison, mixed immunotherapy with combination chemotherapy can achieve a better treatment effect.

Effect of laser immunotherapy and surgery on the treatment of mouse mammary tumors

NASA Astrophysics Data System (ADS)

Chen, Vivian A.; Le, Henry; Li, Xiaosong; Wolf, Roman F.; Ferguson, Halie; Sarkar, Akhee; Liu, Hong; Nordquist, Robert E.; Chen, Wei R.

2010-02-01

Laser immunotherapy using laser photothermal therapy and immunological stimulation could achieve tumor-specific immune responses, as indicated by our previous pre-clinical and preliminary clinical studies. To further study the effect of laser immunotherapy, we conducted an investigation combining laser immunotherapy and surgery. After laser immunotherapy, treated tumors were surgically removed at different time points. The survival rates of treated mice were compared among different groups. Furthermore, the cured mice were rechallenged to test the immunity induced by laser immunotherapy. Our results showed that the mice treated with surgical removal one week after laser immunotherapy had the highest survival rate (77%). When the tumors were removed immediately after laser immunotherapy treatment, the survival rate was 57%. Most cured mice withstood tumor rechallenges, indicating an induction of tumor immunity by laser immunotherapy. The differentiations between different surgery groups indicate that the treated tumors have contributed to the immunological responses of the hosts.

Immune Effects of Chemotherapy, Radiation, and Targeted Therapy and Opportunities for Combination With Immunotherapy.

PubMed

Wargo, Jennifer A; Reuben, Alexandre; Cooper, Zachary A; Oh, Kevin S; Sullivan, Ryan J

2015-08-01

There have been significant advances in cancer treatment over the past several years through the use of chemotherapy, radiation therapy, molecularly targeted therapy, and immunotherapy. Despite these advances, treatments such as monotherapy or monomodality have significant limitations. There is increasing interest in using these strategies in combination; however, it is not completely clear how best to incorporate molecularly targeted and immune-targeted therapies into combination regimens. This is particularly pertinent when considering combinations with immunotherapy, as other types of therapy may have significant impact on host immunity, the tumor microenvironment, or both. Thus, the influence of chemotherapy, radiation therapy, and molecularly targeted therapy on the host anti-tumor immune response and the host anti-host response (ie, autoimmune toxicity) must be taken into consideration when designing immunotherapy-based combination regimens. We present data related to many of these combination approaches in the context of investigations in patients with melanoma and discuss their potential relationship to management of patients with other tumor types. Importantly, we also highlight challenges of these approaches and emphasize the need for continued translational research. Copyright © 2015 Elsevier Inc. All rights reserved.

Erythema Nodosum as the Initial Presentation of Nivolumab-Induced Sarcoidosis-Like Reaction.

PubMed

Laroche, Alexandre; Alarcon Chinchilla, Evelyn; Bourgeault, Emilie; Doré, Marc-André

2018-05-01

We report a case of nivolumab-related sarcoidosis-like syndrome that initially presented with erythema nodosum. Sarcoidosis development has been described in single and combination immunotherapy. A 68-year-old white woman with metastatic ocular amelanotic choroid melanoma was treated with nivolumab. The patient developed histologically confirmed erythema nodosum lesions and pulmonary granuloma sarcoidosis. Nivolumab was discontinued and the patient started ipilimumab therapy. Sarcoidosis-like syndrome with lymphadenopathy is a rare adverse event that is important to recognize since it can be mistaken for metastatic disease progression. Tissue biopsy of new lesions during immunotherapy is an important step in patient evaluation.

GSK's antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development.

PubMed

Brichard, Vincent G; Lejeune, Diane

2007-09-27

From the first evidence that the immune system could recognize tumors, different types of tumor antigens have been identified and deeply characterized. Several different approaches aimed at targeting these antigens have already been the subject of clinical studies. In this field, the GSK Biologicals' approach relying on recombinant proteins combined with an immunological Adjuvant System in a specific clinical setting, has entertained hopes of developing a new class of well tolerated anti-cancer therapy. This methodology led to promising advances with MAGE-A3 immunotherapy in NSCLC and has the potential to be applied to all tumor types.

Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma

PubMed Central

Hu-Lieskovan, Siwen; Mok, Stephen; Moreno, Blanca Homet; Tsoi, Jennifer; Faja, Lidia Robert; Goedert, Lucas; Pinheiro, Elaine M.; Koya, Richard C.; Graeber, Thomas; Comin-Anduix, Begoña; Ribas, Antoni

2016-01-01

Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA-4 antibody ipilimumab was terminated early due to substantial liver toxicities. MEK inhibitors can potentiate the MAPK inhibition in BRAF mutant cells, while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAFV600E driven melanoma, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors and improved in vivo cytotoxicity. Single agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and MHC expression, and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested combination of dabrafenib, trametinib with anti-PD1 therapy in SM1 tumors, and observed superior anti-tumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAFV600E mutant metastatic melanoma. PMID:25787767

[COMBINED IMMUNOTHERAPY OF RECONDITIONAL CHRONIC NON-SPECIFIC VULVOVAGINITIS IN IMMUNOCOMPROMISED GIRLS].

PubMed

Nesterova, I; Kovaleva, S; Chudilova, G; Lomtatidze, L; Krutova, V; Aslanian, I; Tulendinova, A; Malinovskaya, V

2017-05-01

Nonspecific chronic vulvovaginitis (CNV) is often a clinical indicator of immune deficiency, especially in young girls. The established violations of the functioning of various parts of the immune system (IS) in this pathology dictate the need to include in the complex of immunomodulatory therapy. The developed program of combined immunotherapy for immunocompromised girls allows to reduce the severity and duration of exacerbation of CNV, their frequency against the background of a significant reduction in the incidence of ARVI. Positive clinical effects were observed against the background of the restoration of the functioning of the IS. A protective effect was obtained (observation in a catamnesis for 1 year) - the duration of a clinically safe period increased from 6 to 11-11,5 months per year.

Toward innovative combinational immunotherapy: A systems biology perspective.

PubMed

Li, Xue-Tao; Yang, Jin-Ji; Wu, Yi-Long; Hou, Jun

2018-05-08

The treatment of non-small-cell lung cancer (NSCLC) has advanced significantly in the last decades. Especially immune checkpoint inhibitors have shown inconceivable effect on enhancing host anti-tumor activity in NSCLC. However, the limitation of checkpoint blockade monotherapy seems unavoidable in most of the NSCLC patients and only ∼20% of them achieved response to monotherapy with immune checkpoint inhibitors. Thus combining immune checkpoint inhibitors with other agents with different action mechanisms holds a promise to revitalize NSCLC treatment, such as the combination of checkpoint inhibitors with angiogenesis inhibitors, or with chemotherapy, as well as the combination of two checkpoint inhibitors. Recently, various combinational strategies have been explored to setup promising combination regimens and to understand the action mechanisms. In this review, we summarize the suspected synergistic mechanisms of several combinational approaches by reviewing the available preclinical and clinical data. Then we discuss in light of the current knowledge of cancer biology and systems biology the important facets to be examined when setting up a framework for developing immunotherapy-based combination strategies. Copyright © 2018. Published by Elsevier Ltd.

Immunotherapy for Prostate Cancer Enters Its Golden Age

PubMed Central

Boikos, Sosipatros A.; Antonarakis, Emmanuel S.

2012-01-01

In the United States, prostate cancer is the most frequent malignancy in men and ranks second in terms of mortality. Although recurrent or metastatic disease can be managed initially with androgen ablation, most patients eventually develop castration-resistant disease within a number of years, for which conventional treatments (eg, chemotherapy) provide only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer, and this field is evolving rapidly. Encouragingly, the US Food and Drug Administration (FDA) has recently approved two novel immunotherapy agents for patients with advanced cancer: the antigen presenting cell-based product sipuleucel-T and the anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody ipilimumab, based on improvements in overall survival in patients with castration-resistant prostate cancer and metastatic melanoma, respectively. Currently, a number of trials are investigating the role of various immunological approaches for the treatment of prostate cancer, many of them with early indications of success. As immunotherapy for prostate cancer enters its golden age, the challenge of the future will be to design rational combinations of immunotherapy agents with each other or with other standard prostate cancer treatments in an effort to improve patient outcomes further. PMID:22844202

Combining Immune Checkpoint Inhibitors and Kinase-Inhibiting Supramolecular Therapeutics for Enhanced Anticancer Efficacy.

PubMed

Kulkarni, Ashish; Natarajan, Siva Kumar; Chandrasekar, Vineethkrishna; Pandey, Prithvi Raj; Sengupta, Shiladitya

2016-09-29

A major limitation of immune checkpoint inhibitors is that only a small subset of patients achieve durable clinical responses. This necessitates the development of combinatorial regimens with immunotherapy. However, some combinations, such as MEK- or PI3K-inhibitors with a PD1-PDL1 checkpoint inhibitor, are pharmacologically challenging to implement. We rationalized that such combinations can be enabled using nanoscale supramolecular targeted therapeutics, which spatially home into tumors and exert temporally sustained inhibition of the target. Here we describe two case studies where nanoscale MEK- and PI3K-targeting supramolecular therapeutics were engineered using a quantum mechanical all-atomistic simulation-based approach. The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively. Additionally, the temporal sequence of administration impacts the outcome. The combination of supramolecular therapeutics and immunotherapy could emerge as a paradigm shift in the treatment of cancer.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barker, Christopher A., E-mail: barkerc@mskcc.org; Postow, Michael A.

Radiation therapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiation therapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiation therapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiation therapy. The cytokines interferon-α and interleukin-2 have been combined with radiation therapy in several small studies, with some evidence suggesting increased toxicitymore » and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiation therapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested that radiation therapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiation therapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study.« less

Combining MPDL3280A with adoptive cell immunotherapy exerts better antitumor effects against cervical cancer.

PubMed

Zheng, Yi; Yang, Yicheng; Wu, Shu; Zhu, Yongqiang; Tang, Xiaolong; Liu, Xiaopeng

2017-07-04

As the second most common gynecologic malignant tumors with a high mortality rate, cervical cancer jeopardizes women's life worldwide. The low cure rate in cervical cancer patients is mainly attributed to the lack of effective therapies. One feasible novel strategy is to develop immune-based approaches such as adoptive cell immunotherapy of DCCIKs which represents a promising nontoxic antineoplastic immunotherapy preferred in clinic practice. However, the therapeutic effect is not as efficient as anticipated. Possible explanations are tumors exploit immunoregulatory check-points such as programmed death 1(PD1)/PDL1 which provides tumor cells an escape strategy of circumventing immunologic rejection from immune surveillance by hampering activated tumor-specific T cell activities and rendering them functionally exhausted. With reduced transformation activity and enhanced antigenicity, a modified HPV16 E7 (HPV16mE7) was used to load DCs with silenced SOCS1 mediated by a recombinant adenovirus to improve the targetability and efficiency against cervical cancer. Combined with anti-PDL1 antibody MPDL3280A therapy, the co-cultured DCCIKs were transfused into murine models bearing tumor of HPV16 E6/E7 expressing CaSki cells for in vitro/in vivo antitumor activity assay. Although all of the animals succumbed to CaSki tumors even after adoptive DCCIKs transfer or MPDL3280A immunotherapy, the infusion of PDL1 blocking monoclonal antibody with activated T cells cured 40% of animals. These data support PDL1 blockade improves the efficacy of adoptive DCCIKs therapy, providing a new approach of immunotherapy against cervical cancer.

Combining MPDL3280A with adoptive cell immunotherapy exerts better antitumor effects against cervical cancer

PubMed Central

Zheng, Yi; Yang, Yicheng; Wu, Shu; Zhu, Yongqiang; Tang, Xiaolong; Liu, Xiaopeng

2017-01-01

ABSTRACT As the second most common gynecologic malignant tumors with a high mortality rate, cervical cancer jeopardizes women's life worldwide. The low cure rate in cervical cancer patients is mainly attributed to the lack of effective therapies. One feasible novel strategy is to develop immune-based approaches such as adoptive cell immunotherapy of DCCIKs which represents a promising nontoxic antineoplastic immunotherapy preferred in clinic practice. However, the therapeutic effect is not as efficient as anticipated. Possible explanations are tumors exploit immunoregulatory check-points such as programmed death 1(PD1)/PDL1 which provides tumor cells an escape strategy of circumventing immunologic rejection from immune surveillance by hampering activated tumor-specific T cell activities and rendering them functionally exhausted. With reduced transformation activity and enhanced antigenicity, a modified HPV16 E7 (HPV16mE7) was used to load DCs with silenced SOCS1 mediated by a recombinant adenovirus to improve the targetability and efficiency against cervical cancer. Combined with anti-PDL1 antibody MPDL3280A therapy, the co-cultured DCCIKs were transfused into murine models bearing tumor of HPV16 E6/E7 expressing CaSki cells for in vitro/in vivo antitumor activity assay. Although all of the animals succumbed to CaSki tumors even after adoptive DCCIKs transfer or MPDL3280A immunotherapy, the infusion of PDL1 blocking monoclonal antibody with activated T cells cured 40% of animals. These data support PDL1 blockade improves the efficacy of adoptive DCCIKs therapy, providing a new approach of immunotherapy against cervical cancer. PMID:27754760

Laser assisted immunotherapy (LIT) for chemotherapy-resistant neoplasms: recent case reports

NASA Astrophysics Data System (ADS)

Nordquist, Robert E.; Bahavar, Cody; Zhou, Feifan; Hode, Tomas; Chen, Wei R.; Li, Xiaosong; Naylor, Mark F.

2014-02-01

T-cell stimulators such as anti-CTLA-4 antibodies enhance immunologic responses to chemotherapy-resistant solid tumors, such as melanoma, advanced breast cancer, ovarian cancer and pancreatic cancer. The efficacy of these new immunotherapy agents can in theory be enhanced substantially by therapies that stimulate new immunologic (T-cell) responses against the tumor. Laser immunotherapy (LIT) with imiquimod and InCVAX are techniques that produce useful responses in patients with advanced melanoma, the prototypical chemotherapy resistant solid tumor. The mechanism of action of these therapies is thought to be immunological, including the development of new T-cell responses. We have therefore been combining LIT using imiquimod and InCVAX treatment with the new T-cell stimulators (ipilimumab) in cases of stage IV melanoma. While still anecdotal, the use of novel combinations of immunologic therapies should provide much improved responses for chemotherapy-resistant solid tumors (such as melanoma) than was previously possible. Newer T-cell stimulating drugs such as the anti-PD-1 antibodies and anti-PD-L1 antibodies will make this general approach to treating chemoresistant advanced tumors even more effective in the future.

Immunotherapy in urothelial cancer, part 1: T-cell checkpoint inhibition in advanced or metastatic disease.

PubMed

Yu, Steven S; Dorff, Tanya B; Ballas, Leslie K; Sadeghi, Sarmad; Skinner, Eila C; Quinn, David I

2017-06-01

Cancer of the urothelium is the sixth most common cancer in the United States and is seen predominantly in men. Most cases of this disease present as non-muscle-invasive bladder cancer (NMIBC), with cancer recurrence or progression to muscle-invasive cancer in more than 50% of patients after initial therapy. NMIBC is an immune-responsive disease, as indicated by the use of intravesical bacillus Calmette-Guérin as treatment for more than 3 decades. More recently, immunotherapy has seen much progress in a variety of cancers, including advanced and metastatic bladder cancer, in which historical 5-year survival rates are approximately 15%. The advent of T-cell checkpoint inhibitors, especially those directed at programmed death 1 (PD-1) and its ligand (PD-L1), has had a significant effect on the therapy of advanced urothelial cancer. This had led to accelerated approval by the US Food and Drug Administration for atezolizumab and nivolumab in advanced urothelial cancer previously treated with platinum-based chemotherapy. In addition, level 1 evidence supports the use of pembrolizumab over single-agent tubulin-directed chemotherapy in the same setting. Several other treatments with immune-mediating mechanisms of action are in development and hold great promise, including monoclonal antibodies directed at other checkpoint molecules, oncolytic virus therapy, adoptive T-cell therapy, combination immunotherapy, and antibody-drug conjugates. This review focuses on the recent development of T-cell checkpoint inhibitors in advanced and metastatic urothelial cancer and addresses their potential use in combination. It also discusses a spectrum of novel immunotherapies with potential use in urothelial cancer.

Combination Immunotherapy in Non-small Cell Lung Cancer.

PubMed

Marmarelis, Melina E; Aggarwal, Charu

2018-05-08

Checkpoint blockade has changed the treatment landscape in non-small cell lung cancer (NSCLC), but single-agent approaches are effective for only a select subset of patients. Here, we will review the evidence for combination immunotherapies in NSCLC and the clinical data evaluating the efficacy of this approach. Clinical trials evaluating combination PD-1 and CTLA-4 blockade as well as PD-1 in combination with agents targeting IDO1, B7-H3, VEGF, and EGFR show promising results. Additional studies targeting other immune pathways like TIGIT, LAG-3, and cellular therapies are ongoing. Combination immunotherapy has the potential to improve outcomes in NSCLC. Data from early clinical trials is promising and reveals that these agents can be administered together safely without a significant increase in toxicity. Further studies are needed to evaluate their long-term safety and efficacy and to determine appropriate patient selection.

Clinical trial shows safety and effectiveness of new combination immunotherapy for advanced liver cancer | Center for Cancer Research

Cancer.gov

A recently completed phase I clinical trial at the NIH Clinical Center in Bethesda, Maryland, demonstrates that a combination of two immunotherapy drugs to target hepatocellular carcinoma (HCC) was well-tolerated and shrunk tumors in a larger percentage of patients than the standard monotherapy.  Read more...

Postdoctoral Fellows | Center for Cancer Research

Cancer.gov

The Laboratory of Tumor Immunology and Biology (LTIB) functions as a multidisciplinary and interdisciplinary translational research programmatic effort with the goal of developing novel immunotherapies for cancer. The LTIB strategic plan focuses on the development of novel immunotherapeutics for human cancer, not only as monotherapies, but more importantly, in combination with

Anti-DR5 monoclonal antibody-mediated DTIC-loaded nanoparticles combining chemotherapy and immunotherapy for malignant melanoma: target formulation development and in vitro anticancer activity.

PubMed

Ding, Baoyue; Wu, Xin; Fan, Wei; Wu, Zhaoyong; Gao, Jing; Zhang, Wei; Ma, Lulu; Xiang, Wang; Zhu, Quangang; Liu, Jiyong; Ding, Xueying; Gao, Shen

2011-01-01

The increased incidence of malignant melanoma in recent decades, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Novel therapeutic strategies, such as immunotherapy and targeted therapy, are urgently needed for melanoma. In this study, a new active targeting drug delivery system was constructed to combine chemotherapy and active specific immunotherapy. The chemotherapeutic drug, dacarbazine (DTIC), that induces apoptosis through the intrinsic pathway which typically responds to severe DNA damage, was used as a model drug to prepare DTIC-loaded polylactic acid (PLA) nanoparticles (DTIC-NPs), which were covalently conjugated to a highly specific targeting functional TRAIL-receptor 2 (DR5) monoclonal antibody (mAb) that can contribute directly to cancer cell apoptosis or growth inhibition through the extrinsic pathway. Our in vitro experiments demonstrated that DTIC-PLA-DR5 mAb nanoparticles (DTIC-NPs-DR5 mAb) are an active targeting drug delivery system which can specifically target DR5-overexpressing malignant melanoma cells and become efficiently internalized. Most strikingly, compared with conventional DTIC-NPs, DTIC-NPs-DR5 mAb showed significantly enhanced cytotoxicity and increased cell apoptosis in DR5-positive malignant melanoma cells. The DTIC-NPs-DR5 mAb described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to DR5-overexpressing metastatic melanoma.

Boosting Natural Killer Cell-Based Immunotherapy with Anticancer Drugs: a Perspective.

PubMed

Cifaldi, Loredana; Locatelli, Franco; Marasco, Emiliano; Moretta, Lorenzo; Pistoia, Vito

2017-12-01

Natural killer (NK) cells efficiently recognize and kill tumor cells through several mechanisms including the expression of ligands for NK cell-activating receptors on target cells. Different clinical trials indicate that NK cell-based immunotherapy represents a promising antitumor treatment. However, tumors develop immune-evasion strategies, including downregulation of ligands for NK cell-activating receptors, that can negatively affect antitumor activity of NK cells, which either reside endogenously, or are adoptively transferred. Thus, restoration of the expression of NK cell-activating ligands on tumor cells represents a strategic therapeutic goal. As discussed here, various anticancer drugs can fulfill this task via different mechanisms. We envision that the combination of selected chemotherapeutic agents with NK cell adoptive transfer may represent a novel strategy for cancer immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunotherapy of elderly acute myeloid leukemia: light at the end of a long tunnel?

PubMed

Rafelson, William M; Reagan, John L; Fast, Loren D; Lim, Seah H

2017-11-01

Although it is possible to induce remission in the majority of the patients with acute myeloid leukemia (AML), many patients still die due to disease relapse. Immunotherapy is an attractive option. It is more specific. The memory T cells induced by immunotherapy may also provide the long-term tumor immunosurveillance to prevent disease relapse. Although immunotherapy of AML started in the early 1970s, its clinical impact has been disappointing. Recent advances in tumor immunology and immunotherapeutic agents have rekindled interest. Here, we provide a review of the history of AML immunotherapy, discuss why AML is well suited for immunotherapeutic approaches and present the biological obstacles that affect the success of immunotherapy. Finally, we put forward a new paradigm of AML immunotherapy that utilizes a combination of immunotherapeutic agents sequentially to enhance the in vivo tumor immunogenicity and effective priming and propagation of tumor-specific cytotoxic T cells.

Advances in personalized cancer immunotherapy.

PubMed

Kakimi, Kazuhiro; Karasaki, Takahiro; Matsushita, Hirokazu; Sugie, Tomoharu

2017-01-01

There are currently three major approaches to T cell-based cancer immunotherapy, namely, active vaccination, adoptive cell transfer therapy and immune checkpoint blockade. Recently, this latter approach has demonstrated remarkable clinical benefits, putting cancer immunotherapy under the spotlight. Better understanding of the dynamics of anti-tumor immune responses (the "Cancer-Immunity Cycle") is crucial for the further development of this form of treatment. Tumors employ multiple strategies to escape from anti-tumor immunity, some of which result from the selection of cancer cells with immunosuppressive activity by the process of cancer immunoediting. Apart from this selective process, anti-tumor immune responses can also be inhibited in multiple different ways which vary from patient to patient. This implies that cancer immunotherapy must be personalized to (1) identify the rate-limiting steps in any given patient, (2) identify and combine strategies to overcome these hurdles, and (3) proceed with the next round of the "Cancer-Immunity Cycle". Cancer cells have genetic alterations which can provide the immune system with targets by which to recognize and eradicate the tumor. Mutated proteins expressed exclusively in cancer cells and recognizable by the immune system are known as neoantigens. The development of next-generation sequencing technology has made it possible to determine the genetic landscape of human cancer and facilitated the utilization of genomic information to identify such candidate neoantigens in individual cancers. Future immunotherapies will need to be personalized in terms of the identification of both patient-specific immunosuppressive mechanisms and target neoantigens.

Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

NASA Astrophysics Data System (ADS)

Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

2011-03-01

Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

Immunotherapy in NSCLC: A Promising and Revolutionary Weapon.

PubMed

Rolfo, Christian; Caglevic, Christian; Santarpia, Mariacarmela; Araujo, Antonio; Giovannetti, Elisa; Gallardo, Carolina Diaz; Pauwels, Patrick; Mahave, Mauricio

2017-01-01

Lung cancer is the leader malignancy worldwide accounting 1.5 millions of deaths every year. In the United States the 5 year-overall survival is less than 20% for all the newly diagnosed patients. Cisplatin-based cytotoxic chemotherapy for unresectable or metastatic NSCLC patients in the first line of treatment, and docetaxel in the second line, have achieved positive results but with limited benefit in overall survival. Targeted therapies for EGFR and ALK mutant patients have showed better results when compared with chemotherapy, nevertheless most of patients will fail and need to be treated with chemotherapy if they still have a good performance status.Immunotherapy recently has become the most revolutionary treatment in solid tumors patients. First results in unresectable and metastatic melanoma patients treated with an anti CTLA-4 monoclonal antibody showed an unexpected 3-year overall survival of at least 25%.Lung cancer cells have multiple immunosuppressive mechanisms that allow to escape of the immune system and survive, however blocking CTLA-4 pathway with antibodies as monotherapy treatment have not achieved same results than in melanoma patients. PD-1 expression has been demonstrated in different tumor types, suggesting than PD-1 / PD-L1 pathway is a common mechanism used by tumors to avoid immune surveillance and favoring tumor growth. Anti PD-1 and anti PD-L1 antibodies have showed activity in non-small cell lung cancer patients with significant benefit in overall survival, long lasting responses and good safety profile, including naïve and pretreated patients regardless of the histological subtype. Even more, PD-1 negative expression patients achieve similar results in overall survival when compared with patients treated with chemotherapy. In the other side high PD-1 expression patients that undergo immunotherapy treatment achieve better results in terms of survival with lesser toxicity. Combining different immunotherapy treatments, combination of immunotherapy with chemotherapy or with targeted treatment are under research with some promising PRELIMINARY results in non-small cell lung cancer patients.This chapter attempts to summarize the development of immunotherapy treatment in non-small cell lung cancer patients and explain the results that have leaded immunotherapy as a new standard of treatment in selected NSCLC patients.

Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy.

PubMed

O'reilly, Aine; Larkin, James

2017-07-01

The success of the immune checkpoint inhibitors in melanoma has reinvigorated the field of immunotherapy. Immune checkpoint inhibitors are now the standard of care in multiple cancer types including lung cancer, head and neck cancer, urothelial cancer and renal cell cancer. The field of immunotherapy is currently expanding rapidly and will be a focus of research and development for decades to come. Areas covered: This review covers the early development of immune checkpoint inhibitors and the changes that occurred in the drug development paradigm to facilitate the development of immunotherapy. The review will summarise the areas into which immune checkpoint inhibitors have been adopted and will review the data that supported this. Furthermore, we will discuss future developments in immunotherapy and the current landscape regarding maximising the potential of immunotherapy in clinical practice. Expert commentary: In the author's opinion, the potential of immunotherapy is vast. To date immune checkpoint inhibition has already delivered durable responses in a proportion of patients with cancer types which were previously universally lethal. The future of immunotherapy will rely upon the intelligent application of translational research to clinical practice, such that immunotherapy can be effective for a wider population and maintain its current growth.

TH-C-17A-11: Hyperthermia-Driven Immunotherapy Using Non-Invasive Radiowaves

DOE Office of Scientific and Technical Information (OSTI.GOV)

Serda, R; Savage, D; Corr, S

2014-06-15

Purpose: The sad truth is that cancer is blamed for the death of nearly one in four people in the US. Immunotherapy offers hope for stimulating cancer immunity leading to targeted killing of cancer cells and a preventative measure for cancer recurrence. Unfortunately, the clinical efficacy of immunotherapy has not yet been established, however novel approaches are being developed, including combining immunotherapy with traditional chemotherapy, radiotherapy or thermal therapy. Therapeutics such as radiofrequency (RF) ablation and select chemotherapeutics induce mild anticancer immune responses. This project seeks to enhance the immune responses stimulated by these agents by co-delivery of nanoparticle-based chemotherapeuticsmore » and immune modulators in the presence of RF induced hyperthermia. Methods: A 4T1 mouse model of breast cancer is used to test the ability of RF waves to enhance accumulation of nanoparticles in tumor tissue by increasing blood flow and extravation of nanoparticles from hyperpermeable vessels. Images of particle and cell trafficking in the tumor are captured using an integrated RF and confocal imaging system, and tumor growth is monitored by tumor bioluminescence and caliper measurements. Results: Here we demonstrate enhanced intratumoral blood flow induced by non-invasive RF waves and an increase in nanoparticle accumulation in the tumor. IL-12 is shown to have powerful anti-tumor effects leading to tumor regression and the release of Th1-biased cytokines. Doxorubicin nanoparticles combined with adjuvant nanoparticles exhibited superior antitumor effects to single agent therapy. Conclusion: RF therapy combined with nanotherapeutics is a promising approach to enhance the delivery of therapeutics to the tumor and to stimulate a tumor microenvironment that supports the development of cancer-specific immune responses. This research was supported by the National Institute of Health grant numbers U54 CA143837 and U54 CA151668, and the Kanzius Foundation.« less

Combining Immunotherapy with Standard Glioblastoma Therapy

Cancer.gov

This clinical trial is testing standard therapy (surgery, radiation and temozolomide) plus immunotherapy with pembrolizumab with or without a cancer treatment vaccine for patients with newly diagnosed glioblastoma, a common and deadly type of brain tumor.

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

PubMed Central

Davidson, Linda; Netea, Mihai G.; Kullberg, Bart Jan

2018-01-01

Candida spp. are colonizing fungi of human skin and mucosae of the gastrointestinal and genitourinary tract, present in 30–50% of healthy individuals in a population at any given moment. The host defense mechanisms prevent this commensal fungus from invading and causing disease. Loss of skin or mucosal barrier function, microbiome imbalances, or defects of immune defense mechanisms can lead to an increased susceptibility to severe mucocutaneous or invasive candidiasis. A comprehensive understanding of the immune defense against Candida is essential for developing adjunctive immunotherapy. The important role of underlying genetic susceptibility to Candida infections has become apparent over the years. In most patients, the cause of increased susceptibility to fungal infections is complex, based on a combination of immune regulation gene polymorphisms together with other non-genetic predisposing factors. Identification of patients with an underlying genetic predisposition could help determine which patients could benefit from prophylactic antifungal treatment or adjunctive immunotherapy. This review will provide an overview of patient susceptibility to mucocutaneous and invasive candidiasis and the potential for adjunctive immunotherapy. PMID:29371502

Basics of cancer immunotherapy.

PubMed

Fujioka, Yuki; Nishikawa, Hiroyoshi

2016-01-01

The immune system is the body's defense against infectious organisms and other invaders including cancer cells. Cancer immunotherapy, which employs our own immune systems to attack cancer cells, is now emerging as a promising modality of cancer treatment based upon the clinical successes of immune checkpoint blockade and adoptive T cell transfer. In hematologic malignancies, clinical application of anti-PD-1 mAb and CAR (chimeric antigen receptor) T therapy is now being extensively tested in Hodgkin's disease, multiple myeloma, and CD19 + acute lymphocytic leukemia. In sharp contrast to conventional anti-cancer reagents which directly kill cancer cells, cancer immunotherapy activates various types of immune effector cells to attack cancer cells. However, more than half of the treated patients showed no activation of anti-tumor CD8 + killer T cells and CD4 + helper T cells and failed to respond to immune therapies such as immune checkpoint blockade, even when administered in combination regimens. Thus, development of novel immunotherapies to achieve more effective activation of anti-cancer immunity and immuno-monitoring of biomarkers, allowing proper evaluation of immune responses in cancer patients in order to detect responders, are urgent issues. Additionally, we must pay attention to characteristic immunological side effects not observed following treatment with conventional anti-cancer reagents. Herein, we present a summary outline and discuss the future direction of cancer immunotherapy.

The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.

PubMed

Kaidar-Person, Orit; Zagar, Timothy M; Deal, Allison; Moschos, Stergios J; Ewend, Matthew G; Sasaki-Adams, Deanna; Lee, Carrie B; Collichio, Frances A; Fried, David; Marks, Lawrence B; Chera, Bhishamjit S

2017-07-01

Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.

Immune mediated neuropathy following checkpoint immunotherapy.

PubMed

Gu, Yufan; Menzies, Alexander M; Long, Georgina V; Fernando, S L; Herkes, G

2017-11-01

Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy - induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunotherapy in melanoma: Recent advances and future directions.

PubMed

Franklin, C; Livingstone, E; Roesch, A; Schilling, B; Schadendorf, D

2017-03-01

Malignant melanoma contributes the majority of skin cancer related deaths and shows an increasing incidence in the past years. Despite all efforts of early diagnosis, metastatic melanoma still has a poor prognosis and remains a challenge for treating physicians. In recent years, improved knowledge of the pathophysiology and a better understanding of the role of the immune system in tumour control have led to the development and approval of several immunotherapies. Monoclonal antibodies against different immune checkpoints have been revolutionizing the treatment of metastatic and unresectable melanoma. Ipilimumab, a monoclonal antibody against the cytotoxic T-lymphocyte antigen 4 (CTLA-4) as well as nivolumab and pembrolizumab which target the programmed cell death protein 1 (PD-1) have been shown to prolong overall survival in patients with advanced melanoma. The latter substances seem to have an increased response rate and more tolerable safety profile compared to ipilimumab. The combination of a CTLA-4 and a PD-1 inhibitor seems to be superior to the monotherapies, especially in patients with PD-L1 negative tumours. Checkpoint inhibitors are currently being tested in the adjuvant setting with initial data for ipilimumab suggesting efficacy in this context. Talimogene laherparepvec (TVEC) is the first oncolytic virus approved in the therapy of metastatic melanoma offering a treatment option especially for patients with limited disease. In this review, data on these recently developed and approved immunotherapies are presented. However, further studies are necessary to determine the optimal duration, sequencing and combinations of immunotherapies to further improve the outcome of patients with advanced melanoma. Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Deciphering the black box of food allergy mechanisms

PubMed Central

Sampath, Vanitha; Tupa, Dana; Graham, Michelle Toft; Chatila, Talal A.; Spergel, Jonathan M.; Nadeau, Kari C.

2016-01-01

Objective To review our current understanding of immunotherapy, the immune mechanisms underlying food allergy, and the methodological advances that are furthering our understanding of the role of immune cells and other molecules in mediating food allergies. Data Sources Literature searches were performed using the following combination of terms: allergy, immunotherapy, food, and mechanisms. Data from randomized clinical studies using state-of-the-art mechanistic tools were prioritized. Study Selections Articles were selected based on their relevance to food allergy. Results Current standard of care for food allergies is avoidance of allergenic foods and the use of epinephrine in case of severe reaction during unintentional ingestion. During the last few decades, great strides have been made in understanding the cellular and molecular mechanisms underlying food allergy, and this information is spearheading the development of exciting new treatments. Conclusion Immunotherapy protocols are effective in desensitizing individuals to specific allergens; however, recurrence of allergic sensitization is common after discontinuation of therapy. Interestingly, in a subset of individuals, immunotherapy is protective against allergens even after discontinuation of immunotherapy. Whether this protection is permanent is currently unknown because of inadequate long-term follow-up data. Research on understanding the underlying mechanisms may assist in modifying protocols to improve outcome and enable sustained unresponsiveness, rather than a temporary relief against food allergies. The cellular changes brought about by immunotherapy are still a black box, but major strides in our understanding are being made at an exciting pace. PMID:28007085

Deciphering the black box of food allergy mechanisms.

PubMed

Sampath, Vanitha; Tupa, Dana; Graham, Michelle Toft; Chatila, Talal A; Spergel, Jonathan M; Nadeau, Kari C

2017-01-01

To review our current understanding of immunotherapy, the immune mechanisms underlying food allergy, and the methodological advances that are furthering our understanding of the role of immune cells and other molecules in mediating food allergies. Literature searches were performed using the following combination of terms: allergy, immunotherapy, food, and mechanisms. Data from randomized clinical studies using state-of-the-art mechanistic tools were prioritized. Articles were selected based on their relevance to food allergy. Current standard of care for food allergies is avoidance of allergenic foods and the use of epinephrine in case of severe reaction during unintentional ingestion. During the last few decades, great strides have been made in understanding the cellular and molecular mechanisms underlying food allergy, and this information is spearheading the development of exciting new treatments. Immunotherapy protocols are effective in desensitizing individuals to specific allergens; however, recurrence of allergic sensitization is common after discontinuation of therapy. Interestingly, in a subset of individuals, immunotherapy is protective against allergens even after discontinuation of immunotherapy. Whether this protection is permanent is currently unknown because of inadequate long-term follow-up data. Research on understanding the underlying mechanisms may assist in modifying protocols to improve outcome and enable sustained unresponsiveness, rather than a temporary relief against food allergies. The cellular changes brought about by immunotherapy are still a black box, but major strides in our understanding are being made at an exciting pace. Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Immunotherapy in Chronic Lymphocytic Leukaemia (CLL).

PubMed

Freeman, Ciara L; Gribben, John G

2016-02-01

Chronic lymphocytic leukaemia (CLL) is well known to generate impaired immune responses in the host, with the malignant clone residing in well-vascularized tissues and circulating in peripheral blood but also in close proximity to effector cells that are capable, if activated appropriately, of eliciting a cytotoxic response. These, combined with the fact that this is frequently a condition affecting older patients with co-morbidities often unfit for many "traditional" cytotoxic agents with their significant associated toxicities, make CLL an ideal candidate for the development of immunotherapy. The impressive results seen with the addition of a monoclonal antibody, rituximab, to a chemotherapy backbone, for example, is testament to how effective harnessing an immune-mediated response in CLL can be. This review serves to outline the available arsenal of immunotherapies-past and present-demonstrated to have potential in CLL with some perspectives on how the landscape in this disease may evolve in the future.

Adoptive immunotherapy against ovarian cancer.

PubMed

Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

2016-05-17

The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting.

Advances of Immune Checkpoint Inhibitors in Tumor Immunotherapy

NASA Astrophysics Data System (ADS)

Guo, Qiao

2018-01-01

Immune checkpoints are cell surface molecules that can fine-tune the immune responses, they are crucial for modulating the duration and amplitude of immune reactions while maintaining self-tolerance in order to minimize autoimmune responses. Numerous studies have demonstrated that tumors cells can directly express immune-checkpoint molecules, or induce many inhibitory molecules expression in the tumor microenvironment to inhibit the anti-tumor immunity. Releasing these brakes has emerged as an exciting strategy to cure cancer. In the past few years, clinical trials with therapeutic antibodies targeting to the checkpoint molecules CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. In contrast to the conventional treatment, checkpoint inhibitors induce broad and durable antitumor responses. In the future, treatment may involve combination therapy to target different checkpoint molecules and stages of the adaptive immune responses. In this review, we summarized the recent advances of the study and development of other checkpoint molecules in tumor immunotherapy.

Clinical trial tests combinations of immunotherapy drugs for prostate cancer | Center for Cancer Research

Cancer.gov

Metastatic castration-resistant prostate cancer (mCRPC) is a disease that has spread beyond the prostate and no longer responds to hormone therapy. James Gulley, M.D., Ph.D., of the Genitourinary Malignancies Branch is leading a study of combination immunotherapy where patients will be treated with two, three or four drugs that affect the immune system in different ways to

Refining human T-cell immunotherapy of cytomegalovirus disease: a mouse model with 'humanized' antigen presentation as a new preclinical study tool.

PubMed

Lemmermann, Niels A W; Reddehase, Matthias J

2016-12-01

With the cover headline 'T cells on the attack,' the journal Science celebrated individualized cancer immunotherapy by adoptive transfer of T cells as the 'Breakthrough of the Year' 2013 (J. Couzin-Frankel in Science 342:1432-1433, 2013). It is less well recognized and appreciated that individualized T cell immunotherapy of cytomegalovirus (CMV) infection is approaching clinical application for preventing CMV organ manifestations, interstitial CMV pneumonia in particular. This coincident medical development is particularly interesting as reactivated CMV infection is a major viral complication in the state of transient immunodeficiency after the therapy of hematopoietic malignancies by hematopoietic cell transplantation (HCT). It may thus be attractive to combine T cell immunotherapy of 'minimal residual disease/leukemia (MRD)' and CMV-specific T cell immunotherapy to combat both risks in HCT recipients simultaneously, and ideally with T cells derived from the respective HLA-matched HCT donor. Although clinical trials of human CMV-specific T cell immunotherapy were promising in that the incidence of virus reactivation and disease was found to be reduced with statistical significance, animal models are still instrumental for providing 'proof of concept' by directly documenting the prevention of viral multiple-organ histopathology and organ failure under controlled conditions of the absence versus presence of the therapy, which obviously is not feasible in an individual human patient. Further, animal models can make predictions regarding parameters that determine the efficacy of T cell immunotherapy for improved study design in clinical investigations, and they allow for manipulating host and virus genetics. The latter is of particular value as it opens the possibility for epitope specificity controls that are inherently missing in clinical trials. Here, we review a recently developed new mouse model that is more approximated to human CMV-specific T cell immunotherapy by 'humanizing' antigen presentation using antigenically chimeric CMV and HLA-transgenic mice to allow for an in vivo testing of the antiviral function of human CMV-specific T cells. As an important new message, this model predicts that T cell immunotherapy is most efficient if CD4 T cells are equipped with a transduced TCR directed against an epitope presented by MHC/HLA class-I for local delivery of 'cognate' help to CD8 effector T cells at infected MHC/HLA class-II-negative host tissue cells.

2015 Guidance on cancer immunotherapy development in early-phase clinical studies.

PubMed

2015-12-01

The development of cancer immunotherapies is progressing rapidly with a variety of technological approaches. They consist of "cancer vaccines", which are based on the idea of vaccination, "effector cell therapy", classified as passive immunotherapy, and "inhibition of immunosuppression", which intends to break immunological tolerance to autoantigens or immunosuppressive environments characterizing antitumor immune responses. Recent reports showing clinical evidence of efficacy of immune checkpoint inhibitors and adoptive immunotherapies with tumor-infiltrating lymphocytes and tumor-specific receptor gene-modified T cells indicate the beginning of a new era for cancer immunotherapy. This guidance summarizes ideas that will be helpful to those who plan to develop cancer immunotherapy. The aims of this guidance are to discuss and offer important points in early phase clinical studies of innovative cancer immunotherapy, with future progress in this field, and to contribute to the effective development of cancer immunotherapy aligned with the scope of regulatory science. This guidance covers cancer vaccines, effector cell therapy, and inhibition of immunosuppression, including immune checkpoint inhibitors. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Anti-DR5 monoclonal antibody-mediated DTIC-loaded nanoparticles combining chemotherapy and immunotherapy for malignant melanoma: target formulation development and in vitro anticancer activity

PubMed Central

Ding, Baoyue; Wu, Xin; Fan, Wei; Wu, Zhaoyong; Gao, Jing; Zhang, Wei; Ma, Lulu; Xiang, Wang; Zhu, Quangang; Liu, Jiyong; Ding, Xueying; Gao, Shen

2011-01-01

Background The increased incidence of malignant melanoma in recent decades, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Novel therapeutic strategies, such as immunotherapy and targeted therapy, are urgently needed for melanoma. In this study, a new active targeting drug delivery system was constructed to combine chemotherapy and active specific immunotherapy. Methods The chemotherapeutic drug, dacarbazine (DTIC), that induces apoptosis through the intrinsic pathway which typically responds to severe DNA damage, was used as a model drug to prepare DTIC-loaded polylactic acid (PLA) nanoparticles (DTIC-NPs), which were covalently conjugated to a highly specific targeting functional TRAIL-receptor 2 (DR5) monoclonal antibody (mAb) that can contribute directly to cancer cell apoptosis or growth inhibition through the extrinsic pathway. Results Our in vitro experiments demonstrated that DTIC-PLA-DR5 mAb nanoparticles (DTIC-NPs-DR5 mAb) are an active targeting drug delivery system which can specifically target DR5-overexpressing malignant melanoma cells and become efficiently internalized. Most strikingly, compared with conventional DTIC-NPs, DTIC-NPs-DR5 mAb showed significantly enhanced cytotoxicity and increased cell apoptosis in DR5-positive malignant melanoma cells. Conclusion The DTIC-NPs-DR5 mAb described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to DR5-overexpressing metastatic melanoma. PMID:21976975

[Recent Advances in Immunotherapy for Non-Small Cell Lung Cancer].

PubMed

Muto, Satoshi; Suzuki, Hiroyuki

2018-02-01

Cancer immunotherapy for non-small cell lung cancer began around 1970 with nonspecific immunomodulators and cytokine therapies. This has since developed into cell therapy including lymphokine-activated killer cells(LAK)and tumor infiltrating lymphocytes(TIL), as well as cancer vaccine therapy. However, no clear indication of effectiveness has been reported. Despite the high expectation over the effectiveness of cancer vaccine therapy, the treatment strategy was deemed unsuccessful, and focus turned to the study of immune escape mechanism, which is now regarded as standard treatment for non-small cell lung cancer. With the advent of immune checkpoint inhibitors, cancer immunotherapy has finally become a standard treatment for non-small cell lung cancer. There are still several obstacles to overcome including the identification of a predictive biomarker for improved efficacy, as well as the establishment of multidrug or multimodality combination therapy. PD-L1 expression is currently used as a predictive biomarker for anti-PD-1 therapy, but does not meet the expectations of the aimed results. Although tumor mutation burden is considered another promising biomarker, there remain clinical problems, for example the need of next generation sequencer. It was reported that combination therapy of immune checkpoint inhibitor after chemoradiation therapy was also effective. However, it remains unclear of what is required to further improve the clinical effects. In this article, we will review the history of cancer immunotherapy for non-small cell lung cancer and discuss the future prospects.

A robust response to combination immune checkpoint inhibitor therapy in HPV-related small cell cancer: a case report.

PubMed

Ho, Won Jin; Rooper, Lisa; Sagorsky, Sarah; Kang, Hyunseok

2018-05-09

Human papillomavirus-related small cell carcinoma of the head and neck is an extremely rare, aggressive subtype with poor outcomes. Therapeutic options are limited and are largely adopted from small cell lung cancer treatment paradigms. This report describes a 69-year old male who was diagnosed of HPV-related oropharyngeal cancer with mixed small cell and squamous cell pathology which was clinically aggressive and progressed through multimodal platinum-based therapies. Upon manifestation of worsening metastatic disease, the patient was initiated on a combination of ipilimumab and nivolumab. Within 2 months of starting immunotherapy, a robust partial response was observed. During the treatment course, the patient developed immune-related adverse effects including new diabetes mellitus, colitis, and hypothyroidism. The disease-specific survival was 26 months. Combination immunotherapy may be an attractive option for HPV-related small cell head and neck cancers resistant to other treatment modalities and thus warrants further evaluation.

Therapeutic efficacy of tumor-derived heat shock protein 70 immunotherapy combining interleukin-2 on tumor-bearing mice.

PubMed

Fu, Qingguo; Meng, Fandong; Shen, Xiaodong; Guo, Renxuan

2003-02-01

To investigate the therapeutic efficacy of compound immunotherapy of tumor-derived heat shock protein 70 (HSP70) and interleukin-2 (IL-2) on tumor-bearing mice, and to provide reference for translating this strategy to human cancer. Cell culture, techniques for protein extraction and purification, SDS-PAGE, Western blot and capillary electrophoresis for HSP70 detection and purity analysis, and animal experiments were used. Mice were treated with HSP70 5 or 10 microg and IL-2 50 kU, 100 kU or 2 kU (maintaining dosage) at previously designated intervals. Both the mono-administration of either HSP70 or IL-2 and the compound immunotherapy of HSP70 and IL-2 obviously inhibited the growth of the implanted tumor and prolonged the life span of the mice to different extents. However, long periods of tumor-free survival (over 90 days) were demonstrated only in HSP70 10 micro g group, HSP70 10 microg-IL-2 50 kU group, and HSP70 10 microg-IL-2 100 kU group (40%, 40%, 60% respectively). On the other hand, none of the mice in the rest groups achieved long-term survival. Statistical significance was apparent in comparison with the groups without long period survival (P < 0.025 - 0.05). Our research revealed that tumor-derived HSP70 immunotherapy was much more effective than IL-2 alone. And in compound immunotherapy, HSP70 was the main factor in delaying or eradicating the tumors. The proper combination of HSP70 and IL-2 (10 microg HSP70 and 100 kU IL-2 in this experimental mouse model) clearly enhanced the immunotherapy efficacy which indicated that the specific immunotherapy as a main part of tumor immunotherapy assisted by cytokine immunotherapy would be a promising strategy in cancer treatment.

Treatment of Adults with Idiopathic Recurrent Pericarditis: Novel Use of Immunotherapy.

PubMed

Schwier, Nicholas C; Hale, Genevieve M; Davies, Marie L

2017-03-01

Idiopathic recurrent pericarditis (IRP) can be challenging to treat. Even after guideline-directed first-line treatment consisting of aspirin (ASA) or a nonsteroidal antiinflammatory drug (NSAID) in combination with colchicine therapy, recurrences still occur in greater than 20% of patients. Many patients then require treatment with long-term corticosteroids, which is not a favorable option due to their short- and long-term adverse effects. Because it is theorized that the pathophysiology of IRP may possess autoimmune sequelae, the use of immunotherapy for the treatment of IRP has emerged. In this review, we describe the literature associated with immunotherapy used to treat IRP in an adult population as well as provide an overview of the safety and monitoring parameters for each agent. The most common immunotherapies used after patients have had multiple recurrences of IRP are anakinra, intravenous immunoglobulin (IVIG), and azathioprine. In most cases, these immunotherapies are adjunctive therapy, with the goal of tapering and discontinuing immunosuppressive corticosteroids. After reviewing the data, anakinra resulted in more patients discontinuing corticosteroids and prevented further recurrences of pericarditis. IVIG resulted in symptom resolution and no further recurrences in most of the patients. Azathioprine was associated with more than half of patients becoming recurrence free; however, many patients required a restart of corticosteroids due to recurrence. Clinicians should be aware of the adverse effects of immunotherapy, ranging from mild gastrointestinal events to risk of infection and serious blood dyscrasias that may require diligent monitoring. The use of immunotherapy for the treatment of adults with IRP should be restricted to patients who have multiple recurrences. Ideally, immunotherapy would be adjunctive to first-line combination therapy with ASA/NSAID plus colchicine, with the goal of tapering and discontinuing immunosuppressive corticosteroids. Furthermore, clinicians should consider cost, drug-drug and drug-disease interactions, and safety, as well as the quality of the retrospective evidence before considering any immunotherapy. © 2017 Pharmacotherapy Publications, Inc.

PROSTVAC® targeted immunotherapy candidate for prostate cancer.

PubMed

Shore, Neal D

2014-01-01

Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

Treatment of advanced melanoma with laser immunotherapy and ipilimumab.

PubMed

Naylor, Mark F; Zhou, Feifan; Geister, Brian V; Nordquist, Robert E; Li, Xiaosong; Chen, Wei R

2017-05-01

Immunotherapy has become a promising modality for melanoma, especially using checkpoint inhibitors, which revive suppressed T cells against the cancer. Such inhibitors should work better when combined with other treatments which could increase the number and quality of anti-tumor T cells. We treated one patient with advanced (stage IV) melanoma, using the combination of laser immunotherapy (LIT), a novel immunological approach for metastatic cancers that has been shown to stimulate adaptive immunity, and ipilimumab. The patient was treated with LIT, followed with one course of ipilimumab 3 months after the beginning of LIT. After LIT treatment, all treated cutaneous melanoma in head and neck cleared completely. After the application of ipilimumab, all the tumor nodules in the lungs decreased. The patient had remained tumor free for one year. While anecdotal, the responses seen in this patient support the hypothesis that laser immunotherapy increases the number and quality of anti-tumor T cells so that ipilimumab and other checkpoint inhibitors are more effective in enhancing the therapeutic effects. Picture: Schematic of treatment using laser immunotherapy and ipilimumab on a stage IV melanoma patient. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

PubMed Central

Fukumura, Dai; Kloepper, Jonas; Amoozgar, Zohreh; Duda, Dan G.; Jain, Rakesh K.

2018-01-01

Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research. PMID:29508855

Optimizing Tumor Microenvironment for Cancer Immunotherapy: β-Glucan-Based Nanoparticles

PubMed Central

Zhang, Mei; Kim, Julian A.; Huang, Alex Yee-Chen

2018-01-01

Immunotherapy is revolutionizing cancer treatment. Recent clinical success with immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and adoptive immune cellular therapies has generated excitement and new hopes for patients and investigators. However, clinically efficacious responses to cancer immunotherapy occur only in a minority of patients. One reason is the tumor microenvironment (TME), which potently inhibits the generation and delivery of optimal antitumor immune responses. As our understanding of TME continues to grow, strategies are being developed to change the TME toward one that augments the emergence of strong antitumor immunity. These strategies include eliminating tumor bulk to provoke the release of tumor antigens, using adjuvants to enhance antigen-presenting cell function, and employ agents that enhance immune cell effector activity. This article reviews the development of β-glucan and β-glucan-based nanoparticles as immune modulators of TME, as well as their potential benefit and future therapeutic applications. Cell-wall β-glucans from natural sources including plant, fungi, and bacteria are molecules that adopt pathogen-associated molecular pattern (PAMP) known to target specific receptors on immune cell subsets. Emerging data suggest that the TME can be actively manipulated by β-glucans and their related nanoparticles. In this review, we discuss the mechanisms of conditioning TME using β-glucan and β-glucan-based nanoparticles, and how this strategy enables future design of optimal combination cancer immunotherapies. PMID:29535722

Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescence probe-guided surgery and PD-1 adjuvant immunotherapy in 4T1 mouse model

PubMed Central

Li, Yuan; Jin, Zhengyu; Xue, Huadan; Wan, Yihong; Tian, Jie

2017-01-01

An intraoperative technique to accurately identify microscopic tumor residuals could decrease the risk of positive surgical margins. Several lines of evidence support the expression and immunotherapeutic effect of PD-1 in breast cancer. Here, we sought to develop a fluorescence-labeled PD-1 probe for in vivo breast tumor imaging and image-guided surgery. The efficacy of PD-1 monoclonal antibody (PD-1 mAb) as adjuvant immunotherapy after surgery was also assessed. PD-1-IRDye800CW was developed and examined for its application in tumor imaging and image-guided tumor resection in an immunocompetent 4T1 mouse tumor model. Fluorescence molecular imaging was performed to monitor probe biodistribution and intraoperative imaging. Bioluminescence imaging was performed to monitor tumor growth and evaluate postsurgical tumor residuals, recurrences, and metastases. The PD-1-IRDye800CW exhibited a specific signal at the tumor region compared with the IgG control. Furthermore, PD-1-IRDye800CW-guided surgery combined with PD-1 adjuvant immunotherapy inhibited tumor regrowth and microtumor metastases and thus improved survival rate. Our study demonstrates the feasibility of using PD-1-IRDye800CW for breast tumor imaging and image-guided tumor resection. Moreover, PD-1 mAb adjuvant immunotherapy reduces cancer recurrences and metastases emanating from tumor residuals. PMID:29200846

Increased anti-tumor effects using IL2 with anti-TGFβ reveals competition between mouse NK and CD8 T cells

PubMed Central

Alvarez, Maite; Bouchlaka, Myriam N.; Sckisel, Gail D.; Sungur, Can M.; Chen, Mingyi; Murphy, William J.

2014-01-01

Due to increasing interest in the removal of immunosuppressive pathways in cancer, the combination of IL2 with antibodies to neutralize TGFβ, a potent immunosuppressive cytokine, was assessed. Combination immunotherapy resulted in significantly greater anti-tumor effects. These were correlated with significant increases in the numbers and functionality of NK cells, NK progenitors and activated CD8 T cells resulting in the observed anti-tumor effects. Combination immunotherapy was also accompanied with lesser toxicities than IL2 therapy alone. Additionally, we observed a dual competition between NK and activated CD8 T cells such that after immunotherapy, the depletion of either effector population resulted in the increased total expansion of the other population and compensatory anti-tumor effects. This study demonstrates the efficacy of this combination immunotherapeutic regimen as a promising cancer therapy and illustrates the existence of potent competitive regulatory pathways between NK and CD8 T cells in response to systemic activation. PMID:25000978

Immunotherapy of colorectal cancer: new perspectives after a long path.

PubMed

Correale, Pierpaolo; Botta, Cirino; Ciliberto, Domenico; Pastina, Pierpaolo; Ingargiola, Rossana; Zappavigna, Silvia; Tassone, Pierfrancesco; Pirtoli, Luigi; Caraglia, Michele; Tagliaferri, Pierosandro

2016-11-01

Although significant therapeutic improvement has been achieved in the last 10 years, the survival of metastatic colorectal cancer patients remains in a range of 28 to 30 months. Presently, systemic treatment includes combination chemotherapy with oxaliplatin and/or irinotecan together with a backbone of 5-fluorouracil/levofolinate, alone or in combination with monoclonal antibodies to VEGFA (bevacizumab) or EGF receptor (cetuximab and panitumumab). The recent rise of immune checkpoint inhibitors in the therapeutic scenario has renewed scientific interest in the investigation of immunotherapy in metastatic colorectal cancer patients. According to our experience and view, here, we review the immunological strategies investigated for the treatment of this disease, including the use of tumor target-specific cancer vaccines, chemo-immunotherapy and immune checkpoint inhibitors.

P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling.

PubMed

de Almeida Chuffa, Luiz Gustavo; de Moura Ferreira, Grazielle; Lupi, Luiz Antonio; da Silva Nunes, Iseu; Fávaro, Wagner José

2018-01-17

Toll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC. Tumors were chemically induced by a single injection of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses. Although CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce the Thelper (Th1)-mediated immune response. Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could be considered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4.

Statistical controversies in clinical research: early-phase adaptive design for combination immunotherapies.

PubMed

Wages, N A; Slingluff, C L; Petroni, G R

2017-04-01

In recent years, investigators have asserted that the 3 + 3 design lacks flexibility, making its use in modern early-phase trial settings, such as combinations and/or biological agents, inefficient. More innovative approaches are required to address contemporary research questions, such as those posed in trials involving immunotherapies. We describe the implementation of an adaptive design for identifying an optimal treatment regimen, defined by low toxicity and high immune response, in an early-phase trial of a melanoma helper peptide vaccine plus novel adjuvant combinations. Operating characteristics demonstrate the ability of the method to effectively recommend optimal regimens in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined immunotherapy regimens. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of two small molecule inhibitors in relapsed/refractory mantle cell lymphoma. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Requirement for Innate Immunity and CD90+ NK1.1− Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy

PubMed Central

Moskalenko, Marina; Pan, Michael; Fu, Yichun; de Moll, Ellen H.; Hashimoto, Daigo; Mortha, Arthur; Leboeuf, Marylene; Jayaraman, Padmini; Bernardo, Sebastian; Sikora, Andrew G.; Wolchok, Jedd; Bhardwaj, Nina; Merad, Miriam; Saenger, Yvonne

2015-01-01

We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (αTRP1), a native melanoma differentiation antigen. We find that Fcγ receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1−/− mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2γc−/−) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair antitumor effect. Depletion of CD90+NK1.1− lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1− ILCs in chemo-immunotherapy. PMID:25600438

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking

PubMed Central

Conniot, João; Silva, Joana M.; Fernandes, Joana G.; Silva, Liana C.; Gaspar, Rogério; Brocchini, Steve; Florindo, Helena F.; Barata, Teresa S.

2014-01-01

Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options. PMID:25505783

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking

NASA Astrophysics Data System (ADS)

Conniot, João; Silva, Joana; Fernandes, Joana; Silva, Liana; Gaspar, Rogério; Brocchini, Steve; Florindo, Helena; Barata, Teresa

2014-11-01

Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options.

Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with P-MAPA and systemic administration of cisplatin and doxorubicin

PubMed Central

Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Fávaro, Wagner José

2016-01-01

ABSTRACT The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy. PMID:24893914

Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with p - mapa and systemic administration of cisplatin and doxorubicin.

PubMed

Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Favaro, Wagner Jose

2016-01-01

The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy. Copyright® by the International Brazilian Journal of Urology.

Cooperative effect between immunotherapy and antiangiogenic therapy leads to effective tumor rejection in tolerant Her-2/neu mice.

PubMed

Cuadros, Camilo; Dominguez, Ana Lucia; Frost, Gregory I; Borgstrom, Per; Lustgarten, Joseph

2003-09-15

Immunotherapy is an attractive strategy for cancer treatment. However, self-tolerance is one of the major mechanisms that dampen immune responses against self-tumor antigens. We have demonstrated that Her-2/neu transgenic mice (neu mice) are tolerant to neu antigens and contain only a low avidity repertoire for neu. However, this repertoire has antitumor activity. Immunizations of neu mice are capable of activating the low-avidity T cells that, at best, retard the tumor growth. To increase the efficacy of the antitumor responses in neu mice, we hypothesized that immunotherapy in combination with antiangiogenic therapy would be a more efficient strategy for tumor eradication. The rationale for using this combination was that by decreasing the growth rate of the tumor with an antiangiogenic therapy, the low-avidity repertoire of neu mice stimulated by immunotherapeutic intervention would be more effective in destroying the slow growing tumor. To test this hypothesis, we stably expressed a soluble form of the Flt-1 vascular endothelial growth factor receptor (sFlt-1) on N202.1A cells, using a retrovirus vector. Expression of sFlt-1 on N202.1A (N202-Flt) cells significantly inhibited the tumor growth compared with N202.1A parental cells. In contrast to the application of immunotherapy alone or antiangiogenic therapy alone, which delayed the tumor growth, the combination of the two therapies provided complete inhibition of tumor growth in Her-2/neu mice. These results indicate that the use of tumor targeting with immunotherapy in simultaneous combination with antiangiogenic therapy provides a more efficient strategy for the treatment of solid tumors.

Combining Cytotoxic and Immune-Mediated Gene Therapy to Treat Brain Tumors

PubMed Central

Curtin, James F.; King, Gwendalyn D.; Candolfi, Marianela; Greeno, Remy B.; Kroeger, Kurt M.; Lowenstein, Pedro R.; Castro, Maria G.

2006-01-01

Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as ‘immune privileged’, brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another important aspect of implementing gene therapy in the clinical arena is to be able to image the targeting of the therapeutics to the tumors, treatment effectiveness and progression of disease. We have therefore reviewed the most exciting non-invasive, in vivo imaging techniques which can be used in combination with gene therapy to monitor therapeutic efficacy over time. PMID:16248789

Novel cancer immunotherapy agents with survival benefit: recent successes and next steps

PubMed Central

Sharma, Padmanee; Wagner, Klaus; Wolchok, Jedd D.; Allison, James P.

2012-01-01

The US Food and Drug Administration (FDA) recently approved two novel immunotherapy agents, sipuleucel-T and ipilimumab, which showed a survival benefit for patients with metastatic prostate cancer and melanoma, respectively. The mechanisms by which these agents provide clinical benefit are not completely understood. However, knowledge of these mechanisms will be crucial for probing human immune responses and tumour biology in order to understand what distinguishes responders from non-responders. The following next steps are necessary: first, the development of immune-monitoring strategies for the identification of relevant biomarkers; second, the establishment of guidelines for the assessment of clinical end points; and third, the evaluation of combination therapy strategies to improve clinical benefit. PMID:22020206

Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

NASA Astrophysics Data System (ADS)

Park, Jason; Wrzesinski, Stephen H.; Stern, Eric; Look, Michael; Criscione, Jason; Ragheb, Ragy; Jay, Steven M.; Demento, Stacey L.; Agawu, Atu; Licona Limon, Paula; Ferrandino, Anthony F.; Gonzalez, David; Habermann, Ann; Flavell, Richard A.; Fahmy, Tarek M.

2012-10-01

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies.

PubMed

Kato, Daiki; Yaguchi, Tomonori; Iwata, Takashi; Morii, Kenji; Nakagawa, Takayuki; Nishimura, Ryohei; Kawakami, Yutaka

2017-01-01

  Immune checkpoint blockade (ICB) and adoptive cell therapies (ACT) with antigen-receptor gene-engineered T cells have been shown to be successful for a limited number of patients with solid tumors. Responders to ICB therapy typically have T cell-inflamed tumors. Thus, it is important to develop strategies that convert non-T cell-inflamed tumors to T cell-inflamed tumors. Although chimeric antigen receptor transduced T (CAR-T) cell therapy targeting hematological malignancies demonstrated durable clinical responses, the success of gene-engineered T cell therapies in solid tumors is hampered by a lack of unique antigens, antigen loss in cancer cells, and the immune-suppressive tumor microenvironment (TME) of solid tumors. However, gene-engineered T cells possess strong killing activity and cytokine production capacity, which can induce antigen spreading and modulate the TME of non-T cell-inflamed tumors seen in non-responders to ICB therapy. Immune responses against cancer are highly heterogeneous, not only between tumor types, but also within a patient or between different patients with the same type of cancer, indicating that personalized immunotherapy should be employed, based on the immune status of the individual patient. Here, we offer our perspective for personalized combination immunotherapy for solid tumors based on ACT and ICB therapies.

Immunotherapy and immunoescape in colorectal cancer

PubMed Central

Mazzolini, Guillermo; Murillo, Oihana; Atorrasagasti, Catalina; Dubrot, Juan; Tirapu, Iñigo; Rizzo, Miguel; Arina, Ainhoa; Alfaro, Carlos; Azpilicueta, Arantza; Berasain, Carmen; Perez-Gracia, José L; Gonzalez, Alvaro; Melero, Ignacio

2007-01-01

Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma. PMID:17990348

Combinational Targeting of Prostate Carcinoma Cells and Tumors Associated Pericytes with Antibody Based Immunotherapy and Metronomic Chemotherapy

DTIC Science & Technology

2010-02-01

Carcinoma Cells and Tumors Associated Pericytes with Antibody Based Immunotherapy and Metronomic Chemotherapy PRINCIPAL INVESTIGATOR......purity and activity. The colony of TRAMP mice has been expanded to test the efficacy of mAb 225.28 plus cyclophosphamide metronomic therapy in the

Proteasome Inhibitors: A Worthy Partner to Boost Cancer Immunotherapy? | Center for Cancer Research

Cancer.gov

For a number of years, research-ers have been frustrated by their inability to harness patients' immune systems to stem tumor growth. However, recent preclinical data involving the use of immunotherapy in combination with proteasome inhibition suggest this novel approach may be worthy of attention.

Treatment of a Solid Tumor Using Engineered Drug-Resistant Immunocompetent Cells and Cytotoxic Chemotherapy

PubMed Central

Dasgupta, Anindya; Shields, Jordan E.

2012-01-01

Abstract Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI). The strategy relies on the use of cDNA sequences that confer drug resistance and recombinant lentiviral vectors to transfer nucleic acid sequences into immunocompetent cells. In the present study, we evaluated a DRI-based strategy that incorporates the immunocompetent cell line NK-92, which has intrinsic antitumor properties, genetically engineered to be resistant to both temozolomide and trimetrexate. These immune effector cells efficiently lysed neuroblastoma cell lines, which we show are also sensitive to both chemotherapy agents. The antitumor efficacy of the DRI strategy was demonstrated in vivo, whereby neuroblastoma-bearing NOD/SCID/γ-chain knockout (NSG) mice treated with dual drug-resistant NK-92 cell therapy followed by dual cytotoxic chemotherapy showed tumor regression and significantly enhanced survival compared with animals receiving either nonengineered cell-based therapy and chemotherapy, immunotherapy alone, or chemotherapy alone. These data show there is a benefit to using drug-resistant cellular therapy when combined with cytotoxic chemotherapy approaches. PMID:22397715

Immunotherapy in Gynecologic Cancers: Are We There Yet?

PubMed

Pakish, Janelle B; Jazaeri, Amir A

2017-08-24

Immune-targeted therapies have demonstrated durable responses in many tumor types with limited treatment options and poor overall prognosis. This has led to enthusiasm for expanding such therapies to other tumor types including gynecologic malignancies. The use of immunotherapy in gynecologic malignancies is in the early stages and is an active area of ongoing clinical research. Both cancer vaccines and immune checkpoint inhibitor therapy continue to be extensively studied in gynecologic malignancies. Immune checkpoint inhibitors, in particular, hold promising potential in specific subsets of endometrial cancer that express microsatellite instability. The key to successful treatment with immunotherapy involves identification of the subgroup of patients that will derive benefit. The number of ongoing trials in cervical, ovarian, and endometrial cancer will help to recognize these patients and make treatment more directed. Additionally, a number of studies are combining immunotherapy with standard treatment options and will help to determine combinations that will enhance responses to standard therapy. Overall, there is much enthusiasm for immunotherapy approaches in gynecologic malignancies. However, the emerging data shows that with the exception of microsatellite unstable tumors, the use of single-agent immune checkpoint inhibitors is associated with response rates of 10-15%. More effective and likely combinatorial approaches are needed and will be informed by the findings of ongoing trials.

Immunotherapy Added to Antibiotic Treatment Reduces Relapse of Disease in a Mouse Model of Tuberculosis.

PubMed

Mourik, Bas C; Leenen, Pieter J M; de Knegt, Gerjo J; Huizinga, Ruth; van der Eerden, Bram C J; Wang, Jinshan; Krois, Charles R; Napoli, Joseph L; Bakker-Woudenberg, Irma A J M; de Steenwinkel, Jurriaan E M

2017-02-01

Immune-modulating drugs that target myeloid-derived suppressor cells or stimulate natural killer T cells have been shown to reduce mycobacterial loads in tuberculosis (TB). We aimed to determine if a combination of these drugs as adjunct immunotherapy to conventional antibiotic treatment could also increase therapeutic efficacy against TB. In our model of pulmonary TB in mice, we applied treatment with isoniazid, rifampicin, and pyrazinamide for 13 weeks alone or combined with immunotherapy consisting of all-trans retinoic acid, 1,25(OH) 2 -vitamin D3, and α-galactosylceramide. Outcome parameters were mycobacterial load during treatment (therapeutic activity) and 13 weeks after termination of treatment (therapeutic efficacy). Moreover, cellular changes were analyzed using flow cytometry and cytokine expression was assessed at the mRNA and protein levels. Addition of immunotherapy was associated with lower mycobacterial loads after 5 weeks of treatment and significantly reduced relapse of disease after a shortened 13-week treatment course compared with antibiotic treatment alone. This was accompanied by reduced accumulation of immature myeloid cells in the lungs at the end of treatment and increased TNF-α protein levels throughout the treatment period. We demonstrate, in a mouse model of pulmonary TB, that immunotherapy consisting of three clinically approved drugs can improve the therapeutic efficacy of standard antibiotic treatment.

DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer.

PubMed

Terracina, Krista P; Graham, Laura J; Payne, Kyle K; Manjili, Masoud H; Baek, Annabel; Damle, Sheela R; Bear, Harry D

2016-09-01

Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer.

Synergistic antitumor effect of combining metronomic chemotherapy with adoptive cell immunotherapy in nude mice.

PubMed

Shi, Shujing; Tao, Leilei; Song, Haizhu; Chen, Longbang; Huang, Guichun

2014-05-01

Adoptive cell immunotherapy with cytokine-induced killer cell (CIK cell) represents a promising non-toxic anticancer therapy. However, the clinical efficacy of CIK cells is limited because of abnormal tumor vasculature. Metronomic chemotherapy shows promising anticancer activity by its potential antiangiogenic effect and reduced toxicity. We hypothesized that metronomic chemotherapy with paclitaxel could improve the antitumor effect of adoptive CIK cell immunotherapy. Mice health status was analyzed by measuring mice weight and observing mice behavior. Immunohistochemistry was used to investigate the recruitment of CIK cells, the expression of endothelial cell molecules, as well as the hypoxic tumor area. Metronomic paclitaxel synergized with adoptive CIK cell immunotherapy to inhibit the growth of non-small cell lung cancer (NSCLC). Metronomic paclitaxel reduced hypoxic tumor area and increased CIK cell infiltration. Hypoxia impeded the adhesion of CIK cells and reduced the expression of endothelial cell adhesion molecules. In vivo studies demonstrated that more CIK cells were found in endothelial cell adhesion molecules high expressed area. Our study provides a new rationale for combining metronomic chemotherapy with adoptive cell immunotherapy in the treatment of xenograft NSCLC tumors in immunodeficient mice. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach. © 2014 APMIS. Published by John Wiley & Sons Ltd.

The current status of immunotherapy in peritoneal carcinomatosis.

PubMed

Ströhlein, Michael Alfred; Heiss, Markus Maria; Jauch, Karl-Walter

2016-10-01

Peritoneal carcinomatosis (PC) is a cancer disease with an urgent need for effective treatment. Conventional chemotherapy failed to show acceptable results. Cytoreductive surgery and hyperthermic chemoperfusion (HIPEC) are only beneficial in few patients with resectable peritoneal metastasis. Immunotherapy could be attractive against PC, as all requirements for immunotherapy are available in the peritoneal cavity. This review analyzes the present literature for immunotherapy of PC. Advances from immune stimulators, radionucleotide-conjugated- and bispecific antibodies to future developments like adoptive engineered T-cells with chimeric receptors are discussed. The clinical development of catumaxomab, which was the first intraperitoneal immunotherapy to be approved for clinical treatment, is discussed. The requirements for future developments are illustrated. Expert commentary: Immunotherapy of peritoneal carcinomatosis is manageable, showing striking cancer cell killing. Improved profiles of adverse events by therapy-induced cytokine release, enhanced specific killing and optimal treatment schedules within multimodal treatment will be key factors.

1alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta.

PubMed

Taher, Yousef A; van Esch, Betty C A M; Hofman, Gerard A; Henricks, Paul A J; van Oosterhout, Antoon J M

2008-04-15

1alpha,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a potent inhibitor of NF-kappaB expression, can prevent the maturation of dendritic cells in vitro leading to tolerogenic dendritic cells with increased potential to induce regulatory T cells. Herein, we investigated whether the combination of allergen immunotherapy with 1,25(OH)(2)D(3) potentiates the suppressive effects of immunotherapy and whether the immunoregulatory cytokines IL-10 and TGF-beta are involved in the effector phase. OVA-sensitized and challenged BALB/c mice displayed airway hyperresponsiveness (AHR) and increased serum OVA-specific IgE levels, bronchoalveolar lavage eosinophilia, and Th2 cytokine levels. In this model, the dose response of allergen immunotherapy 10 days before OVA inhalation challenge shows strong suppression of asthma manifestations at 1 mg of OVA, but partial suppression of bronchoalveolar lavage eosinophilia, IgE up-regulation, and no reduction of AHR at 100 microg. Interestingly, coadministration of 10 ng of 1,25(OH)(2)D(3) with 100 microg of OVA immunotherapy significantly inhibited AHR and potentiated the reduction of serum OVA-specific IgE levels, airway eosinophilia, and Th2-related cytokines concomitant with increased IL-10 levels in lung tissues and TGF-beta and OVA-specific IgA levels in serum. Similar effects on suboptimal immunotherapy were observed by inhibition of the NF-kappaB pathway using the selective IkappaB kinase 2 inhibitor PS-1145. The suppressive effects of this combined immunotherapy were partially reversed by treatment with mAb to either IL-10R or TGF-beta before OVA inhalation challenge but completely abrogated when both Abs were given. These data demonstrate that 1,25(OH)(2)D(3) potentiates the efficacy of immunotherapy and that the regulatory cytokines IL-10 and TGF-beta play a crucial role in the effector phase of this mouse model.

Magnetic Enrichment of Dendritic Cell Vaccine in Lymph Node with Fluorescent-Magnetic Nanoparticles Enhanced Cancer Immunotherapy

PubMed Central

Jin, Honglin; Qian, Yuan; Dai, Yanfeng; Qiao, Sha; Huang, Chuan; Lu, Lisen; Luo, Qingming; Chen, Jing; Zhang, Zhihong

2016-01-01

Dendritic cell (DC) migration to the lymph node is a key component of DC-based immunotherapy. However, the DC homing rate to the lymphoid tissues is poor, thus hindering the DC-mediated activation of antigen-specific T cells. Here, we developed a system using fluorescent magnetic nanoparticles (α-AP-fmNPs; loaded with antigen peptide, iron oxide nanoparticles, and indocyanine green) in combination with magnetic pull force (MPF) to successfully manipulate DC migration in vitro and in vivo. α-AP-fmNPs endowed DCs with MPF-responsiveness, antigen presentation, and simultaneous optical and magnetic resonance imaging detectability. We showed for the first time that α-AP-fmNP-loaded DCs were sensitive to MPF, and their migration efficiency could be dramatically improved both in vitro and in vivo through MPF treatment. Due to the enhanced migration of DCs, MPF treatment significantly augmented antitumor efficacy of the nanoparticle-loaded DCs. Therefore, we have developed a biocompatible approach with which to improve the homing efficiency of DCs and subsequent anti-tumor efficacy, and track their migration by multi-modality imaging, with great potential applications for DC-based cancer immunotherapy. PMID:27698936

Disparities of Immunotherapy Utilization in Patients with Stage III Cutaneous Melanoma: A National Perspective.

PubMed

Al-Qurayshi, Zaid; Crowther, Jason E; Hamner, John B; Ducoin, Christopher; Killackey, Mary T; Kandil, Emad

2018-05-01

Immunotherapy combined with surgery is associated with better survival than surgery alone in patients with advanced melanoma. This study examined the utilization of immunotherapy in relation to population characteristics and the associated survival benefit. This was a retrospective cohort study utilizing the US National Cancer Database. The study population included 6,165 adult patients (≥18 years) with stage III cutaneous melanoma (median follow-up=32 months). A total of 1,854 patients underwent immunotherapy in addition to surgery, which was associated with a survival benefit over surgery alone (hazard ratio(HR)=0.66, 95% confidence interval(CI)=0.56-0.77, p<0.001). Older age, presence of comorbidities, Medicaid/Medicare insurance, and living in a community with lower average education level were associated with less immunotherapy utilization (all p<0.05). No statistically significant racial disparity in immunotherapy usage was found (p=0.07). Compared to other demographic factors, insurance status was associated with the greatest disparities in immunotherapy utilization and mortality for patients who underwent surgery for advanced melanoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Developing Precision Immunotherapies - Annual Plan

Cancer.gov

Despite remarkable progress, cancer immunotherapies can be toxic to some patients. Learn how NCI-funded research will extend the benefits of immunotherapy to more patients through biomarker research and collaboration.

Economic evaluation of therapeutic cancer vaccines and immunotherapy: A systematic review

PubMed Central

Geynisman, Daniel M; Chien, Chun-Ru; Smieliauskas, Fabrice; Shen, Chan; Tina Shih, Ya-Chen

2014-01-01

Cancer immunotherapy is a rapidly growing field in oncology. One attractive feature of cancer immunotherapy is the purported combination of minimal toxicity and durable responses. However such treatments are often very expensive. Given the wide-spread concern over rising health care costs, it is important for all stakeholders to be well-informed on the cost and cost-effectiveness of cancer immunotherapies. We performed a comprehensive literature review of cost and cost-effectiveness research on therapeutic cancer vaccines and monoclonal antibodies, to better understand the economic impacts of these treatments. We summarized our literature searches into three tables by types of papers: systematic review of economic studies of a specific agent, cost and cost-effectiveness analysis. Our review showed that out of the sixteen immunotherapy agents approved, nine had relevant published economic studies. Five out of the nine studied immunotherapy agents had been covered in systematic reviews. Among those, only one (rituximab for non-Hodgkin lymphoma) was found to be cost-effective. Of the four immunotherapy drugs not covered in systematic reviews (alemtuzumab, ipilimumab, sipuleucel-T, ofatumumab), high incremental cost-effectiveness ratio (ICER) was reported for each. Many immunotherapies have not had economic evaluations, and those that have been studied show high ICERs or frank lack of cost-effectiveness. One major hurdle in improving the cost-effectiveness of cancer immunotherapies is to identify predictive biomarkers for selecting appropriate patients as recipients of these expensive therapies. We discuss the implications surrounding the economic factors involved in cancer immunotherapies and suggest that further research on cost and cost-effectiveness of newer cancer vaccines and immunotherapies are warranted as this is a rapidly growing field with many new drugs on the horizon. PMID:25483656

A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents.

PubMed

Herter, Sylvia; Morra, Laura; Schlenker, Ramona; Sulcova, Jitka; Fahrni, Linda; Waldhauer, Inja; Lehmann, Steffi; Reisländer, Timo; Agarkova, Irina; Kelm, Jens M; Klein, Christian; Umana, Pablo; Bacac, Marina

2017-01-01

The complexity of the tumor microenvironment is difficult to mimic in vitro, particularly regarding tumor-host interactions. To enable better assessment of cancer immunotherapy agents in vitro, we developed a three-dimensional (3D) heterotypic spheroid model composed of tumor cells, fibroblasts, and immune cells. Drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast spheroid areas were demonstrated following treatment with a novel immunocytokine (interleukin-2 variant; IgG-IL2v) and tumor- or fibroblast-targeted T cell bispecific antibody (TCB). Following treatment with IgG-IL2v, activation of T cells, NK cells, and NKT cells was demonstrated by increased expression of the activation marker CD69 and enhanced cytokine secretion. The combination of TCBs with IgG-IL2v molecules was more effective than monotherapy, as shown by enhanced effects on immune cell infiltration; activation; increased cytokine secretion; and faster, more efficient elimination of targeted cells. This study demonstrates that the 3D heterotypic spheroid model provides a novel and versatile tool for in vitro evaluation of cancer immunotherapy agents and allows for assessment of additional aspects of the activity of cancer immunotherapy agents, including analysis of immune cell infiltration and drug targeting.

Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation.

PubMed

Ferris, Robert L; Lenz, Heinz-Josef; Trotta, Anna Maria; García-Foncillas, Jesús; Schulten, Jeltje; Audhuy, François; Merlano, Marco; Milano, Gerard

2018-02-01

Immunoglobulin (Ig) G1 antibodies stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab, an IgG1 isotype monoclonal antibody, is a standard-of-care treatment for locally advanced and recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and metastatic colorectal cancer (CRC). Here we review evidence regarding the clinical relevance of cetuximab-mediated ADCC and other immune functions and provide a biological rationale concerning why this property positions cetuximab as an ideal partner for immune checkpoint inhibitors (ICIs) and other emerging immunotherapies. We performed a nonsystematic review of available preclinical and clinical data involving cetuximab-mediated immune activity and combination approaches of cetuximab with other immunotherapies, including ICIs, in SCCHN and CRC. Indeed, cetuximab mediates ADCC activity in the intratumoral space and primes adaptive and innate cellular immunity. However, counterregulatory mechanisms may lead to immunosuppressive feedback loops. Accordingly, there is a strong rationale for combining ICIs with cetuximab for the treatment of advanced tumors, as targeting CTLA-4, PD-1, and PD-L1 can ostensibly overcome these immunosuppressive counter-mechanisms in the tumor microenvironment. Moreover, combining ICIs (or other immunotherapies) with cetuximab is a promising strategy for boosting immune response and enhancing response rates and durability of response. Cetuximab immune activity-including, but not limited to, ADCC-provides a strong rationale for its combination with ICIs or other immunotherapies to synergistically and fully mobilize the adaptive and innate immunity against tumor cells. Ongoing prospective studies will evaluate the clinical effect of these combination regimens and their immune effect in CRC and SCCHN and in other indications. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Treatment of experimental pythiosis with essential oils of Origanum vulgare and Mentha piperita singly, in association and in combination with immunotherapy.

PubMed

Fonseca, Anelise O S; Pereira, Daniela I B; Botton, Sônia A; Pötter, Luciana; Sallis, Elisa S V; Júnior, Sérgio F V; Filho, Fernando S M; Zambrano, Cristina Gomes; Maroneze, Beatriz P; Valente, Julia S S; Baptista, Cristiane T; Braga, Caroline Q; Ben, Vanessa Dal; Meireles, Mario C A

2015-08-05

This study investigated the in vivo antimicrobial activity of the essential oils of Origanum vulgare and Mentha piperita both singly, associated and in combination with immunotherapy to treat experimental pythiosis. The disease was reproduced in 18 rabbits divided into six groups (n=3): group 1, control; group 2, treated with essential oil of Mentha piperita; group 3, treated with essential oil of Origanum vulgare; group 4, treated with commercial immunotherapic; group 5, treated with a association of oils of M. piperita and O. vulgare and group 6, treated with a combination of both oils plus immunotherapy. Essential oils were added in a topical cream base formula, and lesions were treated daily for 45 days. The animals in groups 4 and 6 received a dose of immunotherapeutic agent every 14 days. The results revealed that the evolution of lesions in groups 5 and 6 did not differ from one another but differed from the other groups. The lesions of group 5 increased 3.16 times every measurement, while those of group 6 increased 1.83 times, indicating that the smallest growth of the lesions occurred when the combination of therapies were used. A rabbit from group 5 showed clinical cure at day 20 of treatment. This research is the pioneer in the treatment of experimental pythiosis using essential oils from medicinal plants and a combination of therapies. This study demonstrated that the use of essential oils can be a viable alternative treatment to cutaneous pythiosis, particularly when used in association or combination with immunotherapy. Copyright © 2015 Elsevier B.V. All rights reserved.

A review of allergoid immunotherapy: is cat allergy a suitable target?

PubMed

Nguyen, Nhung T; Raskopf, Esther; Shah-Hosseini, Kija; Zadoyan, Gregor; Mösges, Ralph

2016-01-01

To modify the course of allergy, different types of specific allergen immunotherapy have been developed such as sublingual immunotherapy and subcutaneous immunotherapy with native allergens or subcutaneous immunotherapy with polymerized allergoids. However, the optimal specific immunotherapy, especially for cat allergy, remains undetermined. Few studies investigating immunotherapy in cat allergy have been published, and the risk of serious adverse reactions and systemic reactions has often been an important issue. Monomeric allergoids have lower allergenic potential while their immunogenicity remains constant, resulting in excellent safety with notable efficacy. Specific immunotherapy with monomeric allergoids could, therefore, be of high value, especially in cat allergy as well as other types of allergy, and bring relief to a great community of patients.

Combination of photodynamic therapy and immunotherapy - evolving role in dermatology

NASA Astrophysics Data System (ADS)

Wang, Xiu-Li; Wang, Hong-Wei; Huang, Zheng

2008-02-01

Photodynamic therapy (PDT) is a promising treatment modality. It offers alternative options in the treatment of cancer and vascular diseases. In cancer treatment, PDT has been used primarily for localized superficial or endoluminal malignant and premalignant conditions. More recently, its application has also been expanded to solid tumors. However, its antitumor efficacy remains debatable and its acceptance still variable. Pre-clinical studies demonstrate that, in addition to the primary local cytotoxicity, PDT might induce secondary host immune responses, which may further enhance PDT's therapeutic effects on primary tumor as well as metastasis. Therefore, PDT-induced local and systemic antitumor immune response might play an important role in successful control of malignant diseases. Furthermore, PDT's antitumor efficacy might also be enhanced through an effective immunoadjuvant or immunomodulator. Our recent clinical data also indicate that improved clinical outcomes can be obtained by a combination of PDT and immunomodulation therapy for the treatment of pre-malignant skin diseases. For instance, the combination of topical ALA-PDT and Imiquimod is effective for the treatment of genital bowenoid papulosis. This presentation will also report our preliminary data in developing combination approaches of PDT and immunotherapy for actinic keratosis (AK), basal cell carcinomas (BCCs) and Bowen's disease.

Recent advances in the use of therapeutic cancer vaccines in genitourinary malignancies.

PubMed

Surolia, Ira; Gulley, James; Madan, Ravi A

2014-12-01

Despite a recent increase in US FDA-approved treatments, genitourinary malignancies remain a source of significant morbidity and mortality. One focus of research is the use of therapeutic cancer vaccines in these diseases, and a significant body of clinical trial experience now exists for refining vaccine strategies to enhance antitumor efficacy and develop immune-based combination regimens. In recent years, clinical data from multiple trials in genitourinary malignancies have enhanced our understanding of the potential for immunotherapy in these cancers. There are also emerging clinical strategies that combine cancer vaccines with chemotherapy, radiation, androgen-deprivation therapy and immune checkpoint inhibitors. This review is based on a search of relevant literature for data presented over the past 5 years from clinical trials of cancer vaccines in prostate, bladder and renal carcinomas. In the coming years, clinical trials informed by decades of preclinical data and emerging clinical data will help to define the role of immunotherapy in genitourinary malignancies. Combination strategies that capitalize on the immune properties of standard treatments will bring greater clinical benefits, and immune-based combinations will likely be moved to the neoadjuvant setting, where they may have optimal clinical impact.

Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas.

PubMed

Malhotra, Sandeep; Kim, Teresa; Zager, Jonathan; Bennett, Joseph; Ebright, Michael; D'Angelica, Michael; Fong, Yuman

2007-04-01

Oncolytic cancer therapy using herpes simplex viruses (HSV) that have direct tumoricidal effects and cancer immunotherapy using the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have each been effective in preclinical testing. NV1034 is a multimutated oncolytic HSV carrying the gene for murine GM-CSF that attempts to combine these 2 anticancer strategies. The purpose of this study was to compare NV1034 to NV1023, the parent HSV mutants lacking GM-CSF, to determine if such combined oncolytic and immunotherapy using a single vector has advantages over oncolytic therapy alone. Expression GM-CSF in vitro did not alter the infectivity, cytotoxicity, or replication of NV1034 compared to the noncytokine-secreting control. Tumors infected with NV1034 produced GM-CSF in picogram quantities. In vivo efficacy of the viruses against murine colorectal carcinoma CT26 and murine hepatoma Hepa l-6 was then tested in subcutaneous tumors in syngeneic Balb/c and C57 L/J mice, respectively. In these immune-competent models, NV1034 and NV1023 each demonstrated potent antitumor activity. Treatment with NV1034 had significantly better antitumor effect compared to treatment with NV1023. Furthermore, there was no difference in the antitumor efficacy of these viruses in mice depleted of CD4+ and CD8+ T lymphocytes. Viral vectors combining oncolytic and immunotherapy are promising agents in treatment of colorectal carcinoma and hepatoma.

Autologous cytokine-induced killer cell immunotherapy may improve overall survival in advanced malignant melanoma patients.

PubMed

Zhang, Yong; Zhu, Yu'nan; Zhao, Erjiang; He, Xiaolei; Zhao, Lingdi; Wang, Zibing; Fu, Xiaomin; Qi, Yalong; Ma, Baozhen; Song, Yongping; Gao, Quanli

2017-11-01

Our study was conducted to explore the efficacy of autologous cytokine-induced killer (CIK) cells in patients with advanced malignant melanoma. Materials & Methods: Here we reviewed 113 stage IV malignant melanoma patients among which 68 patients received CIK cell immunotherapy alone, while 45 patients accepted CIK cell therapy combined with chemotherapy. Results: We found that the median survival time in CIK cell group was longer than the combined therapy group (21 vs 15 months, p = 0.07). In addition, serum hemoglobin level as well as monocyte proportion and lymphocyte count were associated with patients' survival time. These indicated that CIK cell immunotherapy might extend survival time in advanced malignant melanoma patients. Furthermore, serum hemoglobin level, monocyte proportion and lymphocyte count could be prognostic indicators for melanoma.

Immunotherapies in CLL.

PubMed

Park, Jae H; Brentjens, Renier J

2013-01-01

Chronic lymphocytic leukemia (CLL) is the most frequently diagnosed leukemia in the Western world, yet remains essentially incurable. Although initial chemotherapy response rates are high, patients invariably relapse and subsequently develop resistance to chemotherapy. For the moment, allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for patients with CLL, but it is associated with high rates of treatment-related mortality. Immune-based treatment strategies to augment the cytotoxic potential of T cells offer exciting new treatment options for patients with CLL, and provide a unique and powerful spectrum of tools distinct from traditional chemotherapy. Among the most novel and promising of these approaches are chimeric antigen receptor (CAR)-based cell therapies that combine advances in genetic engineering and adoptive immunotherapy.

Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer.

PubMed

Versteven, Maarten; Van den Bergh, Johan M J; Marcq, Elly; Smits, Evelien L J; Van Tendeloo, Viggo F I; Hobo, Willemijn; Lion, Eva

2018-01-01

Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient's antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies.

Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer

PubMed Central

Versteven, Maarten; Van den Bergh, Johan M. J.; Marcq, Elly; Smits, Evelien L. J.; Van Tendeloo, Viggo F. I.; Hobo, Willemijn; Lion, Eva

2018-01-01

Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient’s antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field. Early success of therapeutic antibodies blocking the programmed death-1 (PD-1) pathway has sparked the development of novel inhibitors and combination therapies. Hence, merging immunoregulatory tumor-specific DC strategies with PD-1-targeted approaches is a promising path to explore. In this review, we focus on the role of PD-1-signaling in DC-mediated antitumor immunity. In the quest of exploiting the full potential of DC therapy, different strategies to leverage DC immunopotency by impeding PD-1-mediated immune regulation are discussed, including the most advanced research on targeted therapeutic antibodies, lessons learned from chemotherapy-induced immune activation, and more recent developments with soluble molecules and gene-silencing techniques. An overview of DC/PD-1 immunotherapy combinations that are currently under preclinical and clinical investigation substantiates the clinical potential of such combination strategies. PMID:29599770

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiniker, Susan M., E-mail: shiniker@stanford.edu; Reddy, Sunil A.; Maecker, Holden T.

Purpose: Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte–associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses. Methods and Materials: In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasismore » measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment. Results: Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response. Conclusion: This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.« less

Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses.

PubMed

Woller, Norman; Gürlevik, Engin; Fleischmann-Mundt, Bettina; Schumacher, Anja; Knocke, Sarah; Kloos, Arnold M; Saborowski, Michael; Geffers, Robert; Manns, Michael P; Wirth, Thomas C; Kubicka, Stefan; Kühnel, Florian

2015-10-01

There is evidence that viral oncolysis is synergistic with immune checkpoint inhibition in cancer therapy but the underlying mechanisms are unclear. Here, we investigated whether local viral infection of malignant tumors is capable of overcoming systemic resistance to PD-1-immunotherapy by modulating the spectrum of tumor-directed CD8 T-cells. To focus on neoantigen-specific CD8 T-cell responses, we performed transcriptomic sequencing of PD-1-resistant CMT64 lung adenocarcinoma cells followed by algorithm-based neoepitope prediction. Investigations on neoepitope-specific T-cell responses in tumor-bearing mice demonstrated that PD-1 immunotherapy was insufficient whereas viral oncolysis elicited cytotoxic T-cell responses to a conserved panel of neoepitopes. After combined treatment, we observed that PD-1-blockade did not affect the magnitude of oncolysis-mediated antitumoral immune responses but a broader spectrum of T-cell responses including additional neoepitopes was observed. Oncolysis of the primary tumor significantly abrogated systemic resistance to PD-1-immunotherapy leading to improved elimination of disseminated lung tumors. Our observations were confirmed in a transgenic murine model of liver cancer where viral oncolysis strongly induced PD-L1 expression in primary liver tumors and lung metastasis. Furthermore, we demonstrated that combined treatment completely inhibited dissemination in a CD8 T-cell-dependent manner. Therefore, our results strongly recommend further evaluation of virotherapy and concomitant PD-1 immunotherapy in clinical studies.

Rational Combination Immunotherapy: Understand the Biology.

PubMed

Kaufman, Howard L

2017-05-01

Selecting rational treatment combinations remains a major challenge for improving immunotherapy outcomes. In this issue of Cancer Immunology Research , Zhang and colleagues reduced tumors by inhibiting CD47 in a lung carcinoma model, a treatment that inadvertently induced autophagy through inhibition of the Akt/mTOR pathway. By also targeting autophagy, the therapeutic response improved, highlighting the importance of understanding the biology beneath antitumor immunity. Cancer Immunol Res; 5(5); 355-6. ©2017 AACR See article by Zhang et al., p. 363. ©2017 American Association for Cancer Research.

Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

NASA Astrophysics Data System (ADS)

Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang

2016-10-01

A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.

Renal cell carcinoma in one year: Going inside the news of 2017 - A report of the main advances in RCC cancer research.

PubMed

Mosillo, Claudia; Ciccarese, Chiara; Bimbatti, Davide; Fantinel, Emanuela; Volta, Alberto Dalla; Bisogno, Iolanda; Zampiva, Ilaria; Santoni, Matteo; Massar, Francesco; Brunelli, Matteo; Montironi, Rodolfo; Tortora, Giampaolo; Iacovelli, Roberto

2018-06-01

Very interesting issues regarding RCC treatment have been raised during 2017. We analysed the main news that may potentially modified clinical practice. Conflicting data came from trials testing targeted therapies in the adjuvant setting, supporting the necessity of further investigations. One of the key goals of RCC research is focused on the first-line therapy, with particular interest focus on immunotherapy combinations. Redefine the standard of care with the aim of improving patients' survival represents an imperative need. Enhancing immunotherapy antitumor activity by combining immune checkpoint inhibitors with anti-angiogenetic therapies is a noteworthy research field, with promising results. In addiction, we analysed in the metastatic setting data about the role of cytoreductive nephrectomy and the possibility of delay the start of first-line therapy after an active surveillance period. Based on recent developments, the paper outlines future prospective of RCC research. Copyright © 2018 Elsevier Ltd. All rights reserved.

Immunotherapy for Head and Neck Squamous Cell Carcinoma: A Review of Current and Emerging Therapeutic Options

PubMed Central

Moskovitz, Jessica M.; Moy, Jennifer; Seiwert, Tanguy Y.

2017-01-01

Abstract Advances in the field of cancer immunotherapy have occurred rapidly over the past decade. Exciting results from clinical trials have led to new treatment options and improved survival for patients with a myriad of solid tumor pathologies. However, questions remain unanswered regarding duration and timing of therapy, combination regimens, appropriate biomarkers of disease, and optimal monitoring of therapeutic response. This article reviews emerging immunotherapeutic agents and significant clinical trials that have led to advancements in the field of immuno‐oncology for patients with head and neck squamous cell carcinoma. Implications for Practice. This review article summarizes recently developed agents that harness the immune system to fight head and neck squamous cell carcinoma. A brief review of the immune system and its role in cancer development is included. Recently completed and emerging therapeutic trials centering on the immune system and head and neck cancer are reviewed. PMID:28507203

Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model.

PubMed

Ouyang, Mao; White, Ethan E; Ren, Hui; Guo, Qin; Zhang, Ian; Gao, Hang; Yanyan, Song; Chen, Xuebo; Weng, Yiming; Da Fonseca, Anna; Shah, Sunny; Manuel, Edwin R; Zhang, Leying; Vonderfecht, Steven L; Alizadeh, Darya; Berlin, Jacob M; Badie, Behnam

2016-01-01

Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG.

New Immunotherapy Strategies in Breast Cancer

PubMed Central

Yu, Lin-Yu; Tang, Jie; Zhang, Cong-Min; Zeng, Wen-Jing; Yan, Han; Li, Mu-Peng; Chen, Xiao-Ping

2017-01-01

Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies. PMID:28085094

Immunotherapy throughout the decades: from Noon to now.

PubMed

Finegold, Ira; Dockhorn, Robert J; Ein, Daniel; Dolen, William K; Oppenheimer, John; Potter, Lawrence H

2010-11-01

To review major milestones in the development of subcutaneous allergen immunotherapy in 20-year segments. Review of the literature available in textbooks and journals. Articles and books addressing major achievements in the development of subcutaneous allergy immunotherapy were selected for inclusion in this review. Immunotherapy administration has improved the lives of possibly millions of patients with hay fever. Asthmatic symptoms have been relieved if not ablated in millions as well. Insect venom hypersensitivity became treatable and highly effective. In the beginning years of immunotherapy, it was clear that immunotherapy worked; in the later years, the mechanisms for this efficacy were discovered. In this case, the therapy preceded its validation. Methods, materials, and safety have vastly improved. Postulated mechanisms explain much but not everything. There is still research to be accomplished, improvements to be made, and, of course, patients to be made well. Copyright © 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The Safety of Available Immunotherapy for the Treatment of Glioblastoma

PubMed Central

Farber, S. Harrison; Elsamadicy, Aladine A.; Atik, Fatih; Suryadevara, Carter M.; Chongsathidkiet, Pakawat; Fecci, Peter E.; Sampson, John H.

2017-01-01

Introduction Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM. Areas covered Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM. Expert commentary Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM. PMID:27989218

An unexpected journey: how cancer immunotherapy has paved the way for an HIV-1 cure.

PubMed

Smith, Kellie N; Housseau, Franck

2015-03-01

Over 30 million people worldwide are currently infected with human immunodeficiency virus type-1 (HIV-1). While HIV-1 infection was initially thought to be a death sentence, the advent of combination antiretroviral therapy (cART) in the mid-1990's resulted in decreases in viremia and an extended lifespan for infected persons. Despite this, long-term control of the virus in the absence of drug therapy has yet to be achieved, owing to the rebound in viral load and resumption of disease progression that follows removal of the patient from cART. Currently, the most promising candidates for an HIV-1 cure are immunotherapies that harness the patient's own immune system and induce cytotoxic T lymphocyte (CTL)-mediated clearance of infected cells. Most of these approaches were developed and optimized in the cancer setting and have had varying degrees of success, the findings from which have wide applications to various disease models. In this review, we evaluate the past successes and failures of cancer immunotherapy and how the findings have shaped our journey toward an HIV-1 cure.

Immunotherapeutic interventions of Triple Negative Breast Cancer.

PubMed

Li, Zehuan; Qiu, Yiran; Lu, Weiqi; Jiang, Ying; Wang, Jin

2018-05-30

Triple Negative Breast Cancer (TNBC) is a highly heterogeneous subtype of breast cancer that lacks the expression of oestrogen receptors, progesterone receptors and human epidermal growth factor receptor 2. Although TNBC is sensitive to chemotherapy, the overall outcomes of TNBC are worse than for other breast cancers, and TNBC is still one of the most fatal diseases for women. With the discovery of antigens specifically expressed in TNBC cells and the developing technology of monoclonal antibodies, chimeric antigen receptors and cancer vaccines, immunotherapy is emerging as a novel promising option for TNBC. This review is mainly focused on the tumour microenvironment and host immunity, Triple Negative Breast Cancer and the clinical treatment of TNBC, novel therapies for cancer and immunotherapy for TNBC, and the future outlook for the treatment for TNBC and the interplay between the therapies, including immune checkpoint inhibitors, combination of immune checkpoint inhibitors with targeted treatments in TNBC, adoptive cell therapy, cancer vaccines. The review also highlights recent reports on the synergistic effects of immunotherapy and chemotherapy, antibody-drug conjugates, and exosomes, as potential multifunctional therapeutic agents in TNBC.

Cancer treatment by photodynamic therapy combined with NK-cell-line-based adoptive immunotherapy

NASA Astrophysics Data System (ADS)

Korbelik, Mladen; Sun, Jinghai

1998-05-01

Treatment of solid cancers by photodynamic therapy (PDT) triggers a strong acute inflammatory reaction localized to the illuminated malignant tissue. This event is regulated by a massive release of various potent mediators which have a profound effect not only on local host cell populations, but also attract different types of immune cells to the treated tumor. Phagocytosis of PDT-damaged cancerous cells by antigen presenting cells, such as activated tumor associated macrophages, enables the recognition of even poorly immunogenic tumors by specific immune effector cells and the generation of immune memory populations. Because of its inflammatory/immune character, PDT is exceptionally responsive to adjuvant treatments with various types of immunotherapy. Combining PDT with immuneactivators, such as cytokines or other specific or non-specific immune agents, rendered marked improvements in tumor cures with various cancer models. Another clinically attractive strategy is adoptive immunotherapy, and the prospects of its use in conjunction with PDT are outlined.

Notch Signaling in Myeloid Cells as a Regulator of Tumor Immune Responses

PubMed Central

Hossain, Fokhrul; Majumder, Samarpan; Ucar, Deniz A.; Rodriguez, Paulo C.; Golde, Todd E.; Minter, Lisa M.; Osborne, Barbara A.; Miele, Lucio

2018-01-01

Cancer immunotherapy, which stimulates or augments host immune responses to treat malignancies, is the latest development in the rapidly advancing field of cancer immunology. The basic principles of immunotherapies are either to enhance the functions of specific components of the immune system or to neutralize immune-suppressive signals produced by cancer cells or tumor microenvironment cells. When successful, these approaches translate into long-term survival for patients. However, durable responses are only seen in a subset of patients and so far, only in some cancer types. As for other cancer treatments, resistance to immunotherapy can also develop. Numerous research groups are trying to understand why immunotherapy is effective in some patients but not others and to develop strategies to enhance the effectiveness of immunotherapy. The Notch signaling pathway is involved in many aspects of tumor biology, from angiogenesis to cancer stem cell maintenance to tumor immunity. The role of Notch in the development and modulation of the immune response is complex, involving an intricate crosstalk between antigen-presenting cells, T-cell subpopulations, cancer cells, and other components of the tumor microenvironment. Elegant studies have shown that Notch is a central mediator of tumor-induced T-cell anergy and that activation of Notch1 in CD8 T-cells enhances cancer immunotherapy. Tumor-infiltrating myeloid cells, including myeloid-derived suppressor cells, altered dendritic cells, and tumor-associated macrophages along with regulatory T cells, are major obstacles to the development of successful cancer immunotherapies. In this article, we focus on the roles of Notch signaling in modulating tumor-infiltrating myeloid cells and discuss implications for therapeutic strategies that modulate Notch signaling to enhance cancer immunotherapy.

Safety considerations in providing allergen immunotherapy in the office.

PubMed

Mattos, Jose L; Lee, Stella

2016-06-01

This review highlights the risks of allergy immunotherapy, methods to improve the quality and safety of allergy treatment, the current status of allergy quality metrics, and the future of quality measurement. In the current healthcare environment, the emphasis on outcomes measurement is increasing, and providers must be better equipped in the development, measurement, and reporting of safety and quality measures. Immunotherapy offers the only potential cure for allergic disease and asthma. Although well tolerated and effective, immunotherapy can be associated with serious consequence, including anaphylaxis and death. Many predisposing factors and errors that lead to serious systemic reactions are preventable, and the evaluation and implementation of quality measures are crucial to developing a safe immunotherapy practice. Although quality metrics for immunotherapy are in their infancy, they will become increasingly sophisticated, and providers will face increased pressure to deliver safe, high-quality, patient-centered, evidence-based, and efficient allergy care. The establishment of safety in the allergy office involves recognition of potential risk factors for anaphylaxis, the development and measurement of quality metrics, and changing systems-wide practices if needed. Quality improvement is a continuous process, and although national allergy-specific quality metrics do not yet exist, they are in development.

Multiple model predictive control for optimal drug administration of mixed immunotherapy and chemotherapy of tumours.

PubMed

Sharifi, N; Ozgoli, S; Ramezani, A

2017-06-01

Mixed immunotherapy and chemotherapy of tumours is one of the most efficient ways to improve cancer treatment strategies. However, it is important to 'design' an effective treatment programme which can optimize the ways of combining immunotherapy and chemotherapy to diminish their imminent side effects. Control engineering techniques could be used for this. The method of multiple model predictive controller (MMPC) is applied to the modified Stepanova model to induce the best combination of drugs scheduling under a better health criteria profile. The proposed MMPC is a feedback scheme that can perform global optimization for both tumour volume and immune competent cell density by performing multiple constraints. Although current studies usually assume that immunotherapy has no side effect, this paper presents a new method of mixed drug administration by employing MMPC, which implements several constraints for chemotherapy and immunotherapy by considering both drug toxicity and autoimmune. With designed controller we need maximum 57% and 28% of full dosage of drugs for chemotherapy and immunotherapy in some instances, respectively. Therefore, through the proposed controller less dosage of drugs are needed, which contribute to suitable results with a perceptible reduction in medicine side effects. It is observed that in the presence of MMPC, the amount of required drugs is minimized, while the tumour volume is reduced. The efficiency of the presented method has been illustrated through simulations, as the system from an initial condition in the malignant region of the state space (macroscopic tumour volume) transfers into the benign region (microscopic tumour volume) in which the immune system can control tumour growth. Copyright © 2017 Elsevier B.V. All rights reserved.

Immunoproteomics of Aspergillus for the development of biomarkers and immunotherapies.

PubMed

Kniemeyer, Olaf; Ebel, Frank; Krüger, Thomas; Bacher, Petra; Scheffold, Alexander; Luo, Ting; Strassburger, Maria; Brakhage, Axel A

2016-10-01

Filamentous fungi of the genus Aspergillus play significant roles as pathogens causing superficial and invasive infections as well as allergic reactions in humans. Particularly invasive mycoses caused by Aspergillus species are characterized by high mortality rates due to difficult diagnosis and insufficient antifungal therapy. The application of immunoproteomic approaches has a great potential to identify new targets for the diagnosis, therapy, and vaccine development of diseases caused by Aspergillus species. Serological proteome analyses (SERPA) that combine 2D electrophoresis with Western blotting are still one of the most popular techniques for the identification of antigenic proteins. However, recently a growing number of approaches have been developed to identify proteins, which either provoke an antibody response or which represent targets of T-cell immunity in patients with allergy or fungal infections. Here, we review advances in the studies of immune responses against pathogenic Aspergilli as well as the current status of diagnosis and immunotherapy of Aspergillus infections. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome.

PubMed

Westdorp, Harm; Kolders, Sigrid; Hoogerbrugge, Nicoline; de Vries, I Jolanda M; Jongmans, Marjolijn C J; Schreibelt, Gerty

2017-09-10

Monoallelic germline mutations in one of the DNA mismatch repair (MMR) genes cause Lynch syndrome, with a high lifetime risks of colorectal and endometrial cancer at adult age. Less well known, is the constitutional mismatch repair deficiency (CMMRD) syndrome caused by biallelic germline mutations in MMR genes. This syndrome is characterized by the development of childhood cancer. Patients with CMMRD are at extremely high risk of developing multiple cancers including hematological, brain and intestinal tumors. Mutations in MMR genes impair DNA repair and therefore most tumors of patients with CMMRD are hypermutated. These mutations lead to changes in the translational reading frame, which consequently result in neoantigen formation. Neoantigens are recognized as foreign by the immune system and can induce specific immune responses. The growing evidence on the clinical efficacy of immunotherapies, such as immune checkpoint inhibitors, offers the prospect for treatment of patients with CMMRD. Combining neoantigen-based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. Neoantigen-based vaccines might also be a preventive treatment option in healthy biallelic MMR mutation carriers. Future studies need to reveal the safety and efficacy of immunotherapies for patients with CMMRD. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination.

PubMed

Gong, Jun; Le, Thang Q; Massarelli, Erminia; Hendifar, Andrew E; Tuli, Richard

2018-06-04

Several inhibitors of programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved as a form of immunotherapy for multiple cancers. Ionizing radiation therapy (RT) has been shown to enhance the priming and effector phases of the antitumor T-cell response rendering it an attractive therapy to combine with PD-1/PD-L1 inhibitors. Preclinical data support the rational combination of the 2 modalities and has paved way for the clinical development of the combination across a spectrum of cancers. In this review, we highlight the preclinical and clinical development of combined RT and PD-1/PD-L1 blockade to date. In addition to a comprehensive evaluation of available safety and efficacy data, we discuss important points of consideration in clinical trial design for this promising combination.

1alpha,25-dihydroxy-vitamin-D3 as new immunotherapy in treatment of recurrent spontaneous abortion.

PubMed

Bubanovic, I

2004-01-01

Recurrent spontaneous abortion (RSA) is serious health problem affecting 2-5% of reproducing couples worldwide. It has long been suspected that nearly 80% of the unexplained RSAs are due to immunologic causes. Although the major tissue confronting the mother's immune system is the placental villous trophoblast, the immunological risk to the developing embryo is not great until the time of implantation. In addition, trophoblast is not sensible to lysis by NK cells, TNF-alpha or macrophages, but may be killed by lymphokine activated NK cells (LAK) and may undergo apoptosis in response to TNF-alpha and/or IFN-gamma in vitro. The two most commonly used treatments for RSA are intravenous immunoglobulin (IVIg) and alloimmunization with partner's leukocytes (LIT). We promote vitamin D3 as new immunomodulatory agent in treatment of RSA. Different mechanisms have been proposed to account for the immunosuppressive effect of 1alpha, 25-dihydroxy-vitamin-D3 (VD3). Portion of the VD3 activity involves the downregulation of IL-2, IFN-gamma and TNF-alpha genes transcription. Because immunomodulatory effects of VD3 are very similar to IL-10 effects, acting of VD3 in immunotherapy of RSA syndrome, preeclamptic and eclamptic pregnancy, as well as PIH syndrome, is very reasonable. We propose using of VD3 as immunotherapy or adjuvant therapy in combination with classic immunotherapies of endangered pregnancies.

Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy.

PubMed

Li, Kui; Tian, Hongqi

2018-02-20

Cancer immunotherapy has been increasingly utilised to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionising the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity and, therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced. Small-molecule inhibitors could offer inherent advantages in terms of pharmacokinetics and druggability, thereby providing additional methods for cancer treatment and achieving better therapeutic effects. In this review, we first discuss how PD-1/PD-L1-targeting inhibitors modulate the relationship between immune cells and tumour cells in tumour immunotherapy. Second, we discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with immunotherapy and targeted therapy. Third, this review is the first to summarise the current clinical and preclinical evidence regarding small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint, considering features and responses related to the tumours and to the host immune system.

Case Report: A Non-small Cell Lung Cancer Patient Treated with GcMAF, Sonodynamic Therapy and Tumor Treating Fields.

PubMed

Inui, Toshio; Amitani, Haruka; Kubo, Kentaro; Kuchiike, Daisuke; Uto, Yoshihiro; Nishikata, Takahito; Mette, Martin

2016-07-01

Macrophage activating factor (MAF)-based immunotherapy has a wide application for use in treating many diseases via macrophage activation. Sonodynamic therapy (SDT) using low-intensity ultrasound and tumor treating field (TTF) therapy are novel therapeutic modalities. SDT is usually combined with ozone therapy to improve local hypoxia within the tumor environment. We treated a 77-year-old male diagnosed with non-small cell lung cancer ((NSCLC) stage 3B) using second-generation serum GcMAF and oral colostrum MAF-based immunotherapy combined with SDT, TTF and ozone therapies. This case report demonstrates that GcMAF, oral colostrum MAF, SDT, TTF and ozone therapy can be used for NSCLC without adverse effects. This case report suggests a new concept of cancer treatment using local destruction of cancer tissue, in this case conducted with SDT and TTF therapy, to be used in combination with serum GcMAF and colostrum MAF immunotherapy as a systemic treatment. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Case report: A breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy.

PubMed

Inui, Toshio; Makita, Kaori; Miura, Hirona; Matsuda, Akiko; Kuchiike, Daisuke; Kubo, Kentaro; Mette, Martin; Uto, Yoshihiro; Nishikata, Takahito; Hori, Hitoshi; Sakamoto, Norihiro

2014-08-01

Gc protein-derived macrophage-activating factor (GcMAF) occurs naturally in the human body. It has various functions, such as macrophage activation and antitumor activities. Recently, immunotherapy has become an attractive new strategy in the treatment of cancer. GcMAF-based immunotherapy can be combined with many other therapies. Sonodynamic therapy (SDT) using low-intensity ultrasound is a novel therapeutic modality. Ultrasound has been demonstrated to activate a number of sonosensitive agents allowing for the possibility of non-invasive targeted treatment for both superficial and deep-seated tumors. The current case study demonstrates that GcMAF and SDT can be used in combination with conventional therapies in patients with metastatic cancer, especially where treatment options are limited due to factors such as toxicity. This case study also suggests a new concept of cancer treatment using local destruction of cancer tissue, in this case conducted with SDT, to be used in combination with GcMAF immunotherapy as a systemic treatment. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses

PubMed Central

Woller, Norman; Gürlevik, Engin; Fleischmann-Mundt, Bettina; Schumacher, Anja; Knocke, Sarah; Kloos, Arnold M; Saborowski, Michael; Geffers, Robert; Manns, Michael P; Wirth, Thomas C; Kubicka, Stefan; Kühnel, Florian

2015-01-01

There is evidence that viral oncolysis is synergistic with immune checkpoint inhibition in cancer therapy but the underlying mechanisms are unclear. Here, we investigated whether local viral infection of malignant tumors is capable of overcoming systemic resistance to PD-1-immunotherapy by modulating the spectrum of tumor-directed CD8 T-cells. To focus on neoantigen-specific CD8 T-cell responses, we performed transcriptomic sequencing of PD-1-resistant CMT64 lung adenocarcinoma cells followed by algorithm-based neoepitope prediction. Investigations on neoepitope-specific T-cell responses in tumor-bearing mice demonstrated that PD-1 immunotherapy was insufficient whereas viral oncolysis elicited cytotoxic T-cell responses to a conserved panel of neoepitopes. After combined treatment, we observed that PD-1-blockade did not affect the magnitude of oncolysis-mediated antitumoral immune responses but a broader spectrum of T-cell responses including additional neoepitopes was observed. Oncolysis of the primary tumor significantly abrogated systemic resistance to PD-1-immunotherapy leading to improved elimination of disseminated lung tumors. Our observations were confirmed in a transgenic murine model of liver cancer where viral oncolysis strongly induced PD-L1 expression in primary liver tumors and lung metastasis. Furthermore, we demonstrated that combined treatment completely inhibited dissemination in a CD8 T-cell-dependent manner. Therefore, our results strongly recommend further evaluation of virotherapy and concomitant PD-1 immunotherapy in clinical studies. PMID:26112079

Laser immunotherapy for metastatic pancreatic cancer (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhou, Feifan

2017-02-01

Pancreatic cancer is an extremely malignant disease with high mortality rate. Currently there is no effective therapeutic strategy for highly metastatic pancreatic cancers. Laser immunotherapy (LIT) is a combination therapeutic approach of targeted phototherapy and immunotherapy, which could destroy treated primary tumors with elimination of untreated metastases. LIT affords a remarkable efficacy in suppressing tumor growth in pancreatic tumors in mice, and results in complete tumor regression in many cases. LIT could synergize targeted phototherapy and immunological effects of immunoadjuvant, which represent a promising treatment modality to induce systemic antitumor response through a local intervention, paving the way for the treatment of highly metastatic pancreatic cancers.

Conference Scene: Summary report from EAACI: London 2010.

PubMed

Stiehm, Matthias; Bufe, Albrecht

2010-09-01

Immunotherapy is, to date, the only effective curative method for the treatment of allergic disorders. Great efforts have been made to improve the efficacy, safety and patient compliance with this method. The growing understanding of the immunological mechanisms underlying immunotherapy has led to new approaches for immunotherapy involving the routes of administration and the kinds of molecules used. In addition, new vaccines are being created that combine the advantageous immunological charasteristics of different substances, such as virus-like particles linked to allergens. Many new results from ongoing research into these topics were presented at the 29th congress of the European Academy of Allergy and Clinical Immunology in London.

The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia.

PubMed

Miller, Brian J; Buckley, Peter F

2016-06-01

This article presents the case in favor of clinical trials of adjunctive monoclonal antibody immunotherapy in schizophrenia. Evidence for prenatal and premorbid immune risk factors for the development of schizophrenia in the offspring is highlighted. Then key evidence for immune dysfunction in patients with schizophrenia is considered. Next, previous trials of adjunctive anti-inflammatory or other immunotherapy in schizophrenia are discussed. Then evidence for psychosis as a side effect of immunotherapy for other disorders is discussed. Also presented is preliminary evidence for adjunctive monoclonal antibody immunotherapy in psychiatric disorders. Finally, important considerations in the design and implementation of clinical trials of adjunctive monoclonal antibody immunotherapy in schizophrenia are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of surgery, immunization, and laser immunotherapy on a non-immunogenic metastic tumor model

NASA Astrophysics Data System (ADS)

Chen, Wei R.; Huang, Zheng; Andrienko, Kirill; Stefanov, Stefan; Wolf, Roman F.; Liu, Hong

2006-08-01

Traditional local cancer treatment modalities include surgery and radiation, which has the immediate tumor response due to tumor removal or radiation induced cell death. However, such therapeutic approaches usually do not result in eradiation of tumors, particularly when treating metastatic tumors. In fact, local treatment of primary tumors may stimulate the growth and spread of remote metastasis. Commonly used systemic therapies include chemotherapy and immunotherapy, which target the dividing cells or the immune systems. However, in addition to the severe side effects, chemotherapy often suppresses the immune systems, hence lessening the host's ability to fight the disease. Immunotherapy, on the other hand, aims at educating and stimulating immune systems using either general immune enhancements or antigen-oriented specific immune stimulation. However, so far, the traditional immunotherapy has yielded only limited success in treating cancer patients. A different approach is needed. To combine the advantages of both local therapies for acute and targeted treatment responses and the systemic therapies for stimulation of the immune systems, laser immunotherapy was proposed to use selective photothermal therapy as the local treatment modality and the adjuvant-assisted immunotherapy for systemic control. Laser immunotherapy has show positive results in treating metastatic tumors. In this study, we conducted a comparative study using surgery, freeze-thaw immunization and laser immunotherapy in the treatment of metastatic rat mammary tumors. Our results showed that removal of the primary tumors was unsuccessful at changing the course of tumor progression. The tumor cell lysate immunization delayed the emergence of metastases but did not provide immunity against the tumor challenge. Laser immunotherapy, on the other hand, resulted in regression and eradication.

Forging a link between oncogenic signaling and immunosuppression in melanoma.

PubMed

Khalili, Jahan S; Hwu, Patrick; Lizée, Gregory

2013-02-01

Immunosuppressive tumor microenvironments limit the efficacy of T cell-based immunotherapy. We have recently demonstrated that the inhibition of BRAF V600E with vemurafenib relieves interleukin-1 (IL-1)-induced T-cell suppression as mediated by melanoma tumor associated fibroblasts (TAFs). These results suggest that inhibitors of the MAPK pathway in combination with T cell-based immunotherapies may induce long-lasting and durable responses.

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma.

PubMed

Rini, Brian I; McDermott, David F; Hammers, Hans; Bro, William; Bukowski, Ronald M; Faba, Bernard; Faba, Jo; Figlin, Robert A; Hutson, Thomas; Jonasch, Eric; Joseph, Richard W; Leibovich, Bradley C; Olencki, Thomas; Pantuck, Allan J; Quinn, David I; Seery, Virginia; Voss, Martin H; Wood, Christopher G; Wood, Laura S; Atkins, Michael B

2016-01-01

Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.

Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.

PubMed

De Martin, Eleonora; Michot, Jean-Marie; Papouin, Barbara; Champiat, Stéphane; Mateus, Christine; Lambotte, Olivier; Roche, Bruno; Antonini, Teresa Maria; Coilly, Audrey; Laghouati, Salim; Robert, Caroline; Marabelle, Aurélien; Guettier, Catherine; Samuel, Didier

2018-06-01

Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Immunotherapy: what lies beyond.

PubMed

Casale, Thomas B; Stokes, Jeffrey R

2014-03-01

Allergen immunotherapy has been used to treat allergic diseases, such as asthma, allergic rhinitis, and venom allergy, since first described over a century ago. The current standard of care in the United States involves subcutaneous administration of clinically relevant allergens for several months, building up to eventual monthly injections for typically 3 to 5 years. Recent advances have improved the safety and efficacy of immunotherapy. The addition of omalizumab or Toll-like receptor agonists to standard subcutaneous immunotherapy has proved beneficial. Altering the extract itself, either through chemical manipulation producing allergoids or directly producing recombinant proteins or significant peptides, has been evaluated with promising results. The use of different administration techniques, such as sublingual immunotherapy, is common in Europe and is on the immediate horizon in the United States. Other methods of administering allergen immunotherapy have been studied, including epicutaneous, intralymphatic, intranasal, and oral immunotherapy. In this review we focus on new types and routes of immunotherapy, exploring recent human clinical trial data. The promise of better immunotherapies appears closer than ever before, but much work is still needed to develop novel immunotherapies that induce immunologic tolerance and enhanced clinical efficacy and safety over that noted for subcutaneous allergen immunotherapy. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

HDAC inhibitors as epigenetic regulators for cancer immunotherapy.

PubMed

Conte, Mariarosaria; De Palma, Raffaele; Altucci, Lucia

2018-05-01

In recent years, anti-tumor immunotherapy has shown promising results, and immune-oncology is now emerging as the fourth major wave in the treatment of tumors after radiotherapy, chemotherapy and molecular targeted therapy. Understanding the impact of the immune system on neoplastic cells is crucial to improve its effectiveness against cancer. The stratification of patients who might benefit from immunotherapy as well as the personalization of medicine have contributed to the discovery of new immunotherapeutic targets and molecules. In the present review, we discuss the mechanistic role of histone deacetylase inhibitors (HDACi) as potential immunomodulating agents to treat cancer. Our current understanding of the use of HDACi in combination with various immunotherapeutic approaches, such as immunomodulating agents and cancer vaccines, is also addressed. The potential clinical applications of the growing number of novel epigenetic drugs for cancer immunotherapy are widening, and some of these therapies are already in clinical trials. Copyright © 2018 Elsevier Ltd. All rights reserved.

Development of new immunotherapy treatments in different cancer types.

PubMed

Stanculeanu, D L; Daniela, Zob; Lazescu, A; Bunghez, R; Anghel, R

2016-01-01

Cancer immunotherapy involves the use of therapeutic modalities that determine a manipulation of the immune system by using immune agents such as cytokines, vaccines, cell therapies and humoral, transfection agents. Immunotherapy of cancer has to stimulate the host's anti-tumor response by increasing the effector cell number and the production of soluble mediators and decrease the host's suppressor mechanisms by inducing tumor killing environment and by modulating immune checkpoints. Immunotherapy seems to work better in more immunogenic tumors. Making a review of literature, the article presents the new immunologic treatments in cancers less presented in the latest conferences, cancers in which, immunotherapy is still under investigation. Bladder cancer was the first indication for which immunotherapy was used in 1970. A promising clinical research in bladder cancer is the use of immune checkpoint inhibitors. Although breast cancer is considered immunologically silent, several preclinical and clinical studies suggested that immunotherapy has the potential to improve the clinical outcomes for patients with breast cancer. Cervical cancer, brain cancer, head and neck cancer and colorectal and esophageal cancers are cancer types for which new immune-based cancer treatments are currently under development. Recent agents used in clinical trials will be described in before mentioned cancers.

Development of new immunotherapy treatments in different cancer types

PubMed Central

Stanculeanu, DL; Daniela, Zob; Lazescu, A; Bunghez, R; Anghel, R

2016-01-01

Cancer immunotherapy involves the use of therapeutic modalities that determine a manipulation of the immune system by using immune agents such as cytokines, vaccines, cell therapies and humoral, transfection agents. Immunotherapy of cancer has to stimulate the host’s anti-tumor response by increasing the effector cell number and the production of soluble mediators and decrease the host’s suppressor mechanisms by inducing tumor killing environment and by modulating immune checkpoints. Immunotherapy seems to work better in more immunogenic tumors. Making a review of literature, the article presents the new immunologic treatments in cancers less presented in the latest conferences, cancers in which, immunotherapy is still under investigation. Bladder cancer was the first indication for which immunotherapy was used in 1970. A promising clinical research in bladder cancer is the use of immune checkpoint inhibitors. Although breast cancer is considered immunologically silent, several preclinical and clinical studies suggested that immunotherapy has the potential to improve the clinical outcomes for patients with breast cancer. Cervical cancer, brain cancer, head and neck cancer and colorectal and esophageal cancers are cancer types for which new immune-based cancer treatments are currently under development. Recent agents used in clinical trials will be described in before mentioned cancers. PMID:27974927

Classification of current anticancer immunotherapies

PubMed Central

Vacchelli, Erika; Pedro, José-Manuel Bravo-San; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N.; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P.; Coussens, Lisa; Dhodapkar, Madhav V.; Eggermont, Alexander M.; Fearon, Douglas T.; Fridman, Wolf H.; Fučíková, Jitka; Gabrilovich, Dmitry I.; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M.; Klein, Eva; Knuth, Alexander; Lewis, Claire E.; Liblau, Roland; Lotze, Michael T.; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J.; Mittendorf, Elizabeth A.; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E.; Pienta, Kenneth J.; Porgador, Angel; Prendergast, George C.; Rabinovich, Gabriel A.; Restifo, Nicholas P.; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J.; Speiser, Daniel E.; Spisek, Radek; Srivastava, Pramod K.; Talmadge, James E.; Tartour, Eric; Van Der Burg, Sjoerd H.; Van Den Eynde, Benoît J.; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S.; Whiteside, Theresa L.; Wolchok, Jedd D.; Zitvogel, Laurence; Zou, Weiping

2014-01-01

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

Antiangiogenic therapy improves the antitumor effect of adoptive cell immunotherapy by normalizing tumor vasculature.

PubMed

Shi, Shujing; Chen, Longbang; Huang, Guichun

2013-12-01

Abnormal tumor vasculature and subsequent tumor hypoxia contribute to immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma and inhibiting their antitumor efficacy. These obstacles might explain why the promising approach of adoptive cell immunotherapy does not exert significant antitumor activity. Hypoxia contributes to immune suppression by activating hypoxia-inducible factor (HIF-1) and the vascular endothelial growth factor pathway, which plays a determining role in promoting tumor cell growth and survival. Tumor hypoxia creates an immunosuppressive microenvironment via the accumulation and subsequent polarization of inflammatory cells toward immune suppression phenotypes, such as myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. Antiangiogenic therapy could normalize tumor vasculature and decrease hypoxic tumor area and thus may be an effective modality to potentiate immunotherapy. Adoptive cell immunotherapy alone is not efficient enough to decrease tumor growth as its antitumor effect is inhibited by the immunosuppressive hypoxic tumor microenvironment. This review describes that combination of antiangiogenic therapy with adoptive cell immunotherapy can exert synergistic antitumor effect, which will contribute to improve strategies for future anticancer therapies.

ErbB-targeted CAR T-cell immunotherapy of cancer.

PubMed

Whilding, Lynsey M; Maher, John

2015-01-01

Chimeric antigen receptor (CAR) based immunotherapy has been under development for the last 25 years and is now a promising new treatment modality in the field of cancer immunotherapy. The approach involves genetically engineering T cells to target malignant cells through expression of a bespoke fusion receptor that couples an HLA-independent antigen recognition domain to one or more intracellular T-cell activating modules. Multiple clinical trials are now underway in several centers to investigate CAR T-cell immunotherapy of diverse hematologic and solid tumor types. The most successful results have been achieved in the treatment of patients with B-cell malignancies, in whom several complete and durable responses have been achieved. This review focuses on the preclinical and clinical development of CAR T-cell immunotherapy of solid cancers, targeted against members of the ErbB family.

Dexamethasone, Intravenous Immunoglobulin, and Rituximab Combination Immunotherapy for Pediatric Opsoclonus-Myoclonus Syndrome.

PubMed

Pranzatelli, Michael R; Tate, Elizabeth D

2017-08-01

Although pulse-dose dexamethasone is increasingly favored for treating pediatric opsoclonus-myoclonus syndrome (OMS), and multimodal immunotherapy is associated with improved clinical response, there have been no neuroimmunologic studies of dexamethasone-based multimodal disease-modifying therapy. In this observational retrospective study, 19 children with OMS (with or without associated neuroblastoma) underwent multibiomarker evaluation for neuroinflammation. Nine children of varying OMS severity, duration, and treatment status were treated empirically with pulse dexamethasone, intravenous immunoglobulin (IVIg), and rituximab combination immunotherapy (DEXIR-CI). Another 10 children on dexamethasone alone or with IVIg at initial evaluation only provided a comparison group. Motor severity (total score) was scored rater-blinded via videotapes using the validated OMS Evaluation Scale. DEXIR-CI was associated with a 69% reduction in group total score (P = 0.004) and was clinically well tolerated. Patients given the dexamethasone combination exhibited significantly lowered B cell frequencies in cerebrospinal fluid (-94%) and blood (-76%), normalizing the cerebrospinal fluid B cell percentage. The number of patients with positive inflammatory markers dropped 87% (P = 0.002) as did the number of markers. Cerebrospinal fluid oligoclonal bands were positive in four of nine pretreatment patients but zero of six post-treatment patients. In the comparison group, partial response to dexamethasone alone or with IVIg was associated with multiple positive markers for neuroinflammation despite an average of seven months of treatment. Multimechanistic dexamethasone-based combination immunotherapy increases the therapeutic armamentarium for OMS, providing a viable option for less severely affected individuals. Partial response to dexamethasone with or without IVIg is indicative of ongoing neuroinflammation and should be treated promptly and accordingly. Copyright © 2017 Elsevier Inc. All rights reserved.

An assay that may predict the development of IgG enhancing allergen-specific IgE binding during birch immunotherapy

PubMed Central

Selb, R.; Eckl-Dorna, J.; Vrtala, S.; Valenta, R.; Niederberger, V.

2017-01-01

Background It has been shown that birch pollen immunotherapy can induce IgG antibodies which enhance IgE binding to Bet v 1. We aimed to develop a serological assay to predict the development of antibodies which enhance IgE binding to Bet v 1 during immunotherapy. Methods In 18 patients treated by Bet v 1-fragment-specific immunotherapy, the effects of IgG antibodies specific for the fragments on the binding of IgE antibodies to Bet v 1 were measured by ELISA. Blocking and possible enhancing effects on IgE binding were compared with skin sensitivity to Bet v 1 after treatment. Results We found that fragment-specific IgG enhanced IgE binding to Bet v 1 in two patients who also showed an increase of skin sensitivity to Bet v 1. Conclusion Our results indicate that it may be possible to develop serological tests which predict the induction of unfavourable IgG antibodies enhancing the binding of IgE to Bet v 1 during immunotherapy. PMID:23998344

Current clinical trials testing combinations of immunotherapy and radiation.

PubMed

Crittenden, Marka; Kohrt, Holbrook; Levy, Ronald; Jones, Jennifer; Camphausen, Kevin; Dicker, Adam; Demaria, Sandra; Formenti, Silvia

2015-01-01

Preclinical evidence of successful combinations of ionizing radiation with immunotherapy has inspired testing the translation of these results to the clinic. Interestingly, the preclinical work has consistently predicted the responses encountered in clinical trials. The first example came from a proof-of-principle trial started in 2001 that tested the concept that growth factors acting on antigen-presenting cells improve presentation of tumor antigens released by radiation and induce an abscopal effect. Granulocyte-macrophage colony-stimulating factor was administered during radiotherapy to a metastatic site in patients with metastatic solid tumors to translate evidence obtained in a murine model of syngeneic mammary carcinoma treated with cytokine FLT-3L and radiation. Subsequent clinical availability of vaccines and immune checkpoint inhibitors has triggered a wave of enthusiasm for testing them in combination with radiotherapy. Examples of ongoing clinical trials are described in this report. Importantly, most of these trials include careful immune monitoring of the patients enrolled and will generate important data about the proimmunogenic effects of radiation in combination with a variety of immune modulators, in different disease settings. Results of these studies are building a platform of evidence for radiotherapy as an adjuvant to immunotherapy and encourage the growth of this novel field of radiation oncology. Copyright © 2015 Elsevier Inc. All rights reserved.

Armed Therapeutic Viruses – A Disruptive Therapy on the Horizon of Cancer Immunotherapy

PubMed Central

Bauzon, Maxine; Hermiston, Terry

2014-01-01

For the past 150 years cancer immunotherapy has been largely a theoretical hope that recently has begun to show potential as a highly impactful treatment for various cancers. In particular, the identification and targeting of immune checkpoints have given rise to exciting data suggesting that this strategy has the potential to activate sustained antitumor immunity. It is likely that this approach, like other anti-cancer strategies before it, will benefit from co-administration with an additional therapeutic and that it is this combination therapy that may generate the greatest clinical outcome for the patient. In this regard, oncolytic viruses are a therapeutic moiety that is well suited to deliver and augment these immune-modulating therapies in a highly targeted and economically advantageous way over current treatment. In this review, we discuss the blockade of immune checkpoints, how oncolytic viruses complement and extend these therapies, and speculate on how this combination will uniquely impact the future of cancer immunotherapy. PMID:24605114

[Specific immunotherapy with depigmented allergoids].

PubMed

Klimek, L; Thorn, C; Pfaar, O

2010-01-01

Specific immunotherapy is the only available causative treatment for IgE-mediated allergic conditions. The state of the art is treatment via the subcutaneous route with crude extracts in a water solution, with physically linked (semidepot) extracts or chemically modified semidepot extracts (allergoids). A relatively new purification method combines depigmentation followed by polymerization with glutaraldehyde. This modification results in increased tolerance with a reduction in both local and systemic adverse effects. As controlled clinical trials have shown, the effectiveness is comparable to that of specific immunotherapy with crude allergen extracts. Recent data suggest that the modified polymerized allergoids allow a safe rush titration in a few days or even in 1 day (ultra-rush titration).

Ultrasound induced cancer immunotherapy.

PubMed

Unga, Johan; Hashida, Mitsuru

2014-06-01

Recently, the use of ultrasound (US) has been shown to have potential in cancer immunotherapy. High intensity focused US destruction of tumors may lead to immunity forming in situ in the body by immune cells being exposed to the tumor debris and immune stimulatory substances that are present in the tumor remains. Another way of achieving anti-cancer immune responses is by using US in combination with microbubbles and nanobubbles to deliver genes and antigens into cells. US leads to bubble destruction and the forces released to direct delivery of the substances into the cytoplasm of the cells thus circumventing the natural barriers. In this way tumor antigens and antigen-encoding genes can be delivered to immune cells and immune response stimulating genes can be delivered to cancer cells thus enhancing immune responses. Combination of bubbles with cell-targeting ligands and US provides an even more sophisticated delivery system whereby the therapy is not only site specific but also cell specific. In this review we describe how US has been used to achieve immunity and discuss the potential and possible obstacles in future development. Copyright © 2014 Elsevier B.V. All rights reserved.

Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.

PubMed

Olson, Brian M; Gamat, Melissa; Seliski, Joseph; Sawicki, Thomas; Jeffery, Justin; Ellis, Leigh; Drake, Charles G; Weichert, Jamey; McNeel, Douglas G

2017-12-01

Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches. Cancer Immunol Res; 5(12); 1074-85. ©2017 AACR . ©2017 American Association for Cancer Research.

New routes of allergen immunotherapy.

PubMed

Aricigil, Mitat; Muluk, Nuray Bayar; Sakarya, Engin Umut; Sakalar, Emine Güven; Senturk, Mehmet; Reisacher, William R; Cingi, Cemal

2016-11-01

Allergen immunotherapy is the only cure for immunoglobulin E mediated type I respiratory allergies. Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are the most common treatments. In this article, we reviewed new routes of allergen immunotherapy. Data on alternative routes to allow intralymphatic immunotherapy (ILIT), epicutaneous immunotherapy (EPIT), local nasal immunotherapy (LNIT), oral immunotherapy (OIT), and oral mucosal immunotherapy (OMIT) were gathered from the literature and were discussed. ILIT features direct injection of allergens into lymph nodes. ILIT may be clinically effective after only a few injections and induces allergen-specific immunoglobulin G, similarly to SCIT. A limitation of ILIT is that intralymphatic injections are required. EPIT features allergen administration by using patches mounted on the skin. EPIT seeks to target epidermal antigen-presenting Langerhans cells rather than mast cells or the vasculature; this should reduce both local and systemic adverse effects. LNIT involves the spraying of allergen extracts into the nasal cavity. Natural or chemically modified allergens (the latter, termed allergoids, lack immunoglobulin E reactivity) are prepared in a soluble form. OIT involves the regular administration of small amounts of a food allergen by mouth and commences with low oral doses, which are then increased as tolerance develops. OMIT seeks to deliver allergenic proteins to an expanded population of Langerhans cells in the mucosa of the oral cavity. ILIT, EPIT, LNIT, OIT, and OMIT are new routes for allergen immunotherapy. They are safe and effective.

Leveraging natural killer cells for cancer immunotherapy.

PubMed

Grossenbacher, Steven K; Aguilar, Ethan G; Murphy, William J

2017-05-01

Natural killer (NK) cells are potent antitumor effector cells of the innate immune system. Based on their ability to eradicate tumors in vitro and in animal models, significant enthusiasm surrounds the prospect of leveraging human NK cells as vehicles for cancer immunotherapy. While interest in manipulating the effector functions of NK cells has existed for over 30 years, there is renewed optimism for this approach today. Although T cells receive much of the clinical and preclinical attention when it comes to cancer immunotherapy, new strategies are utilizing adoptive NK-cell immunotherapy and monoclonal antibodies and engineered molecules which have been developed to specifically activate NK cells against tumors. Despite the numerous challenges associated with the preclinical and clinical development of NK cell-based therapies for cancer, NK cells possess many unique immunological properties and hold the potential to provide an effective means for cancer immunotherapy.

Defining the critical hurdles in cancer immunotherapy.

PubMed

Fox, Bernard A; Schendel, Dolores J; Butterfield, Lisa H; Aamdal, Steinar; Allison, James P; Ascierto, Paolo Antonio; Atkins, Michael B; Bartunkova, Jirina; Bergmann, Lothar; Berinstein, Neil; Bonorino, Cristina C; Borden, Ernest; Bramson, Jonathan L; Britten, Cedrik M; Cao, Xuetao; Carson, William E; Chang, Alfred E; Characiejus, Dainius; Choudhury, A Raja; Coukos, George; de Gruijl, Tanja; Dillman, Robert O; Dolstra, Harry; Dranoff, Glenn; Durrant, Lindy G; Finke, James H; Galon, Jerome; Gollob, Jared A; Gouttefangeas, Cécile; Grizzi, Fabio; Guida, Michele; Håkansson, Leif; Hege, Kristen; Herberman, Ronald B; Hodi, F Stephen; Hoos, Axel; Huber, Christoph; Hwu, Patrick; Imai, Kohzoh; Jaffee, Elizabeth M; Janetzki, Sylvia; June, Carl H; Kalinski, Pawel; Kaufman, Howard L; Kawakami, Koji; Kawakami, Yutaka; Keilholtz, Ulrich; Khleif, Samir N; Kiessling, Rolf; Kotlan, Beatrix; Kroemer, Guido; Lapointe, Rejean; Levitsky, Hyam I; Lotze, Michael T; Maccalli, Cristina; Maio, Michele; Marschner, Jens-Peter; Mastrangelo, Michael J; Masucci, Giuseppe; Melero, Ignacio; Melief, Cornelius; Murphy, William J; Nelson, Brad; Nicolini, Andrea; Nishimura, Michael I; Odunsi, Kunle; Ohashi, Pamela S; O'Donnell-Tormey, Jill; Old, Lloyd J; Ottensmeier, Christian; Papamichail, Michael; Parmiani, Giorgio; Pawelec, Graham; Proietti, Enrico; Qin, Shukui; Rees, Robert; Ribas, Antoni; Ridolfi, Ruggero; Ritter, Gerd; Rivoltini, Licia; Romero, Pedro J; Salem, Mohamed L; Scheper, Rik J; Seliger, Barbara; Sharma, Padmanee; Shiku, Hiroshi; Singh-Jasuja, Harpreet; Song, Wenru; Straten, Per Thor; Tahara, Hideaki; Tian, Zhigang; van Der Burg, Sjoerd H; von Hoegen, Paul; Wang, Ena; Welters, Marij Jp; Winter, Hauke; Withington, Tara; Wolchok, Jedd D; Xiao, Weihua; Zitvogel, Laurence; Zwierzina, Heinz; Marincola, Francesco M; Gajewski, Thomas F; Wigginton, Jon M; Disis, Mary L

2011-12-14

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

Defining the critical hurdles in cancer immunotherapy

PubMed Central

2011-01-01

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. PMID:22168571

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blanchard, Miran; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota; Shim, Kevin G.

Purpose: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responsesmore » capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination therapy model that addresses the need for both systemic and local control in oligometastatic melanoma.« less

Immunotherapeutic strategies for cancer treatment: a novel protein transfer approach for cancer vaccine development.

PubMed

Shashidharamurthy, Rangaiah; Bozeman, Erica N; Patel, Jaina; Kaur, Ramneet; Meganathan, Jeyandra; Selvaraj, Periasamy

2012-11-01

Cancer cells have developed numerous ways to escape immune surveillance and gain unlimited proliferative capacity. Currently, several chemotherapeutic agents and radiotherapy, either alone or in combination, are being used to treat malignancies. However, both of these therapies are associated with several limitations and detrimental side effects. Therefore, recent scientific investigations suggest that immunotherapy is among the most promising new approaches in modern cancer therapy. The focus of cancer immunotherapy is to boost both acquired and innate immunity against malignancies by specifically targeting tumor cells, and leaving healthy cells and tissues unharmed. Cellular, cytokine, gene, and monoclonal antibody therapies have progressively become promising immunotherapeutic approaches that are being tested for several cancers in preclinical models as well as in the clinic. In this review, we discuss recent advances in these immunotherapeutic approaches, focusing on new strategies that allow the expression of specific immunostimulatory molecules on the surface of tumor cells to induce robust antitumor immunity. © 2011 Wiley Periodicals, Inc.

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

PubMed Central

Luevano, Martha; Madrigal, Alejandro; Saudemont, Aurore

2012-01-01

Natural killer (NK) cells are part of the innate immune system and are an alluring option for immunotherapy due to their ability to kill infected cells or cancer cells without prior sensitization. Throughout the past 20 years, different groups have been able to reproduce NK cell development in vitro, and NK cell ontogeny studies have provided the basis for the establishment of protocols to produce NK cells in vitro for immunotherapy. Here, we briefly discuss NK cell development and NK cell immunotherapy approaches. We review the factors needed for NK cell differentiation in vitro, which stem cell sources have been used, published protocols, challenges and future directions for Good Manufacturing Practice protocols. PMID:22705914

Promising role for Gc-MAF in cancer immunotherapy: from bench to bedside

PubMed Central

Saburi, Ehsan; Saburi, Amin; Ghanei, Mostafa

2017-01-01

Immunotherapy has been used for years in many types of cancer therapy. Recently, cancer immunotherapy has focused on mechanisms which can enhance the development of cell-mediated immunity. Anticancer medications are administered to inhibit immunosuppressive factors such as nagalase enzyme, which is produced by neoplastic cells and destroys macrophage activating factor (Gc-MAF). Anti-neoplastics medications can also enhance immune-cell activity against tumors. Such medications show great potential in cancer immunotherapy using natural human mechanisms against neoplasms. PMID:29201312

Noninvasive Imaging of Immune Checkpoint Ligand PD-L1 in Tumors and Metastases for Guiding Immunotherapy

PubMed Central

Chatterjee, Samit; Lesniak, Wojciech G.

2017-01-01

Immunotherapy holds great promise in cancer treatment. The challenges in advancing immunotherapies lie in patient stratification and monitoring therapy. Noninvasive detection of immune checkpoint ligand PD-L1 can serve as an important biomarker for guidance and monitoring of immunotherapy. Here in, we provide an overview of our efforts to develop clinically translatable PD-L1-specific imaging agents for quantitative and real-time assessment of PD-L1 expression in tumor microenvironment. PMID:28707500

Cancer immunotherapy drives implementation science in oncology.

PubMed

Speiser, Daniel E; Flatz, Lukas

2014-01-01

Cancer immunotherapy has come a long way. The hope that immunological approaches may help cancer patients has sparked many initiatives in research and development (R&D). For many years, progress was modest and disappointments were frequent. Today, the increasing scientific and medical knowledge has established a solid basis for improvements. Considerable clinical success was first achieved for patients with hematological cancers. More recently, immunotherapy has entered center stage in the development of novel therapies against solid cancers. Together with R&D in angiogenesis, the field of immunology has fundamentally extended the scientific scope, which has evolved from a cancer-cell-centered view to a comprehensive and integrated vision of tumor biology. Current R&D is focused on a large array of possible disease mechanisms, driven by cancer cells, and amplified by tumor stroma, inflammatory and immunological actors, blood and lymph vessels, and the “macroenvironment," i.e. systemic mechanisms of the host, particularly of the haematopoietic system. Contrasting to this large spectrum of pathophysiological events promoting tumor growth, only a small number of biological mechanisms, namely of the immune system, have the potential to counteract tumor growth. They are of prime interest because therapeutic enhancement may result in clinical benefit for patients. This special issue is dedicated to immunotherapeutics against cancer, with particular emphasis on vaccination and combination therapies, providing updates and extended insight in this booming field.

Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

PubMed Central

Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

2013-01-01

Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas. PMID:24202450

Improved Endpoints for Cancer Immunotherapy Trials

PubMed Central

Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd

2010-01-01

Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737

Clinical trial investigates experimental drug for advanced pancreatic cancer | Center for Cancer Research

Cancer.gov

The pancreas, a large gland that sits behind the stomach, produces enzymes that aid digestion and hormones that regulate blood sugar. Pancreatic cancer develops when cells that make up the ducts in the pancreas start to grow out of control. Udo Rudloff, M.D., is leading a clinical trial of a combination immunotherapy regimen to optimally help the immune system attack the tumor.

In situ photoimmunotherapy for melanoma: an ongoing phase I clinical trial

NASA Astrophysics Data System (ADS)

Naylor, Mark F.; Nordquist, Robert E.; Teague, T. Kent; Perry, Lisa A.; Chen, Wei R.

2007-02-01

In situ Photoimmunotherapy (ISPI) was developed to treat metastatic tumors using a combination of phototherapy and immunotherapy. It utilizes local intervention through photothermal destruction of existing solid tumors and through immune response modifier to elicit host anti-tumor responses. Such combination in pre-clinical studies has shown promise in cancer treatment by eradicating the primary tumors and also controlling metastases at distant sites. ISPI has been used in our preliminary clinical studies for melanoma patients and the outcome has been extremely encouraging. In 2006, we began enrolling patients in a new phase I immunotherapy trial for advanced cutaneous melanoma. This trial is based on our previous results which indicated that we had developed an effective treatment for advanced melanoma. Of the first six patients treated, (4 stage IV, and 2 surgically unresectable stage III), 2 of the stage IV patients are still alive, one tumor free, and one with a possible treatable recurrence after 2 1/2 years. We have also discovered that recurrences of the skin cancer can be retreated by the same technique and that treatment seems to blunt the virulence of the disease and make it more treatable. These initial results indicate that ISPI probably will have the ability to prolong survival in selected cases of advanced melanoma, and potentially cure a significant percentage of treated patients.

A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet.

PubMed

D'Errico, Gabriele; Machado, Heather L; Sainz, Bruno

2017-12-01

Immunotherapy is the new trend in cancer treatment due to the selectivity, long lasting effects, and demonstrated improved overall survival and tolerance, when compared to patients treated with conventional chemotherapy. Despite these positive results, immunotherapy is still far from becoming the perfect magic bullet to fight cancer, largely due to the facts that immunotherapy is not effective in all patients nor in all cancer types. How and when will immunotherapy overcome these hurdles? In this review we take a step back to walk side by side with the pioneers of immunotherapy in order to understand what steps need to be taken today to make immunotherapy effective across all cancers. While early scientists, such as Coley, elicited an unselective but effective response against cancer, the search for selectivity pushed immunotherapy to the side in favor of drugs focused on targeting cancer cells. Fortunately, the modern era would revive the importance of the immune system in battling cancer by releasing the brakes or checkpoints (anti-CTLA-4 and anti-PD-1/PD-L1) that have been holding the immune system at bay. However, there are still many hurdles to overcome before immunotherapy becomes a universal cancer therapy. For example, we discuss how the redundant and complex nature of the immune system can impede tumor elimination by teeter tottering between different polarization states: one eliciting anti-cancer effects while the other promoting cancer growth and invasion. In addition, we highlight the incapacity of the immune system to choose between a fight or repair action with respect to tumor growth. Finally we combine these concepts to present a new way to think about the immune system and immune tolerance, by introducing two new metaphors, the "push the accelerator" and "repair the car" metaphors, to explain the current limitations associated with cancer immunotherapy.

Activation of human CD141+ and CD1c+ dendritic cells in vivo with combined TLR3 and TLR7/8 ligation.

PubMed

Pearson, Frances E; Chang, Karshing; Minoda, Yoshihito; Rojas, Ingrid M Leal; Haigh, Oscar L; Daraj, Ghazal; Tullett, Kirsteen M; Radford, Kristen J

2018-04-01

Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141 + and CD1c + myeloid and CD123 + plasmacytoid dendritic cells (DC) develop from human cord blood CD34 + cells in immunodeficient mice. CD141 + DC are the human equivalents of murine CD8 + /CD103 + DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte responses, making them attractive targets to exploit for the development of new cancer immunotherapies. We used CD34 + -engrafted NSG-A2 mice to investigate activation of DC subsets by synthetic dsRNA or ssRNA analogs polyinosinic-polycytidylic acid/poly I:C and Resiquimod/R848, agonists for TLR3 and TLR8, respectively, both of which are expressed by CD141 + DC. Injection of hu mice with these agonists resulted in upregulation of costimulatory molecules CD80, CD83 and CD86 by CD141 + and CD1c + DC alike, and their combination further enhanced expression of these molecules by both subsets. When combined, poly I:C and R848 enhanced serum levels of key cytokines associated with cross-presentation and the induction of cytotoxic T lymphocyte responses including IFN-α, IFN-β, IL-12 and CXCL10. These data advocate a combination of poly I:C and R848 TLR agonists as means of activating human DC for immunotherapy. © 2018 Australasian Society for Immunology Inc.

Immunotherapy for Dogs: Running Behind Humans

PubMed Central

Klingemann, Hans

2018-01-01

A number of excellent reviews on the potential of canine cancer immunotherapy are available, but many extrapolate from observations in humans when in fact only very few immunotherapies have been developed for canines that have shown efficacy in well-designed studies. Pharmaceutical and biotech companies are aware that the market for more expensive immunotherapies in canines is limited resulting in limited funding for clinical trials. However, dogs and other pets deserve access to this new form of cancer therapy. The purpose of this brief review is to summarize the current status of available immunotherapies for dogs and their near-term prospects, provided we can effectively translate discoveries and progress in humans to canines. PMID:29459862

Sublingual immunotherapy: World Allergy Organization position paper 2013 update.

PubMed

Canonica, Giorgio Walter; Cox, Linda; Pawankar, Ruby; Baena-Cagnani, Carlos E; Blaiss, Michael; Bonini, Sergio; Bousquet, Jean; Calderón, Moises; Compalati, Enrico; Durham, Stephen R; van Wijk, Roy Gerth; Larenas-Linnemann, Désirée; Nelson, Harold; Passalacqua, Giovanni; Pfaar, Oliver; Rosário, Nelson; Ryan, Dermot; Rosenwasser, Lanny; Schmid-Grendelmeier, Peter; Senna, Gianenrico; Valovirta, Erkka; Van Bever, Hugo; Vichyanond, Pakit; Wahn, Ulrich; Yusuf, Osman

2014-03-28

We have prepared this document, "Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update", according to the evidence-based criteria, revising and updating chapters of the originally published paper, "Sublingual Immunotherapy: World Allergy Organization Position Paper 2009", available at http://www.waojournal.org. Namely, these comprise: "Mechanisms of sublingual immunotherapy;" "Clinical efficacy of sublingual immunotherapy" - reporting all the data of all controlled trials published after 2009; "Safety of sublingual immunotherapy" - with the recently published Grading System for adverse reactions; "Impact of sublingual immunotherapy on the natural history of respiratory allergy" - with the relevant evidences published since 2009; "Efficacy of SLIT in children" - with detailed analysis of all the studies; "Definition of SLIT patient selection" - reporting the criteria for eligibility to sublingual immunotherapy; "The future of immunotherapy in the community care setting"; "Methodology of clinical trials according to the current scientific and regulatory standards"; and "Guideline development: from evidence-based medicine to patients' views" - including the evolution of the methods to make clinical recommendations.Additionally, we have added new chapters to cover a few emerging crucial topics: "Practical aspects of schedules and dosages and counseling for adherence" - which is crucial in clinical practice for all treatments; "Perspectives and new approaches" - including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, "Raising public awareness about sublingual immunotherapy", as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail.

Salmonella Immunotherapy Improves the Outcome of CHOP Chemotherapy in Non-Hodgkin Lymphoma-Bearing Mice

PubMed Central

Bascuas, Thais; Moreno, María; Grille, Sofía; Chabalgoity, José A.

2018-01-01

We have previously shown that Salmonella immunotherapy is effective to treat B-cell non-Hodgkin lymphoma (B-NHL) in mice. However, this model involves animals with high tumor burden, whereas in the clinics B-NHL patients are usually treated with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy prior to immunotherapy. Recently, we have described a NHL-B preclinical model using CHOP chemotherapy to achieve MRD in immunocompetent animals that closely resemble patients’ conditions. In this work, we assessed the efficacy of Salmonella immunotherapy in B-NHL-bearing mice undergoing chemotherapy. Salmonella administration significantly delayed tumor growth and prolonged survival of chemotherapy-treated NHL-bearing animals. Mice receiving the CHOP–Salmonella combined therapy showed increased numbers of tumor-infiltrating leukocytes and a different profile of cytokines and chemokines expressed in the tumor microenvironment. Further, Salmonella immunotherapy in CHOP-treated animals also enhanced NK cells cytotoxic activity as well as induced systemic lymphoma-specific humoral and cellular responses. Chemotherapy treatment profoundly impacted on the general health status of recipient animals, but those receiving Salmonella showed significantly better overall body condition. Altogether, the results clearly demonstrated that Salmonella immunotherapy could be safely used in individuals under CHOP treatment, resulting in a better prognosis. These results give strong support to consider Salmonella as a neoadjuvant therapy in a clinical setting. PMID:29410666

Emerging role of immunotherapy in urothelial carcinoma-Future directions and novel therapies.

PubMed

Park, Jong Chul; Hahn, Noah M

2016-12-01

Tremendous advances in our understanding of the tumor immunology and molecular biology of urothelial carcinoma (UC) have led to the recent approval of immunotherapy as a novel option for patients with UC with advanced disease. Despite the promising data of novel immune checkpoint inhibitors, only a small subset of patients with UC achieves durable remissions. Because an optimal antitumor response requires coordination of multiple immune, tumor, and microenvironment effector cells, novel approaches targeting distinct mechanisms of action likely in combination are needed. In addition, discovery of reliable immune biomarkers, understanding of mechanisms of resistance, and novel clinical trial designs are warranted for maximum benefit of UC immunotherapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Synergistic suppression of autoimmune arthritis through concurrent treatment with tolerogenic DC and MSC

PubMed Central

Li, Rong; Zhang, Yujuan; Zheng, Xiufen; Peng, Shanshan; Yuan, Keng; Zhang, Xusheng; Min, Weiping

2017-01-01

Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive immune-mediated joint deterioration. Current treatments are not antigen specific and are associated with various adverse. We have previously demonstrated that tolerogenic dendritic cells (Tol-DC) are potent antigen-specific immune regulators, which hold great promise in immunotherapy of autoimmune diseases. In this study, we aimed to develop new immunotherapy by combining Tol-DC and mesenchymal stem cells (MSC). We demonstrated that RelB gene silencing resulted in generation of Tol-DC that suppressed T cell responses and selectively promoted Treg generation. The combination of MSC synergized the tolerogenic capacity of Tol-DC in inhibition of T cell responses. In murine collagen-induced arthritis (CIA) model, we demonstrated that progression of arthritis was inhibited with administration of RelB gene-silenced Tol-DC or MSC. This therapeutic effect was remarkably enhanced with concurrent treatment of combination Tol-DC and MSC as demonstrated by improved clinical symptoms, decreased clinical scores and attenuated joint damage. These therapeutic effects were associated with suppression of CII-specific T cell responses, polarization of Th and inhibition of proinflammatory cytokines, and reduced cartilage degeneration. This study for the first time demonstrates a new approach to treat autoimmune inflammatory joint disease with concurrent treatment of RelB gene-silenced Tol-DC and MSC. PMID:28230210

The combination of radiotherapy and immunotherapy using glycated chitosan as an immunological stimulant

NASA Astrophysics Data System (ADS)

Chang, Chun-Yuan; Leu, Jyh-Der; Wang, Chung-Yi; Chen, Wei R.; Lee, Yi-Jang

2015-03-01

Immunotherapy has been reported to effectively treat various cancers. In addition, scientists are dedicated in finding whether the combination of radiotherapy and immunotherapy can efficiently suppress cancer progression and recurrence. Although radiotherapy has been widely used for breast cancer, better strategies to overcome the latestage breast cancer remains explored. The glycated chitosan (GC), a novel immunological stimulant, was demonstrated to trigger local immune response facilitating the enhancement of radiosensitivity. Our previous study also revealed that the cell mortality and invasive ability were decreased under GC treatment, but the underlying mechanism remains unclear. In this study, we used 4T1-3R-L, a derived murine breast cancer cell line from the spontaneous metastasized liver lesion. We combined ionizing radiation with GC to treat 4T1-3R-L and found the expression of DNA damage-related genes such as gamma-H2AX was more than radiation alone In addition, the cell cycle distribution and colony forming assay showed an increased sub-G1 population and decreased cell survival rate after IR combined GC treatment. Taken together, we sought to elucidate the underlying mechanism by the investigation of DNA damage repair process when IR combined with GC, and to explore another advantage of GC to aid other cancer treatments. Based on our most updated results, the GC treatment is able to effectively increase the radiosensitivity through an immune-responsive signaling transduction, indicating that GC could be a valuable therapeutic strategy for treating against advanced breast cancers.

Abeta DNA vaccination for Alzheimer's disease: focus on disease prevention.

PubMed

Cribbs, David H

2010-04-01

Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, in the advent of Abeta-antibody immune complex-induced adverse events the patients will have to receive immuno-supperssive therapy for an extended period until the anti Abeta antibody levels drop naturally as the effects of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.

Review of the 25th annual scientific meeting of the International Society for Biological Therapy of Cancer.

PubMed

Balwit, James M; Kalinski, Pawel; Sondak, Vernon K; Coulie, Pierre G; Jaffee, Elizabeth M; Gajewski, Thomas F; Marincola, Francesco M

2011-05-12

Led by key opinion leaders in the field, the 25th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC) provided a scientific platform for ~500 attendees to exchange cutting-edge information on basic, clinical, and translational research in cancer immunology and immunotherapy. The meeting included keynote addresses on checkpoint blockade in cancer therapy and recent advances in therapeutic vaccination against cancer induced by Human Papilloma Virus 16. Participants from 29 countries interacted through oral presentations, panel discussions, and posters on topics that included dendritic cells and cancer, targeted therapeutics and immunotherapy, innate/adaptive immune interplay in cancer, clinical trial endpoints, vaccine combinations, countering negative regulation, immune cell trafficking to tumor microenvironment, and adoptive T cell transfer. In addition to the 50 oral presentations and >180 posters on these topics, a new SITC/iSBTc initiative to create evidence-based Cancer Immunotherapy Guidelines was announced. The SITC/iSBTc Biomarkers Taskforce announced the release of recommendations on immunotherapy biomarkers and a highly successful symposium on Immuno-Oncology Biomarkers that took place on the campus of the National Institutes of Health (NIH) immediately prior to the Annual Meeting. At the Annual Meeting, the NIH took the opportunity to publicly announce the award of the U01 grant that will fund the Cancer Immunotherapy Trials Network (CITN). In summary, the Annual Meeting gathered clinicians and scientists from academia, industry, and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy.

A patient with scirrhous stomach cancer treated with combination of hyperthermotherapy and 5-aminolevulinic acid (ALA).

PubMed

Saito, Masashi; Yano, Kazuhito; Kamigaki, Takashi; Goto, Shigenori

2013-07-01

A 35-year-old female with scirrhous stomach cancer (stage IV) was treated with a combination of 5-aminolevulinic acid (ALA), sodium dichloroacetate (DCA), hyperthermotherapy, and immunotherapy as terminal care. The patient survived for one year and seven months, during which her quality of life was markedly improved and she returned to work. The patient was diagnosed with poorly-differentiated adenocarcinoma and progressive signet-ring cell carcinoma, accompanied by left ovarian metastasis, peritoneal dissemination, and right hydronephrosis stage IV, and treated with combination chemotherapy with tegafur-gimeracil-oteracil potassium (TS-1) and docetaxel. Oral ALA and DCA were concomitantly administered at 50 mg each three times a day (150 mg/day, respectively). In addition, hyperthermotherapy using thermotron was concomitantly performed at 2- to 3-week intervals. Cellular immunotherapy with αβ T- and immature dendritic cells was also performed. The disease did not progress for 11 months, her quality of life was markedly improved, and she was able to return to work. However, the signs of enlargement of the ovarian metastatic lesion were noted later, for which chemotherapy with four cycles of second-line paclitaxel and a half dose of irinotecan and cisplatin as third-line treatment were performed. Combination of ALA/DCA, hyperthermotherapy, and cellular immunotherapy may be a low-invasive palliative therapy superior in maintaining quality of life of tumor-bearing terminally ill individuals.

Immune modulatory effects of radiotherapy as basis for well-reasoned radioimmunotherapies.

PubMed

Rückert, Michael; Deloch, Lisa; Fietkau, Rainer; Frey, Benjamin; Hecht, Markus; Gaipl, Udo S

2018-06-01

Radiotherapy (RT) has been known for decades as a local treatment modality for malign and benign disease. In order to efficiently exploit the therapeutic potential of RT, an understanding of the immune modulatory properties of ionizing radiation is mandatory. These should be used for improvement of radioimmunotherapies for cancer in particular. We here summarize the latest research and review articles about immune modulatory properties of RT, with focus on radiation dose and on combination of RT with selected immunotherapies. Based on the knowledge of the manifold immune mechanisms that are triggered by RT, thought-provoking impulse for multimodal radioimmunotherapies is provided. It has become obvious that ionizing radiation induces various forms of cell death and associated processes via DNA damage initiation and triggering of cellular stress responses. Immunogenic cell death (ICD) is of special interest since it activates the immune system via release of danger signals and via direct activation of immune cells. While RT with higher single doses in particular induces ICD, RT with a lower dose is mainly responsible for immune cell recruitment and for attenuation of an existing inflammation. The counteracting immunosuppression emanating from tumor cells can be overcome by combining RT with selected immunotherapies such as immune checkpoint inhibition, TGF-β inhibitors, and boosting of immunity with vaccination. In order to exploit the full power of RT and thereby develop efficient radioimmunotherapies, the dose per fraction used in RT protocols, the fractionation, the quality, and the quantity of certain immunotherapies need to be qualitatively and chronologically well-matched to the individual immune status of the patient.

Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies.

PubMed

Monjazeb, Arta M; Kent, Michael S; Grossenbacher, Steven K; Mall, Christine; Zamora, Anthony E; Mirsoian, Annie; Chen, Mingyi; Kol, Amir; Shiao, Stephen L; Reddy, Abhinav; Perks, Julian R; T N Culp, William; Sparger, Ellen E; Canter, Robert J; Sckisel, Gail D; Murphy, William J

2016-09-01

Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR. ©2016 American Association for Cancer Research.

Amyloid-ß-directed immunotherapy for Alzheimer's disease

PubMed Central

Lannfelt, L; Relkin, N R; Siemers, E R

2014-01-01

Lannfelt L, Relkin NR, Siemers ER (Uppsala University, Uppsala, Sweden; Weill Cornell Medical College, New York, NY; and Eli Lilly and Co., Indianapolis, IN, USA). Amyloid-ß-directed immunotherapy for Alzheimer’s disease. (Key Symposium). J Intern Med 2014; 275: 284–295. Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing Aß-directed immunotherapies that have passed clinical development Phase IIa. PMID:24605809

Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer?

PubMed Central

Lazzari, Chiara; Karachaliou, Niki; Bulotta, Alessandra; Viganó, Mariagrazia; Mirabile, Aurora; Brioschi, Elena; Santarpia, Mariacarmela; Gianni, Luca; Rosell, Rafael; Gregorc, Vanesa

2018-01-01

Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported. PMID:29662546

Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer?

PubMed

Lazzari, Chiara; Karachaliou, Niki; Bulotta, Alessandra; Viganó, Mariagrazia; Mirabile, Aurora; Brioschi, Elena; Santarpia, Mariacarmela; Gianni, Luca; Rosell, Rafael; Gregorc, Vanesa

2018-01-01

Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported.

Stereotactic ablative body radiotherapy combined with immunotherapy: present status and future perspectives.

PubMed

Rekers, N H; Troost, E G C; Zegers, C M L; Germeraad, W T V; Dubois, L J; Lambin, P

2014-10-01

Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Therapeutic vaccines for leishmaniasis.

PubMed

Khamesipour, Ali

2014-11-01

Numerous therapeutic strategies are used to treat leishmaniasis. The treatment of cutaneous leishmaniasis (CL) is solely depends on antimonate derivatives with safety issues and questionable efficacy and there is no fully effective modality to treat CL caused by Leishmania tropica and Leishmania braziliensis. There is no prophylactic vaccine available against any form of leishmaniasis. Immunotherapy for CL has a long history; immunotherapy trials of first and second generation vaccines showed promising results. The current article briefly covers the prophylactic vaccines and explains different immunotherapy strategies that have been used to treat leishmaniasis. This paper does not include experimental vaccines and only lays emphasis on human trials and those vaccines which reached human trials. Immunotherapy is currently used to successfully treat several disorders; Low cost, limited side effects and no possibility to develop resistance make immunotherapy a valuable choice especially for infectious disease with chemotherapy problems. Efforts are needed to explore the immunological surrogate marker(s) of cure and protection in leishmaniasis and overcome the difficulties in standardization of crude Leishmania vaccines. One of the reasons for anti-leishmaniasis vaccine failure is lack of an appropriate adjuvant. So far, not enough attention has been paid to develop vaccines for immunotherapy of leishmaniasis.

Prospects for adoptive immunotherapy of pancreatic cancer using chimeric antigen receptor-engineered T-cells.

PubMed

Alrifai, Doraid; Sarker, Debashis; Maher, John

2016-01-01

Adoptive immunotherapy using chimeric antigen receptor (CAR) engineered T-cells is emerging as a powerful new approach to cancer immunotherapy. CARs are fusion molecules that couple the antibody-like binding of a native cell surface target to the delivery of a bespoke T-cell activating signal. Recent studies undertaken by several centers have demonstrated highly compelling efficacy in patients with acute and chronic B-cell malignancies. However, comparable therapeutic activity has not been achieved in solid tumors. Modern management of pancreatic ductal adenocarcinoma (PDAC) remains ineffective, reflected in the virtual equivalence of annual incidence and mortality statistics for this tumor type. Increasing evidence indicates that these tumors are recognized by the immune system, but deploy powerful evasion strategies that limit natural immune surveillance and render efforts at immunotherapy challenging. Here, we review preclinical and clinical studies that have been initiated or completed in an effort to develop CAR-based immunotherapy for PDAC. We also consider the hurdles to the effective clinical development of this exciting new therapeutic modality.

Intralesional Immunotherapy for Metastatic Melanoma: The Oldest and Newest Treatment in Oncology

PubMed Central

Faries, Mark B.

2017-01-01

The last few years have yielded exciting developments in immunotherapy for cancer. The promise of cancer immunotherapy has been well known for many years, but had generally produced limited or inconsistent benefit to patients. Intralesional therapies, which are in fact one of the oldest forms of immunotherapy, are also demonstrating benefits in the modern age. This review discusses the origins of intralesional immunotherapy and its underlying rationale. It also discusses the reemergence of this mode of therapy into the modern era, which is where Donald L. Morton, subject of this edition of the journal, plays a major role. The review also discusses current areas of investigation. Given the intuitive advantages of this strategy and the demonstrated, expanding areas of clinical responses, it is likely that intralesional immunotherapy will remain a useful component of cancer treatment into the future. PMID:27481003

SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery

PubMed Central

2011-01-01

Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies. PMID:21929757

Future directions in bladder cancer immunotherapy: towards adaptive immunity

PubMed Central

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed. PMID:26860539

Future directions in bladder cancer immunotherapy: towards adaptive immunity.

PubMed

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.

Radiation-Induced Chromosomal Aberrations and Immunotherapy: Micronuclei, Cytosolic DNA, and Interferon-Production Pathway.

PubMed

Durante, Marco; Formenti, Silvia C

2018-01-01

Radiation-induced chromosomal aberrations represent an early marker of late effects, including cell killing and transformation. The measurement of cytogenetic damage in tissues, generally in blood lymphocytes, from patients treated with radiotherapy has been studied for many years to predict individual sensitivity and late morbidity. Acentric fragments are lost during mitosis and create micronuclei (MN), which are well correlated to cell killing. Immunotherapy is rapidly becoming a most promising new strategy for metastatic tumors, and combination with radiotherapy is explored in several pre-clinical studies and clinical trials. Recent evidence has shown that the presence of cytosolic DNA activates immune response via the cyclic GMP-AMP synthase/stimulator of interferon genes pathway, which induces type I interferon transcription. Cytosolic DNA can be found after exposure to ionizing radiation either as MN or as small fragments leaking through nuclear envelope ruptures. The study of the dependence of cytosolic DNA and MN on dose and radiation quality can guide the optimal combination of radiotherapy and immunotherapy. The role of densely ionizing charged particles is under active investigation to define their impact on the activation of the interferon pathway.

Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy

NASA Astrophysics Data System (ADS)

He, Chunbai; Duan, Xiaopin; Guo, Nining; Chan, Christina; Poon, Christopher; Weichselbaum, Ralph R.; Lin, Wenbin

2016-08-01

Advanced colorectal cancer is one of the deadliest cancers, with a 5-year survival rate of only 12% for patients with the metastatic disease. Checkpoint inhibitors, such as the antibodies inhibiting the PD-1/PD-L1 axis, are among the most promising immunotherapies for patients with advanced colon cancer, but their durable response rate remains low. We herein report the use of immunogenic nanoparticles to augment the antitumour efficacy of PD-L1 antibody-mediated cancer immunotherapy. Nanoscale coordination polymer (NCP) core-shell nanoparticles carry oxaliplatin in the core and the photosensitizer pyropheophorbide-lipid conjugate (pyrolipid) in the shell (NCP@pyrolipid) for effective chemotherapy and photodynamic therapy (PDT). Synergy between oxaliplatin and pyrolipid-induced PDT kills tumour cells and provokes an immune response, resulting in calreticulin exposure on the cell surface, antitumour vaccination and an abscopal effect. When combined with anti-PD-L1 therapy, NCP@pyrolipid mediates regression of both light-irradiated primary tumours and non-irradiated distant tumours by inducing a strong tumour-specific immune response.

Immunotherapy for Ovarian Cancer: What's Next?

PubMed Central

Kandalaft, Lana E.; Powell, Daniel J.; Singh, Nathan; Coukos, George

2011-01-01

In the past decade, we have witnessed important gains in the treatment of ovarian cancer; however, additional advances are required to reduce mortality. With compelling evidence that ovarian cancers are immunogenic tumors, immunotherapy should be further pursued and optimized. The dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory antibodies, create new opportunities in ovarian cancer therapeutics. Herein, we review current progress and future prospects in vaccine and adoptive T-cell therapy development as well as immunomodulatory therapy tools available for immediate clinical testing. PMID:21079136

Development of an Oral Barley Beta-Glucan Adjuvant That Augments the Tumoricidal Activity of Antibodies or Vaccines Used for the Immunotherapy of Breast Cancer

DTIC Science & Technology

2003-07-01

These Data provided strong evidence for the efficacy of an oral beta - glucan adjuvant for use in combination with anti-tumor antibodies such as...oral beta - glucan . The data showing that antibodies must activate complement and deposit iC3b on tumors means that antibodies that do not to activate complement would not benefit from oral beta - glucan .

3D Models of Immunotherapy

Cancer.gov

This collaborative grant is developing 3D models of both mouse and human biology to investigate aspects of therapeutic vaccination in order to answer key questions relevant to human cancer immunotherapy.

T cells redirected to EphA2 for the immunotherapy of glioblastoma.

PubMed

Chow, Kevin K H; Naik, Swati; Kakarla, Sunitha; Brawley, Vita S; Shaffer, Donald R; Yi, Zhongzhen; Rainusso, Nino; Wu, Meng-Fen; Liu, Hao; Kew, Yvonne; Grossman, Robert G; Powell, Suzanne; Lee, Dean; Ahmed, Nabil; Gottschalk, Stephen

2013-03-01

Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.

Conjunctival provocation tests: a predictive factor for patients' seasonal allergic rhinoconjunctivitis symptoms.

PubMed

Kruse, Kristian; Gerwin, Eva; Eichel, Andrea; Shah-Hosseini, Kija; Mösges, Ralph

2015-01-01

No parameters currently exist that can reliably predict the impact of preseasonal immunotherapy on the symptoms occurring during the season. The purpose of our studies was to prove a correlation between preseasonal conjunctival allergen challenge and coseasonal primary clinical endpoints using the total combined score, ie, a combination of symptoms and medication score, as the primary outcome parameter. Twelve weeks before both the birch and the grass pollen seasons, 2 separate prospective, double-blind, randomized, controlled studies were conducted followed by posttrial observations for each study during the active season. In the studies, patients who reacted to conjunctival allergen challenge were treated with sublingual immunotherapy tablets that contain either birch and/or alder or grass pollen allergoids. In all, 158 patients were included in the grass and 160 in the tree pollen study; of these, 100 and 109 patients, respectively, took part in the posttrial observations. When comparing patients with and without a positive reaction in the final conjunctival allergen challenge, the results revealed a significant difference in the total combined score (grass: P < .001; birch: P = .025). The same applied to the rescue medication score (P = .005; P = .025). A significant difference regarding the rhinoconjunctivitis symptom score was shown in the grass pollen study (P = .002), and the difference of well days was significant in the tree pollen study (P = .049). When comparing patients based on their reaction to allergen challenge after immunotherapy, each study leads to similarly significant results. Therefore, conjunctival allergen challenge can be used effectively as a parameter to predict allergic rhinoconjunctivitis symptoms during the season in patients treated with preseasonal sublingual immunotherapy tablets. Whether this can be transferred to untreated patients needs to be determined. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy.

PubMed

Chowdhury, P S; Chamoto, K; Honjo, T

2018-02-01

Programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects. A brief history and development of PD-1 blockade, from the initial discovery of PD-1 to the recent clinical output of this therapy, have been summarized here. Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy. The key to improve the PD-1 blockade therapy is the development of combination therapies. As this approach has garnered worldwide interest, here, we have summarized the recent trends in the development of PD-1 blockade-based combination therapies and the ongoing clinical trials. These include combinations with checkpoint inhibitors, radiation therapy, chemotherapy and several other existing cancer treatments. Importantly, FDA has approved PD-1 blockade agent to be used in combination with either CTLA-4 blockade or chemotherapy. Responsiveness to the PD-1 blockade therapy is affected by tumour and immune system-related factors. The role of the immune system, especially T cells, in determining the responsiveness has been poorly studied compared with those factors related to the tumour side. Energy metabolism has emerged as one of the important regulatory mechanisms for the function and differentiation of T cells. We have documented here the recent results regarding the augmentation of PD-1 blockade efficacy by augmenting mitochondrial energy metabolism of T cell. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Treatment of hay fever.

PubMed Central

Wood, S F

1989-01-01

The range of treatments for hay fever available to the general practitioner has changed considerably in recent years. New antihistamines have addressed the problem of sedation and moved towards one daily dose; nasally applied corticosteroids avoid the need for systemic steroid therapy and its potential adverse effect; and regulatory decisions have set a trend away from immunotherapy in general practice. However, knowledge about the mechanism of action of immunotherapy is increasing and new developments with improved safety profiles include allergen polymers, allergoids, oral immunotherapy and nasal immunotherapy. Choice of treatment depends, as always, on the individual circumstances of the patient and his or her disease. PMID:2556545

Workshop on challenges, insights, and future directions for mouse and humanized models in cancer immunology and immunotherapy: a report from the associated programs of the 2016 annual meeting for the Society for Immunotherapy of cancer.

PubMed

Zloza, Andrew; Karolina Palucka, A; Coussens, Lisa M; Gotwals, Philip J; Headley, Mark B; Jaffee, Elizabeth M; Lund, Amanda W; Sharpe, Arlene H; Sznol, Mario; Wainwright, Derek A; Wong, Kwok-Kin; Bosenberg, Marcus W

2017-09-19

Understanding how murine models can elucidate the mechanisms underlying antitumor immune responses and advance immune-based drug development is essential to advancing the field of cancer immunotherapy. The Society for Immunotherapy of Cancer (SITC) convened a workshop titled, "Challenges, Insights, and Future Directions for Mouse and Humanized Models in Cancer Immunology and Immunotherapy" as part of the SITC 31st Annual Meeting and Associated Programs on November 10, 2016 in National Harbor, MD. The workshop focused on key issues in optimizing models for cancer immunotherapy research, with discussions on the strengths and weaknesses of current models, approaches to improve the predictive value of mouse models, and advances in cancer modeling that are anticipated in the near future. This full-day program provided an introduction to the most common immunocompetent and humanized models used in cancer immunology and immunotherapy research, and addressed the use of models to evaluate immune-targeting therapies. Here, we summarize the workshop presentations and subsequent panel discussion.

Gamma-delta (γδ) T cells: friend or foe in cancer development?

PubMed

Zhao, Yijing; Niu, Chao; Cui, Jiuwei

2018-01-10

γδ T cells are a distinct subgroup of T cells containing T cell receptors (TCRs) γ and TCR δ chains with diverse structural and functional heterogeneity. As a bridge between the innate and adaptive immune systems, γδ T cells participate in various immune responses during cancer progression. Because of their direct/indirect antitumor cytotoxicity and strong cytokine production ability, the use of γδ T cells in cancer immunotherapy has received a lot of attention over the past decade. Despite the promising potential of γδ T cells, the efficacy of γδ T cell immunotherapy is limited, with an average response ratio of only 21%. In addition, research over the past 2 years has shown that γδ T cells could also promote cancer progression by inhibiting antitumor responses, and enhancing cancer angiogenesis. As a result, γδ T cells have a dual effect and can therefore be considered as being both "friends" and "foes" of cancer. In order to solve the sub-optimal efficiency problem of γδ T cell immunotherapy, we review recent observations regarding the antitumor and protumor activities of major structural and functional subsets of human γδ T cells, describing how these subsets are activated and polarized, and how these events relate to subsequent effects in cancer immunity. A mixture of both antitumor or protumor γδ T cells used in adoptive immunotherapy, coupled with the fact that γδ T cells can be polarized from antitumor cells to protumor cells appear to be the likely reasons for the mild efficacy seen with γδ T cells. The future holds the promise of depleting the specific protumor γδ T cell subgroup before therapy, choosing multi-immunocyte adoptive therapy, modifying the cytokine balance in the cancer microenvironment, and using a combination of γδ T cells adoptive immunotherapy with immune checkpoint inhibitors.

Novel Immunotherapies for Autoimmune Hepatitis

PubMed Central

Cassim, Shamir; Bilodeau, Marc; Vincent, Catherine; Lapierre, Pascal

2017-01-01

Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4+ T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects. PMID:28184367

Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

PubMed Central

Beatty, Gregory L.; Li, Yan; Long, Kristen B.

2017-01-01

INTRODUCTION CD40 is a promising therapeutic target for cancer immunotherapy. In patients with advanced solid malignancies, CD40 agonists have demonstrated some anti-tumor activity and a manageable toxicity profile. A 2nd generation of CD40 agonists has now been designed with optimized Fc receptor (FcR) binding based on preclinical evidence suggesting a critical role for FcR engagement in defining the potency of CD40 agonists in vivo. AREAS COVERED We provide a comprehensive review using PubMed and Google Patent databases on the current clinical status of CD40 agonists, strategies for applying CD40 agonists in cancer therapy, and the preclinical data that supports and is guiding the future development of CD40 agonists. EXPERT COMMENTARY There is a wealth of preclinical data that provide rationale on several distinct approaches for using CD40 agonists in cancer immunotherapy. This data illustrates the need to strategically combine CD40 agonists with other clinically active treatment regimens in order to realize the full potential of activating CD40 in vivo. Thus, critical to the success of this class of immune-oncology drugs, which have the potential to restore both innate and adaptive immunosurveillance, will be the identification of biomarkers for monitoring and predicting responses as well as informing mechanisms of treatment resistance. PMID:27927088

Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors.

PubMed

Lechner, Melissa G; Russell, Sarah M; Bass, Rikki S; Epstein, Alan L

2011-11-01

In this article, the role of chemokines and costimulatory molecules in the immunotherapy of experimental murine solid tumors and immunotherapy used in ongoing clinical trials are presented. Chemokine networks regulate physiologic cell migration that may be disrupted to inhibit antitumor immune responses or co-opted to promote tumor growth and metastasis in cancer. Recent studies highlight the potential use of chemokines in cancer immunotherapy to improve innate and adaptive cell interactions and to recruit immune effector cells into the tumor microenvironment. Another critical component of antitumor immune responses is antigen priming and activation of effector cells. Reciprocal expression and binding of costimulatory molecules and their ligands by antigen-presenting cells and naive lymphocytes ensures robust expansion, activity and survival of tumor-specific effector cells in vivo. Immunotherapy approaches using agonist antibodies or fusion proteins of immunomodulatory molecules significantly inhibit tumor growth and boost cell-mediated immunity. To localize immune stimulation to the tumor site, a series of fusion proteins consisting of a tumor-targeting monoclonal antibody directed against tumor necrosis and chemokines or costimulatory molecules were generated and tested in tumor-bearing mice. While several of these reagents were initially shown to have therapeutic value, combination therapies with methods to delete suppressor cells had the greatest effect on tumor growth. In conclusion, a key conclusion that has emerged from these studies is that successful immunotherapy will require both advanced methods of immunostimulation and the removal of immunosuppression in the host.

Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors

PubMed Central

Lechner, Melissa G; Russell, Sarah M; Bass, Rikki S; Epstein, Alan L

2011-01-01

In this article, the role of chemokines and costimulatory molecules in the immunotherapy of experimental murine solid tumors and immunotherapy used in ongoing clinical trials are presented. Chemokine networks regulate physiologic cell migration that may be disrupted to inhibit antitumor immune responses or coopted to promote tumor growth and metastasis in cancer. Recent studies highlight the potential use of chemokines in cancer immunotherapy to improve innate and adaptive cell interactions and to recruit immune effector cells into the tumor microenvironment. Another critical component of antitumor immune responses is antigen priming and activation of effector cells. Reciprocal expression and binding of costimulatory molecules and their ligands by antigen-presenting cells and naive lymphocytes ensures robust expansion, activity and survival of tumor-specific effector cells in vivo. Immunotherapy approaches using agonist antibodies or fusion proteins of immunomodulatory molecules significantly inhibit tumor growth and boost cell-mediated immunity. To localize immune stimulation to the tumor site, a series of fusion proteins consisting of a tumor-targeting monoclonal antibody directed against tumor necrosis and chemokines or costimulatory molecules were generated and tested in tumor-bearing mice. While several of these reagents were initially shown to have therapeutic value, combination therapies with methods to delete suppressor cells had the greatest effect on tumor growth. In conclusion, a key conclusion that has emerged from these studies is that successful immunotherapy will require both advanced methods of immunostimulation and the removal of immunosuppression in the host. PMID:22053884

Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma.

PubMed

Kroesen, Michiel; Büll, Christian; Gielen, Paul R; Brok, Ingrid C; Armandari, Inna; Wassink, Melissa; Looman, Maaike W G; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

2016-06-01

Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and decreasing the number and function of myeloid-derived suppressor cells (MDSC). Collectively, these data imply further testing of other epigenetic modulators with immunotherapy and provide a strong basis for clinical testing of anti-GD2 plus Vorinostat combination therapy in NBL patients.

New targeted therapies in pancreatic cancer.

PubMed

Seicean, Andrada; Petrusel, Livia; Seicean, Radu

2015-05-28

Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways.

Anti-amyloid beta to tau - based immunization: Developments in immunotherapy for Alzheimer disease.

PubMed

Lambracht-Washington, Doris; Rosenberg, Roger N

2013-08-01

Immunotherapy might provide an effective treatment for Alzheimer disease (AD). A unique feature of AD immunotherapies is that an immune response against a self antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focussed on two possible targets in this regard: One is the inhibition of accumulation and deposition of Amyloid beta 1-42 (Aβ42), which is one of the major peptides found in senile plaques and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations) is already in several stages of clinical trials, tau based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phoshorylated tau was found, high interest has again focussed on further development of tau based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. And last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects as these two pathologies are likely synergistic; an approach which has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, present on overview on halted, ongoing and upcoming clinical trials together with ongoing preclinical studies targeting tau or Aβ42.

Enhancing dendritic cell immunotherapy for melanoma using a simple mathematical model.

PubMed

Castillo-Montiel, E; Chimal-Eguía, J C; Tello, J Ignacio; Piñon-Zaráte, G; Herrera-Enríquez, M; Castell-Rodríguez, A E

2015-06-09

The immunotherapy using dendritic cells (DCs) against different varieties of cancer is an approach that has been previously explored which induces a specific immune response. This work presents a mathematical model of DCs immunotherapy for melanoma in mice based on work by Experimental Immunotherapy Laboratory of the Medicine Faculty in the Universidad Autonoma de Mexico (UNAM). The model is a five delay differential equation (DDEs) which represents a simplified view of the immunotherapy mechanisms. The mathematical model takes into account the interactions between tumor cells, dendritic cells, naive cytotoxic T lymphocytes cells (inactivated cytotoxic cells), effector cells (cytotoxic T activated cytotoxic cells) and transforming growth factor β cytokine (T G F-β). The model is validated comparing the computer simulation results with biological trial results of the immunotherapy developed by the research group of UNAM. The results of the growth of tumor cells obtained by the control immunotherapy simulation show a similar amount of tumor cell population than the biological data of the control immunotherapy. Moreover, comparing the increase of tumor cells obtained from the immunotherapy simulation and the biological data of the immunotherapy applied by the UNAM researchers obtained errors of approximately 10 %. This allowed us to use the model as a framework to test hypothetical treatments. The numerical simulations suggest that by using more doses of DCs and changing the infusion time, the tumor growth decays compared with the current immunotherapy. In addition, a local sensitivity analysis is performed; the results show that the delay in time " τ", the maximal growth rate of tumor "r" and the maximal efficiency of tumor cytotoxic cells rate "aT" are the most sensitive model parameters. By using this mathematical model it is possible to simulate the growth of the tumor cells with or without immunotherapy using the infusion protocol of the UNAM researchers, to obtain a good approximation of the biological trials data. It is worth mentioning that by manipulating the different parameters of the model the effectiveness of the immunotherapy may increase. This last suggests that different protocols could be implemented by the Immunotherapy Laboratory of UNAM in order to improve their results.

Immunotherapy targets metastatic breast cancer–cell mutations

Cancer.gov

A novel approach to immunotherapy developed by NCI researchers led to the complete regression of breast cancer in a patient who was unresponsive to all other treatments. The findings were published in Nature Medicine.

DNA-based immunotherapy for HPV-associated head and neck cancer.

PubMed

Aggarwal, Charu

2016-10-01

Squamous cell carcinoma of the head and neck (SCCHN) accounts for 3% of all cancers. Most patients present with locally advanced disease, where multimodality therapies are used with curative intent. Despite favorable early local treatment results, about one third of the patients will eventually develop metastatic disease. Immunotherapy offers a novel therapeutic strategy beyond cytotoxic chemotherapy, with initial approvals in melanoma and non-small-cell lung cancer. HPV-associated SCCHN is a distinct subset, with unique epidemiology and treatment outcomes. Both subsets of SCCHN (HPV-related or not) are particularly favorable for immunotherapy, as immune evasion and dysregulation have been shown to play a key role in the initiation and progression of disease. This review focuses on the latest developments in immunotherapy in SCCHN, with a particular focus on DNA-based approaches including vaccine and adoptive cellular therapies.

Melanoma immunotherapy: historical precedents, recent successes and future prospects.

PubMed

Raaijmakers, Marieke I G; Rozati, Sima; Goldinger, Simone M; Widmer, Daniel S; Dummer, Reinhard; Levesque, Mitchell P

2013-02-01

The idea of cancer immunotherapy has been around for more than a century; however, the first immunotherapeutic ipilimumab, an anti-CTLA-4 antibody, has only recently been approved by the US FDA for melanoma. With an increasing understanding of the immune response, it is expected that more therapies will follow. This review aims to provide a general overview of immunotherapy in melanoma. We first explain the development of cancer immunotherapy more than a century ago and the general opinions about it over time. This is followed by a general overview of the immune reaction in order to give insight into the possible targets for therapy. Finally, we will discuss the current therapies for melanoma, their shortcomings and why it is important to develop patient stratification criteria. We conclude with an overview of recent discoveries and possible future therapies.

Potentiality of immunotherapy against hepatocellular carcinoma

PubMed Central

Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

2015-01-01

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future. PMID:26420958

Potentiality of immunotherapy against hepatocellular carcinoma.

PubMed

Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Uemura, Yasushi; Nakatsura, Tetsuya

2015-09-28

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the new-found field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future.

Safety of Accelerated Schedules of Subcutaneous Allergen Immunotherapy with House Dust Mite Extract in Patients with Atopic Dermatitis

PubMed Central

Kim, Myoung-Eun; Kim, Jeong-Eun; Sung, Joon-Mo; Lee, Jin-Woo; Choi, Gil-Soon

2011-01-01

The safety of accelerated schedules of allergen immunotherapy (ASAI) in patients with bronchial asthma (BA) has been reported but there are little data on the safety of ASAI for patients with atopic dermatitis (AD). In this study, we investigated the safety of ASAI in patients with AD. Sixty patients with AD and 18 patients with BA sensitized to house dust mites (HDM) were studied. A maximum maintenance dose of HDM extract, adsorbed to aluminum hydroxide, was administered to patients by subcutaneous injection with either a 3-day protocol (rush immunotherapy) or 1-day protocol (ultra-rush immunotherapy). Systemic reactions were observed 4 of 15 patients (26.7%) with AD during rush immunotherapy, 13 of 45 patients (28.9%) with AD during ultra-rush immunotherapy, and 4 of 18 patients (22.2%) with BA during rush immunotherapy (P > 0.05). No severe or near fatal systemic reactions occurred in 78 subjects of this study. Systemic reactions developed within 4 hr after administration of the maximum allergen dose in 20 of 21 patients (95.2%) with AD and BA who showed systemic reactions during rush or ultra-rush immunotherapy. In conclusion, ASAI was safe and well tolerated in patients with AD. ASAI can be a useful therapeutic option for AD. PMID:21935270

Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

NASA Astrophysics Data System (ADS)

Li, Xiaosong; Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Nordquist, Robert E.; Chen, Wei R.

2011-02-01

Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

Genetic modification of T cells improves the effectiveness of adoptive tumor immunotherapy.

PubMed

Jakóbisiak, Marek; Gołab, Jakub

2010-10-01

Appropriate combinations of immunotherapy and gene therapy promise to be more effective in the treatment of cancer patients than either of these therapeutic approaches alone. One such treatment is based on the application of patients' cytotoxic T cells, which can be activated, expanded, and genetically engineered to recognize particular tumor-associated antigens (TAAs). Because T cells recognizing TAAs might become unresponsive in the process of tumor development as a result of tumor evasion strategies, immunogenic viral antigens or alloantigens could be used for the expansion of cytotoxic T cells and then redirected through genetic engineering. This therapeutic approach has already demonstrated promising results in melanoma patients and could be used in the treatment of many other tumors. The graft-versus-leukemia, or more generally graft-versus-tumor, reaction based on the application of a donor lymphocyte infusion can also be ameliorated through the incorporation of suicide genes into donor lymphocytes. Such lymphocytes could be safely and more extensively used in tumor patients because they could be eliminated should a severe graft-versus-host reaction develop.

Combination Therapy with a Second-Generation Androgen Receptor Antagonist and a Metastasis Vaccine Improves Survival in a Spontaneous Prostate Cancer Model

PubMed Central

Ardiani, Andressa; Farsaci, Benedetto; Rogers, Connie J.; Protter, Andy; Guo, Zhimin; King, Thomas H.; Apelian, David; Hodge, James W.

2013-01-01

Purpose Enzalutamide, a second-generation androgen antagonist, was approved by the FDA for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study is performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment. Experimental Design Male C57BL/6 or TRAMP prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiological and immunological effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was evaluated. Finally, the combination of enzalutamide and Twist-vaccine to improve TRAMP mice overall survival was evaluated. Results Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4+ T-cell proliferation and Treg functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the Twist-vaccine’s ability to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared to other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors. Conclusions These data support the combination of enzalutamide and immunotherapy as a promising treatment strategy for CRPC. PMID:24048332

Inhibition of p-STAT3 Enhances IFN-α Efficacy Against Metastatic Melanoma in a Murine Model

PubMed Central

Kong, Ling-Yuan; Gelbard, Alexander; Wei, Jun; Reina-Ortiz, Chantal; Wang, Yongtao; Yang, Eric C.; Hailemichael, Yared; Fokt, Izabela; Jayakumar, Arumugam; Qiao, Wei; Fuller, Gregory N.; Overwijk, Willem W.; Priebe, Waldemar; Heimberger, Amy B.

2010-01-01

Purpose Melanoma is a common and deadly tumor that upon metastasis to the central nervous system (CNS) has a median survival duration of less than 6 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. We hypothesized that WP1193, a novel inhibitor of STAT3 signaling, would enhance the anti-tumor activity of IFN-α against metastatic melanoma. Experimental Design Combinational therapy of STAT3 blockade agents with IFN-α was investigated in a metastatic and an established syngeneic intracerebral murine tumor model of melanoma. The immunological in vivo mechanisms of efficacy were investigated by T cell and NK cell cytotoxic assays. Results IFN-α immunotherapy was synergistic with WP1193 demonstrating marked in vivo efficacy against metastatic and established intracerebral melanoma. At autopsy, it was noted that there was a decreased trend in mice with melanoma developing leptomeningeal disease (LMD) treated with combinational therapy. The combinational approach enhanced both NK and T cell-mediated anti-tumor cytotoxicity. Conclusions The immune modulatory effects of STAT3 blockade can enhance the therapeutic efficacy of IFN-α immunotherapy by enhancing both innate and adaptive cytotoxic T cell activities. This combination therapy has the potential in the treatment of metastatic melanoma that is typically refractory to this type of immune therapeutic approach. PMID:20388845

Strategies for individualizing management of patients with metastatic melanoma: a managed care perspective.

PubMed

Goldstein, Daniel A; Zeichner, Simon B

2015-09-01

The management of metastatic melanoma has been revolutionized in recent years with the development of both targeted therapy and immunotherapy. Although potentially extending the life expectancy for patients, these therapies also significantly increase the healthcare expenditure. In this paper, we review the monthly costs for drugs approved by the FDA since 2011. Additionally, factors that affect the cost, such as dosing strategies, biomarkers, combination therapies, and political/legislative issues, will be discussed.

Basis for molecular diagnostics and immunotherapy for esophageal cancer.

PubMed

Abdo, Joe; Agrawal, Devendra K; Mittal, Sumeet K

2017-01-01

Esophageal cancer (EC) is an extremely aggressive neoplasm, diagnosed in about 17,000 Americans every year with a mortality rate of more than 80% within five years and a median overall survival of just 13 months. For decades, the go-to regimen for esophageal cancer patients has been the use of taxane and platinum-based chemotherapy regimens, which has yielded the field's most dire survival statistics. Areas covered: Combination immunotherapy and a more robust molecular diagnostic platform for esophageal tumors could improve patient management strategies and potentially extend lives beyond the current survival figures. Analyzing a panel of biomarkers including those affiliated with taxane and platinum resistance (ERCC1 and TUBB3) as well as immunotherapy effectiveness (PD-L1) would provide oncologists more information on how to optimize first-line therapy for EC. Expert commentary: Of the 12 FDA-approved therapies in EC, zero target the genome. A majority of the approved drugs either target or are effected by proteomic expression. Therefore, a broader understanding of diagnostic biomarkers could give more clarity and direction in treating esophageal cancer in concert with a greater use of immunotherapy.

IL-2 and Beyond in Cancer Immunotherapy.

PubMed

Wrangle, John M; Patterson, Alicia; Johnson, C Bryce; Neitzke, Daniel J; Mehrotra, Shikhar; Denlinger, Chadrick E; Paulos, Chrystal M; Li, Zihai; Cole, David J; Rubinstein, Mark P

2018-02-01

The development of the T- and natural killer (NK) cell growth factor IL-2 has been a sentinel force ushering in the era of immunotherapy in cancer. With the advent of clinical grade recombinant IL-2 in the mid-1980s, oncologists could for the first time directly manipulate lymphocyte populations with systemic therapy. By itself, recombinant IL-2 can induce clinical responses in up to 15% of patients with metastatic cancer or renal cell carcinoma. When administered with adoptively transferred tumor-reactive lymphocytes, IL-2 promotes T cell engraftment and response rates of up to 50% in metastatic melanoma patients. Importantly, these IL-2-driven responses can yield complete and durable responses in a subset of patients. However, the use of IL-2 is limited by toxicity and concern of the expansion of T regulatory cells. To overcome these limitations and improve response rates, other T cell growth factors, including IL-15 and modified forms of IL-2, are in clinical development. Administering T cell growth factors in combination with other agents, such as immune checkpoint pathway inhibitors, may also improve efficacy. In this study, we review the development of T- and NK cell growth factors and highlight current combinatorial approaches based on these reagents.

Novel in silico technology in combination with microarrays: a state-of-the-art technology for allergy diagnosis and management?

PubMed

Melioli, Giovanni; Passalacqua, Giovanni; Canonica, Giorgio W

2014-12-01

'Allergen microarrays, in poly-sensitized allergic patients, represent a real value added in the accurate IgE profiling and in the identification of allergen(s) to administer for an effective allergen immunotherapy.' Allergen microarrays (AMA) were developed in the early 2000s to improve the diagnostic pathway of patients with allergic reactions. Nowadays, AMA are constituted by more than 100 different components (either purified or recombinant), representing genuine and cross-reacting molecules from plants and animals. The cost of the procedure had suggested its use as third-level diagnostics (following in vivo- and in vitro-specific IgE tests) in poly-sensitized patients. The complexity of the interpretation had inspired the development of in silico technologies to help clinicians in their work. Both machine learning techniques and expert systems are now available. In particular, an expert system that has been recently developed not only identifies positive and negative components but also lists dangerous components and classifies patients based on their potential responsiveness to allergen immunotherapy, on the basis of published algorithms. For these characteristics, AMA represents the state-of-the-art technology for allergy diagnosis in poly-sensitized patients.

Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.

PubMed

Cirone, Pasquale; Bourgeois, Jacqueline M; Shen, Feng; Chang, Patricia L

2004-10-01

An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated.

Post-exposure treatment of Ebola virus using passive immunotherapy: proposal for a new strategy.

PubMed

Chippaux, Jean-Philippe; Boyer, Leslie V; Alagón, Alejandro

2015-01-01

Better treatments are urgently needed for the management of Ebola virus epidemics in Equatorial Africa. We conducted a systematic review of the literature on the use of passive immunotherapy for the treatment or prevention of Ebola virus disease. We placed findings from this review into the context of passive immunotherapy currently used for venom-induced disease, and recent improvements in manufacturing of polyvalent antivenom products. Passive immunotherapy appears to be one of the most promising specific treatments for Ebola. However, its potential has been incompletely evaluated, considering the overall experience and recent improvement of immunotherapy. Development and use of heterologous serum derivatives could protect people exposed to Ebola viruses with reasonable cost and logistics. Hyperimmune equine IgG fragments and purified polyclonal whole IgG deserve further consideration as treatment for exposure to the Ebola virus.

Engineering nanoparticle strategies for effective cancer immunotherapy.

PubMed

Yoon, Hong Yeol; Selvan, Subramanian Tamil; Yang, Yoosoo; Kim, Min Ju; Yi, Dong Kee; Kwon, Ick Chan; Kim, Kwangmeyung

2018-03-21

Cancer immunotherapy has been emerging in recent years, due to the inherent nature of the immune system. Although recent successes of immunotherapeutics in clinical application have attracted development of a novel immunotherapeutics, the off-target side effect and low immunogenicity of them remain challenges for the effective cancer immunotherapy. Theranostic nanoparticle system may one of key technology to address these issues by offering targeted delivery of various types of immunotherapeutics, resulting in significant improvements in the tumor immunotherapy. However, appropriate design or engineering of nanoparticles will be needed to improve delivery efficiency of antigen, adjuvant and therapeutics, resulting in eliciting antitumor immunity. Here, we review the current state of the art of cancer immunotherapeutic strategies, mainly based on nanoparticles (NPs). This includes NP-based antigen/adjuvant delivery vehicles to draining lymph nodes, and tumor antigen-specific T-lymphocytes for cancer immunotherapy. Several NP-based examples are shown for immune checkpoint modulation and immunogenic cell death. These overall studies demonstrate the great potential of NPs in cancer immunotherapy. Finally, engineering NP strategies will provide great opportunities to improve therapeutic effects as well as optimization of treatment processes, allowing to meet the individual needs in the cancer immunotherapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Immunotherapy of allergic contact dermatitis.

PubMed

Spiewak, Radoslaw

2011-08-01

The term 'immunotherapy' refers to treating diseases by inducing, enhancing or suppressing immune responses. As allergy is an excessive, detrimental immune reaction to otherwise harmless environmental substances, immunotherapy of allergic disease is aimed at the induction of tolerance toward sensitizing antigens. This article focuses on the historical developments, present state and future outlook for immunotherapy with haptens as a therapeutic modality for allergic contact dermatitis. Inspired by the effectiveness of immunotherapy in respiratory allergies, attempts were undertaken at curing allergic contact dermatitis by means of controlled administration of the sensitizing haptens. Animal and human experiments confirmed that tolerance to haptens can be induced most effectively when the induction of tolerance precedes attempted sensitization. In real life, however, therapy is sought by people who are already sensitized and an effective reversal of hypersensitivity seems more difficult to achieve. Decades of research on Rhus hypersensitivity led to a conclusion that immunotherapy can suppress Rhus dermatitis, however, only to a limited degree, for a short period of time, and at a high risk of side effects, which makes this method therapeutically unprofitable. Methodological problems with most available studies of immunotherapy of contact allergy to nickel make any definite conclusions impossible at this stage.

Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic)

PubMed Central

Ishii, Kazusa; Barrett, Austin J.

2016-01-01

There have been major advances in our understanding of the multiple interactions between malignant cells and the innate and adaptive immune system. While the attention of immunologists has hitherto focused on solid tumors, the specific immunobiology of acute leukemias is now becoming defined. These discoveries have pointed the way to immune interventions building on the established graft-versus-leukemia (GVL) effect from hematopoietic stem-cell transplant (HSCT) and extending immunotherapy beyond HSCT to individuals with acute leukemia with a diversity of immune manipulations early in the course of the leukemia. At present, clinical results are in their infancy. In the coming years larger studies will better define the place of immunotherapy in the management of acute leukemias and lead to treatment approaches that combine conventional chemotherapy, immunotherapy and HSCT to achieve durable cures. PMID:26834952

The interplay of immunotherapy and chemotherapy: harnessing potential synergies.

PubMed

Emens, Leisha A; Middleton, Gary

2015-05-01

Although cancer chemotherapy has historically been considered immune suppressive, it is now accepted that certain chemotherapies can augment tumor immunity. The recent success of immune checkpoint inhibitors has renewed interest in immunotherapies, and in combining them with chemotherapy to achieve additive or synergistic clinical activity. Two major ways that chemotherapy promotes tumor immunity are by inducing immunogenic cell death as part of its intended therapeutic effect and by disrupting strategies that tumors use to evade immune recognition. This second strategy, in particular, is dependent on the drug, its dose, and the schedule of chemotherapy administration in relation to antigen exposure or release. In this Cancer Immunology at the Crossroads article, we focus on cancer vaccines and immune checkpoint blockade as a forum for reviewing preclinical and clinical data demonstrating the interplay between immunotherapy and chemotherapy. ©2015 American Association for Cancer Research.

Cancer immunotherapy in children

Cancer.gov

More often than not, cancer immunotherapies that work in adults are used in modified ways in children. Seldom are new therapies developed just for children, primarily because of the small number of pediatric patients relative to the adult cancer patient

State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous.

PubMed

Jones, Stacie M; Burks, A Wesley; Dupont, Christophe

2014-02-01

IgE-mediated food allergy is a global health problem that affects millions of persons and affects every aspect of life for the patient. Developing effective treatment strategies to augment current practice standards of strict dietary avoidance of antigens and availability of self-injectable epinephrine has been a major focus of research teams, advocacy groups, funding agencies, and patients and their families. Significant progress has been made through the development of allergen-specific immunotherapy encompassing 3 major forms of treatment: oral, sublingual, and epicutaneous immunotherapy. These therapies are in various stages of clinical investigation, with some successes noted in clinical outcomes and modulation of immune mechanisms toward effective therapy. Here we review recent progress and areas of concern for the role of these forms of immunotherapy as an emerging treatment for food allergy. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Development of Halo Nevi in a Lung Cancer Patient: A Novel Immune-Related Cutaneous Event from Atezolizumab.

PubMed

Birnbaum, Mathew R; Ma, Michelle W; Casey, Michael A; Amin, Bijal D; Jacobson, Mark; Cheng, Haiying; McLellan, Beth N

2017-10-01

Immunotherapy-induced vitiligo is an immune-related adverse event (irAE) observed in metastatic melanoma patients treated with immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) pathways. To date, the development of leukoderma, poliosis, and halo nevi during immunotherapy has largely been reported in metastatic melanoma patients. We report a case of immunotherapy-induced leukoderma presenting as halo nevi in a patient with non-small cell lung cancer (NSCLC) treated with atezolizumab, a programmed cell death ligand (PD-L1) antibody. Immunotherapy-induced vitiligo in metastatic melanoma patients may be associated with improved survival, but it remains to be determined whether its occurrence in non-melanoma cancers has the same prognostic significance.

J Drugs Dermatol. 2017;16(10):1047-1049.

A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now.

PubMed

Bellmunt, Joaquin; Powles, Thomas; Vogelzang, Nicholas J

2017-03-01

The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated. Several checkpoint targets (programmed death ligand-1 [PD-L1] programmed cell death protien-1 [PD-1], and cytotoxic T-lymphocyte associated protein 4 [CTLA4]) have received the most attention in the treatment of bladder cancer, and have inhibitor agents either approved or in late-stage development. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Atezolizumab is the only member of this class currently approved for the treatment of bladder cancer, but nivolumab, pembrolizumab, durvalumab, and avelumab all have positive results for this indication, and approvals are anticipated in the near future. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in immune system functioning. Copyright © 2017 Elsevier Ltd. All rights reserved.

Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN–JDRF Type 1 Diabetes Combination Therapy Assessment Group

PubMed Central

Matthews, J B; Staeva, T P; Bernstein, P L; Peakman, M; von Herrath, M

2010-01-01

Like many other complex human disorders of unknown aetiology, autoimmune-mediated type 1 diabetes may ultimately be controlled via a therapeutic approach that combines multiple agents, each with differing modes of action. The numerous advantages of such a strategy include the ability to minimize toxicities and realize synergies to enhance and prolong efficacy. The recognition that combinations might offer far-reaching benefits, at a time when few single agents have yet proved themselves in well-powered trials, represents a significant challenge to our ability to conceive and implement rational treatment designs. As a first step in this process, the Immune Tolerance Network, in collaboration with the Juvenile Diabetes Research Foundation, convened a Type 1 Diabetes Combination Therapy Assessment Group, the recommendations of which are discussed in this Perspective paper. PMID:20629979

Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice

PubMed Central

Hu, Zheng; Xia, Jinxing; Fan, Wei; Wargo, Jennifer; Yang, Yong-Guang

2016-01-01

A major factor hindering the exploration of adoptive immunotherapy in preclinical settings is the limited availability of tumor-reactive human T cells. Here we developed a humanized mouse model that permits large-scale production of human T cells expressing the engineered melanoma antigen MART-1-specific TCR. Humanized mice, made by transplantation of human fetal thymic tissue and CD34+ cells virally-transduced with HLA class I-restricted melanoma antigen (MART-1)-specific TCR gene, showed efficient development of MART-1-TCR+ human T cells with predominantly CD8+ cells. Importantly, MART-1-TCR+CD8+ T cells developing in these mice were capable of mounting antigen-specific responses in vivo, as evidenced by their proliferation, phenotypic conversion and IFN-γ production following MART-1 peptide immunization. Moreover, these MART-1-TCR+CD8+ T cells mediated efficient killing of melanoma cells in an HLA/antigen-dependent manner. Adoptive transfer of in vitro expanded MART-1-TCR+CD8+ T cells induced potent antitumor responses that were further enhanced by IL-15 treatment in melanoma-bearing recipients. Finally, a short incubation of MART-1-specific T cells with rapamycin acted synergistically with IL-15, leading to significantly improved tumor-free survival in recipients with metastatic melanoma. These data demonstrate the practicality of using humanized mice to produce potentially unlimited source of tumor-specific human T cells for experimental and preclinical exploration of cancer immunotherapy. This study also suggests that pretreatment of tumor-reactive T cells with rapamycin in combination with IL-15 administration may be a novel strategy to improve the efficacy of adoptive T cell therapy. PMID:26824989

A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer.

PubMed

Dijkgraaf, Eveline M; Santegoets, Saskia J A M; Reyners, An K L; Goedemans, Renske; Nijman, Hans W; van Poelgeest, Mariëtte I E; van Erkel, Arien R; Smit, Vincent T H B M; Daemen, Toos A H H; van der Hoeven, Jacobus J M; Melief, Cornelis J M; Welters, Marij J P; Kroep, Judith R; van der Burg, Sjoerd H

2015-10-13

Preclinical tumor models show that chemotherapy has immune modulatory properties which can be exploited in the context of immunotherapy. The purpose of this study was to determine the feasibility and immunogenicity of combinations of such an immunomodulatory chemotherapeutic agent with immunotherapy, p53 synthetic long peptide (SLP) vaccine and Pegintron (IFN-α) in patients with platinum-resistant p53-positive epithelial ovarian cancer (EOC). This is a phase 1/2 trial in which patients sequential 6 cycles of gemcitabine (1000 mg/kg2 iv; n = 3), gemcitabine with Pegintron before and after the first gemcitabine cycle (Pegintron 1 μg/kg sc; n = 6), and gemcitabine and Pegintron combined with p53 SLP vaccine (0.3 mg/peptide, 9 peptides; n = 6). At baseline, 22 days after the 2nd and 6th cycle, blood was collected for immunomonitoring. Toxicity, CA-125, and radiologic response were evaluated after 3 and 6 cycles of chemotherapy. None of the patients enrolled experienced dose-limiting toxicity. Predominant grade 3/4 toxicities were nausea/vomiting and dyspnea. Grade 1/2 toxicities consisted of fatigue (78%) and Pegintron-related flu-like symptoms (72%). Gemcitabine reduced myeloid-derived suppressor cells (p = 0.0005) and increased immune-supportive M1 macrophages (p = 0.04). Combination of gemcitabine and Pegintron stimulated higher frequencies of circulating proliferating CD4+ and CD8+ T-cells but not regulatory T-cells. All vaccinated patients showed strong vaccine-induced p53-specific T-cell responses. Combination of gemcitabine, the immune modulator Pegintron and therapeutic peptide vaccination is a viable approach in the development of combined chemo-immunotherapeutic regimens to treat cancer.

Colorectal cancer vaccines: antiidiotypic antibody, recombinant protein, and viral vector.

PubMed

Basak, S; Eck, S; Gutzmer, R; Smith, A J; Birebent, B; Purev, E; Staib, L; Somasundaram, R; Zaloudik, J; Li, W; Jacob, L; Mitchell, E; Speicher, D; Herlyn, D

2000-06-01

The colorectal cancer antigen GA733 (also termed CO17-1A, KSI-4, Ep-CAM, KSA) has proved to be a useful target in passive immunotherapy with monoclonal antibody and in active immunotherapy with antiidiotypic antibodies in cancer patients. The GA733 antigen was molecularly cloned and expressed in baculovirus (BV), adenovirus (AV), and vaccinia virus (VV). Recombinant BV-, VV-, and AV-GA733 induced antigen-specific cytotoxic antibodies and proliferative and delayed-type hypersensitive lymphocytes. However, only the AV recombinant induced antigen-specific cytolytic T lymphocytes and regression of established tumors. Cured mice were protected against challenge with antigen-negative tumors, indicating antigen spreading of immune responses. In a model of active immunotherapy against the murine homologue of the human GA733 antigen, murine epithelial glycoprotein (mEGP), BV-derived mEGP protein in various adjuvants did not protect mice against a challenge with mEGP-positive tumors. AV mEGP, only when combined with interleukin-2, significantly inhibited growth of established mEGP-positive tumors. This is in contrast to the same vaccine expressing the human antigen that was effective without interleukin-2. AV GA733, in combination with interleukin-2, is a candidate vaccine for colorectal cancer patients.

Pseudoprogression in microsatellite instability-high colorectal cancer during treatment with combination T cell mediated immunotherapy: a case report and literature review

PubMed Central

Chae, Young Kwang; Wang, Si; Nimeiri, Halla; Kalyan, Aparna; Giles, Francis J.

2017-01-01

Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden. Tumor regression was subsequently observed and patient has remained in stable disease. Despite the substantial radiological progression, the symptomatic improvement reported by the patient led us to the decision of treatment continuation based on the suspicion of pseudoprogression, illustrating the importance of clinical evaluation in medical decision making while managing patients on immunotherapy. Additionally, the patient's MSI-high status contributes to his good, maintained response to PD-L1 blockade. Our case provides a frame of reference for fluctuation in tumor burden associated with pseudoprogression. Here we also evaluate the incidence and scale of pseudoprogression across solid tumor types. PMID:28915720

Immunotherapy for Prostate Cancer: Where Do We Go From Here?-PART 2: Checkpoint Inhibitors, Immunotherapy Combinations, Tumor Microenvironment Modulation, and Cellular Therapies.

PubMed

Patel, Amar; Fong, Lawrence

2018-06-15

Therapeutic approaches that harness the power of the immune system to eliminate cancer cells have produced a paradigm shift in the management of a variety of malignancies. Prostate cancer has been a particularly active area of investigation in cancer immunotherapy, with significant laboratory and clinical evidence suggesting that this disease can be a viable target for cytotoxic immune cells. In the first article of this series, we discussed the diverse vaccination approaches that have been employed to prime native antigen-specific responses against prostate cancer, highlighting successes such as sipuleucel-T, as well as the significant challenges that remain. Here we focus on alternative methods of harnessing both adaptive and innate antitumor immunity to target prostate cancer cells. Approaches that enhance the activation of T cells, modulation of the tumor microenvironment to abrogate its inherent immunosuppressive mechanisms, and engineering of antigen-specific antibody and cellular products to target tumor cells will be discussed. We will then look ahead to provide a perspective on how this growing collection of immunotherapeutic approaches may ultimately be combined to target prostate cancer from a variety of angles.

Immunotherapies: Exploiting the Immune System for Cancer Treatment

PubMed Central

Cato, Caleb; Geiger, Joseph; Henry, Denise; Hernandez, Jennifer; Kaur, Preet; Teskey, Garrett; Tran, Andrew

2018-01-01

Cancer is a condition that has plagued humanity for thousands of years, with the first depictions dating back to ancient Egyptian times. However, not until recent decades have biological therapeutics been developed and refined enough to safely and effectively combat cancer. Three unique immunotherapies have gained traction in recent decades: adoptive T cell transfer, checkpoint inhibitors, and bivalent antibodies. Each has led to clinically approved therapies, as well as to therapies in preclinical and ongoing clinical trials. In this review, we outline the method by which these 3 immunotherapies function as well as any major immunotherapeutic drugs developed for treating a variety of cancers. PMID:29725606

Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells.

PubMed

Klampatsa, Astero; Achkova, Daniela Y; Davies, David M; Parente-Pereira, Ana C; Woodman, Natalie; Rosekilly, James; Osborne, Georgina; Thayaparan, Thivyan; Bille, Andrea; Sheaf, Michael; Spicer, James F; King, Juliet; Maher, John

2017-05-01

Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4 + T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma. Copyright © 2017 Elsevier B.V. All rights reserved.

IgE-based Immunotherapy of Cancer -A Comparative Oncology Approach

PubMed Central

Singer, Josef; Jensen-Jarolim, Erika

2014-01-01

Antibody-based immunotherapies are important therapy options in human oncology. Although human humoral specific immunity is constituted of five different immunoglobulin classes, currently only IgG-based immunotherapies have proceeded to clinical application. This review, however, discusses the benefits and difficulties of IgE-based immunotherapy of cancer, with special emphasis on how to translate promising preclinical results into clinical studies. Pursuing the “Comparative Oncology” approach, novel drug candidates are investigated in clinical trials with veterinary cancer patients, most often dogs. By this strategy drug development could be speeded up, animal experiments could be reduced and novel therapy options could be introduced benefitting humans as well as man’s best friend. PMID:25264496

Immunotherapy in prostate cancer: challenges and opportunities.

PubMed

Noguchi, Masanori; Koga, Noriko; Moriya, Fukuko; Itoh, Kyogo

2016-01-01

Although treatment options for castration-resistant prostate cancer (CRPC) have increased over the last decade, there remains a need for strategies that can provide durable disease control and long-term benefit. Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of CRPC. To date, there are multiple strategies to target the immune system, and several approaches including therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in clinical trials. With regard to this, we report the results of the most recent clinical trials investigating immunotherapy in CRPC and discuss the future development of immunotherapy for CRPC, as well as the potential importance of biomarkers in the future progress of this field.

Therapeutic vaccines for substance dependence.

PubMed

Kosten, Thomas R; Biegel, Diane

2002-10-01

Several immunotherapies are under development for nicotine, cocaine and phencyclidine and a cocaine vaccine has started human trials. These therapies promise a new approach to diseases that have had limited treatment success and tremendous morbidity. Both the cocaine and nicotine addiction immunotherapies have reduced 'relapse' to drug use in animal model systems. To date, the active cocaine vaccine has few side effects and induces considerable antibody titers after active immunization in humans. Studies with the monoclonal phencyclidine immunotherapy provide intriguing evidence of sustained protection for months after single-dose administration. Other immunotherapy may include treatment of drug overdose, prevention of brain or cardiac toxicity and protection of a fetus during pregnancy in a drug abuser.

Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study

PubMed Central

Chen, Dian-Jun; Li, Xiao-Song; Zhao, Hui; Fu, Yan; Kang, Huan-Rong; Yao, Fang-Fang; Hu, Jia; Qi, Nan; Zhang, Huan-Huan; Du, Nan; Chen, Wei-R

2017-01-01

The present study aimed to evaluate the efficacy and safety of in situ immunotherapy with dinitrophenyl (DNP) hapten in combination with laser therapy for patients with malignant melanoma (MM). Between February 2008 and March 2012, 72 patients with stage III or IV MM were enrolled. Patients received in situ DNP alone (n=32) or in combination with laser therapy (n=32), and each group received dacarbazine chemotherapy. The levels of peripheral cluster of differentiation (CD)4+CD25+ regulatory T cells (Tregs), interleukin (IL)-10 and tumor growth factor (TGF)-β were detected by ELISA. The association between delayed-type hypersensitivity (DTH) and survival time was evaluated. Although peripheral Treg levels significantly decreased over time in the two groups (P<0.001), there was no significant difference between the treatment groups (P=0.098). Patients receiving the combination treatment exhibited significantly higher interferon-γ production by CD8+ and CD4+ T cells (both P<0.001), as well as significantly reduced levels of IL-10, TGF-β1 and TGF-β2. In addition, patients in the combination treatment group experienced significantly longer overall survival (OS; P=0.024) and disease-free survival (DFS; P=0.007) times; a DTH response of ≥15 mm was also associated with increased OS time and DFS time (P≤0.001). Finally, no severe adverse events were observed in either treatment group. Overall, in situ immunization with DNP in combination with laser immunotherapy may activate focal T cells, producing a regional antitumor immune response that increases cell-mediated immunity and improves survival in MM patients. Thus, this may represent a novel therapeutic strategy for patients with unresectable, advanced MM. PMID:28454272

Dinitrophenyl hapten with laser immunotherapy for advanced malignant melanoma: A clinical study.

PubMed

Chen, Dian-Jun; Li, Xiao-Song; Zhao, Hui; Fu, Yan; Kang, Huan-Rong; Yao, Fang-Fang; Hu, Jia; Qi, Nan; Zhang, Huan-Huan; Du, Nan; Chen, Wei-R

2017-03-01

The present study aimed to evaluate the efficacy and safety of in situ immunotherapy with dinitrophenyl (DNP) hapten in combination with laser therapy for patients with malignant melanoma (MM). Between February 2008 and March 2012, 72 patients with stage III or IV MM were enrolled. Patients received in situ DNP alone (n=32) or in combination with laser therapy (n=32), and each group received dacarbazine chemotherapy. The levels of peripheral cluster of differentiation (CD)4 + CD25 + regulatory T cells (Tregs), interleukin (IL)-10 and tumor growth factor (TGF)-β were detected by ELISA. The association between delayed-type hypersensitivity (DTH) and survival time was evaluated. Although peripheral Treg levels significantly decreased over time in the two groups (P<0.001), there was no significant difference between the treatment groups (P=0.098). Patients receiving the combination treatment exhibited significantly higher interferon-γ production by CD8 + and CD4 + T cells (both P<0.001), as well as significantly reduced levels of IL-10, TGF-β1 and TGF-β2. In addition, patients in the combination treatment group experienced significantly longer overall survival (OS; P=0.024) and disease-free survival (DFS; P=0.007) times; a DTH response of ≥15 mm was also associated with increased OS time and DFS time (P≤0.001). Finally, no severe adverse events were observed in either treatment group. Overall, in situ immunization with DNP in combination with laser immunotherapy may activate focal T cells, producing a regional antitumor immune response that increases cell-mediated immunity and improves survival in MM patients. Thus, this may represent a novel therapeutic strategy for patients with unresectable, advanced MM.

Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update.

PubMed

Nagai, Hiroki; Muto, Manabu

2018-06-01

Over the last two decades, molecular-targeted agents have become mainstream treatment for many types of malignancies and have improved the overall survival of patients. However, most patients eventually develop resistance to these targeted therapies. Recently, immunotherapies such as immune checkpoint inhibitors have revolutionized the treatment paradigm for many types of malignancies. Immune checkpoint inhibitors have been approved for treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, bladder cancer and gastric cancer. However, oncologists have been faced with immune-related adverse events caused by immune checkpoint inhibitors; these are generally mild but can be fatal in some cases. Because immune checkpoint inhibitors have distinct toxicity profiles from those of chemotherapy or targeted therapy, many oncologists are not familiar with the principles for optimal management of immune-related adverse events, which require early recognition and appropriate treatment without delay. To achieve this, oncologists must educate patients and health-care workers, develop checklists of appropriate tests for immune-related adverse events and collaborate closely with organ specialists. Clinical questions that remain include whether immune checkpoint inhibitors should be administered to patients with autoimmune disease and whether patients for whom immune-related adverse events lead to delays in immunotherapy should be retreated. In addition, the predicted use of combination immunotherapies in the near future means that oncologists will face a higher incidence and severity of immune-related adverse events. This review provides an overview of the optimal management of immune-related adverse events attributed to immune checkpoint inhibitors.

Oncology meets immunology: the cancer-immunity cycle.

PubMed

Chen, Daniel S; Mellman, Ira

2013-07-25

The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

Inhibitors of the PD-1 Pathway in Tumor Therapy

PubMed Central

LaFleur, Martin W.; Muroyama, Yuki; Drake, Charles G.; Sharpe, Arlene H.

2018-01-01

The programmed death 1 (PD-1) pathway delivers inhibitory signals that function as a brake for immune responses. This pathway limits the initiation and duration of immune responses, thereby protecting tissues from immune-mediated damage and autoimmune diseases. However, the PD-1 pathway also inhibits immune responses to tumors. The critical role of PD-1 in preventing antitumor immunity is demonstrated by the transformative effects of PD-1 pathway blockade in a broad range of cancers with the hallmark of durability of response. Despite this success, most patients do not respond to PD-1 monotherapy, and some patients experience adverse events. In this review, we discuss the functions of the PD-1 pathway and its translation to cancer immunotherapy. We also consider current challenges and opportunities for PD-1 cancer immunotherapy, including mechanisms of response and resistance, identification of biomarkers of response to PD-1 therapy, characterization and treatment of PD-1 therapy–related adverse events, and development of safe and effective combination therapies. PMID:29311378

[Immunotherapies for drug addictions].

PubMed

Montoya, Ivan

2008-01-01

Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders.

Inmunoterapias para las adicciones a las drogas Immunotherapies for Drug Addictions

PubMed Central

Montoya, Iván D.

2008-01-01

Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders. PMID:18551223

Novel approaches and perspectives in allergen immunotherapy.

PubMed

Hoffmann, H J; Valovirta, E; Pfaar, O; Moingeon, P; Schmid, J M; Skaarup, S H; Cardell, L-O; Simonsen, K; Larché, M; Durham, S R; Sørensen, P

2017-07-01

In this review, we report on relevant current topics in allergen immunotherapy (AIT) which were broadly discussed during the first Aarhus Immunotherapy Symposium (Aarhus, Denmark) in December 2015 by leading clinicians, scientists and industry representatives in the field. The aim of this symposium was to highlight AIT-related aspects of public health, clinical efficacy evaluation, mechanisms, development of new biomarkers and an overview of novel therapeutic approaches. Allergy is a public health issue of high socioeconomic relevance, and development of evidence-based action plans to address allergy as a public health issue ought to be on national and regional agendas. The underlying mechanisms are in the focus of current research that lays the ground for innovative therapies. Standardization and harmonization of clinical endpoints in AIT trials as well as current knowledge about potential biomarkers have substantiated proof of effectiveness of this disease-modifying therapeutic option. Novel treatments such as peptide immunotherapy, intralymphatic immunotherapy and use of recombinant allergens herald a new age in which AIT may address treatment of allergy as a public health issue by reaching a large fraction of patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immunotherapy for the treatment of drug abuse.

PubMed

Kosten, Thomas; Owens, S Michael

2005-10-01

Antibody therapy (as either active or passive immunization) is designed primarily to prevent drugs of abuse from entering the central nervous system (CNS). Antidrug antibodies reduce rush, euphoria, and drug distribution to the brain at doses that exceed the apparent binding capacity of the antibody. This is accomplished through a pharmacokinetic antagonism, which reduces the amount of drug in the brain, the rate of clearance across the blood-brain barrier, and the volume of drug distribution. Because the antibodies remain primarily in the circulatory system, they have no apparent central nervous system side effects. Active immunization with drug-protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with 1 cocaine and 3 nicotine vaccines in Phase 2 human trials. Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine (PCP) in preclinical animal models. Antibodies have 2 immediate clinical applications in drug abuse treatment: to treat drug overdose and to reduce relapse to drug use in addicted patients. The specificity of the therapies, the lack of addiction liability, minimal side effects, and long-lasting protection against drug use offer major therapeutic benefit over conventional small molecule agonists and antagonists. Immunotherapies can also be combined with other antiaddiction medications and enhance behavioral therapies. Current immunotherapies already show efficacy, but improved antigen design and antibody engineering promise highly specific and rapidly developed treatments for both existing and future addictions.

[Adoptive Cell Therapy with Immune Checkpoint Blockade].

PubMed

Aruga, Atsushi

2017-09-01

Cancer immunotherapy are taking a leading role of cancer therapy due to the development of the immune checkpoint blockade. To date, however, only about 20% of patients have clinical responses and the cancer-specific T cells in cancer site are required to obtain beneficial effects. There has been an innovative development in the field of adoptive cell therapy, especially receptor gene-modified T cells in recent years. The effector cells mostly express PD-1, therefore the cytotoxic reactivity of the effector cells are inhibited by PD-L1. The combination of the adoptive cell therapy and the immune checkpoint blockade is expected to enhance efficacy. On the other hand, the immune-related adverse events may also be enhanced, therefore, it is needed to develop the combination therapy carefully, improving the cancer antigen-specificity or dealing with the cytokine release syndrome.

Recent advances in T-cell immunotherapy for haematological malignancies.

PubMed

Rouce, Rayne H; Sharma, Sandhya; Huynh, Mai; Heslop, Helen E

2017-03-01

In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds. © 2016 John Wiley & Sons Ltd.

Prospects for TIM3-Targeted Antitumor Immunotherapy.

PubMed

Ngiow, Shin Foong; Teng, Michele W L; Smyth, Mark J

2011-11-01

New insights into the control of T-cell activation and proliferation have led to the identification of checkpoint proteins that either up- or downmodulate T-cell reactivity. Monoclonal antibody immunotherapies that are reactive with cytotoxic T lymphocyte antigen 4 or programmed death receptor 1 have shown promising therapeutic outcomes in mice and humans with established cancer, highlighting the fact that cancer immunotherapy using T-cell checkpoint inhibitors is one of the most promising new therapeutic approaches. T-cell immunoglobulin and mucin domain 3 (TIM3) is one of many similar inhibitory molecules that are gaining attention as targets, but it remains relatively poorly studied in oncology. This review discusses our recent probing of the mechanism of action of anti-TIM3 antibody against established spontaneous and experimental tumors in mice, in the context of the exciting possibility of rationally combining agents that promote tumor-specific T-cell activation, proliferation, effector function, and survival. ©2011 AACR.

Cancer immunotherapy-targeted glypican-3 or neoantigens.

PubMed

Shimizu, Yasuhiro; Suzuki, Toshihiro; Yoshikawa, Toshiaki; Tsuchiya, Nobuhiro; Sawada, Yu; Endo, Itaru; Nakatsura, Tetsuya

2018-03-01

Immune checkpoint inhibitors have ushered in a new era in cancer therapy, although other therapies or combinations thereof are still needed for many patients for whom these drugs are ineffective. In this light, we have identified glypican-3 an HLA-24, HLA-A2 restriction peptide with extreme cancer specificity. In this paper, we summarize results from a number of related clinical trials showing that glypican-3 peptide vaccines induce specific CTLs in most patients (UMIN Clinical Trials Registry: UMIN000001395, UMIN000005093, UMIN000002614, UMN000003696, and UMIN000006357). We also describe the current state of personalized cancer immunotherapy based on neoantigens, and assess, based on our own research and experience, the potential of such therapy to elicit cancer regression. Finally, we discuss the future direction of cancer immunotherapy. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Lymphoma immunotherapy: vaccines, adoptive cell transfer and immunotransplant

PubMed Central

Brody, Joshua; Levy, Ronald

2017-01-01

Therapy for non-Hodgkin lymphoma has benefited greatly from basic science and clinical research such that chemotherapy and monoclonal antibody therapy have changed some lymphoma subtypes from uniformly lethal to curable, but the majority of lymphoma patients remain incurable. Novel therapies with less toxicity and more specific targeting of tumor cells are needed and immunotherapy is among the most promising of these. Recently completed randomized trials of idiotype vaccines and earlier-phase trials of other vaccine types have shown the ability to induce antitumor T cells and some clinical responses. More recently, trials of adoptive transfer of antitumor T cells have demonstrated techniques to increase the persistence and antitumor effect of these cells. Herein, we discuss lymphoma immunotherapy clinical trial results and what lessons can be taken to improve their effect, including the combination of vaccination and adoptive transfer in an approach we have dubbed ‘immunotransplant’. PMID:20636025

Immunotherapy Response Assessment in Neuro-Oncology (iRANO): A Report of the RANO Working Group

PubMed Central

Okada, Hideho; Weller, Michael; Huang, Raymond; Finocchiaro, Gaetano; Gilbert, Mark R.; Wick, Wolfgang; Ellingson, Benjamin M.; Hashimoto, Naoya; Pollack, Ian F.; Brandes, Alba A.; Franceschi, Enrico; Herold-Mende, Christel; Nayak, Lakshmi; Panigrahy, Ashok; Pope, Whitney B.; Prins, Robert; Sampson, John H.; Wen, Patrick Y.; Reardon, David A.

2015-01-01

Immunotherapy represents a promising area of therapy among neuro-oncology patients. However, early phase studies reveal unique challenges associated with assessment of radiological changes reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumor regression, can still occur following initial apparent progression or appearance of new lesions. Refinement of response assessment criteria for neuro-oncology patients undergoing immunotherapy is therefore warranted. A multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describes immunotherapy response assessment for neuro-oncology (iRANO) criteria that are based on guidance for determination of tumor progression outlined by the immune-related response criteria (irRC) and the response assessment in neuro-oncology (RANO) working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease (PD) within six months of initiating immunotherapy including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for use of corticosteroids. The role of advanced imaging techniques and measurement of clinical benefit endpoints including neurologic and immunologic functions are reviewed. The iRANO guidelines put forth herein will evolve successively to improve their utility as further experience from immunotherapy trials in neuro-oncology accumulate. PMID:26545842

Cancer Immunotherapy and Personalized Medicine: Emerging Technologies and Biomarker-Based Approaches.

PubMed

Maciejko, Laura; Smalley, Munisha; Goldman, Aaron

2017-09-01

The vision and strategy for the 21st century treatment of cancer calls for a personalized approach in which therapy selection is designed for each individual patient. While genomics has led the field of personalized cancer medicine over the past several decades by connecting patient-specific DNA mutations with kinase-targeted drugs, the recent discovery that tumors evade immune surveillance has created unique challenges to personalize cancer immunotherapy. In this mini-review we will discuss how personalized medicine has evolved recently to accommodate the emerging era of cancer immunotherapy. Moreover, we will discuss novel platform technologies that have been engineered to address some of the persisting limitations. Beginning with early evidence in personalized medicine, we discuss how biomarker-driven approaches to predict clinical success have evolved to account for the heterogeneous tumor ecosystem. In the emerging field of cancer immunotherapy, this challenge requires the use of a novel set of tools, distinct from the classic approach of next-generation genomic sequencing-based strategies. We will introduce new techniques that seek to tailor immunotherapy by re-programming patient-autologous T-cells, and new technologies that are emerging to predict clinical efficacy by mapping infiltration of lymphocytes, and harnessing fully humanized platforms that reconstruct and interrogate immune checkpoint blockade, ex-vivo . While cancer immunotherapy is now leading to durable outcomes in difficult-to-treat cancers, success is highly variable. Developing novel approaches to study cancer immunotherapy, personalize treatment to each patient, and achieve greater outcomes is penultimate to developing sustainable cures in the future. Numerous techniques are now emerging to help guide treatment decisions, which go beyond simple biomarker-driven strategies, and are now we are seeking to interrogate the entirety of the dynamic tumor ecosystem.

The research status of immune checkpoint blockade by anti-CTLA4 and anti-PD1/PD-l1 antibodies in tumor immunotherapy in China: A bibliometrics study.

PubMed

Zhao, Xiaoqin; He, Liangmei; Mao, Kaiyun; Chen, Daming; Jiang, Hongbo; Liu, Zhiping

2018-04-01

Using bibliometrics, we analyzed the research status of immune checkpoint blockade (ICB, a popular tumor immunotherapy method represented by antibodies targeted CTLA-4 and PD-1/PD-L1) in tumor immunotherapy in China during the past 2 decades. Articles in Science Citation Index Expanded (SCI-EXPANDED), patents in Thomson Innovation, and drugs in Cortellis Competitive Intelligence in the field of ICB for tumor immunotherapy from 1996 to 2015 were the subjects of bibliometric analysis. Using database-attached software and Excel, quantitative analyses were performed including examination of the number of documents, citation frequency, h-index, key projects, quantity of publications, public patents, and status of new drug research. The number of publications from 1996 to 2015 in the field of ICB for tumor immunotherapy that came out of China was 380, which was 14.3% of the total publications worldwide and was second only to that of the USA. In the past decade, China has rapidly increased the number of publications and patents in this field. However, indicators of publication influence, such as citation frequency and h-index, were far behind other advanced countries. In addition, the total number of patents in China was much lower than that of the USA. China has introduced 5 drugs for ICB that are being developed for the healthcare market. Tumor immunotherapy research such as ICB in China has developed rapidly with increasing influence in the last 2 decades. However, there is still a relatively large gap compared with the USA. It is expected that China will have greater influence on tumor immunotherapy research in the near future.

The research status of immune checkpoint blockade by anti-CTLA4 and anti-PD1/PD-l1 antibodies in tumor immunotherapy in China

PubMed Central

Zhao, Xiaoqin; He, Liangmei; Mao, Kaiyun; Chen, Daming; Jiang, Hongbo; Liu, Zhiping

2018-01-01

Abstract Purpose: Using bibliometrics, we analyzed the research status of immune checkpoint blockade (ICB, a popular tumor immunotherapy method represented by antibodies targeted CTLA-4 and PD-1/PD-L1) in tumor immunotherapy in China during the past 2 decades. Methods: Articles in Science Citation Index Expanded (SCI-EXPANDED), patents in Thomson Innovation, and drugs in Cortellis Competitive Intelligence in the field of ICB for tumor immunotherapy from 1996 to 2015 were the subjects of bibliometric analysis. Using database-attached software and Excel, quantitative analyses were performed including examination of the number of documents, citation frequency, h-index, key projects, quantity of publications, public patents, and status of new drug research. Results: The number of publications from 1996 to 2015 in the field of ICB for tumor immunotherapy that came out of China was 380, which was 14.3% of the total publications worldwide and was second only to that of the USA. In the past decade, China has rapidly increased the number of publications and patents in this field. However, indicators of publication influence, such as citation frequency and h-index, were far behind other advanced countries. In addition, the total number of patents in China was much lower than that of the USA. China has introduced 5 drugs for ICB that are being developed for the healthcare market. Conclusion: Tumor immunotherapy research such as ICB in China has developed rapidly with increasing influence in the last 2 decades. However, there is still a relatively large gap compared with the USA. It is expected that China will have greater influence on tumor immunotherapy research in the near future. PMID:29642147

Adoptive Immunotherapy with T Lymphocytes Engineered for Enhanced Survival | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the NCI have developed a method of genetically engineering lymphocytes to expressed elevated levels of cytokine proteins. This technology is useful for improving cellular adoptive immunotherapies to treat a range of infectious diseases and cancers.

Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma

PubMed Central

Kroesen, Michiel; Büll, Christian; Gielen, Paul R.; Brok, Ingrid C.; Armandari, Inna; Wassink, Melissa; Looman, Maaike W. G.; Boon, Louis; den Brok, Martijn H.; Hoogerbrugge, Peter M.; Adema, Gosse J.

2016-01-01

ABSTRACT Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical efficacy in high-risk NBL patients. Targeted therapy using histone deacetylase inhibitors (HDACi) is currently being explored in cancer treatment and already shows promising results. Using our recently developed transplantable TH-MYCN NBL model, we here report that the HDAC inhibitor Vorinostat synergizes with anti-GD2 mAb therapy in reducing NBL tumor growth. Further mechanistic studies uncovered multiple mechanisms for the observed synergy, including Vorinostat-induced specific NBL cell death and upregulation of the tumor antigen GD2 on the cell surface of surviving NBL cells. Moreover, Vorinostat created a permissive tumor microenvironment (TME) for tumor-directed mAb therapy by increasing macrophage effector cells expressing high levels of Fc-receptors (FcR) and decreasing the number and function of myeloid-derived suppressor cells (MDSC). Collectively, these data imply further testing of other epigenetic modulators with immunotherapy and provide a strong basis for clinical testing of anti-GD2 plus Vorinostat combination therapy in NBL patients. PMID:27471639

Critical features and challenges associated with imaging in patients undergoing cancer immunotherapy.

PubMed

Solinas, Cinzia; Porcu, Michele; Hlavata, Zuzana; De Silva, Pushpamali; Puzzoni, Marco; Willard-Gallo, Karen; Scartozzi, Mario; Saba, Luca

2017-12-01

Manipulating an individual's immune system through immune checkpoint blockade is revolutionizing the paradigms of cancer treatment. Peculiar patterns and kinetics of response have been observed with these new drugs, rendering the assessment of tumor burden particularly challenging in cancer immunotherapy. The mechanisms of action for immune checkpoint blockade, based upon engagement of the adaptive immune system, can generate unusual response patterns, including pseudoprogression, hyperprogression, atypical and delayed responses. In patients treated with immune checkpoint blockade and radiotherapy, a reduction in tumor burden at metastatic sites distant from the irradiation field (abscopal effect) has been observed, with synergistic systemic immune effects provoked by this combination. New toxicities have also been observed, due to excessive immune activity in several organs, including lung, colon, liver and endocrine glands. Efforts to standardize assessment of cancer immunotherapy responses include novel consensus guidelines derived by modifying World Health Organization (WHO) and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. The aim of this review is to evaluate imaging techniques currently used routinely in the clinic and those being used as investigational tools in immunotherapy clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies.

PubMed

Marciscano, Ariel E; Madan, Ravi A

2018-03-08

Bacillus Calmette-Guérin in urothelial carcinoma, high-dose interleukin-2 in renal cell carcinoma, and sipuleucel-T in prostate cancer serve as enduring examples that the host immune response can be harnessed to promote effective anti-tumor immunity in genitourinary malignancies. Recently, cancer immunotherapy with immune checkpoint inhibitors has transformed the prognostic landscape leading to durable responses in a subset of urothelial carcinoma and renal cell carcinoma patients with traditionally poor prognosis. Despite this success, many patients fail to respond to immune checkpoint inhibitors and progression/relapse remains common. Furthermore, modest clinical activity has been observed with ICIs as a monotherapy in advanced PCa. As such, novel treatment approaches are warranted and improved biomarkers for patient selection and treatment response are desperately needed. Future efforts should focus on exploring synergistic and rational combinations that safely and effectively boost response rates and survival in genitourinary malignancies. Specific areas of interest include (1) evaluating the optimal sequencing, disease burden, and timing of immuno-oncology agents with other anti-cancer therapeutics and (2) validating novel biomarkers of response to immunotherapy to optimize patient selection and to identify individuals most likely to benefit from immunotherapy across the heterogenous spectrum of genitourinary malignancies.

Immunotherapy for high-grade glioma.

PubMed

Dixit, Sanjay

2014-05-01

4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Oncology, San Francisco, CA, USA, 21-24 November 2013. Aside from temozolomide, there has been no major breakthrough for decades to improve outcome for high-grade glioma. Bevacizumab failed to show a survival advantage in two large studies - AVaglio and RTOG-0825 - and no other novel chemotherapy agents seem to be appearing on the horizon for this universally fatal disease. Consequently, the neuro-oncology fraternity is turning to immunotherapy. This became apparent in this meeting, considering a number of delegates focused their attention to presentations on immunotherapy. The ReACT study demonstrated the safety and efficacy of the combination of a promising peptide vaccine, rindopepimut, and bevacizumab with longer survival seen in patients with a higher antibody titer. Several presentations reassured that dendritic cell-based immunotherapy is safe and can generate a lasting immune response. Employing gene therapy, increased intratumor 5-fluorouracil chemotherapy concentration can be achieved using TOCA 511, and temozolomide-resistant transgenic lymphocytes could be produced through retroviral coding. Blocking immune checkpoints PDL-01, CTLA-4 and indoleamine 2,3-dioxygenase through monoclonal antibodies appears promising.

Basis for molecular diagnostics and immunotherapy for esophageal cancer

PubMed Central

Abdo, Joe; Agrawal, Devendra K.; Mittal, Sumeet K.

2017-01-01

Introduction Esophageal cancer is an extremely aggressive neoplasm, diagnosed in about 17,000 Americans every year with a mortality rate of more than 80% within five years and a median overall survival of just 13 months. For decades, the go-to regimen for esophageal cancer patients has been the use of taxane and platinum-based chemotherapy regimens, which has yielded the field’s most dire survival statistics. Areas covered Combination immunotherapy and a more robust molecular diagnostic platform for esophageal tumors could improve patient management strategies and potentially extend lives beyond the current survival figures. Analyzing a panel of biomarkers including those affiliated with taxane and platinum resistance (ERCC1 and TUBB3) as well as immunotherapy effectiveness (PD-L1) would provide oncologists more information on how to optimize first-line therapy for esophageal cancer. Expert commentary Of the 12 FDA-approved therapies in esophageal cancer, zero target the genome. A majority of the approved drugs either target or are effected by proteomic expression. Therefore, a broader understanding of diagnostic biomarkers could give more clarity and direction in treating esophageal cancer in concert with a greater use of immunotherapy. PMID:27838937

TNF-α and Tumor Lysate Promote the Maturation of Dendritic Cells for Immunotherapy for Advanced Malignant Bone and Soft Tissue Tumors

PubMed Central

Miwa, Shinji; Nishida, Hideji; Tanzawa, Yoshikazu; Takata, Munetomo; Takeuchi, Akihiko; Yamamoto, Norio; Shirai, Toshiharu; Hayashi, Katsuhiro; Kimura, Hiroaki; Igarashi, Kentaro; Mizukoshi, Eishiro; Nakamoto, Yasunari; Kaneko, Shuichi; Tsuchiya, Hiroyuki

2012-01-01

Background Dendritic cells (DCs) play a pivotal role in the immune system. There are many reports concerning DC-based immunotherapy. The differentiation and maturation of DCs is a critical part of DC-based immunotherapy. We investigated the differentiation and maturation of DCs in response to various stimuli. Methods Thirty-one patients with malignant bone and soft tissue tumors were enrolled in this study. All the patients had metastatic tumors and/or recurrent tumors. Peripheral blood mononuclear cells (PBMCs) were suspended in media containing interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF). These cells were then treated with or without 1) tumor lysate (TL), 2) TL + TNF-α, 3) OK-432. The generated DCs were mixed and injected in the inguinal or axillary region. Treatment courses were performed every week and repeated 6 times. A portion of the cells were analyzed by flow cytometry to determine the degree of differentiation and maturation of the DCs. Serum IFN-γ and serum IL-12 were measured in order to determine the immune response following the DC-based immunotherapy. Results Approximately 50% of PBMCs differentiated into DCs. Maturation of the lysate-pulsed DCs was slightly increased. Maturation of the TL/TNF-α-pulsed DCs was increased, commensurate with OK-432-pulsed DCs. Serum IFN-γ and serum IL-12 showed significant elevation at one and three months after DC-based immunotherapy. Conclusions Although TL-pulsed DCs exhibit tumor specific immunity, TL-pulsed cells showed low levels of maturation. Conversely, the TL/TNF-α-pulsed DCs showed remarkable maturation. The combination of IL-4/GM-CSF/TL/TNF-α resulted in the greatest differentiation and maturation for DC-based immunotherapy for patients with bone and soft tissue tumors. PMID:23300824

Current update of adoptive immunotherapy using cytokine-induced killer cells to eliminate malignant gliomas.

PubMed

Ryu, Je Il; Han, Myung Hoon; Cheong, Jin Hwan; Kim, Jae Min; Kim, Choong Hyun

2017-03-01

The therapeutic outcome for those with malignant glioma is poor, even though diverse therapeutic modalities have been developed. Immunotherapy has emerged as a therapeutic approach for malignant gliomas, making it possible to selectively treat tumors while sparing normal tissue. Here, we review clinical trials of adoptive immunotherapy approaches for malignant gliomas. We also describe a clinical trial that examined the efficacy and safety of autologous cytokine-induced killer (CIK) cells along with concomitant chemoradiotherapy for newly diagnosed glioblastoma. These CIK cells identify and kill autologous tumor cells. This review focuses on the use of adoptive immunotherapy for malignant gliomas and reviews the current literature on the concept of antitumor activity mediated by CIK cells.

Sublingual immunotherapy for allergic rhinitis: where are we now?

PubMed

Incorvaia, Cristoforo; Mauro, Marina; Ridolo, Erminia

2015-01-01

Sublingual immunotherapy (SLIT) was introduced in the 1980s as a safer option to subcutaneous immunotherapy and in the latest decade achieved significant advances. Its efficacy in allergic rhinitis is supported by a number of meta-analyses. The development of SLIT preparations in tablets to fulfill the requirements of regulatory agencies for quality of allergen extracts made available optimal products for grass-pollen-induced allergic rhinitis. Preparations of other allergens based on the same production methods are currently in progress. A notable outcome of SLIT, that is shared with subcutaneous immunotherapy, is the evident cost-effectiveness, showing significant cost savings as early as 3 months from starting the treatment, that become as high as 80% compared with drug treatment in the ensuing years.

Immunotherapy for high-grade glioma: how to go beyond Phase I/II clinical trials.

PubMed

van Gool, Stefaan

2013-10-01

Evaluation of: Lasky JL 3rd, Panosyan EH, Plant A et al. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 33, 2047-2056 (2013). Immunotherapy for children and adults with high-grade glioma (HGG) is an emerging innovative treatment approach, which aims at stimulating the body's own immune system against HGG by using autologous dendritic cells pulsed with autologous tumor lysate as a therapeutic vaccine. This is the third report on immunotherapy for HGG in children, bringing additional knowledge and experience to the scientific community. However, at the same time, this and other manuscripts urge for the next step in treatment development.

Engineering nanoparticles to overcome barriers to immunotherapy

PubMed Central

Toy, Randall

2016-01-01

Abstract Advances in immunotherapy have led to the development of a variety of promising therapeutics, including small molecules, proteins and peptides, monoclonal antibodies, and cellular therapies. Despite this wealth of new therapeutics, the efficacy of immunotherapy has been limited by challenges in targeted delivery and controlled release, that is, spatial and temporal control on delivery. Particulate carriers, especially nanoparticles have been widely studied in drug delivery and vaccine research and are being increasingly investigated as vehicles to deliver immunotherapies. Nanoparticle‐mediated drug delivery could provide several benefits, including control of biodistribution and transport kinetics, the potential for site‐specific targeting, immunogenicity, tracking capability using medical imaging, and multitherapeutic loading. There are also a unique set of challenges, which include nonspecific uptake by phagocytic cells, off‐target biodistribution, permeation through tissue (transport limitation), nonspecific immune‐activation, and poor control over intracellular localization. This review highlights the importance of understanding the relationship between a nanoparticle's size, shape, charge, ligand density and elasticity to its vascular transport, biodistribution, cellular internalization, and immunogenicity. For the design of an effective immunotherapy, we highlight the importance of selecting a nanoparticle's physical characteristics (e.g., size, shape, elasticity) and its surface functionalization (e.g., chemical or polymer modifications, targeting or tissue‐penetrating peptides) with consideration of its reactivity to the targeted microenvironment (e.g., targeted cell types, use of stimuli‐sensitive biomaterials, immunogenicity). Applications of this rational nanoparticle design process in vaccine development and cancer immunotherapy are discussed. PMID:29313006

New developments in allergen immunotherapy.

PubMed

Vadlamudi, Anusha; Shaker, Marcus

2015-10-01

Allergic rhinitis, conjunctivitis, and asthma impact quality of life and cost billions of dollars in lost wages, productivity, and medical expenditures. Allergen immunotherapy is the only therapy that alters the allergen immune response, resulting in fewer symptoms upon natural exposure. This review summarizes recent immunotherapy developments. Subcutaneous immunotherapy (SCIT) remains a disease modifying treatment for allergic rhinoconjunctivitis and asthma with rare complications of therapy. Recent evidence suggests that SCIT may be effective in select cases of atopic dermatitis, particularly for patients with dust mite sensitivity. Sublingual immunotherapy (SLIT) tablets are now commercially available for grass and ragweed allergy and appear to have a superior safety profile to SCIT with similar long-term effectiveness, because as with SCIT, symptom improvement persists after the SLIT course is completed. SLIT tablets are administered daily at home (after initial supervised dosing) and may be used shortly before and during the target pollen seasons in a precoseasonal fashion (instead of perennial dosing). Research continues into experimental approaches using oral food allergen immunotherapy (OIT) to modify the natural history of food allergies. Although a proportion of patients in OIT trials experience sustained unresponsiveness, many do not and current recommendations limit the use of OIT to research protocols. Patients have new well tolerated and effective options for more convenient treatment of asthma and allergic rhinoconjunctivitis associated with grass and ragweed allergy. SCIT remains effective for polysensitized patients and may be an option for some patients with atopic dermatitis. Research continues into novel food allergy treatments.

Oral and sublingual immunotherapy for egg allergy.

PubMed

Romantsik, Olga; Tosca, Maria Angela; Zappettini, Simona; Calevo, Maria Grazia

2018-04-20

Clinical egg allergy is a common food allergy. Current management relies upon strict allergen avoidance. Oral immunotherapy might be an optional treatment, through desensitization to egg allergen. To determine the efficacy and safety of oral and sublingual immunotherapy in children and adults with immunoglobulin E (IgE)-mediated egg allergy as compared to a placebo treatment or an avoidance strategy. We searched 13 databases for journal articles, conference proceedings, theses and trials registers using a combination of subject headings and text words (last search 31 March 2017). We included randomized controlled trials (RCTs) comparing oral immunotherapy or sublingual immunotherapy administered by any protocol with placebo or an elimination diet. Participants were children or adults with clinical egg allergy. We retrieved 97 studies from the electronic searches. We selected studies, extracted data and assessed the methodological quality. We attempted to contact the study investigators to obtain the unpublished data, wherever possible. We used the I² statistic to assess statistical heterogeneity. We estimated a pooled risk ratio (RR) with 95% confidence interval (CI) for each outcome using a Mantel-Haenzel fixed-effect model if statistical heterogeneity was low (I² value less than 50%). We rated the quality of evidence for all outcomes using GRADE. We included 10 RCTs that met our inclusion criteria, that involved a total of 439 children (oral immunotherapy 249; control intervention 190), aged 1 year to 18 years. Each study used a different oral immunotherapy protocol; none used sublingual immunotherapy. Three studies used placebo and seven used an egg avoidance diet as the control. Primary outcomes were: an increased amount of egg that can be ingested and tolerated without adverse events while receiving allergen-specific oral immunotherapy or sublingual immunotherapy, compared to control; and a complete recovery from egg allergy after completion of oral immunotherapy or sublingual immunotherapy, compared to control. Most children (82%) in the oral immunotherapy group could ingest a partial serving of egg (1 g to 7.5 g) compared to 10% of control group children (RR 7.48, 95% CI 4.91 to 11.38; RD 0.73, 95% CI 0.67 to 0.80). Fewer than half (45%) of children receiving oral immunotherapy were able to tolerate a full serving of egg compared to 10% of the control group (RR 4.25, 95% CI 2.77 to 6.53; RD 0.35, 95% CI 0.28 to 0.43). All 10 trials reported numbers of children with serious adverse events (SAEs) and numbers of children with mild-to-severe adverse events. SAEs requiring epinephrine/adrenaline presented in 21/249 (8.4%) of children in the oral immunotherapy group, and none in the control group. Mild-to-severe adverse events were frequent; 75% of children presented mild-to-severe adverse events during oral immunotherapy treatment versus 6.8% of the control group (RR 8.35, 95% CI 5.31 to 13.12). Of note, seven studies used an egg avoidance diet as the control. Adverse events occurred in 4.2% of children, which may relate to accidental ingestion of egg-containing food. Three studies used a placebo control with adverse events present in 2.6% of children. Overall, there was inconsistent methodological rigour in the trials. All studies enrolled small numbers of children and used different methods to provide oral immunotherapy. Eight included studies were judged to be at high risk of bias in at least one domain. Furthermore, the quality of evidence was judged to be low due to small numbers of participants and events, and possible biases. Frequent and increasing exposure to egg over one to two years in people who are allergic to egg builds tolerance, with almost everyone becoming more tolerant compared with a minority in the control group and almost half of people being totally tolerant of egg by the end of treatment compared with 1 in 10 people who avoid egg. However, nearly all who received treatment experienced adverse events, mainly allergy-related. We found that 1 in 12 children had serious allergic reactions requiring adrenaline, and some people gave up oral immunotherapy. It appears that oral immunotherapy for egg allergy is effective, but confidence in the trade-off between benefits and harms is low; because there was a small number of trials with few participants, and methodological problems with some trials.

Role of Antigen Spread and Distinctive Characteristics of Immunotherapy in Cancer Treatment.

PubMed

Gulley, James L; Madan, Ravi A; Pachynski, Russell; Mulders, Peter; Sheikh, Nadeem A; Trager, James; Drake, Charles G

2017-04-01

Immunotherapy is an important breakthrough in cancer. US Food and Drug Administration-approved immunotherapies for cancer treatment (including, but not limited to, sipuleucel-T, ipilimumab, nivolumab, pembrolizumab, and atezolizumab) substantially improve overall survival across multiple malignancies. One mechanism of action of these treatments is to induce an immune response against antigen-bearing tumor cells; the resultant cell death releases secondary (nontargeted) tumor antigens. Secondary antigens prime subsequent immune responses (antigen spread). Immunotherapy-induced antigen spread has been shown in clinical studies. For example, in metastatic castration-resistant prostate cancer patients, sipuleucel-T induced early immune responses to the immunizing antigen (PA2024) and/or the target antigen (prostatic acid phosphatase). Thereafter, most patients developed increased antibody responses to numerous secondary proteins, several of which are expressed in prostate cancer with functional relevance in cancer. The ipilimumab-induced antibody profile in melanoma patients shows that antigen spread also occurs with immune checkpoint blockade. In contrast to chemotherapy, immunotherapy often does not result in short-term changes in conventional disease progression end points (eg, progression-free survival, tumor size), which may be explained, in part, by the time taken for antigen spread to occur. Thus, immune-related response criteria need to be identified to better monitor the effectiveness of immunotherapy. As immunotherapy antitumor effects take time to evolve, immunotherapy in patients with less advanced cancer may have greater clinical benefit vs those with more advanced disease. This concept is supported by prostate cancer clinical studies with sipuleucel-T, PSA-TRICOM, and ipilimumab. We discuss antigen spread with cancer immunotherapy and its implications for clinical outcomes. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Han; Sonoda, Koh-Hei, E-mail: sonodak@med.kyushu-u.ac.jp; Hijioka, Kuniaki

2009-04-17

Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8{sup +} T cells reduced pathological preretinal NV,more » with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8{sup +} T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.« less

Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization.

PubMed

Zhang, Han; Sonoda, Koh-Hei; Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro

2009-04-17

Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8+ T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8+ T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

Immune checkpoint inhibitors for metastatic bladder cancer.

PubMed

Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

2018-03-01

Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies

PubMed Central

Barrett, David M.; Shestova, Olga; Hofmann, Ted J.; Perazzelli, Jessica; Klichinsky, Michael; Aikawa, Vania; Nazimuddin, Farzana; Kozlowski, Miroslaw; Scholler, John; Lacey, Simon F.; Melenhorst, Jan J.; Morrissette, Jennifer J.D.; Christian, David A.; Hunter, Christopher A.; Kalos, Michael; Porter, David L.; June, Carl H.; Grupp, Stephan A.

2016-01-01

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies PMID:27571406

Postdoctoral Fellow | Center for Cancer Research

Cancer.gov

The Laboratory of Tumor Immunology and Biology (LTIB) functions as a multidisciplinary and interdisciplinary translational research programmatic effort with the goal of developing novel immunotherapies for cancer. The LTIB strategic plan focuses on the development of novel immunotherapeutics for human cancer, not only as monotherapies, but more importantly, in combination with other immune-mediating modalities, and other conventional or experimental therapies, as part of an immuno-oncology programmatic effort. Within this effort are several research groups, a clinical trials group, and multiple collaborations with intramural and extramural scientific and clinical investigators and with investigators in the private sector. The program takes advantage of the uniqueness of the NCI intramural program in that it spans high-risk basic discovery research in immunology, genomics and tumor biology, through preclinical translational research, to paradigm-shifting clinical trials. Focus is placed on the design and development of novel "off-the-shelf" recombinant immunotherapeutics that can be used in clinical studies at numerous institutions. A major strength of the program is the rapid translation of preclinical studies to hypothesis-generating clinical trials. We are looking for postdoctoral fellows interested in learning immunology and immunotherapy, as well as those postdoctoral fellows with a background and/or interest in experimental pathology.  The position is available immediately. The appointment duration is up to 5 years. Stipends are commensurate with education and experience.

Treatment strategies for Aspergillus infections.

PubMed

Chiller, Tom M.; Stevens, David A.

2000-04-01

Infections caused by Aspergillus species consist of many different disease presentations, ranging from relatively benign asthma in atopic disease to life-threatening systemic invasive infections. The spectrum of disease manifestations is determined by a combination of genetic predisposition, host immune system defects, and virulence of the Aspergillus species. For the purposes of this discussion, we will address three principal entities: invasive aspergillosis, both primary and disseminated, pulmonary aspergilloma, and allergic bronchopulmonary aspergillosis. Amphotericin B is the standard of treatment for severe Aspergillus infections, despite the fact that mortality in these patients remains high. Alternative therapies such as combination regimens and itraconazole also have efficacy against Aspergillus infections. We discuss the role of current therapies, the potential role of drugs in development, and the results of ongoing research with combination and immunotherapies. Copyright 2000 Harcourt Publishers Ltd.

Recent advances and future of immunotherapy for glioblastoma.

PubMed

Kamran, Neha; Calinescu, Alexandra; Candolfi, Marianela; Chandran, Mayuri; Mineharu, Yohei; Asad, Antonela S; Koschmann, Carl; Nunez, Felipe J; Lowenstein, Pedro R; Castro, Maria G

2016-10-01

Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.

Cellular immunotherapy for malignant gliomas.

PubMed

Lin, Yi; Okada, Hideho

2016-10-01

Cancer immunotherapy has made much progress in recent years. Clinical trials evaluating a variety of immunotherapeutic approaches are underway in patients with malignant gliomas. Thanks to recent advancements in cell engineering technologies, infusion of ex vivo prepared immune cells have emerged as promising strategies of cancer immunotherapy. Herein, the authors review recent and current studies using cellular immunotherapies for malignant gliomas. Specifically, they cover the following areas: a) cellular vaccine approaches using tumor cell-based or dendritic cell (DC)-based vaccines, and b) adoptive cell transfer (ACT) approaches, including lymphokine-activated killer (LAK) cells, γδ T cells, tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR)-T cells and T-cell receptor (TCR) transduced T cells. While some of the recent studies have shown promising results, the ultimate success of cellular immunotherapy in brain tumor patients would require improvements in the following areas: 1) feasibility in producing cellular therapeutics; 2) identification and characterization of targetable antigens given the paucity and heterogeneity of tumor specific antigens; 3) the development of strategies to promote effector T-cell trafficking; 4) overcoming local and systemic immune suppression, and 5) proper interpretation of imaging data for brain tumor patients receiving immunotherapy.

Cellular immunotherapy for malignant gliomas

PubMed Central

Lin, Yi

2016-01-01

Introduction Cancer immunotherapy has made much progress in recent years. Clinical trials evaluating a variety of immunotherapeutic approaches are underway in patients with malignant gliomas. Thanks to recent advancements in cell engineering technologies, infusion of ex vivo prepared immune cells have emerged as promising strategies of cancer immunotherapy. Areas covered Herein, the authors review recent and current studies using cellular immunotherapies for malignant gliomas. Specifically, they cover the following areas: a) cellular vaccine approaches using tumor cell-based or dendritic cell (DC)-based vaccines, and b) adoptive cell transfer (ACT) approaches, including lymphokine-activated killer (LAK) cells, γδ T cells, tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR)-T cells and T-cell receptor (TCR) transduced T cells. Expert opinion While some of the recent studies have shown promising results, the ultimate success of cellular immunotherapy in brain tumor patients would require improvements in the following areas: 1) feasibility in producing cellular therapeutics; 2) identification and characterization of targetable antigens given the paucity and heterogeneity of tumor specific antigens; 3) the development of strategies to promote effector T-cell trafficking; 4) overcoming local and systemic immune suppression, and 5) proper interpretation of imaging data for brain tumor patients receiving immunotherapy. PMID:27434205

Implementation of immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC).

PubMed

Tsiara, Anna; Liontos, Michalis; Kaparelou, Maria; Zakopoulou, Roubini; Bamias, Aristotelis; Dimopoulos, Meletios-Athanasios

2018-04-01

Mechanisms of tumor immune surveillance and immune escape have been recently elucidated and led to the development of a new therapeutic field in oncology, that of immunotherapy. Immunotherapy aims to reactivate the immune system against cancer. Neoplasias like non-small cell lung cancer (NSCLC) are of particular interest and clinical studies with immunotherapeutic agents have shown significant survival benefit. Several agents have gained corresponding regulatory approvals. In particular, nivolumab, pembrolizumab and atezolizumab have been approved for second-line treatment of NSCLC, pembrolizumab is the only immune checkpoint inhibitor that has been approved in the first-line treatment and durvalumab is approved in the locally advanced disease. In this review, we aim to present the implementation of immunotherapy in the treatment of advanced NSCLC. We will discuss not only the approved regimens but also the future perspectives, the serious adverse events such as hyperprogression and the possible predictive markers that will aid the selection of the patients that will benefit from immunotherapy.

Implementation of immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC)

PubMed Central

Liontos, Michalis; Kaparelou, Maria; Zakopoulou, Roubini; Bamias, Aristotelis; Dimopoulos, Meletios-Athanasios

2018-01-01

Mechanisms of tumor immune surveillance and immune escape have been recently elucidated and led to the development of a new therapeutic field in oncology, that of immunotherapy. Immunotherapy aims to reactivate the immune system against cancer. Neoplasias like non-small cell lung cancer (NSCLC) are of particular interest and clinical studies with immunotherapeutic agents have shown significant survival benefit. Several agents have gained corresponding regulatory approvals. In particular, nivolumab, pembrolizumab and atezolizumab have been approved for second-line treatment of NSCLC, pembrolizumab is the only immune checkpoint inhibitor that has been approved in the first-line treatment and durvalumab is approved in the locally advanced disease. In this review, we aim to present the implementation of immunotherapy in the treatment of advanced NSCLC. We will discuss not only the approved regimens but also the future perspectives, the serious adverse events such as hyperprogression and the possible predictive markers that will aid the selection of the patients that will benefit from immunotherapy. PMID:29862233

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

PubMed

Bonomi, P D; Gandara, D; Hirsch, F R; Kerr, K M; Obasaju, C; Paz-Ares, L; Bellomo, C; Bradley, J D; Bunn, P A; Culligan, M; Jett, J R; Kim, E S; Langer, C J; Natale, R B; Novello, S; Pérol, M; Ramalingam, S S; Reck, M; Reynolds, C H; Smit, E F; Socinski, M A; Spigel, D R; Vansteenkiste, J F; Wakelee, H; Thatcher, N

2018-06-14

Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or anti-angiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results. Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥ 200) and/or gene copy numbers of EGFR (e.g., ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥ 10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with anti-angiogenic agents. Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or anti-angiogenic agents remain limited.

Reconceptualizing cancer immunotherapy based on plant production systems

PubMed Central

Hefferon, Kathleen

2017-01-01

Plants can be used as inexpensive and facile production platforms for vaccines and other biopharmaceuticals. More recently, plant-based biologics have expanded to include cancer immunotherapy agents. The following review describes the current state of the art for plant-derived strategies to prevent or reduce cancers. The review discusses avenues taken to prevent infection by oncogenic viruses, solid tumors and lymphomas. Strategies including cancer vaccines, monoclonal antibodies and virus nanoparticles are described, and examples are provided. The review ends with a discussion of the implications of plant-based cancer immunotherapy for developing countries. PMID:28884013

Adoptive Immunotherapy for Cancer or Viruses

PubMed Central

Maus, Marcela V.; Fraietta, Joseph A.; Levine, Bruce L.; Kalos, Michael; Zhao, Yangbing; June, Carl H.

2015-01-01

Adoptive immunotherapy, or the infusion of lymphocytes, is a promising approach for the treatment of cancer and certain chronic viral infections. The application of the principles of synthetic biology to enhance T cell function has resulted in substantial increases in clinical efficacy. The primary challenge to the field is to identify tumor-specific targets to avoid off-tissue, on-target toxicity. Given recent advances in efficacy in numerous pilot trials, the next steps in clinical development will require multicenter trials in order to establish adoptive immunotherapy as a mainstream technology. PMID:24423116

Altered Th17/Treg Ratio in Recurrent Miscarriage after Treatment with Paternal Lymphocytes and Vitamin D3: a Double-Blind Placebo-Controlled Study.

PubMed

Rafiee, Mitra; Gharagozloo, Marjan; Ghahiri, Ataollah; Mehrabian, Ferdous; Maracy, Mohammad R; Kouhpayeh, Shirin; Pieper, Ina Laura; Rezaei, Abbas

2015-12-01

Recurrent miscarriage (RM) affects 2-5% of pregnant women. Paternal lymphocyte immunotherapy is a common treatment for RM patients but the outcome has not been consistent. Therefore, combined therapy with other immunosuppressive drugs such as 1a, 25-dihydroxy-vitamin-D3 (vitamin D3) may improve the outcome. To investigate the effect of vitamin D3 on the balance of two essential T cells subsets, T helper (Th) 17 and T regulatory (Treg) cells, which contribute to the immune tolerance during pregnancy. The expression levels of CD4 and forkhead box protein 3 (FOXP3) in Treg cells, and the expression levels of CD4 and IL-17 in Th17 cells, were evaluated pre- and 3 months post-immunotherapy in RM patients treated with a combination of paternal lymphocytes and vitamin D3 compared with RM patients receiving lymphocyte immunotherapy alone. Vitamin D3 therapy decreased the frequency of Th17 cells in addition to reducing the Th17/Treg ratio in peripheral blood of RM patients compared with the control group (p<0.05). Considering that RM patients have a higher Th17/Treg ratio in peripheral blood, vitamin D3 may be a candidate therapeutic approach in this disease.

Clinical Development of Cell Therapies: Setting the Stage for Academic Success.

PubMed

Abou-El-Enein, M; Volk, H-D; Reinke, P

2017-01-01

Cellular therapies have potential to treat a wide range of diseases with autologous immunotherapies showing unprecedented therapeutic promise in clinical trials. Such therapies are mainly developed by academic researchers applying small-scale production, targeting rare and unmet medical needs. Here, we highlight the clinical translation of immunotherapy product in an academic setting, which may serve as a success model for early academic development of cell-based therapeutics. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Immunotherapy Expands Lung Cancer Treatment Options

Cancer.gov

Results from a large clinical trial show combining the immune checkpoint inhibitor pembrolizumab (Keytruda) with chemotherapy helped some patients with advanced cancer live longer. As this Cancer Currents post explains, the results will immediately affect patient care.

Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer

PubMed Central

Garcia, Patrick Vianna; Apolinário, Letícia Montanholi; Böckelmann, Petra Karla; Nunes, Iseu da Silva; Duran, Nelson; Fávaro, Wagner José

2015-01-01

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC. PMID:26191134

Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer.

PubMed

Garcia, Patrick Vianna; Apolinário, Letícia Montanholi; Böckelmann, Petra Karla; da Silva Nunes, Iseu; Duran, Nelson; Fávaro, Wagner José

2015-01-01

The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC.

EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy.

PubMed

Calderon, Moises A; Demoly, Pascal; Gerth van Wijk, Roy; Bousquet, Jean; Sheikh, Aziz; Frew, Anthony; Scadding, Glenis; Bachert, Claus; Malling, Hans J; Valenta, Rudolph; Bilo, Beatrice; Nieto, Antonio; Akdis, Cezmi; Just, Jocelyne; Vidal, Carmen; Varga, Eva M; Alvarez-Cuesta, Emilio; Bohle, Barbara; Bufe, Albrecht; Canonica, Walter G; Cardona, Victoria; Dahl, Ronald; Didier, Alain; Durham, Stephen R; Eng, Peter; Fernandez-Rivas, Montserrat; Jacobsen, Lars; Jutel, Marek; Kleine-Tebbe, Jörg; Klimek, Ludger; Lötvall, Jan; Moreno, Carmen; Mosges, Ralph; Muraro, Antonella; Niggemann, Bodo; Pajno, Giovanni; Passalacqua, Giovanni; Pfaar, Oliver; Rak, Sabina; Senna, Gianenrico; Senti, Gabriela; Valovirta, Erkka; van Hage, Marianne; Virchow, Johannes C; Wahn, Ulrich; Papadopoulos, Nikolaos

2012-10-30

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe's policy-makers to coordinate actions and improve individual and public health in allergy by:Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.

Immunotherapies for Hodgkin's lymphoma

PubMed Central

Kasamon, Yvette L.; Ambinder, Richard F.

2013-01-01

Multiple immune evasion strategies characterize the pathobiology of Hodgkin's lymphoma. These must be considered when developing and testing immunotherapeutic approaches for this disease. The clinical experience with adoptive immunotherapy of Epstein–Barr virus positive tumors, and with monoclonal antibodies directed against CD30, CD20, and other antigens, is herein reviewed. PMID:18023356

Cancer Immunotherapy Using Virus-like Particles | NCI Technology Transfer Center | TTC

Cancer.gov

A considerable effort has been devoted to identifying and targeting specific extracellular cancer markers using antibody based therapies. However, diminished access to new cancer cell surface markers has limited the development of corresponding antibodies. NCI Technology Transfer Center is seeking to license cancer immunotherapy using virus-like particles.

Anti-Aß immunotherapy in Alzheimer's disease; relevance of transgenic mouse studies to clinical trials

PubMed Central

Wilcock, Donna M.; Colton, Carol A.

2009-01-01

Therapeutic approaches to the treatment of Alzheimer's disease are focused primarily on the Aß peptide which aggregates to form amyloid deposits in the brain. The amyloid hypothesis states that amyloid is the precipitating factor that results in the other pathologies of Alzheimer's, namely neurofibrillary tangles and neurodegeneration, as well as the clinical dementia. One such therapy that has attracted significant attention is anti-Aß immunotherapy. First described in 1999, immunotherapy uses anti-Aß antibodies to lower brain amyloid levels. Active immunization, in which Aß is combined with an adjuvant to stimulate an immune response producing antibodies and passive immunization, in which antibodies are directly injected, were shown to lower brain amyloid levels and improve cognition in multiple transgenic mouse models. Mechanisms of action were studied in these mice and revealed a complex set of mechanisms that depended on the type of antibody used. When active immunization advanced to clinical trials a subset of patients developed meningoencephalitis; an event not predicted in mouse studies. However, it was suspected that a T-cell response due to the type of adjuvant used was the cause of the meningoencephalitis and studies in mice indicated alternative methods of vaccination. Passive immunization has also advanced to phase III clinical trials on the basis of successful transgenic mouse studies. Reports from the active immunization clinical trial indicated that, indeed, amyloid levels in brain were reduced. While APP transgenic mouse models are useful in studying amyloid pathology these mice do not generate significant tau pathology or neuron loss. Continued development of new mouse models that do generate all of these pathologies will be critical in more accurately testing therapeutics and predicting the clinical outcome of such therapeutics. PMID:19096156

Sipuleucel-T: Prototype for development of anti-tumor vaccines.

PubMed

Carballido, Estrella; Fishman, Mayer

2011-04-01

Prostate cancer immunotherapy officially debuted with the recent FDA approval of Sipuleucel-T. The novel trend of cancer immunotherapy relies on the identification of particular tumor-associated antigens, like prostatic acid phosphatase (PAP). Sipuleucel-T consists of autologous dendritic cells activated in vitro with recombinant fusion protein PA2024, PAP-linked to granulocyte-macrophage colony-stimulating factor. Sipuleucel-T represents a prototype for the development of cancer vaccines. Preclinical and clinical data as well as landmark studies for the existing narrow chemotherapy alternatives and early immunotherapy trials will be discussed. The pivotal trial demonstrated a 4.1-month difference of median survival, but with no effect on time to progression in asymptomatic or minimally symptomatic metastatic castrate-resistant patients. Several immunologic effects were observed in the treated population, including antibody and T cell-specific activity to P2024 and PAP. With all new therapies the extent of clinical and objective benefits versus encountered limitations should be evaluated. This review highlights the events and decisions in the process of the development of Sipuleucel-T. We discuss how this successful immunotherapy outcome challenges us to use it as a starting point for variations to or try to amplify practical anticancer progress within the antitumor vaccine paradigm.

Rush allergen specific immunotherapy protocol in feline atopic dermatitis: a pilot study of four cats.

PubMed

Trimmer, Ann M; Griffin, Craig E; Boord, Mona J; Rosenkrantz, Wayne S

2005-10-01

Rush immunotherapy has been shown to be as safe as conventional immunotherapy in canine atopic patients. Rush immunotherapy has not been reported in the feline atopic patient. The purpose of this pilot study was to determine a safe protocol for rush immunotherapy in feline atopic patients. Four atopic cats diagnosed by history, physical examination and exclusion of appropriate differential diagnoses were included in the study. Allergens were identified via liquid phase immunoenzymatic testing (VARL: Veterinary Allergy Reference Labs, Pasadena, CA). Cats were premedicated with 1.5 mg triamcinolone orally 24 and 2 h prior to first injection and 10 mg hydroxyzine PO 24, 12 and 2 h prior to first injection. An intravenous catheter was placed prior to first injection. Allergen extracts (Greer Laboratories, Lenoir, North Carolina) were all administered subcutaneously at increasing protein nitrogen units (pnu) every 30 minutes for 5 h to maintenance dose of 15,000 pnus ml-1. Vital signs were assessed every 15 minutes. Two cats developed mild pruritus and the subsequent injection was delayed 30 minutes. No changes in either cat's vital signs were noted, nor was there any further pruritus. All four cats successfully completed rush immunotherapy. Two cats developed a dermal swelling on the dorsal neck one week later. In these four cats, this protocol appeared to be a safe regimen to reach maintenance therapy. A larger sample of feline patients is needed to determine the incidence of adverse reactions and to follow the success of ASIT based upon this method of induction.

Thunder and lightning: immunotherapy and oncolytic viruses collide.

PubMed

Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C

2011-06-01

For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) associated with partial melanoma response under anti-CTLA-4 and anti-PD-1 combination.

PubMed

Amini-Adle, Mona; Piperno, Muriel; Tordo, Jérémie; Dubois, Valérie; Marabelle, Aurélien; Thomas, Luc; Dalle, Stéphane

2018-03-26

The patient, a-70-year-old male developed severe inflammatory polyarthritis associated with diffuse pitting edema in the hands and feet (A) six weeks after the initiation of ipilimumab and nivolumab for a heavily metastatic melanoma (B). Synovitis was present in wrists, metacarpophalangeal, and proximal interphalangeal joints. C-reactive protein level was elevated (169 comparing to 7 before immunotherapy introduction). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide

PubMed Central

Melcher, Alan; Parato, Kelley; Rooney, Cliona M; Bell, John C

2011-01-01

For the last several decades, the development of antitumor immune-based strategies and the engineering and testing of oncolytic viruses (OVs) has occurred largely in parallel tracks. Indeed, the immune system is often thought of as an impediment to successful oncolytic virus delivery and efficacy. More recently, however, both preclinical and clinical results have revealed potential synergy between these two promising therapeutic strategies. Here, we summarize some of the evidence that supports combining OVs with immuno-therapeutics and suggest new ways to mount a multipronged biological attack against cancers. PMID:21505424

Trial Watch: Adoptive cell transfer for anticancer immunotherapy.

PubMed

Vacchelli, Erika; Eggermont, Alexander; Fridman, Wolf Hervé; Galon, Jérôme; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2013-05-01

Adoptive cell transfer (ACT) represents a prominent form of immunotherapy against malignant diseases. ACT is conceptually distinct from dendritic cell-based approaches (which de facto constitute cellular vaccines) and allogeneic transplantation (which can be employed for the therapy of hematopoietic tumors) as it involves the isolation of autologous lymphocytes exhibiting antitumor activity, their expansion/activation ex vivo and their reintroduction into the patient. Re-infusion is most often performed in the context of lymphodepleting regimens (to minimize immunosuppression by host cells) and combined with immunostimulatory interventions, such as the administration of Toll-like receptor agonists. Autologous cells that are suitable for ACT protocols can be isolated from tumor-infiltrating lymphocytes or generated by engineering their circulating counterparts for the expression of transgenic tumor-specific T-cell receptors. Importantly, lymphocytes can be genetically modified prior to re-infusion for increasing their persistence in vivo, boosting antitumor responses and minimizing side effects. Moreover, recent data indicate that exhausted antitumor T lymphocytes may be rejuvenated in vitro by exposing them to specific cytokine cocktails, a strategy that might considerably improve the clinical success of ACT. Following up the Trial Watch that we published on this topic in the third issue of OncoImmunology (May 2012), here we summarize the latest developments in ACT-related research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of this form of cellular immunotherapy.

Integrating Novel Therapeutic Monoclonal Antibodies into the Management of Head and Neck Cancer

PubMed Central

Bauman, Julie E.; Ferris, Robert L.

2014-01-01

Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive malignancy. Interest in developing novel immunotherapies in HNSCC has been reawakened by the success of cetuximab, a therapeutic monoclonal antibody (mAb) against the epidermal growth factor receptor which likely relies on immune as well as anti-signaling mechanisms. We focus on novel therapeutic mAb in current clinical development against established mechanisms of immune evasion in HNSCC, targeting: tumor antigens (TA), with resultant potential to induce antibody-dependent cell-mediated cytotoxicity and T cell activation; immunosuppressive cytokines; co-stimulatory Tumor Necrosis Factor (TNF)-family receptors; and co-inhibitory immune checkpoint receptors. Clinical trials of immunotherapeutic mAb as monotherapy, in combination with cytolytic standard therapies exposing TA or in combination with other immunomodulatory mAb, are urgently needed in HNSCC. PMID:24222079

The Abscopal Effect Associated With a Systemic Anti-melanoma Immune Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stamell, Emily F.; Wolchok, Jedd D.; Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York

2013-02-01

The clearance of nonirradiated tumors after localized radiation therapy is known as the abscopal effect. Activation of an antitumor immune response has been proposed as a mechanism for the abscopal effect. Here we report a patient with metastatic melanoma who received palliative radiation to his primary tumor with subsequent clearance of all his nonirradiated in-transit metastases. Anti-MAGEA3 antibodies were found upon serological testing, demonstrating an association between the abscopal effect and a systemic antitumor immune response. A brain recurrence was then treated with a combination of stereotactic radiosurgery and immunotherapy with ipilimumab. The patient experienced a complete remission that includedmore » resolution of nodal metastases, with a concomitant increase in MAGEA3 titers and a new response to the cancer antigen PASD1. This case supports the immune hypothesis for the abscopal effect, and illustrates the potential of combining radiotherapy and immunotherapy in the treatment of melanoma.« less

A comparative evaluation of efficacy of chemotherapy, immunotherapy and immunochemotherapy in visceral leishmaniasis-an experimental study.

PubMed

Joshi, Jyoti; Malla, Nancy; Kaur, Sukhbir

2014-08-01

Visceral leishmaniasis (VL) represents the second most challenging infectious disease worldwide, leading to nearly 500,000 new cases and 60,000 deaths annually. Ninety per cent of VL cases occur in five countries namely Bangladesh, India, Nepal, Sudan and Brazil. No licensed vaccine is available till date against any form of leishmaniasis. High toxicity and increasing resistance to the current chemotherapeutic regimens have further complicated the situation in VL endemic regions of the world. To combat this situation, immunochemotherapy can provide a solution. In the present study, an attempt has been made to assess the in vivo antileishmanial efficacy of chemotherapy, immunotherapy and immunochemotherapy with the use of a first generation antigen Killed Leishmania donovani (KLD) along with a standard drug sodium stibogluconate (SSG) and a newly tested antileishmanial cisplatin. Inbred BALB/c mice were infected with 10(7) promastigotes/0.1 ml of Leishmania donovani. A month after infection, these animals were given specific immunotherapy (KLD/KLD+MPL-A) or chemotherapy (SSG/cisplatin) or immunochemotherapy (SSG+KLD/SSG+KLD+MPL-A/cisplatin+KLD/cisplatin+KLD+MPL-A). Animals were sacrificed on 1, 15 and 30(th) day post treatment. The efficacy of these combinations was assessed in terms of parasite load and by immunological investigations. Infected mice and normal mice served as controls. Results showed that combination of drug and KLD significantly reduced the parasite burden, enhanced the DTH (Delayed Type Hypersensitivity) responses, showed increased levels of IgG2a and decreased levels of IgG1 as compared to mice given chemotherapy or immunotherapy alone. Further maximum protection was provided by SSG+KLD+MPL-A and it was most effective as depicted by 98.5% reduction in parasite load, a potent increase in IFN-γ levels and a significant decrease in IL-10 and IL-4 levels thus skewing the immune response towards Th1 type. Hence, immunochemotherapy is more effective in control of VL in comparison to chemotherapy or immunotherapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Current state of immunotherapy for bladder cancer.

PubMed

Kassouf, Wassim; Kamat, Ashish M

2004-12-01

Bacillus Calmette-Guerin (BCG) has been shown to be the most effective agent for the treatment of superficial bladder cancer since its approval by the US Food and Drug Administration for the treatment of carcinoma in situ of the bladder in 1990. Recently, augmentation of BCG immunotherapy with interferon-alpha2b and other agents is emerging as salvage therapy for those patients who fail initial treatment. This review summarizes the role of various immunotherapeutic agents in the treatment of bladder cancer, with special emphasis on the appropriate administration and schedule of BCG therapy as well as salvage with the combination of BCG with interferon-alpha2b.

Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors.

PubMed

Ghosh, Arnab; Politikos, Ioannis; Perales, Miguel-Angel

2017-11-01

For several decades, hematopoietic cell transplantation (HCT) has been considered the standard curative therapy for many patients with hematological malignancies. In addition to the cytotoxic effects of the chemotherapy and radiation used in the conditioning regimen, the benefits of HCT are derived from a reset of the immune system and harnessing the ability of donor T cells to eliminate malignant cells. With the dawn of the era of immunotherapies in the form of checkpoint inhibitors and chimeric antigen receptor (CAR) T cells, the role of HCT has evolved. Immunotherapy with checkpoint inhibitors is increasingly being used for relapsed Hodgkin and non-Hodgkin lymphoma after autologous HCT. Checkpoint inhibitors are also being tested after allogeneic HCT with observable benefits in treating hematological malignancies, but with a potential risk of increased graft versus host disease and transplant-related mortality. Immunotherapy with Cluster of differentiation 19 CAR T cells are powerful options with aggressive B-cell malignancies both for therapy and as induction leading to allogeneic HCT. Although immunotherapies with checkpoint inhibition and CAR T cells are increasingly being used to treat hematological malignancies, HCT remains a standard of care for most of the diseases with the best chance of cure. Combination of these therapies with HCT has the potential to more effectively treat hematological malignancies.

Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential.

PubMed

van de Ven, Koen; Borst, Jannie

2015-01-01

In 2013, cancer immunotherapy was named 'breakthrough of the year' based on the outcome of clinical trials with blocking antibodies to the T-cell co-inhibitory receptors CTLA-4 and PD-1. This success has emphasized that cytotoxic T-cell responses to cancer can occur, but are limited by peripheral tolerance and by immunosuppression in the tumor microenvironment. Targeting of CTLA-4, PD-1 or its ligands partly overcomes these limitations and can now be applied in multiple immunogenic cancer types. Furthermore, an increased success rate is expected from combining CTLA-4 and/or PD-1 blocking with deliberate engagement of T-cell co-stimulatory receptors, particularly TNF receptor (R) family members. The TNFR family includes CD27 (Tnfrsf7), for which an agonistic antibody has recently entered clinical trials. In this review, we describe how CD27 co-stimulation impacts the T-cell response, with the purpose to illuminate how CD27 agonism can be exploited in cancer immunotherapy.

In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer

NASA Astrophysics Data System (ADS)

Lizotte, P. H.; Wen, A. M.; Sheen, M. R.; Fields, J.; Rojanasopondist, P.; Steinmetz, N. F.; Fiering, S.

2016-03-01

Nanotechnology has tremendous potential to contribute to cancer immunotherapy. The ‘in situ vaccination’ immunotherapy strategy directly manipulates identified tumours to overcome local tumour-mediated immunosuppression and subsequently stimulates systemic antitumour immunity to treat metastases. We show that inhalation of self-assembling virus-like nanoparticles from cowpea mosaic virus (CPMV) reduces established B16F10 lung melanoma and simultaneously generates potent systemic antitumour immunity against poorly immunogenic B16F10 in the skin. Full efficacy required Il-12, Ifn-γ, adaptive immunity and neutrophils. Inhaled CPMV nanoparticles were rapidly taken up by and activated neutrophils in the tumour microenvironment as an important part of the antitumour immune response. CPMV also exhibited clear treatment efficacy and systemic antitumour immunity in ovarian, colon, and breast tumour models in multiple anatomic locations. CPMV nanoparticles are stable, nontoxic, modifiable with drugs and antigens, and their nanomanufacture is highly scalable. These properties, combined with their inherent immunogenicity and demonstrated efficacy against a poorly immunogenic tumour, make CPMV an attractive and novel immunotherapy against metastatic cancer.

Designer vaccine nanodiscs for personalized cancer immunotherapy

NASA Astrophysics Data System (ADS)

Kuai, Rui; Ochyl, Lukasz J.; Bahjat, Keith S.; Schwendeman, Anna; Moon, James J.

2017-04-01

Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumour exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high-density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (that is, CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumour growth. Nanodiscs eliminated established MC-38 and B16F10 tumours when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.

Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy.

PubMed

Chen, Yamei; Liu, Delong

2014-01-01

As a result of the recent advances in molecular immunology, virology, genetics, and cell processing, chimeric antigen receptor (CAR)-directed cancer therapy has finally arrived for clinical application. CAR-directed adoptive immunotherapy represents a novel form of gene therapy, cellular therapy, and immunotherapy, a combination of three in one. Early phase clinical trial was reported in patients with refractory chronic lymphoid leukemia with 17p deletion. Accompanying the cytokine storm and tumor lysis syndrome was the shocking disappearance of the leukemia cells refractory to chemotherapy and monoclonal antibodies. CAR therapy was reproduced in both children and adults with refractory acute lymphoid leukemia. The CAR technology is being explored for solid tumor therapy, such as glioma. Close to 30 clinical trials are underway in the related fields (www.clinicaltrials.gov). Further improvement in gene targeting, cell expansion, delivery constructs (such as using Sleeping Beauty or Piggyback transposons) will undoubtedly enhance clinical utility. It is foreseeable that CAR-engineered T cell therapy will bring targeted cancer therapy into a new era.

Porous silicon advances in drug delivery and immunotherapy

PubMed Central

Savage, D; Liu, X; Curley, S; Ferrari, M; Serda, RE

2013-01-01

Biomedical applications of porous silicon include drug delivery, imaging, diagnostics and immunotherapy. This review summarizes new silicon particle fabrication techniques, dynamics of cellular transport, advances in the multistage vector approach to drug delivery, and the use of porous silicon as immune adjuvants. Recent findings support superior therapeutic efficacy of the multistage vector approach over single particle drug delivery systems in mouse models of ovarian and breast cancer. With respect to vaccine development, multivalent presentation of pathogen-associated molecular patterns on the particle surface creates powerful platforms for immunotherapy, with the porous matrix able to carry both antigens and immune modulators. PMID:23845260

Immunotherapy in the management of sepsis.

PubMed Central

Fagan, E. A.; Singer, M.

1995-01-01

The pathophysiological effects of severe sepsis, septic shock and related syndromes result from tissues damaged by the uncontrolled production of the mediators of inflammation. Early deaths are related primarily to the acute effects of the systemic inflammatory response. Later deaths are related more closely to the consequences of multiple organ dysfunction. Monoclonal antibodies and other immunotherapies have been developed against bacterial products, cytokines and other mediators involved in this systemic inflammatory response. Immunotherapies may improve outcome in the critically ill with sepsis if used early and as part of the therapeutic regimen of antimicrobial agents and intensive care support. PMID:7724438

Potential for immunotherapy in soft tissue sarcoma

PubMed Central

Tseng, William W; Somaiah, Neeta; Engleman, Edgar G

2015-01-01

Soft tissue sarcomas (STS) are rare, heterogeneous tumors of mesenchymal origin. Despite optimal treatment, a large proportion of patients will develop recurrent and metastatic disease. For these patients, current treatment options are quite limited. Significant progress has been made recently in the use of immunotherapy for the treatment of other solid tumors (e.g. prostate cancer, melanoma). There is a strong rationale for immunotherapy in STS, based on an understanding of disease biology. For example, STS frequently have chromosomal translocations which result in unique fusion proteins and specific subtypes have been shown to express cancer testis antigens. In this review, we discuss the current status of immunotherapy in STS, including data from human studies with cancer vaccines, adoptive cell therapy, and immune checkpoint blockade. Further research into STS immunology is needed to help design logical, subtype-specific immunotherapeutic strategies. PMID:25625925

Sublingual immunotherapy: World Allergy Organization position paper 2013 update

PubMed Central

2014-01-01

We have prepared this document, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update”, according to the evidence-based criteria, revising and updating chapters of the originally published paper, “Sublingual Immunotherapy: World Allergy Organization Position Paper 2009”, available at http://www.waojournal.org. Namely, these comprise: “Mechanisms of sublingual immunotherapy;” “Clinical efficacy of sublingual immunotherapy” – reporting all the data of all controlled trials published after 2009; “Safety of sublingual immunotherapy” – with the recently published Grading System for adverse reactions; “Impact of sublingual immunotherapy on the natural history of respiratory allergy” – with the relevant evidences published since 2009; “Efficacy of SLIT in children” – with detailed analysis of all the studies; “Definition of SLIT patient selection” – reporting the criteria for eligibility to sublingual immunotherapy; “The future of immunotherapy in the community care setting”; “Methodology of clinical trials according to the current scientific and regulatory standards”; and “Guideline development: from evidence-based medicine to patients' views” – including the evolution of the methods to make clinical recommendations. Additionally, we have added new chapters to cover a few emerging crucial topics: “Practical aspects of schedules and dosages and counseling for adherence” – which is crucial in clinical practice for all treatments; “Perspectives and new approaches” – including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, “Raising public awareness about sublingual immunotherapy”, as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail. PMID:24679069

Helper T lymphocyte response in the peripheral blood of patients with intraepithelial neoplasia submitted to immunotherapy with pegylated interferon-α.

PubMed

Michelin, Márcia Antoniazi; Montes, Letícia; Nomelini, Rosekeila Simões; Trovó, Marco Aurélio; Murta, Eddie Fernando Candido

2015-03-10

Immunotherapy in cancer patients is a very promising treatment and the development of new protocols and the study of the mechanisms of regression is imperative. The objective of this study was to evaluate the production of cytokines in helper T (CD4+) lymphocytes during immunotherapy with pegylated IFN-α in patients with cervical intraepithelial neoplasia (CIN). We conducted a prospective study with 17 patients with CIN II-III using immunotherapy with pegylated IFN-α subcutaneouly weekly, and using flow cytometry we evaluated the peripheric CD4+ T lymphocytes. The results show that in the regression group the patients presented a significant increase in the amount of IFN-γ during the entire immunotherapy, compared with the group without a response. The amount of CD4+ T lymphocytes positive for IL-2, IL-4, IL-10 and TGF-β is significantly lower in patients with good clinical response. The results also demonstrate that patients with regression have a higher amount of intracellular TNF-α in CD4+ T lymphocytes before the start of treatment. Analyzing these data sets, it can be concluded that immunotherapy is a viable clinical treatment for patients with high-grade CIN and that the regression is dependent on the change in the immune response to a Th1 pattern.

Doxil Synergizes with Cancer Immunotherapies to Enhance Antitumor Responses in Syngeneic Mouse Models

PubMed Central

Rios-Doria, Jonathan; Durham, Nicholas; Wetzel, Leslie; Rothstein, Raymond; Chesebrough, Jon; Holoweckyj, Nicholas; Zhao, Wei; Leow, Ching Ching; Hollingsworth, Robert

2015-01-01

Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8+ T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity. PMID:26408258

Characterization of Scedosporium apiospermum Glucosylceramides and Their Involvement in Fungal Development and Macrophage Functions

PubMed Central

Rollin-Pinheiro, Rodrigo; Liporagi-Lopes, Livia Cristina; de Meirelles, Jardel Vieira; de Souza, Lauro M.; Barreto-Bergter, Eliana

2014-01-01

Scedosporium apiospermum is an emerging fungal pathogen that causes both localized and disseminated infections in immunocompromised patients. Glucosylceramides (CMH, GlcCer) are the main neutral glycosphingolipids expressed in fungal cells. In this study, glucosylceramides (GlcCer) were extracted and purified in several chromatographic steps. Using high-performance thin layer chromatography (HPTLC) and electrospray ionization mass spectrometry (ESI-MS), N-2′-hydroxyhexadecanoyl-1-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine was identified as the main GlcCer in S. apiospermum. A monoclonal antibody (Mab) against this molecule was used for indirect immunofluorescence experiments, which revealed that this CMH is present on the surface of the mycelial and conidial forms of S. apiospermum. Treatment of S. apiospermum conidia with the Mab significantly reduced fungal growth. In addition, the Mab also enhanced the phagocytosis and killing of S. apiospermum by murine cells. In vitro assays were performed to evaluate the CMHs for their cytotoxic activities against the mammalian cell lines L.929 and RAW, and an inhibitory effect on cell proliferation was observed. Synergistic in vitro interactions were observed between the Mab against GlcCer and both amphotericin B (AmB) and itraconazole. Because Scedosporium species develop drug resistance, the number of available antifungal drugs is limited; our data indicate that combining immunotherapy with the available drugs might be a viable treatment option. These results suggest that in S. apiospermum, GlcCer are most likely cell wall components that are targeted by antifungal antibodies, which directly inhibit fungal development and enhance macrophage function; furthermore, these results suggest the combined use of monoclonal antibodies against GlcCer and antifungal drugs for antifungal immunotherapy. PMID:24878570

Characterization of Scedosporium apiospermum glucosylceramides and their involvement in fungal development and macrophage functions.

PubMed

Rollin-Pinheiro, Rodrigo; Liporagi-Lopes, Livia Cristina; de Meirelles, Jardel Vieira; Souza, Lauro M de; Barreto-Bergter, Eliana

2014-01-01

Scedosporium apiospermum is an emerging fungal pathogen that causes both localized and disseminated infections in immunocompromised patients. Glucosylceramides (CMH, GlcCer) are the main neutral glycosphingolipids expressed in fungal cells. In this study, glucosylceramides (GlcCer) were extracted and purified in several chromatographic steps. Using high-performance thin layer chromatography (HPTLC) and electrospray ionization mass spectrometry (ESI-MS), N-2'-hydroxyhexadecanoyl-1-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine was identified as the main GlcCer in S. apiospermum. A monoclonal antibody (Mab) against this molecule was used for indirect immunofluorescence experiments, which revealed that this CMH is present on the surface of the mycelial and conidial forms of S. apiospermum. Treatment of S. apiospermum conidia with the Mab significantly reduced fungal growth. In addition, the Mab also enhanced the phagocytosis and killing of S. apiospermum by murine cells. In vitro assays were performed to evaluate the CMHs for their cytotoxic activities against the mammalian cell lines L.929 and RAW, and an inhibitory effect on cell proliferation was observed. Synergistic in vitro interactions were observed between the Mab against GlcCer and both amphotericin B (AmB) and itraconazole. Because Scedosporium species develop drug resistance, the number of available antifungal drugs is limited; our data indicate that combining immunotherapy with the available drugs might be a viable treatment option. These results suggest that in S. apiospermum, GlcCer are most likely cell wall components that are targeted by antifungal antibodies, which directly inhibit fungal development and enhance macrophage function; furthermore, these results suggest the combined use of monoclonal antibodies against GlcCer and antifungal drugs for antifungal immunotherapy.

Emerging monoclonal antibodies against Clostridium difficile infection.

PubMed

Péchiné, Séverine; Janoir, Claire; Collignon, Anne

2017-04-01

Clostridium difficile infections are characterized by a high recurrence rate despite antibiotic treatments and there is an urgent need to develop new treatments such as fecal transplantation and immonotherapy. Besides active immunotherapy with vaccines, passive immunotherapy has shown promise, especially with monoclonal antibodies. Areas covered: Herein, the authors review the different assays performed with monoclonal antibodies against C. difficile toxins and surface proteins to treat or prevent primary or recurrent episodes of C. difficile infection in animal models and in clinical trials as well. Notably, the authors lay emphasis on the phase III clinical trial (MODIFY II), which allowed bezlotoxumab to be approved by the Food and Drug Administration and the European Medicines Agency. They also review new strategies for producing single domain antibodies and nanobodies against C. difficile and new approaches to deliver them in the digestive tract. Expert opinion: Only two human Mabs against TcdA and TcdB have been tested alone or in combination in clinical trials. However, many animal model studies have provided rationale for the use of Mabs and nanobodies in C. difficile infection and pave the way for further clinical investigation.

Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers

PubMed Central

Kievit, Forrest M.; Zhang, Miqin

2012-01-01

Cancer nanotheranostics aims to combine imaging and therapy of cancer through use of nanotechnology. The ability to engineer nanomaterials to interact with cancer cells at the molecular level can significantly improve the effectiveness and specificity of therapy to cancers that are currently difficult to treat. In particular, metastatic cancers, drug-resistant cancers, and cancer stem cells impose the greatest therapeutic challenge that requires targeted therapy to treat effectively. Targeted therapy can be achieved with appropriate designed drug delivery vehicles such as nanoparticles, adult stem cells, or T cells in immunotherapy. In this article, we first review the different types of materials commonly used to synthesize nanotheranostic particles and their use in imaging. We then discuss biological barriers that these nanoparticles encounter and must bypass to reach the target cancer cells, including the blood, liver, kidneys, spleen, and particularly the blood-brain barrier. We then review how nanotheranostics can be used to improve targeted delivery and treatment of cancer cells using nanoparticles, adult stem cells, and T cells in immunotherapy. Finally, we discuss development of nanoparticles to overcome current limitations in cancer therapy. PMID:21842473

Checkpoint inhibitors in triple-negative breast cancer (TNBC): Where to go from here.

PubMed

Kwa, Maryann J; Adams, Sylvia

2018-05-15

Advances in cancer immunotherapy and a growing body of research have focused on the role of the antitumor response in breast cancer. Triple-negative breast cancer (TNBC) is the most immunogenic breast cancer subtype, and there is strong evidence that tumor-infiltrating lymphocytes in TNBC have prognostic value and are associated with clinical outcome and improved survival. Evading antitumor immunity is a hallmark for the development and progression of cancer. Immunotherapy studies have focused on the role of the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway in maintaining immunosuppression in the tumor microenvironment. Blockade of the PD-1/PD-L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity and is actively being investigated in TNBC, with encouraging results. In this article, the authors review the current literature on checkpoint inhibitors in TNBC with a focus on PD-1/PD-L1 antibodies and discuss combination strategies and novel approaches for improving antitumor immunity and clinical outcome. Cancer 2018;124:2086-103. © 2018 American Cancer Society. © 2018 American Cancer Society.

Delivery of therapeutics with nanoparticles: what's new in cancer immunotherapy?

PubMed

Fontana, Flavia; Liu, Dongfei; Hirvonen, Jouni; Santos, Hélder A

2017-01-01

The application of nanotechnology to the treatment of cancer or other diseases has been boosted during the last decades due to the possibility to precise deliver drugs where needed, enabling a decrease in the drug's side effects. Nanocarriers are particularly valuable for potentiating the simultaneous co-delivery of multiple drugs in the same particle for the treatment of heavily burdening diseases like cancer. Immunotherapy represents a new concept in the treatment of cancer and has shown outstanding results in patients treated with check-point inhibitors. Thereby, researchers are applying nanotechnology to cancer immunotherapy toward the development of nanocarriers for delivery of cancer vaccines and chemo-immunotherapies. Cancer nanovaccines can be envisioned as nanocarriers co-delivering antigens and adjuvants, molecules often presenting different physicochemical properties, in cancer therapy. A wide range of nanocarriers (e.g., polymeric, lipid-based and inorganic) allow the co-formulation of these molecules, or the delivery of chemo- and immune-therapeutics in the same system. Finally, there is a trend toward the use of biologically inspired and derived nanocarriers. In this review, we present the recent developments in the field of immunotherapy, describing the different systems proposed by categories: polymeric nanoparticles, lipid-based nanosystems, metallic and inorganic nanosystems and, finally, biologically inspired and derived nanovaccines. WIREs Nanomed Nanobiotechnol 2017, 9:e1421. doi: 10.1002/wnan.1421 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

DOE PAGES

Jeanbart, Laura; Kourtis, Iraklis C.; van der Vlies, André J.; ...

2015-05-16

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6c hi Ly6g ₋monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 daysmore » post-injection in tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6c lo Ly6g + granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1 int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6c hi macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8 + T cells in melanoma cells expressing OVA. Ultimately, these findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies.« less

6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeanbart, Laura; Kourtis, Iraklis C.; van der Vlies, André J.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6c hi Ly6g ₋monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 daysmore » post-injection in tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6c lo Ly6g + granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1 int Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6c hi macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8 + T cells in melanoma cells expressing OVA. Ultimately, these findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies.« less

Immunotherapy in ovarian cancer.

PubMed

Odunsi, K

2017-11-01

Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells. In an effort to understand whether the immune system plays a role in controlling ovarian cancer, our group and others demonstrated that the presence of tumor infiltrating lymphocytes (TILs) is associated with improved clinical outcome in ovarian cancer patients. Recently, we hypothesized that the quality of infiltrating T cells could also be a critical determinant of outcome in ovarian cancer patients. In the past decade, several immune-based interventions have gained regulatory approval in many solid tumors and hematologic malignancies. These interventions include immune checkpoint blockade, cancer vaccines, and adoptive cell therapy. There are currently no approved immune therapies for ovarian cancer. Immunotherapy in ovarian cancer will have to consider the immune suppressive networks within the ovarian tumor microenvironment; therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies, and allow for treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies, while minimizing toxicities. In this review, the current understanding of the host immune response in ovarian cancer patients will be briefly reviewed, progress in immune therapies, and future directions for exploiting immune based strategies for long lasting durable cure. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer.

PubMed

Lin, Mao; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, Lizhi; Xu, Kecheng

2017-10-10

In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 -15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer.

Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer

PubMed Central

Lin, Mao; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, Lizhi; Xu, Kecheng

2017-01-01

In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 –15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer. PMID:29137237

Clinical trial combines enzalutamide with immunotherapy for advanced prostate cancer | Center for Cancer Research

Cancer.gov

Dr. Ravi Madan, Clinical Director of the Genitourinary Malignancies Branch, is conducting a clinical trial for men who have metastatic prostate cancer but have not yet been treated with chemotherapy, abiraterone or enzalutamide.

Coadministration of cruzipain and GM-CSF DNAs, a new immunotherapeutic vaccine against Trypanosoma cruzi infection.

PubMed

Cerny, Natacha; Sánchez Alberti, Andrés; Bivona, Augusto E; De Marzi, Mauricio C; Frank, Fernanda M; Cazorla, Silvia I; Malchiodi, Emilio L

2016-01-01

Therapeutic vaccine research and development are especially important in Chagas disease considering the characteristics of the chronic infection and the number of people in the Americas living with a parasite infection for decades. We have previously reported the efficacy of attenuated Salmonella enterica (S) carrying plasmid encoding cruzipain (SCz) to protect against Trypanosoma cruzi infection. In the present work we investigated whether Cz DNA vaccine immunotherapy could be effective in controlling an ongoing T. cruzi infection in mice. We here report the intramuscular administration of naked Cz DNA or the oral administration of Salmonella as Cz DNA delivery system as therapeutic vaccines in mice during acute or chronic infection. The coadministration of a plasmid encoding GM-CSF improved vaccine performance, indicating that the stimulation of innate immune cells is needed in the event of an ongoing infection. These therapeutic vaccines were able to address the response to a protective and sustained Th1 biased profile not only against Cz but also against a variety of parasite antigens. The combined therapeutic vaccine during the chronic phase of infection prevents tissue pathology as shown by a reduced level of enzyme activity characteristic of tissue damage and a tissue status compatible with normal tissue. The obtained results suggest that immunotherapy with Cz and GM-CSF DNAs, either alone or in combination with other drug treatments, may represent a promising alternative for Chagas disease therapy.

Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma

PubMed Central

Zolkind, Paul; Przybylski, Dariusz; Marjanovic, Nemanja; Nguyen, Lan; Lin, Tianxiang; Johanns, Tanner; Alexandrov, Anton; Zhou, Liye; Allen, Clint T.; Miceli, Alexander P.; Schreiber, Robert D.; Artyomov, Maxim; Dunn, Gavin P.; Uppaluri, Ravindra

2018-01-01

Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics. PMID:29423108

Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model

PubMed Central

McGinnis, Gwendolyn J.; Friedman, David; Young, Kristina H.; Torres, Eileen Ruth S.; Thomas, Charles R.; Gough, Michael J.; Raber, Jacob

2017-01-01

Background Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. Results Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). Materials and Methods Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. Conclusions Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation. PMID:27893434

Amyloid beta peptide immunotherapy in Alzheimer disease.

PubMed

Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

2014-12-01

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

PubMed Central

2012-01-01

Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy. Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies. Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases. Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits. We call upon Europe’s policy-makers to coordinate actions and improve individual and public health in allergy by: Promoting awareness of the effectiveness of allergen specific immunotherapy Updating national healthcare policies to support allergen specific immunotherapy Prioritising funding for allergen specific immunotherapy research Monitoring the macroeconomic and health economic parameters of allergy Reinforcing allergy teaching in medical disciplines and specialties The effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade. PMID:23110958

Options for investigative postsurgical therapy for gastric cancer, and case report of using the option for combined immunotherapy and chemotherapy.

PubMed

Gerhardt, P

2001-02-01

The investigative therapy for a senior patient after radical subtotal gastroesophagectomy for regional lymph node and proximal esophagus metastasized adenocarcinoma (stage IIIA, T3, N 1 M0) of the cardioesophageal junction is reported. The case has several unusual features: (1) the patient is the author and is not a physician; (2) in the absence of codified postsurgical treatment, he used his academic biomedical background, commercial associations, and international contacts to find and prioritize six clinically tested options for investigative postsurgical therapy; (3) after unsuccessful efforts to append ongoing clinical trials of new immunotherapies for breast adenocarcinoma (the first two therapy options), an innovative protocol was designed and gained allowance by the U.S. Food and Drug Administration for his use of combined nonspecific immunotherapy and chemotherapy based on extensive trials in South Korea that showed the synergistic effect of the two postsurgical therapies used together. A potent, new, nonspecific immunostimulant (DetoxPC) was injected subcutaneously in 10 diminishing doses during 105 weeks. Two standard chemotherapeutic drugs (5-fluorouracil and mitomycin-C) were injected intravenously in six equal doses during three weeks. Five years after the surgery, the patient enjoys good health without signs or symptoms of recurrence or metastasis. He discusses his perspectives on future clinical trials and on a patient actively pursuing investigative postsurgical therapy for a malignancy when otherwise poor survival is indicated.

Inhibition of CSF1 Receptor Improves the Anti-tumor Efficacy of Adoptive Cell Transfer Immunotherapy

PubMed Central

Tsui, Christopher; Xu, Jingying; Robert, Lídia; Wu, Lily; Graeber, Thomas; West, Brian L.; Bollag, Gideon; Ribas, Antoni

2013-01-01

Colony stimulating factor-1 (CSF-1) recruits tumor-infiltrating myeloid cells (TIMs) that suppress tumor immunity, including M2 macrophages and myeloid derived suppressor cells (MDSC). The CSF-1 receptor (CSF-1R) is a tyrosine kinase that is targetable by small molecule inhibitors such as PLX3397. In this study, we used a syngeneic mouse model of BRAFV600E-driven melanoma to evaluate the ability of PLX3397 to improve the efficacy of adoptive T-cell therapy (ACT). In this model, we found that combined treatment produced superior anti-tumor responses compared with single treatments. In mice receiving the combined treatment, a dramatic reduction of TIMs and a skewing of MHCIIlow to MHCIIhi macrophages was observed. Further, mice receiving the combined treatment exhibited an increase in tumor-infiltrating lymphocytes (TILs) and T cells, as revealed by real-time imaging in vivo. In support of these observations, TILs from these mice released higher levels of IFN-γ. In conclusion, CSF-1R blockade with PLX3397 improved the efficacy of ACT immunotherapy by inhibiting the intratumoral accumulation of immune suppressive macrophages. PMID:24247719

The efficiency of peptide immunotherapy for respiratory allergy.

PubMed

Incorvaia, Cristoforo; Montagni, Marcello; Ridolo, Erminia

2016-06-01

Allergen immunotherapy (AIT) was introduced more than a century ago and is yet the only disease-modifying treatment for allergy. AIT is currently conducted with whole allergen extracts and several studies clearly support its efficacy in the treatment of respiratory allergies, however the need for a long treatment - that affects costs and patients compliance - and possible IgE-mediated adverse events are still unresolved issues. Peptide immunotherapy is based on the use of short synthetic peptides which represent major T-cell epitopes of the allergen with markedly reduced ability to cross-link IgE and activate mast cells and basophils. Data from clinical trials confirmed the efficacy and tolerability of peptide immunotherapy in patients with cat allergy, with a sustained clinical effect after a short course treatment. Peptide therapy is a promising safe and effective new specific treatment for allergy to be developed for the most important allergens causing rhinitis or asthma.

Delivering safer immunotherapies for cancer

PubMed Central

Milling, Lauren; Zhang, Yuan; Irvine, Darrell J.

2017-01-01

Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential. PMID:28545888

Propionibacterium acnes in the pathogenesis and immunotherapy of acne vulgaris.

PubMed

Liu, Pei-Feng; Hsieh, Yao-Dung; Lin, Ya-Ching; Two, Aimee; Shu, Chih-Wen; Huang, Chun-Ming

2015-01-01

Acne vulgaris, a multi-factorial disease, is one of the most common skin diseases, affecting an estimated 80% of Americans at some point during their lives. The gram-positive and anaerobic Propionibacterium acnes (P. acnes) bacterium has been implicated in acne inflammation and pathogenesis. Therapies for acne vulgaris using antibiotics generally lack bacterial specificity, promote the generation of antibiotic-resistant bacterial strains, and cause adverse effects. Immunotherapy against P. acnes or its antigens (sialidase and CAMP factor) has been demonstrated to be effective in mice, attenuating P. acnes-induced inflammation; thus, this method may be applied to develop a potential vaccine targeting P. acnes for acne vulgaris treatment. This review summarizes reports describing the role of P. acnes in the pathogenesis of acne and various immunotherapy-based approaches targeting P. acnes, suggesting the potential effectiveness of immunotherapy for acne vulgaris as well as P. acnes-associated diseases.

Cancer nanoimmunotherapy using advanced pharmaceutical nanotechnology.

PubMed

Li, Wei; Wei, Huafeng; Li, Huafei; Gao, Jie; Feng, Si-Shen; Guo, Yajun

2014-11-01

Immunotherapy is a promising option for cancer treatment that might cure cancer with fewer side effects by primarily activating the host's immune system. However, the effect of traditional immunotherapy is modest, frequently due to tumor escape and resistance of multiple mechanisms. Pharmaceutical nanotechnology, which is also called cancer nanotechnology or nanomedicine, has provided a practical solution to solve the limitations of traditional immunotherapy. This article reviews the latest developments in immunotherapy and nanomedicine, and illustrates how nanocarriers (including micelles, liposomes, polymer-drug conjugates, solid lipid nanoparticles and biodegradable nanoparticles) could be used for the cellular transfer of immune effectors for active and passive nanoimmunotherapy. The fine engineering of nanocarriers based on the unique features of the tumor microenvironment and extra-/intra-cellular conditions of tumor cells can greatly tip the triangle immunobalance among host, tumor and nanoparticulates in favor of antitumor responses, which shows a promising prospect for nanoimmunotherapy.

Peptide vaccines and peptidomimetics targeting HER and VEGF proteins may offer a potentially new paradigm in cancer immunotherapy

PubMed Central

Kaumaya, Pravin TP; Foy, Kevin Chu

2013-01-01

The ErbB family (HER-1, HER-2, HER-3 and HER-4) of receptor tyrosine kinases has been the focus of cancer immunotherapeutic strategies while antiangiogenic therapies have focused on VEGF and its receptors VEGFR-1 and VEGFR-2. Agents targeting receptor tyrosine kinases in oncology include therapeutic antibodies to receptor tyrosine kinase ligands or the receptors themselves, and small-molecule inhibitors. Many of the US FDA-approved therapies targeting HER-2 and VEGF exhibit unacceptable toxicities, and show problems of efficacy, development of resistance and unacceptable safety profiles that continue to hamper their clinical progress. The combination of dif ferent peptide vaccines and peptidomimetics targeting specific molecular pathways that are dysregulated in tumors may potentiate anticancer immune responses, bypass immune tolerance and circumvent resistance mechanisms. The focus of this review is to discuss efforts in our laboratory spanning two decades of rationally developing peptide vaccines and therapeutics for breast cancer. This review highlights the prospective benefit of a new, untapped category of therapies biologically targeted to EGF receptor (HER-1), HER-2 and VEGF with potential peptide ‘blockbusters‘ that could lay the foundation of a new paradigm in cancer immunotherapy by creating clinical breakthroughs for safe and efficacious cancer cures. PMID:22894670

[The use of passive rabies immunotherapy: from the past to the future].

PubMed

Bourhy, Hervé; Dacheux, Laurent; Ribadeau-Dumas, Florence

2010-01-01

Rabies is a fatal disease transmitted by infected animals by bite, scratch, licking on broken skin or contamination of mucosis by saliva. The regimen of post-exposure prophylaxis for people not previously vaccinated, that is currently recommended by WHO, consists of a combination of wound cleaning, active immunization and passive immunization when the exposure is of category 3. Most of the products available on the market, in particular human rabies immunoglobulins, highly purified equine rabies immunoglobulins and the derived F(ab')(2) fragments, are now characterized by high potency and safety. Although the interest of passive anti-rabies immunization was first demonstrated in the first half of the 20th century, there is still an inadequate supply of these products to the target populations mostly in developing countries. Therefore, it is urgent to set-up training and information actions for healthcare personnel on the need to use passive immunotherapy and the lack of adverse effects of the related products. For the future, we hope that a scale up of production and a lower price will improve the accessibility to these products. The development of new products based on monoclonal antibodies and molecular biology, and which may be cheaper, is promising. © Société de Biologie, 2010.

Porous silicon advances in drug delivery and immunotherapy.

PubMed

Savage, David J; Liu, Xuewu; Curley, Steven A; Ferrari, Mauro; Serda, Rita E

2013-10-01

Biomedical applications of porous silicon include drug delivery, imaging, diagnostics and immunotherapy. This review summarizes new silicon particle fabrication techniques, dynamics of cellular transport, advances in the multistage vector approach to drug delivery, and the use of porous silicon as immune adjuvants. Recent findings support superior therapeutic efficacy of the multistage vector approach over single particle drug delivery systems in mouse models of ovarian and breast cancer. With respect to vaccine development, multivalent presentation of pathogen-associated molecular patterns on the particle surface creates powerful platforms for immunotherapy, with the porous matrix able to carry both antigens and immune modulators. Copyright © 2013 Elsevier Ltd. All rights reserved.

Immunotherapy is different: Implications for vaccine clinical trial design.

PubMed

Simon, Richard

2017-09-02

Cancer Immunotherapetics differ fundamentally from most cancer therapies in that they involve manipulation of the immune system to induce an anti-tumor response. This fundamental difference results in differences in the pre-clinical and clinical development of immunotherapeutics. Even the regulatory culture of developing one drug at a time and demonstrating that it, when added to standard therapy, prolongs patient survival, is often not suitable for the development of effective immunotherapy regimens. In this commentary, we explore some of these differences and describe novel clinical trial designs which may be useful in immunotherapeutics regimen development.

[Clinical Development of Immune Checkpoint Inhibitors in Patients with Small Cell Lung Cancer].

PubMed

Zhang, Shuang; Liu, Jingjing; Cheng, Ying

2017-09-20

Small cell lung cancer (SCLC) is a poorly differentiated high-grade neuroendocrine tumor, accounts for approximately 14% of all lung cancers. SCLC is characterized by rapid growth, early metastasis without effective treatments after recurrence. It is urgently need to improve the therapy of patients with SCLC. In recent years Tumor immunotherapy has shown promising efficacy, especially in immune checkpoints including inhibitors programmed cell-death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These immune checkpoint inhibitors of the researches are changing the clinical practice of many kinds of solid tumor. SCLC is a potential ideal type of tumor immunotherapy for tobacco exposure and the highest mutational load. In this report, the authors review the current state of the immunotherapy in SCLC, to discussing the problems, challenge and application development prospect.

Helper T Lymphocyte Response in the Peripheral Blood of Patients with Intraepithelial Neoplasia Submitted to Immunotherapy with Pegylated Interferon-α

PubMed Central

Michelin, Márcia Antoniazi; Montes, Letícia; Nomelini, Rosekeila Simões; Trovó, Marco Aurélio; Murta, Eddie Fernando Candido

2015-01-01

Immunotherapy in cancer patients is a very promising treatment and the development of new protocols and the study of the mechanisms of regression is imperative. The objective of this study was to evaluate the production of cytokines in helper T (CD4+) lymphocytes during immunotherapy with pegylated IFN-α in patients with cervical intraepithelial neoplasia (CIN). We conducted a prospective study with 17 patients with CIN II-III using immunotherapy with pegylated IFN-α subcutaneouly weekly, and using flow cytometry we evaluated the peripheric CD4+ T lymphocytes. The results show that in the regression group the patients presented a significant increase in the amount of IFN-γ during the entire immunotherapy, compared with the group without a response. The amount of CD4+ T lymphocytes positive for IL-2, IL-4, IL-10 and TGF-β is significantly lower in patients with good clinical response. The results also demonstrate that patients with regression have a higher amount of intracellular TNF-α in CD4+ T lymphocytes before the start of treatment. Analyzing these data sets, it can be concluded that immunotherapy is a viable clinical treatment for patients with high-grade CIN and that the regression is dependent on the change in the immune response to a Th1 pattern. PMID:25764160

Novel strategies for controlling Streptococcus pyogenes infection and associated diseases: from potential peptide vaccines to antibody immunotherapy.

PubMed

Pandey, Manisha; Sekuloski, Silvana; Batzloff, Michael R

2009-07-01

Infections caused by group A streptococcus (GAS) represent a public health problem in both developing and developed countries. The current available methods of prevention are either inadequate or ineffective, which is highlighted by the resurgence in invasive GAS infections over the past two decades. The management of GAS and associated diseases requires new and improved approaches. This review discusses various potential approaches in controlling GAS infections, ranging from prophylactic vaccines to antibody immunotherapy.

FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | Poster

Cancer.gov

By Frank Blanchard, Staff Writer The U.S. Food and Drug Administration (FDA) recently approved dinutuximab (ch14.18) as an immunotherapy for neuroblastoma, a rare type of childhood cancer that offers poor prognosis for about half of the children who are affected. The National Cancer Institute’s (NCI) Biopharmaceutical Development Program (BDP) at the Frederick National

Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer.

PubMed

Shrimali, Rajeev K; Yu, Zhiya; Theoret, Marc R; Chinnasamy, Dhanalakshmi; Restifo, Nicholas P; Rosenberg, Steven A

2010-08-01

Adoptive cell transfer (ACT)-based immunotherapies can mediate objective cancer regression in animal models and in up to 70% of patients with metastatic melanoma; however, it remains unclear whether the tumor vasculature impedes the egress of tumor-specific T cells, thus hindering this immunotherapy. Disruption of the proangiogenic interaction of vascular endothelial growth factor (VEGF) with its receptor (VEGFR-2) has been reported to "normalize" tumor vasculature, enhancing the efficacy of chemotherapeutic agents by increasing their delivery to the tumor intersitium. We thus sought to determine whether disrupting VEGF/VEGFR-2 signaling could enhance the effectiveness of ACT in a murine cancer model. The administration of an antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularized, B16 melanoma (P = 0.009) and improve survival (P = 0.003). Additive effects of an antibody against VEGFR-2 in conjunction with ACT were seen in this model (P = 0.013). Anti-VEGF, but not anti-VEGFR-2, antibody significantly increased infiltration of transferred cells into the tumor. Thus, normalization of tumor vasculature through disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells into the tumor and improve ACT-based immunotherapy. These studies provide a rationale for the exploration of combining antiangiogenic agents with ACT for the treatment of patients with cancer.

Treatment failure in patients with HPV 16-induced vulvar intraepithelial neoplasia: understanding different clinical responses to immunotherapy.

PubMed

van Esch, Edith M G; Welters, Marij J P; Jordanova, Ekaterina S; Trimbos, J Baptist M Z; van der Burg, Sjoerd H; van Poelgeest, Mariëtte I E

2012-07-01

Failure of the immune system to launch a strong and effective immune response to high-risk HPV is related to viral persistence and the development of anogenital (pre)malignant lesions such as vulvar intraepithelial neoplasia (VIN). Different forms of immunotherapy, aimed at overcoming the inertia of the immune system, have been developed and met with clinical success. Unfortunately these, in principal successful, therapeutic approaches also fail to induce clinical responses in a substantial number of cases. In this review, the authors summarize the traits of the immune response to HPV in healthy individuals and in patients with HPV-induced neoplasia. The potential mechanisms involved in the escape of HPV-induced lesions from the immune system indicate gaps in our knowledge. Finally, the interaction between the immune system and VIN is discussed with a special focus on the different forms of immunotherapy applied to treat VIN and the potential causes of therapy failure. The authors conclude that there are a number of pre-existing conditions that determine the patients' responsiveness to immunotherapy. An immunotherapeutic strategy in which different aspects of immune failure are attacked by complementary approaches, will improve the clinical response rate.

Antigen Loss Variants: Catching Hold of Escaping Foes.

PubMed

Vyas, Maulik; Müller, Rolf; Pogge von Strandmann, Elke

2017-01-01

Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.

Minocycline successfully treats exaggerated granulomatous hypersensitivity reaction to Mw immunotherapy.

PubMed

Vinay, Keshavamurthy; Narang, Tarun; Saikia, Uma N; Kumaran, Muthu Sendhil; Dogra, Sunil

2017-03-01

Mycobacterium W (Mw) vaccine has been found to be effective in the treatment of leprosy and warts. Despite increasing use of Mw immunotherapy, data on its safety is limited. We report a series of eight patients who developed persisting injection site granulomatous reaction following Mw immunotherapy and were successfully treated with minocycline. Eight patients with persistent nodular swelling at the site of Mw injections were identified. Seven of them had received Mw immunotherapy for cutaneous warts and one for verrucous epidermal nevus. The lesions were firm, erythematous, succulent, non-tender nodules confined to the sites of Mw vaccine injections. In 6 of these patients nodules also involved the previously injected areas. Skin biopsy from all patients showed eosinophil rich inflammation admixed with histiocytes and lymphocytes. In addition granulomas were seen in all with septal and nodular panniculitis in four patients. Broken and granular acid-fast bacilli were identified in two cases. All patients were treated with oral minocycline 100 mg/day for a mean of 9 weeks and showed good clinical response. Granulomatous reaction is a rare but significant adverse effect of Mw immunotherapy at cosmetically and functionally imperative sites. Oral minocycline appears to be effective therapy in this situation. © 2016 Wiley Periodicals, Inc.

Tenure Track Investigator | Center for Cancer Research

Cancer.gov

The Neuro-Oncology Branch (NOB), Center for Cancer Research (CCR) of the National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (HHS), Bethesda, MD, is actively recruiting for a tenure-track principal investigator to work in the area of immunology and/or immunotherapy.  The NOB Immunology/Immunotherapy Investigator will be tasked with forming and leading an independent research program.  This position will build the basic immunology program in the NOB and complement ongoing and planned translational research and clinical trials evaluating the effects of immunotherapy in patients with primary brain tumors.  This program will be able to access biospecimens generated from ongoing and planned immunotherapy protocols within the NOB, thus creating an opportunity to perform correlative studies to interrogate the complex biology of immunologic response, toxicity, and treatment resistance.  Demonstrated expertise in scientific inquiries in immunotherapy and/or immunology are essential, but prior work in brain tumors is not required.  This is an exciting opportunity to join a growing trans-institutional research team that promotes and supports collaborations across the basic, translational, and clinical research spectrum to develop novel therapeutics for individuals with primary central nervous system malignancies that will globally influence the field.

A Randomized Phase 2 Study of ADXS11-001 Listeria monocytogenes-Listeriolysin O Immunotherapy With or Without Cisplatin in Treatment of Advanced Cervical Cancer.

PubMed

Basu, Partha; Mehta, Ajay; Jain, Minish; Gupta, Sudeep; Nagarkar, Rajnish V; John, Subhashini; Petit, Robert

2018-05-01

A global unmet medical need exists for effective treatments for persistent, recurrent, or metastatic cervical cancer, as patients have a short life expectancy. Recently, immunotherapies have shown promising survival benefits for patients with advanced forms of cancer. Axalimogene filolisbac (ADXS11-001), a Listeria monocytogenes immunotherapy with a broad effect on the immune system, is under investigation for treatment of human papillomavirus-associated cancers including cervical cancer. This phase 2 study evaluated the safety and efficacy of ADXS11-001, administered with or without cisplatin, in patients with recurrent/refractory cervical cancer following prior chemotherapy and/or radiotherapy. A total of 109 patients were treated, and 69 were evaluable for tumor response at equal to or more than 3 months postbaseline. Median overall survival (OS) was comparable between treatment groups (ADXS11-001: 8.28 months; 95% confidence interval [CI], 5.85-10.5 months; ADXS11-001 + cisplatin: 8.78 months; 95% CI, 7.4-13.3 months). The 12- and 18-month milestone OS rates were 30.9% versus 38.9%, and 23.6% versus 25.9% for each group, respectively (34.9% and 24.8% combined). Median progression-free survival (6.10 vs 6.08 months) and the overall response rate (17.1% vs 14.7%) were similar for both groups. ADXS11-001 was generally well tolerated; adverse events were predominantly mild to moderate in severity and not related to treatment. More adverse events were reported in the combination group (429 vs 275). These promising safety and efficacy results, including the encouraging 12-month 34.9% combined OS rate, warrant further investigation of ADXS11-001 for treatment of recurrent/refractory cervical cancer.

Immunologically active biomaterials for cancer therapy.

PubMed

Ali, Omar A; Mooney, David J

2011-01-01

Our understanding of immunological regulation has progressed tremendously alongside the development of materials science, and at their intersection emerges the possibility to employ immunologically active biomaterials for cancer immunotherapy. Strong and sustained anticancer, immune responses are required to clear large tumor burdens in patients, but current approaches for immunotherapy are formulated as products for delivery in bolus, which may be indiscriminate and/or shortlived. Multifunctional biomaterial particles are now being developed to target and sustain antigen and adjuvant delivery to dendritic cells in vivo, and these have the potential to direct and prolong antigen-specific T cell responses. Three-dimensional immune cell niches are also being developed to regulate the recruitment, activation and deployment of immune cells in situ to promote potent antitumor responses. Recent studies demonstrate that materials with immune targeting and stimulatory capabilities can enhance the magnitude and duration of immune responses to cancer antigens, and preclinical results utilizing material-based immunotherapy in tumor models show a strong therapeutic benefit, justifying translation to and future testing in the clinic.

Primed tumor-reactive multifunctional CD62L+ human CD8+T-cells for immunotherapy

PubMed Central

Wölfl, Matthias; Merker, Katharina; Morbach, Henner; Van Gool, Stefaan W.; Eyrich, Matthias; Greenberg, Philip D.; Schlegel, Paul G.

2011-01-01

T-cell mediated immunotherapy against malignancies has been shown to be effective for certain types of cancer. However ex vivo expansion of tumor-reactive T-cells has been hindered by the low precursor frequency of such cells, often requiring multiple rounds of stimulation, resulting in full differentiation, loss of homing receptors and potential exhaustion of the expanded T-cells. Here we show that when using highly purified naïve CD8+ T-cells, a single stimulation with peptide pulsed, IFNγ/LPS-matured dendritic cells in combination with the sequential use of IL-21, IL-7 and IL-15 is sufficient for extensive expansion of antigen-specific T-cells. Short-term expanded T-cells were tumor-reactive, multifunctional and retained a central memory-like phenotype (CD62L+, CCR7+, CD28+). The procedure is highly reproducible and robust as demonstrated for different healthy donors and for cancer patients. Such short-term tumor-antigen-primed, multifunctional T-cells may therefore serve as a platform to target different malignancies accessible to immunotherapy. PMID:20972785

Use of cord blood derived T-cells in cancer immunotherapy: milestones achieved and future perspectives.

PubMed

Lo Presti, Vania; Nierkens, Stefan; Boelens, Jaap Jan; van Til, Niek P

2018-03-01

Hematopoietic cell transplantation is a potentially lifesaving procedure for patients with hematological malignancies who are refractory to conventional chemotherapy and/or irradiation treatment. Umbilical cord blood (CB) transplantation, as a hematopoietic stem and progenitor cell (HSPC) source, has several advantages over bone marrow transplantation with respect to matching and prompt availability for transplantation. Additionally, CB has some inherent features, such as rapid expansion of T cells, lower prevalence of graft-versus-host disease and higher graft versus tumor efficacy that make this HSPC cell source more favorable over other HSPC sources. Areas covered: This review summarizes the current CB and CB derived T cell applications aiming to better disease control for hematological malignancies and discusses future directions to more effective therapies. Expert commentary: CB transplantation could be used as a platform to extract cord blood derived T cells for ex vivo expansion and/or gene modification to improve cellular immunotherapies. In addition, combining cord blood gene-engineered T cell products with vaccination strategies, such as cord blood derived dendritic cell based vaccines, may provide synergistic immunotherapies with enhanced anti-tumor effects.

Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

PubMed

Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

2013-01-01

Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer.

Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

PubMed Central

Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

2013-01-01

Introduction Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. Methods We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Results Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Conclusions Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer. PMID:23799045

[Small-cell lung cancer: epidemiology, diagnostics and therapy].

PubMed

Pešek, Miloš; Mužík, Jan

Authors present actual overview of information on diagnostic and therapeutic procedures in small-cell lung cancer (SCLC). This highly aggressive type of lung cancer is diagnosed in 14.8 % of Czech lung cancer patients. Vast majority of those patients (87 %) suffer from advanced and metastatic disease in the time of diagnosis. In this issue are presented prognostic factors, staging diagnostic procedures and therapeutic recommendations. The backbone of actual SCLC treatment is combined chemotherapy and radiotherapy and less frequently, carefully in selected cases, surgical procedures. SCLC should be have as chemosensitive, chemoresistent or chemorefractory disease. Actual cytostatic combinations used in 1st line treatment, different schedules of chemoradiotherapy, drugs used in second line treatment and schedules and timing of prophylactic brain irradiation are presented. In near future, perspectively, there are some promissible data on antitumour immunotherapy based on anti CTLA-4 and anti PD-1/PE-L1 antibodies also in SCLC patients.Key words: cancer immunotherapy - concomitant chemoradiotherapy - chemotherapy - chest radiotherapy - lung resections - prophylactic brain irradiation - small cell lung cancer.

Immunotherapy of Malignant Disease Using Chimeric Antigen Receptor Engrafted T Cells

PubMed Central

Maher, John

2012-01-01

Chimeric antigen receptor- (CAR-) based immunotherapy has been under development for almost 25 years, over which period it has progressed from a new but cumbersome technology to an emerging therapeutic modality for malignant disease. The approach involves the genetic engineering of fusion receptors (CARs) that couple the HLA-independent binding of cell surface target molecules to the delivery of a tailored activating signal to host immune cells. Engineered CARs are delivered most commonly to peripheral blood T cells using a range of vector systems, most commonly integrating viral vectors. Preclinical refinement of this approach has proceeded over several years to the point that clinical testing is now being undertaken at several centres, using increasingly sophisticated and therapeutically successful genetic payloads. This paper considers several aspects of the pre-clinical and clinical development of CAR-based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies. PMID:23304553

BCG: A throwback from the stone age of vaccines opened the path for bladder cancer immunotherapy.

PubMed

Morales, Alvaro

2017-06-01

It is 40 years since the initial documentation of the efficacy of bacille Calmette-Guérin (BCG) in the management of non-muscle invasive bladder cancer (NMIBC) and probably an opportune a time as any to retrace the origins of this development and to reflect on the progress that has occurred on the use of immune modifiers in the treatment of NMIBC. A PubMed search for publications on the history of BCG was conducted, and those related to the development of the vaccine for protection against tuberculosis as well as those published in the last 40 years related to its use for treatment for NMIBC were selected for review. A manual search was also carried out for recent articles on immunotherapy for NMIBC failing to respond to BCG. Publications were selected for their usefulness in exemplifying the development of BCG as an antineoplastic agent, elucidating its mechanisms of action of BCG or introducing significant modifications in treatment regimens resulting in enhancement of its efficacy. Alternative innovative immunotherapeutic approaches were chosen to illustrate current trends in the management of this disease. Well thought-out modifications of the original protocol resulted in enhanced efficacy of the vaccine, which currently ranks as the best-known and most-used and investigated agent for high risk NMIBC. Despite its efficacy, a considerable number (30%-40%) of these tumors fail to respond to BCG. In addition, as a live bacterium it carries the potential for serious adverse effects and some patients are unable to tolerate it. These shortcomings have created the need for new agents. These range from other mycobacteria and viruses to monoclonal antibodies alone or in combination with other agents currently at various stages of development. After 4 decades of use, BCG remains the most effective agent against high risk NMIBC, but it still holds substantial drawbacks. The enduring use of immunotherapy for NMIBC has created a propitious environment to search for better alternatives. There are an increasing number of promising in vitro, animal and early human clinical trials to anticipate a significant therapeutic alternative in the foreseeable future.

Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report.

PubMed

Burks, A Wesley; Calderon, Moises A; Casale, Thomas; Cox, Linda; Demoly, Pascal; Jutel, Marek; Nelson, Harold; Akdis, Cezmi A

2013-05-01

Allergy immunotherapy (AIT) is an effective treatment for allergic asthma and rhinitis, as well as venom-induced anaphylaxis. In addition to reducing symptoms, AIT can change the course of allergic disease and induce allergen-specific immune tolerance. In current clinical practice immunotherapy is delivered either subcutaneously or sublingually; some allergens, such as grass pollen, can be delivered through either route, whereas others, such as venoms, are only delivered subcutaneously. Both subcutaneous and sublingual immunotherapy appear to have a duration of efficacy of up to 12 years, and both can prevent the development of asthma and new allergen sensitivities. In spite of the advances with AIT, safer and more effective AIT strategies are needed, especially for patients with asthma, atopic dermatitis, or food allergy. Novel approaches to improve AIT include use of adjuvants or recombinant allergens and alternate routes of administration. As part of the PRACTALL initiatives, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology nominated an expert team to develop a comprehensive consensus report on the mechanisms of AIT and its use in clinical practice, as well as unmet needs and ongoing developments in AIT. This resulting report is endorsed by both academies. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Alternative products to treat allergic rhinitis and alternative routes for allergy immunotherapy.

PubMed

Ipci, Kagan; Oktemer, Tugba; Muluk, Nuray Bayar; Şahin, Ethem; Altıntoprak, Niyazi; Bafaqeeh, Sameer Ali; Kurt, Yasemin; Mladina, Ranko; Šubarić, Marin; Cingi, Cemal

2016-09-01

Some alternative products instead of immunotherapy are used in patients with allergic rhinitis (AR). In this paper, alternative products to treat allergic rhinitis and alternative routes for allergy immunotherapy are reviewed. Alternative products and methods used instead of immunotherapy are tea therapy, acupuncture, Nigella sativa, cinnamon bark, Spanish needle, acerola, capsaicin (Capsicum annum), allergen-absorbing ointment, and cellulose powder. N. sativa has been used in AR treatment due to its anti-inflammatory effects. N. sativa oil also inhibits the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The beneficial effects of N. sativa seed supplementation on the symptoms of AR may be due to its antihistaminic properties. To improve the efficacy of immunotherapy, some measures are taken regarding known immunotherapy applications and alternative routes of intralymphatic immunotherapy and epicutaneous immunotherapy are used. There are alternative routes and products to improve the efficacy of immunotherapy.

A Feedback Control Model of Comprehensive Therapy for Treating Immunogenic Tumours

NASA Astrophysics Data System (ADS)

Tang, Biao; Xiao, Yanni; Tang, Sanyi; Cheke, Robert A.

Surgery is the traditional method for treating cancers, but it often fails to cure patients for complex reasons so new therapeutic approaches that include both surgery and immunotherapy have recently been proposed. These have been shown to be effective, clinically, in inhibiting cancer cells while allowing retention of immunologic memory. This comprehensive strategy is guided by whether a population of tumour cells has or has not exceeded a threshold density. Conditions for successful control of tumours in an immune tumour system were modeled and the related dynamics were addressed. A mathematical model with state-dependent impulsive interventions is formulated to describe combinations of surgery with immunotherapy. By analyzing the properties of the Poincaré map, we examine the global dynamics of the immune tumour system with state-dependent feedback control, including the existence and stability of the semi-trivial order-1 periodic solution and the positive order-k periodic solution. The main results showed that surgery alone can only control the tumour size below a certain level while there is no immunologic memory. If comprehensive therapy involving combining surgery with immunotherapy is considered, then not only can the cancers be controlled below a certain level, but the immune system can also retain its activity. The existence of positive order-k periodic solutions implies that periodical therapy is needed to control the cancers. However, choosing the treatment frequency and the strength of the therapy remains challenging, and hence a strategy of individual-based therapy is suggested.

Recent Successes and Future Directions in Immunotherapy of Cutaneous Melanoma

PubMed Central

Sadozai, Hassan; Gruber, Thomas; Hunger, Robert Emil; Schenk, Mirjam

2017-01-01

The global health burden associated with melanoma continues to increase while treatment options for metastatic melanoma are limited. Nevertheless, in the past decade, the field of cancer immunotherapy has witnessed remarkable advances for the treatment of a number of malignancies including metastatic melanoma. Although the earliest observations of an immunological antitumor response were made nearly a century ago, it was only in the past 30 years, that immunotherapy emerged as a viable therapeutic option, in particular for cutaneous melanoma. As such, melanoma remains the focus of various preclinical and clinical studies to understand the immunobiology of cancer and to test various tumor immunotherapies. Here, we review key recent developments in the field of immune-mediated therapy of melanoma. Our primary focus is on therapies that have received regulatory approval. Thus, a brief overview of the pathophysiology of melanoma is provided. The purported functions of various tumor-infiltrating immune cell subsets are described, in particular the recently described roles of intratumoral dendritic cells. The section on immunotherapies focuses on strategies that have proved to be the most clinically successful such as immune checkpoint blockade. Prospects for novel therapeutics and the potential for combinatorial approaches are delineated. Finally, we briefly discuss nanotechnology-based platforms which can in theory, activate multiple arms of immune system to fight cancer. The promising advances in the field of immunotherapy signal the dawn of a new era in cancer treatment and warrant further investigation to understand the opportunities and barriers for future progress. PMID:29276510

Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared to Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States

PubMed Central

Oh, Anna; Tran, Dang M; McDowell, Leann C; Keyvani, Dor; Barcelon, Jay Andrew; Merino, Oscar; Wilson, Leslie

2018-01-01

BACKGROUND The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations to third-party payer systems, physicians, and patients. OBJECTIVE Develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as first-line therapy in metastatic melanoma while accounting for differential effectiveness in PD-L1 positive and negative patients. METHODS A three-state Markov model (‘PD-L1 positive stable disease’, ‘PD-L1 negative stable disease’, and ‘Progression and/or Death’) was developed using a US societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 US dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted. RESULTS Nivolumab-ipilimumab combination therapy is not the cost effective choice ($454,092 per progression-free quality-adjusted-life-year [PFQALY]) compared to nivolumab monotherapy in our base case analysis at a willingness-to-pay threshold of $100,000/PFQALY. Both combination therapy and nivolumab monotherapy were cost-effective choices compared to ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment but combination therapy had an improved ICER of $295,903/PFQALY. Combination therapy became dominated by nivolumab when 68% of the sample was PD-L1 positive. In addition, the cost of ipilimumab would have to decrease to <$21,555 per dose for combination therapy to have an ICER <$100,000/PFQALY, and to <$19,151 (a 42% reduction) to be more cost-effective than nivolumab monotherapy. CONCLUSIONS Nivolumab-ipilimumab combination therapy is not cost-effective compared to nivolumab monotherapy, which is the most cost-effective option. Professionals in managed care settings should consider the pharmacoeconomic implications of these new immunotherapies as they make value-based formulary decisions and future cost-effectiveness studies are completed. PMID:28530525

Immunotherapy targeting α-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders.

PubMed

Lindström, Veronica; Ihse, Elisabet; Fagerqvist, Therese; Bergström, Joakim; Nordström, Eva; Möller, Christer; Lannfelt, Lars; Ingelsson, Martin

2014-01-01

Immunotherapy targeting α-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. α-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of α-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against α-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting α-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other α-synucleinopathies.

Active treatment for food allergy.

PubMed

Kobernick, Aaron K; Burks, A Wesley

2016-10-01

Food allergy has grown in rapidly in prevalence, currently affecting 5% of adults and 8% of children. Management strategy is currently limited to 1) food avoidance and 2) carrying and using rescue intramuscular epinephrine/adrenaline and oral antihistamines in the case of accidental ingestion; there is no FDA approved treatment. Recently, oral, sublingual and epicutaneous immunotherapy have been developed as active treatment of food allergy, though none have completed phase 3 study. Efficacy and safety studies of immunotherapy have been variable, though there is clearly signal that immunotherapy will be a viable option to desensitize patients. The use of bacterial adjuvants, anti-IgE monoclonal antibodies, and Chinese herbal formulations either alone or in addition to immunotherapy may hold promise as future options for active treatment. Active prevention of food allergy through early introduction of potentially offending foods in high-risk infants will be an important means to slow the rising incidence of sensitization. Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Recombinant proteins and peptides as diagnostic and therapeutic reagents for arthropod allergies.

PubMed

Ramos, John Donnie A; Valmonte, Gardette R; de Guia, Roldan M

2007-01-01

Domestic arthropods are chief sources of potent allergens that trigger sensitization and stimulate IgE-mediated allergies. Diagnosis and immunotherapy of arthropod allergies rely on the use of natural allergen extracts which are associated with low specificity and efficacy, the risk of anaphylactic reactions, and the extended period of treatment. Most of the problems associated with natural allergen extracts for allergy diagnosis and immunotherapy can be circumvented with the use of recombinant allergens and peptides. Recombinant allergens are recently developed for microarray-based multi-allergen tests which provide component-resolved diagnosis (CRD) of the patient's sensitization profile. Moreover, recombinant protein technology and peptide chemistry have been used to construct isoallergens, allergen mutants, allergoids, T and B cell peptides, hypoallergens, and mimotopes with reduced allergenicity but enhanced immunogenicity for allergen-specific immunotherapy (SIT) and vaccination. The basics of recombinant arthropod allergen technology are in place providing a lucid future for the advancement of diagnosis and immunotherapy of arthropod allergies.

[AIDS: "We will win"].

PubMed

Chabrier, H

1989-11-13

An international colloquium on AIDS held near Paris from October 26-28, 1989, unlike the World Conference on AIDS in Montreal the year before, was able to find reasons for optimism. Significant progress was reported in immunotherapy and in chemotherapy. Successful experiments in vaccinating monkeys against the AIDS virus were reported from the US, France, and Zaire. Time is needed to prove the efficacy of the vaccines because of the slow development in AIDS. A vaccine is being tested by Jonas Salk and collaborators in 75 seropositive volunteers who do not yet show full blown disease but who have very low levels of T4 lymphocytes. Plans are underway for a larger test on 500 seropositive patients at different stages of infection. According to Salk, the new chemical and logical approach toward AIDS will allow combinations of immunotherapy and chemotherapy to destroy the virus. R. Gallo of France listed as accomplishments of the past year a better understanding of the virus, improved case management techniques, increased ability to control Kaposi's sarcoma, considerable progress in the search for a vaccine, and detection of immune proteins that affect the virus. New biological markers permit establishment of correlations between cellular modifications and the progress of the disease as well as the precise effects of treatment. The new immune system drugs immuthiol and DDI are expected to reach the market soon. Patients very soon will be able to receive less toxic alternative treatments, which can be combined for greater efficacy once their toxic interactions are understood.

Coadministration of cruzipain and GM-CSF DNAs, a new immunotherapeutic vaccine against Trypanosoma cruzi infection

PubMed Central

Cerny, Natacha; Sánchez Alberti, Andrés; Bivona, Augusto E; De Marzi, Mauricio C; Frank, Fernanda M; Cazorla, Silvia I; Malchiodi, Emilio L

2016-01-01

Therapeutic vaccine research and development are especially important in Chagas disease considering the characteristics of the chronic infection and the number of people in the Americas living with a parasite infection for decades. We have previously reported the efficacy of attenuated Salmonella enterica (S) carrying plasmid encoding cruzipain (SCz) to protect against Trypanosoma cruzi infection. In the present work we investigated whether Cz DNA vaccine immunotherapy could be effective in controlling an ongoing T. cruzi infection in mice. We here report the intramuscular administration of naked Cz DNA or the oral administration of Salmonella as Cz DNA delivery system as therapeutic vaccines in mice during acute or chronic infection. The coadministration of a plasmid encoding GM-CSF improved vaccine performance, indicating that the stimulation of innate immune cells is needed in the event of an ongoing infection. These therapeutic vaccines were able to address the response to a protective and sustained Th1 biased profile not only against Cz but also against a variety of parasite antigens. The combined therapeutic vaccine during the chronic phase of infection prevents tissue pathology as shown by a reduced level of enzyme activity characteristic of tissue damage and a tissue status compatible with normal tissue. The obtained results suggest that immunotherapy with Cz and GM-CSF DNAs, either alone or in combination with other drug treatments, may represent a promising alternative for Chagas disease therapy. PMID:26312947

[Novel dianostics and therapeutics with ultrasound technologies and nanotechnologies].

PubMed

Suzuki, Ryo; Oda, Yusuke; Omata, Daiki; Sawaguchi, Yoshikazu; Negishi, Yoichi; Maruyama, Kazuo

2013-01-01

Ultrasound is a good tool for theranostics due to have multi-potency both of diagnostics with sonography and therapeutics with high intensity focused ultrasound (HIFU). In addition, microbubbles and nanobubbles are utilized as not only contrast imaging agent but also enhancer of drug and gene delivery by combination of ultrasound. Recently, we developed novel liposomal nanobubbles (Bubble liposomes) which were containing perfluoropropane. Bubble liposomes induced jet stream by low intensity ultrasound exposure and resulted in enhancing permeability of cell membrane. This phenomenon has been utilized as driving force for drug and gene delivery. On the other hand, the combination of Bubble liposomes and high intensity ultrasound induces strong jet stream and increase temperature. This condition can directly damage to tumor cells, we are applying this for cancer therapy. Therefore, their combination has potency for various cancer therapies such as gene therapy, immunotherapy and hyperthermia. In this review, we discuss about cancer therapy by the combination of Bubble liposomes and ultrasound.

BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy.

PubMed

Dörrie, Jan; Babalija, Lek; Hoyer, Stefanie; Gerer, Kerstin F; Schuler, Gerold; Heinzerling, Lucie; Schaft, Niels

2018-01-18

BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAF V600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs. vemurafenib (Vem) and cobimetinib (Cobi) on the activation and functionality of chimeric antigen receptor (CAR)-transfected T cells. We co-cultured CAR-transfected CD8⁺ T cells and target cells with clinically relevant concentrations of the inhibitors and determined the antigen-induced cytokine secretion. All BRAFi/MEKi reduced this release as single agents, with Dabra having the mildest inhibitory effect, and Dabra + Tram having a clearly milder inhibitory effect than Vem + Cobi. A similar picture was observed for the upregulation of the activation markers CD25 and CD69 on CAR-transfected T cells after antigen-specific stimulation. Most importantly, the cytolytic capacity of the CAR-T cells was significantly inhibited by Cobi and Vem + Cobi, whereas the other kinase inhibitors showed no effect. Therefore, the combination Dabra + Tram would be more suitable for combining with T-cell-based immunotherapy than Vem + Cobi.

Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation - Positive Advanced Non-Small Cell Lung Cancer (CheckMate 370).

PubMed

Spigel, David R; Reynolds, Craig; Waterhouse, David; Garon, Edward B; Chandler, Jason; Babu, Sunil; Thurmes, Paul; Spira, Alexander; Jotte, Robert; Zhu, Jin; Lin, Wen Hong; Blumenschein, George

2018-05-01

Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation-positive advanced non-small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation-positive NSCLC. Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation-positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017. Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response. These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

PubMed Central

Wyluda, Edward J; Cheng, Jihua; Schell, Todd D; Haley, Jeremy S; Mallon, Carol; Neves, Rogerio I; Robertson, Gavin; Sivik, Jeffrey; Mackley, Heath; Talamo, Giampaolo; Drabick, Joseph J

2015-01-01

We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9–12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment. PMID:25806780

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy.

PubMed

Wyluda, Edward J; Cheng, Jihua; Schell, Todd D; Haley, Jeremy S; Mallon, Carol; Neves, Rogerio I; Robertson, Gavin; Sivik, Jeffrey; Mackley, Heath; Talamo, Giampaolo; Drabick, Joseph J

2015-01-01

We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment.

Development of cockroach immunotherapy by the Inner-City Asthma Consortium

PubMed Central

Wood, Robert A.; Togias, Alkis; Wildfire, Jeremy; Visness, Cynthia M.; Matsui, Elizabeth C.; Gruchalla, Rebecca; Hershey, Gurjit; Liu, Andrew H.; O’Connor, George T.; Pongracic, Jacqueline A.; Zoratti, Edward; Little, Frederic; Granada, Mark; Kennedy, Suzanne; Durham, Stephen R.; Shamji, Mohamed H.; Busse, William W.

2014-01-01

Background Cockroach allergy is a key contributor to asthma morbidity in children living in urban environments. Objective We sought to document immune responses to cockroach allergen and provide direction for the development of immunotherapy for cockroach allergy. Methods Four pilot studies were conducted: (1) an open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and children; (2) a randomized, double-blind biomarker study of cockroach SLIT versus placebo in adults; (3) a randomized, double-blind biomarker study of 2 doses of cockroach SLIT versus placebo in children; and (4) an open-label safety and biomarker study of cockroach subcutaneous immunotherapy (SCIT) in adults. Results The adult SLIT trial (n = 54; age, 18–54 years) found a significantly greater increase in cockroach-specific IgE levels between the active and placebo groups (geometric mean ratio, 1.92; P < .0001) and a trend toward increased cockroach-specific IgG4 levels in actively treated subjects (P = .09) but no evidence of functional blocking antibody response. The pediatric SLIT trial (n = 99; age, 5–17 years) found significant differences in IgE, IgG, and IgG4 responses between both active groups and the placebo group but no consistent differences between the high- and low-dose groups. In the SCIT study the treatment resulted in significant changes from baseline in cockroach IgE, IgG4, and blocking antibody levels. The safety profile of cockroach immunotherapy was reassuring in all studies. Conclusions The administration of cockroach allergen by means of SCIT is immunologically more active than SLIT, especially with regard to IgG4 levels and blocking antibody responses. No safety concerns were raised in any age group. These pilot studies suggest that immunotherapy with cockroach allergen is more likely to be effective with SCIT. PMID:24184147

Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators.

PubMed

Le Mercier, Isabelle; Lines, J Louise; Noelle, Randolph J

2015-01-01

In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy.

Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators

PubMed Central

Le Mercier, Isabelle; Lines, J. Louise; Noelle, Randolph J.

2015-01-01

In the last two years, clinical trials with blocking antibodies to the negative checkpoint regulators CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. Multiple negative checkpoint regulators protect the host against autoimmune reactions but also restrict the ability of T cells to effectively attack tumors. Releasing these brakes has emerged as an exciting strategy for cancer treatment. Conversely, these pathways can be manipulated to achieve durable tolerance for treatment of autoimmune diseases and transplantation. In the future, treatment may involve combination therapy to target multiple cell types and stages of the adaptive immune responses. In this review, we describe the current knowledge on the recently discovered negative checkpoint regulators, future targets for immunotherapy. PMID:26347741

Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

PubMed Central

Nagarsheth, Nisha; Wicha, Max S.; Zou, Weiping

2017-01-01

The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer. PMID:28555670

Biomarkers for Allergen Immunotherapy: A "Panoromic" View.

PubMed

Moingeon, Philippe

2016-02-01

Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Lighting a Fire in the Tumor Microenvironment Using Oncolytic Immunotherapy.

PubMed

Achard, Carole; Surendran, Abera; Wedge, Marie-Eve; Ungerechts, Guy; Bell, John; Ilkow, Carolina S

2018-05-01

Oncolytic virus (OV) therapy is potentially a game-changing cancer treatment that has garnered significant interest due to its versatility and multi-modal approaches towards tumor eradication. In the field of cancer immunotherapy, the immunological phenotype of the tumor microenvironment (TME) is an important determinant of disease prognosis and therapeutic success. There is accumulating data that OVs are capable of dramatically altering the TME immune landscape, leading to improved antitumor activity alone or in combination with assorted immune modulators. Herein, we review how OVs disrupt the immunosuppressive TME and can be used strategically to create a "pro-immune" microenvironment that enables and promotes potent, long-lasting host antitumor immune responses. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

3D Microfluidic model for evaluating immunotherapy efficacy by tracking dendritic cell behaviour toward tumor cells.

PubMed

Parlato, Stefania; De Ninno, Adele; Molfetta, Rosa; Toschi, Elena; Salerno, Debora; Mencattini, Arianna; Romagnoli, Giulia; Fragale, Alessandra; Roccazzello, Lorenzo; Buoncervello, Maria; Canini, Irene; Bentivegna, Enrico; Falchi, Mario; Bertani, Francesca Romana; Gerardino, Annamaria; Martinelli, Eugenio; Natale, Corrado; Paolini, Rossella; Businaro, Luca; Gabriele, Lucia

2017-04-24

Immunotherapy efficacy relies on the crosstalk within the tumor microenvironment between cancer and dendritic cells (DCs) resulting in the induction of a potent and effective antitumor response. DCs have the specific role of recognizing cancer cells, taking up tumor antigens (Ags) and then migrating to lymph nodes for Ag (cross)-presentation to naïve T cells. Interferon-α-conditioned DCs (IFN-DCs) exhibit marked phagocytic activity and the special ability of inducing Ag-specific T-cell response. Here, we have developed a novel microfluidic platform recreating tightly interconnected cancer and immune systems with specific 3D environmental properties, for tracking human DC behaviour toward tumor cells. By combining our microfluidic platform with advanced microscopy and a revised cell tracking analysis algorithm, it was possible to evaluate the guided efficient motion of IFN-DCs toward drug-treated cancer cells and the succeeding phagocytosis events. Overall, this platform allowed the dissection of IFN-DC-cancer cell interactions within 3D tumor spaces, with the discovery of major underlying factors such as CXCR4 involvement and underscored its potential as an innovative tool to assess the efficacy of immunotherapeutic approaches.

Emerging Insight into MAPK Inhibitors and Immunotherapy in Colorectal Cancer.

PubMed

Pancione, Massimo; Giordano, Guido; Parcesepe, Pietro; Cerulo, Luigi; Coppola, Luigi; Curatolo, Anais Del; Conciatori, Fabiana; Milella, Michele; Porras, Almudena

2017-01-01

Our understanding of the genetic and non-genetic molecular alterations associated with colorectal cancer (CRC) progression and therapy resistance has markedly expanded in the recent years. In addition to their effects on tumor biology, targeted therapies can have effects on host immune responses. However, the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity need to be comprehensively defined. There is good evidence in the literature that alterations in different members of the MAPK superfamily (mainly ERKs and p38 MAPKs) modify the inflammatory response and antitumor immunity, enhancing metastatic features of the tumors. In addition, a plethora of alterations that emerge at relapse often converge on the activation of MAPKs, particularly, ERKs, which act in concert with other oncogenic signals to modulate cellular homeostasis and clonal evolution during targeted therapies. Herein, we discuss how this knowledge can be translated into drug development strategies aimed at increasing tumor antigenicity and antitumor immune responses. Insights from these studies could provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of CRC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Immunotherapy (For Parents)

MedlinePlus

... for kids to fight infection (this is called neutropenia ). Types of Immunotherapy The aim of immunotherapy is ... be used to help children who are experiencing neutropenia. Side Effects Like other cancer treatments, immunotherapy can ...

Epicutaneous immunotherapy for food allergy as a novel pathway for oral tolerance induction.

PubMed

Mondoulet, Lucie; Dioszeghy, Vincent; Thébault, Claude; Benhamou, Pierre-Henri; Dupont, Christophe

2015-01-01

Epicutaneous immunotherapy is a developing technique, aiming at desensitizing patients with food allergy with less risks that oral ingestion or injection could generate. Several clinical trials have been performed and are currently running, in milk and peanut allergy, assessing the safety of the technique and its efficacy. Preclinical models indicate a major role in the mechanisms of desensitization, for example, Tregs and epigenetic modifications.

Cells as advanced therapeutics: State-of-the-art, challenges, and opportunities in large scale biomanufacturing of high-quality cells for adoptive immunotherapies.

PubMed

Dwarshuis, Nate J; Parratt, Kirsten; Santiago-Miranda, Adriana; Roy, Krishnendu

2017-05-15

Therapeutic cells hold tremendous promise in treating currently incurable, chronic diseases since they perform multiple, integrated, complex functions in vivo compared to traditional small-molecule drugs or biologics. However, they also pose significant challenges as therapeutic products because (a) their complex mechanisms of actions are difficult to understand and (b) low-cost bioprocesses for large-scale, reproducible manufacturing of cells have yet to be developed. Immunotherapies using T cells and dendritic cells (DCs) have already shown great promise in treating several types of cancers, and human mesenchymal stromal cells (hMSCs) are now extensively being evaluated in clinical trials as immune-modulatory cells. Despite these exciting developments, the full potential of cell-based therapeutics cannot be realized unless new engineering technologies enable cost-effective, consistent manufacturing of high-quality therapeutic cells at large-scale. Here we review cell-based immunotherapy concepts focused on the state-of-the-art in manufacturing processes including cell sourcing, isolation, expansion, modification, quality control (QC), and culture media requirements. We also offer insights into how current technologies could be significantly improved and augmented by new technologies, and how disciplines must converge to meet the long-term needs for large-scale production of cell-based immunotherapies. Copyright © 2017 Elsevier B.V. All rights reserved.

Oral immunotherapy for food allergy: A Spanish guideline. Immunotherapy egg and milk Spanish guide (items guide). Part I: Cow milk and egg oral immunotherapy: Introduction, methodology, rationale, current state, indications contraindications and oral immunotherapy build-up phase.

PubMed

Martorell, A; Alonso, E; Echeverría, L; Escudero, C; García-Rodríguez, R; Blasco, C; Bone, J; Borja-Segade, J; Bracamonte, T; Claver, A; Corzo, J L; De la Hoz, B; Del Olmo, R; Dominguez, O; Fuentes-Aparicio, V; Guallar, I; Larramona, H; Martín-Muñoz, F; Matheu, V; Michavila, A; Ojeda, I; Ojeda, P; Piquer, M; Poza, P; Reche, M; Rodríguez Del Río, P; Rodríguez, M; Ruano, F; Sánchez-García, S; Terrados, S; Valdesoiro, L; Vazquez-Ortiz, M

Cow's milk and egg are the most frequent causes of food allergy in the first years of life. Treatments such as oral immunotherapy (OIT) have been investigated as an alternative to avoidance diets. No clinical practice guides on the management of OIT with milk and egg are currently available. To develop a clinical guide on OIT based on the available scientific evidence and the opinions of experts. A review was made of studies published in the period between 1984 and June 2016, Doctoral Theses published in Spain, and summaries of communications at congresses (SEAIC, SEICAP, EAACI, AAAAI), with evaluation of the opinion consensus established by a group of experts pertaining to the scientific societies SEICAP and SEAIC. Recommendations have been established regarding the indications, requirements and practical aspects of the different phases of OIT, as well as special protocols for patients at high risk of suffering adverse reactions. A clinical practice guide is presented for the management of OIT with milk and egg, based on the opinion consensus of Spanish experts. Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Enhanced therapeutic effect of APAVAC immunotherapy in combination with dose-intense chemotherapy in dogs with advanced indolent B-cell lymphoma.

PubMed

Marconato, L; Stefanello, D; Sabattini, S; Comazzi, S; Riondato, F; Laganga, P; Frayssinet, P; Pizzoni, S; Rouquet, N; Aresu, L

2015-09-22

The aim of this non-randomized controlled trial was to compare time to progression (TTP), lymphoma-specific survival (LSS), and safety of an autologous vaccine (consisting of hydroxyapatite ceramic powder and Heat Shock Proteins purified from the dogs' tumors, HSPPCs-HA) plus chemotherapy versus chemotherapy alone in dogs with newly diagnosed, clinically advanced, histologically confirmed, multicentric indolent B-cell lymphoma. The vaccine was prepared from dogs' resected lymph nodes and administered as an intradermal injection. Forty-five client-owned dogs were enrolled: 20 dogs were treated with dose-intense chemotherapy, and 25 received concurrent immunotherapy. Both treatment arms were well tolerated, with no exacerbated toxicity in dogs also receiving the vaccine. TTP was significantly longer for dogs treated with chemo-immunotherapy versus those receiving chemotherapy only (median, 209 versus 85 days, respectively, P=0.015). LSS was not significantly different between groups: dogs treated with chemo-immunotherapy had a median survival of 349 days, and those treated with chemotherapy only had a median survival of 200 days (P=0.173). Among vaccinated dogs, those mounting an immune response had a significantly longer TTP and LSS than those with no detectable response (P=0.012 and P=0.003, respectively). Collectively these results demonstrate that vaccination with HSPPCs-HA may produce clinical benefits with no increased toxicity, thereby providing a strategy for enhancing chemotherapy in dogs with advanced indolent lymphoma. Copyright © 2015 Elsevier Ltd. All rights reserved.

Therapeutic vaccines in HBV: lessons from HCV.

PubMed

Barnes, Eleanor

2015-02-01

Currently, millions of people infected with hepatitis B virus (HBV) are committed to decades of treatment with anti-viral therapy to control viral replication. However, new tools for immunotherapy that include both viral vectors and molecular checkpoint inhibitors are now available. This has led to a resurgence of interest in new strategies to develop immunotherapeutic strategies with the aim of inducing HBeAg seroconversion--an end-point that has been associated with a decrease in the rates of disease progression. Ultimately, a true cure will involve the elimination of covalently closed circular DNA which presents a greater challenge for immunotherapy. In this manuscript, I describe the development of immunotherapeutic strategies for HBV that are approaching or currently in clinical studies, and draw on observations of T cell function in natural infection supported by recent animal studies that may lead to additional rational vaccine strategies using checkpoint inhibitors. I also draw on our recent experience in developing potent vaccines for HCV prophylaxis based on simian adenoviral and MVA vectors used in prime-boost strategies in both healthy volunteers and HCV infected patients. I have shown that the induction of T cell immune responses is markedly attenuated when administered to people with persistent HCV viremia. These studies and recently published animal studies using the woodchuck model suggest that potent vaccines based on DNA or adenoviral vectored vaccination represent a rational way forward. However, combining these with drugs to suppress viral replication, alongside checkpoint inhibitors may be required to induce long-term immune control.

Safety of allergen immunotherapy: a review of premedication and dose adjustment.

PubMed

Morris, A Erika; Marshall, Gailen D

2012-03-01

From the first allergen immunotherapy proposed in the early 1900s to the present day, numerous studies have proven the efficacy of allergen immunotherapy for the treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma and stinging insect hypersensitivity. The major risk, however small, with allergen immunotherapy is anaphylaxis. There has been considerable interest and debate regarding risk factors for immunotherapy reactions (local and systemic) and interventions to reduce the occurrence of these reactions. One of these interventions that is especially debated regards dose adjustment for various reasons, but in particular for local reactions. In this review, we discuss the safety of immunotherapy and provide a comprehensive review of the literature regarding immunotherapy schedules and doses.

Cytomegalovirus-targeted immunotherapy and glioblastoma: hype or hope?

PubMed

Ferguson, Sherise D; Srinivasan, Visish M; Ghali, Michael Gz; Heimberger, Amy B

2016-01-01

Malignant gliomas, including glioblastoma (GBM), are the most common primary brain tumors. Despite extensive research only modest gains have been made in long-term survival. Standard of care involves maximizing safe surgical resection followed by concurrent chemoradiation with temozolomide. Immunotherapy for GBM is an area of intense research in recent years. New immunotherapies, although promising, have not been integrated into standard practice. Human cytomegalovirus (HCMV) is a DNA virus of the family Herpesviridae. Human seroprevalence is approximately 80%, and in most cases, is associated with asymptomatic infection. HCMV may be an important agent in the initiation, promotion and/or progression of tumorigenesis. Regardless of a possible etiologic role in GBM, interest has centered on exploiting this association for development of immunomodulatory therapies.

Clinical trial explores new glioblastoma treatment regimen | Center for Cancer Research

Cancer.gov

On average, a patient with glioblastoma lives for only about a year after diagnosis. In a new clinical trial, CCR researchers will test whether a combination of a vaccine made from the patient’s tumor with another immunotherapy treatment can increase survival rates. Read more...  

Lung Squamous Cell Carcinoma Stem Cells as Immunotherapy Targets

DTIC Science & Technology

2017-08-01

will examine the importance of candidate genes in CSC activity using blocking antibodies, knockdown or CRISPR strategies coupled with transplantation...Aim 1. Engineer isogenic human and murine BRG1 mutant cell lines using CRISPR -Cas9 to dissect the mechanisms behind the sensitivity to combined EZH2

[Antitumor effect of recombinant Xenopus laevis vascular endothelial growth factor (VEGF) as a vaccine combined with adriamycin on EL4 lymphoma in mice].

PubMed

Niu, Ting; Liu, Ting; Jia, Yong-Qian; Liu, Ji-Yan; Wu, Yang; Hu, Bing; Tian, Ling; Yang, Li; Kan, Bing; Wei, Yu-Quan

2005-09-01

To explore the antitumor effect of immunotherapy with recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a vaccine combined with adriamycin on lymphoma model in mice. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomized into four groups: combination therapy, adriamycin alone, xVEGF alone and normal saline (NS) groups, and then were given relevant treatments. The growth of tumor, the survival rate of tumor-bearing mice, and the potential toxicity of regimens above were observed. Anti-VEGF antibody-producing B cells (APBCs) were detected by enzyme-linked immunospot (ELISPOT) assay. In addition, microvessel density (MVD) of tumor was detected by immunohistochemistry, and tumor cell apoptosis was also detected by TUNEL staining. The tumor volumes of mice were significantly smaller in combination group than those in other three groups (P < 0.05). Complete regression of tumor was observed in 3 of 10 mice in combination group. Forty-eight days after inoculation of tumor cells, the survival rate of mice was significantly higher in combination group than in NS group (P < 0.01). The anti-VEGF APBC count in combination group or xVEGF group was significantly higher, compared with that in adriamycin group or NS group (P < 0.01). MVD in tumor tissues was significantly lower in combination group than those in other three groups (P < 0.05). Moreover, tumor cell apoptosis was significantly higher in combination group than those in other three groups (P < 0.05). In this experimental study, the use of xVEGF vaccine and adriamycin as a combination of immunotherapy with chemotherapy has sucessfully produced synergistic antitumor effect on lymphoma in mice.

199 Development of a National Guideline on Skin Testing and Immunotherapy

PubMed Central

Linnemann, Désirée Larenas; Ortega Martell, José Antonio; del Rio, Blanca; Rodriguez-Perez, Noel; Arias-Cruz, Alfredo; Estrada, Alan

2012-01-01

Background Several international guidelines exist on allergen immunotherapy (AIT) –eg American, European, British, Spanish, Italian- but local conditions that reign in each country limit their applicability. We present the steps we followed to develop a National Guideline on AIT, taking into account local legislation, extracts available, costs and patient preference. Methods Firstly a Nation-wide survey on the practice of skin testing and AIT was undertaken among all members of Mexican Allergist Societies. Secondly, based on the replies obtained with the survey clinical questions were formulated on critical points and issues susceptible for improvement, as diagnosed by the survey. Thirdly, all 6 Regional Allergist Societies were visited to obtain the opinion of their members on the clinical questions concerning how immunotherapy could best be practiced under local Mexican conditions. This led to the Consensed experience. Fourthly, 6 experts looked for the replies to the clinical questions reviewing the literature and assigning quality of evidence to the articles on the specific issues treated by each clinical question. Results To develop the final document the GRADE approach was used. For each clinical question both, knowledge from the local consensed experience and the evidence-based replies were taken into account, as well as cost, patient preference and safety to make a set of recommendations and suggestions on the most crucial aspects of skin testing and AIT. Forming centers of allergists in Mexico corrected the final draft. The final document came out as the January issue of Revista Mexicana Alergia and was presented by the authors in a National Course on Immunotherapy (May 2011), with—apart from the lectures—a more workshop-like part to allow for practical exercising and discussion. The updated questions on allergen immunotherapy for the final board exam are based on the Guideline. Allergy-residents developed a slide-show. In 2012 Regional Allergist Societies shall be visited again. Conclusions We present a democratic way of how a National Guideline can be developed, supported by evidence-based medicine and local experience in a country where little is legislated on this respect and quality improvement has to be stimulated by the professional community. We show how implementation can be enhanced.

TIL 2.0: More effective and predictive T-cell products by enrichment for defined antigen specificities.

PubMed

Schober, Kilian; Busch, Dirk H

2016-06-01

Adoptive transfer of in vitro-expanded T cells derived from tumor-infiltrating lymphocytes (TILs) in melanoma patients started the era of tumor immunotherapy three decades ago. The approach has demonstrated remarkable clinical responses in several studies since. Reinfusion of TIL-derived T cells represents a highly personalized form of immunotherapy, taking into account the enormous interindividual tumor heterogeneity. However, despite its successes, TIL therapy does not lead to objective clinical responses in all cases. It is thus crucial to find out which tumor antigens are particularly valuable targets and to develop strategies to enhance the reactivity of T-cell products toward them. In this issue of the European Journal of Immunology, Kelderman et al. [Eur. J. Immunol. 2016. 46: 1351-1360] present a platform for the generation of antigen-specific TIL therapy. Combining recently developed technologies for clinical identification and enrichment of antigen-specific CD8(+) T cells, such as MHC Streptamers and UV-mediated peptide exchange, the authors could enrich T-cell populations with defined antigen specificities from melanoma-derived TILs. This T-cell product showed higher reactivity against autologous tumor cell lines than bulk TIL-derived T cells. The novel platform might enable the generation of more effective and predictable TIL-derived T-cell products for future clinical applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

In vitro immunotherapy potency assays using real-time cell analysis

PubMed Central

Cerignoli, Fabio; Abassi, Yama A.; Lamarche, Brandon J.; Guenther, Garret; Santa Ana, David; Guimet, Diana; Zhang, Wen; Zhang, Jing

2018-01-01

A growing understanding of the molecular interactions between immune effector cells and target tumor cells, coupled with refined gene therapy approaches, are giving rise to novel cancer immunotherapeutics with remarkable efficacy in the clinic against both solid and liquid tumors. While immunotherapy holds tremendous promise for treatment of certain cancers, significant challenges remain in the clinical translation to many other types of cancers and also in minimizing adverse effects. Therefore, there is an urgent need for functional potency assays, in vitro and in vivo, that could model the complex interaction of immune cells with tumor cells and can be used to rapidly test the efficacy of different immunotherapy approaches, whether it is small molecule, biologics, cell therapies or combinations thereof. Herein we report the development of an xCELLigence real-time cytolytic in vitro potency assay that uses cellular impedance to continuously monitor the viability of target tumor cells while they are being subjected to different types of treatments. Specialized microtiter plates containing integrated gold microelectrodes enable the number, size, and surface attachment strength of adherent target tumor cells to be selectively monitored within a heterogeneous mixture that includes effector cells, antibodies, small molecules, etc. Through surface-tethering approach, the killing of liquid cancers can also be monitored. Using NK92 effector cells as example, results from RTCA potency assay are very well correlated with end point data from image-based assays as well as flow cytometry. Several effector cells, i.e., PBMC, NK, CAR-T were tested and validated as well as biological molecules such as Bi-specific T cell Engagers (BiTEs) targeting the EpCAM protein expressed on tumor cells and blocking antibodies against the immune checkpoint inhibitor PD-1. Using the specifically designed xCELLigence immunotherapy software, quantitative parameters such as KT50 (the amount of time it takes to kill 50% of the target tumor cells) and % cytolysis are calculated and used for comparing the relative efficacy of different reagents. In summary, our results demonstrate the xCELLigence platform to be well suited for potency assays, providing quantitative assessment with high reproducibility and a greatly simplified work flow. PMID:29499048

A randomized trial of immunotherapy for persistent genital warts

PubMed Central

Jardine, David; Lu, Jieqiang; Pang, James; Palmer, Cheryn; Tu, Quanmei; Chuah, John; Frazer, Ian H.

2012-01-01

Aim To determine whether immunotherapy with HPV6 L1 virus like particles (VLPs) without adjuvant (VLP immunotherapy) reduces recurrence of genital warts following destructive therapy. Trial design A randomized placebo controlled blinded study of treatment of recurrent genital warts amenable to destructive therapy, conducted independently in Australia and China. Methods Patients received conventional destructive therapy of all evident warts together with intramuscular administration of 1, 5 or 25 µg of VLP immunotherapy, or of placebo immunotherapy (0.9% NaCl), as immunotherapy at week 0 and week 4. Primary outcome, assessed at week 8, was recurrence of visible warts. Results Of 33 protocol compliant Brisbane recipients of placebo immunotherapy, 11 were disease free at two months, and a further 9 demonstrated reduction of > 50% in total wart area. Wart area reduction following destructive treatment correlated with prior duration of disease. Among 102 protocol compliant Brisbane recipients of VLP immunotherapy, disease reduction was significantly greater than among the placebo immunotherapy (50% ± s.e.m. 7%) recipients for subjects receiving 5 µg or 25 µg of VLP immunotherapy/dose (71% ± s.e.m.7%) but not for those receiving 1 µg VLP immunotherapy/dose (42% ± 7%). Of 52 protocol compliant placebo immunotherapy recipients in Wenzhou, 37 were disease free at two months, and a further 8 had > 50% disease reduction. Prior disease duration was much shorter in Wenzhou subject (8.1 ± 1.1 mo) than in Brisbane subjects (53.7 ± 5.5 mo). No significant reduction in mean wart area was observed for the 168 Wenzhou protocol compliant subjects who also received VLP immunotherapy. Conclusions This study confirms the findings in a previous open label trial that administration of VLP immunotherapy may assist in clearance of recurrent genital warts in patients for whom destructive therapy is unsuccessful and that unsuccessful destructive therapy is more common with increasing prior disease duration. PMID:22634446

Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects.

PubMed

Shi, Huan; Sun, Meili; Liu, Lin; Wang, Zhehai

2014-09-21

Chimeric antigen receptors (CARs) are recombinant receptors that combine the specificity of an antigen-specific antibody with the T-cell's activating functions. Initial clinical trials of genetically engineered CAR T cells have significantly raised the profile of T cell therapy, and great efforts have been made to improve this approach. In this review, we provide a structural overview of the development of CAR technology and highlight areas that require further refinement. We also discuss critical issues related to CAR therapy, including the optimization of CAR T cells, the route of administration, CAR toxicity and the blocking of inhibitory molecules.

Delta One T Cells for Immunotherapy of Chronic Lymphocytic Leukemia: Clinical-Grade Expansion/Differentiation and Preclinical Proof of Concept.

PubMed

Almeida, Afonso R; Correia, Daniel V; Fernandes-Platzgummer, Ana; da Silva, Cláudia L; da Silva, Maria Gomes; Anjos, Diogo Remechido; Silva-Santos, Bruno

2016-12-01

The Vδ1 + subset of γδ T lymphocytes is a promising candidate for cancer immunotherapy, but the lack of suitable expansion/differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a Vδ1 + T-cell-based protocol that is good manufacturing practice compatible and devoid of feeder cells for prompt clinical translation. We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (more than 2-3 weeks) Vδ1 + T cells from the peripheral blood of healthy donors and patients with chronic lymphocytic leukemia (CLL). We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL). We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinical-grade cell culture bags) and differentiation of cytotoxic Vδ1 + (DOT) cells. These expressed the natural cytotoxicity receptors, NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss of function; indeed, DOT cells proliferated and produced abundant IFNγ and TNFα, but importantly no IL17, in vivo Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL. We provide a clinical-grade method and the preclinical proof of principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL. Clin Cancer Res; 22(23); 5795-804. ©2016 AACR. ©2016 American Association for Cancer Research.

Efficient clearance of Aβ protofibrils in AβPP-transgenic mice treated with a brain-penetrating bifunctional antibody.

PubMed

Syvänen, Stina; Hultqvist, Greta; Gustavsson, Tobias; Gumucio, Astrid; Laudon, Hanna; Söderberg, Linda; Ingelsson, Martin; Lannfelt, Lars; Sehlin, Dag

2018-05-24

Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Despite recent progress targeting aggregated forms of Aβ, low antibody brain penetrance remains a challenge. In the present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed Aβ protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble Aβ protofibrils. Aβ protein precursor (AβPP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFv8D3), in comparison with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158). Soluble Aβ protofibrils and total Aβ in the brain were measured by enzyme-linked immunosorbent assay (ELISA). Brain distribution of radiolabeled antibodies was visualized by positron emission tomography (PET) and ex vivo autoradiography. ELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble Aβ protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no Aβ protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed different brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect Aβ levels by different mechanisms. With a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood-brain barrier can be used to increase the efficacy of Aβ immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs.

Scope for innovation in immunotherapy from the financial market's point of view: Phacilitate Immunotherapy Leaders' Forum 2012.

PubMed

Zilian, Olav

2012-10-01

In the vast area of immunotherapies, the development of monoclonal antibodies as a therapeutic concept emerged as a quantum leap out of the area of traditional vaccines (Köhler and Milstein) in vitro selection and optimisation made it possible to elaborate a single biological molecule from the molecular plethora of an individual adaptive immune response and to utilize such a cloned antibody repeatedly in a generalized fashion whenever the therapeutic indication is given to humans. At present, some 25 therapeutic monoclonal antibodies are currently being marketed in oncology, exceeding sales of USD20bn in 2011. A total of about 270 antibodies are currently in Phase II and III clinical development. Working on the assumption of usually lower attrition rates for antibody candidates, we expect approximately 120 of these 270 antibodies to be finally approved. This poses some key questions. What level of differentiation is required so that the coming new antibody drugs can command premium pricing when members of the founding generation become generic and inexpensive? What will global demand for antibody drugs be in view of the rising buying power in emerging pharmaceutical ('pharmerging') markets, but which is still not comparable with that of developed ones? What would the next quantum leaps be that might potentially push antibody technology on to a next level by disruptive innovation? Presentations given at the Phacilitate Immunotherapy Leaders' Forum 2012 (9-11 May in Barcelona) reflected on these questions and provided some stimulating perspectives.

E-ADA activity in lymphocytes of an experimental model of pythiosis treated with immunotherapy.

PubMed

Bach, Barbara Charlotte; Leal, Daniela Bitencourt Rosa; Jaques, Jeandre Augusto dos Santos; Souza, Viviane do Carmo Gonçalves; Ruchel, Jader Betsch; Schlemmer, Karine Bizzi; Zanette, Régis Adriel; Hecktheuer, Pedro Abib; de Lima Pereira, Patrique; Casali, Emerson André; Alves, Sydney Hartz; Santurio, Janio Morais

2013-08-01

Pythiosis is a life-threatening disease caused by the oomycete Pythium insidiosum. Some authors have suggested the involvement of a Th2-like immune response in the infected host, which leads to extensive tissue damage. The switch from a Th2 to a Th1 response pattern is one hypothesis to explain the curative properties of immunotherapy. Taking into account the importance of immunotherapy for pythiosis treatment and the contribution of adenine nucleotides in the immunoregulation of the host, we evaluated the ecto-adenosine deaminase (E-ADA; EC 3·5.4·4) activity in lymphocytes from rabbits inoculated with P. insidiosum. Rabbits were inoculated with 1 milliliter of zoospores subcutaneously injected into the lateral thorax; after developing lesions, the rabbits received eight doses of immunotherapy. E-ADA activity was measured in lymphocytes and the adenine nucleotides and adenosine levels were quantitatively determined in serum. Rabbits with characteristic lesions of pythiosis showed a decreased E-ADA activity (82·36%), a decreased adenosine triphosphate concentration (54·04%) and a higher adenosine concentration (2·51 fold), when compared with controls, after 28 days of inoculation. However, after the immunotherapy, the rabbits showed an increase in the E-ADA activity when compared with control (78·62%), contributing for the change in the immune response. Our results reinforce the hypothesis that the change from a Th2 to a Th1 immune response with the participation of the purinergic system could be responsible for the curative properties of immunotherapy. Copyright © 2012 John Wiley & Sons, Ltd.

Cancer vaccine development: Designing tumor cells for greater immunogenicity

PubMed Central

Bozeman, Erica N.; Shashidharamurthy, Rangaiah; Paulos, Simon A.; Palaniappan, Ravi; D’Souza, Martin; Selvaraj, Periasamy

2014-01-01

Cancer vaccine development is one of the most hopeful and exhilarating areas in cancer research. For this reason, there has been a growing interest in the development and application of novel immunotherapies for the treatment of cancer with the focus being on stimulating the immune system to target tumor cells specifically while leaving normal cells unharmed. From such research has emerged a host of promising immunotherapies such as dendritic cell-based vaccines, cytokine therapies and gene transfer technology. These therapies seek to counteract the poor immunogenicity of tumors by augmenting the host’s immune system with a variety of immunostimulatory proteins such as cytokines and costimulatory molecules. While such therapies have proven effective in the induction of anti-tumor immunity in animal models, they are less than optimal and pose a high risk of clinical infeasibility. Herein, we further discuss these immunotherapies as well as a feasible and efficient alternative that, in pre-clinical animal models, allows for the expression of specific immunostimulatory molecules on the surface of tumor cells by a novel protein transfer technology. PMID:20036822

Issues in stinging insect allergy immunotherapy: a review.

PubMed

Finegold, Ira

2008-08-01

The treatment of insect allergy by desensitization still continues to present with some unanswered questions. This review will focus mainly on articles that have dealt with these issues in the past 2 years. With the publication in 2007 of Allergen Immunotherapy: a practice parameter second update, many of the key issues were reviewed and summarized. Other recent studies deal with omalizumab pretreatment of patients with systemic mastocytosis and very severe allergic reactions to immunotherapy. It would appear that venom immunotherapy is somewhat unique compared to inhalant allergen immunotherapy in that premedication prior to rush protocols may not be necessary and that intervals of therapy may be longer than with allergen immunotherapy. The use of concomitant medications such as beta-blockers may be indicated in special situations. Angiotensin-converting enzyme inhibitors can be stopped temporarily before venom injections to prevent reactions. The issue of when to discontinue immunotherapy remains unsettled and should be individualized to patient requirements. The newest revision of the Immunotherapy Parameters provides much needed information concerning successful treatment with immunotherapy of Hymenoptera-sensitive patients.

Chimeric Antigen Receptors that Recognize Mesothelin for Cancer Immunotherapy | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the NCI have developed chimeric antigen receptors (CARs) with a high affinity for mesothelin to be used as an immunotherapy to treat pancreatic cancer, ovarian cancer, and mesothelioma. Cells that express CARs, most notably T cells, are highly reactive against their specific tumor antigen in an MHC-unrestricted manner to generate an immune response that promotes robust tumor cell elimination when infused into cancer patients.

Immunogenic Antigen Selective Cancer Immunotherapy | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the National Institute on Aging working on cancer immunotherapy and detection report the use of SPANX-B polypeptides in the treatment and identification of cancer. Specific human malignancies targeted for the treatments disclosed include melanoma and lung, colon, renal, ovarian and breast carcinomas. The NIA seeks parties interested in licensing or collaborative research to further develop, evaluate, or commercialize SPANX-B polypeptides in the treatment and identification of cancer.

A Platform for Designing Genome-Based Personalized Immunotherapy or Vaccine against Cancer

PubMed Central

Gupta, Sudheer; Chaudhary, Kumardeep; Dhanda, Sandeep Kumar; Kumar, Rahul; Kumar, Shailesh; Sehgal, Manika; Nagpal, Gandharva

2016-01-01

Due to advancement in sequencing technology, genomes of thousands of cancer tissues or cell-lines have been sequenced. Identification of cancer-specific epitopes or neoepitopes from cancer genomes is one of the major challenges in the field of immunotherapy or vaccine development. This paper describes a platform Cancertope, developed for designing genome-based immunotherapy or vaccine against a cancer cell. Broadly, the integrated resources on this platform are apportioned into three precise sections. First section explains a cancer-specific database of neoepitopes generated from genome of 905 cancer cell lines. This database harbors wide range of epitopes (e.g., B-cell, CD8+ T-cell, HLA class I, HLA class II) against 60 cancer-specific vaccine antigens. Second section describes a partially personalized module developed for predicting potential neoepitopes against a user-specific cancer genome. Finally, we describe a fully personalized module developed for identification of neoepitopes from genomes of cancerous and healthy cells of a cancer-patient. In order to assist the scientific community, wide range of tools are incorporated in this platform that includes screening of epitopes against human reference proteome (http://www.imtech.res.in/raghava/cancertope/). PMID:27832200

Phage display peptide libraries in molecular allergology: from epitope mapping to mimotope-based immunotherapy.

PubMed

Luzar, J; Štrukelj, B; Lunder, M

2016-11-01

Identification of allergen epitopes is a key component in proper understanding of the pathogenesis of type I allergies, for understanding cross-reactivity and for the development of mimotope immunotherapeutics. Phage particles have garnered recognition in the field of molecular allergology due to their value not only in competitive immunoscreening of peptide libraries but also as immunogenic carriers of allergen mimotopes. They integrate epitope discovery technology and immunization functions into a single platform. This article provides an overview of allergen mimotopes identified through the phage display technique. We discuss the contribution of phage display peptide libraries in determining dominant B-cell epitopes of allergens, in developing mimotope immunotherapy, in understanding cross-reactivity, and in determining IgE epitope profiles of individual patients to improve diagnostics and individualize immunotherapy. We also discuss the advantages and pitfalls of the methodology used to identify and validate the mimotopes. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4+ T cells tolerized by peptide immunotherapy

PubMed Central

McPherson, Rhoanne C; Konkel, Joanne E; Prendergast, Catriona T; Thomson, John P; Ottaviano, Raffaele; Leech, Melanie D; Kay, Oliver; Zandee, Stephanie E J; Sweenie, Claire H; Wraith, David C; Meehan, Richard R; Drake, Amanda J; Anderton, Stephen M

2014-01-01

Clinically effective antigen-based immunotherapy must silence antigen-experienced effector T cells (Teff) driving ongoing immune pathology. Using CD4+ autoimmune Teff cells, we demonstrate that peptide immunotherapy (PIT) is strictly dependent upon sustained T cell expression of the co-inhibitory molecule PD-1. We found high levels of 5-hydroxymethylcytosine (5hmC) at the PD-1 (Pdcd1) promoter of non-tolerant T cells. 5hmC was lost in response to PIT, with DNA hypomethylation of the promoter. We identified dynamic changes in expression of the genes encoding the Ten-Eleven-Translocation (TET) proteins that are associated with the oxidative conversion 5-methylcytosine and 5hmC, during cytosine demethylation. We describe a model whereby promoter demethylation requires the co-incident expression of permissive histone modifications at the Pdcd1 promoter together with TET availability. This combination was only seen in tolerant Teff cells following PIT, but not in Teff that transiently express PD-1. Epigenetic changes at the Pdcd1 locus therefore determine the tolerizing potential of TCR-ligation. DOI: http://dx.doi.org/10.7554/eLife.03416.001 PMID:25546306

Do immunotherapy and beta cell replacement play a synergistic role in the treatment of type 1 diabetes?

PubMed

Li, Dong-Sheng; Warnock, Garth L; Tu, Han-Jun; Ao, Ziliang; He, Zehua; Lu, Hong; Dai, Long-Jun

2009-10-07

Type 1 diabetes (T1D) is the result of the autoimmune response against pancreatic insulin-producing ss-cells. Its ultimate consequence is beta-cell insufficiency-mediated dysregulation of blood glucose control. In terms of T1D treatment, immunotherapy addresses the cause of T1D, mainly through re-setting the balance between autoimmunity and regulatory mechanisms. Regulatory T cells play an important role in this immune intervention. An alternative T1D treatment is beta-cell replacement, which can reverse the consequence of the disease by replacing destroyed beta-cells in the diabetic pancreas. The applicable insulin-producing cells can be directly obtained from islet transplantation or generated from other cell sources such as autologous adult stem cells, embryonic stem cells, and induced pluripotent stem cells. In this review, we summarize the recent research progress and analyze the possible advantages and disadvantages of these two therapeutic options especially focusing on the potential synergistic effect on T1D treatment. Exploring the optimal combination of immunotherapy and beta-cell replacement will pave the way to the most effective cure for this devastating disease.

Novel immunotherapies for hematological malignancies

PubMed Central

Nelson, Michelle H.; Paulos, Chrystal M.

2014-01-01

Summary The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise the state of the art in immunotherapy with a focus on strategies that exploit the patient’s immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematological malignancies, including (i) conventional monoclonal therapies like rituximab, (ii) engineered monoclonal antibodies called bispecific T cell engagers (BiTEs), (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4 and IDO), and (iv) adoptive cell transfer (ACT) therapy with T cells engineered to express chimeric antigen receptors (CARs) or T-cell receptors (TCRs). We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients. PMID:25510273

IFN-λ cancer immunotherapy: new kid on the block.

PubMed

Lasfar, Ahmed; Gogas, Helen; Zloza, Andrew; Kaufman, Howard L; Kirkwood, John M

2016-07-01

Interferon-lambda (IFN-λ) is a new IFN type, related to IFN-α, that is commonly used in the clinic. However, significant side effects accompanying IFN-α treatment limit enthusiasm for IFN-α. In this review, we discuss the current landscape of IFN-α use in oncology and describe the biologic characteristics of IFN-λ. IFN-λ offers unique advantages, including a more tumor cell selective targeting, lower off-target binding and an ability to generate both innate and adaptive immune responses. IFN-λ has also demonstrated therapeutic benefit in murine cancer models. IFN-λ may be used in clinic as a single agent or in combination with other immunotherapy agents, such as immune checkpoint inhibitors. Further clinical trials will be needed to fully elucidate the potential of this novel agent in oncology.

Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

PubMed

Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

2015-01-01

Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.

New Therapies in Head and Neck Cancer.

PubMed

Santuray, Rodell T; Johnson, Daniel E; Grandis, Jennifer R

2018-05-01

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high rates of mortality and morbidity. Beginning with cetuximab, investigators continue to optimize antibody technology to target cell-surface receptors that promote HNSCC growth. Small molecules and oligonucleotides have also emerged as therapeutic inhibitors of key receptor-mediated signaling pathways. Although many such therapies have been disappointing in clinical trials as single agents, they continue to be studied in combination with standard therapies. Approvals of pembrolizumab and nivolumab opened a new era of immunotherapy that aims to stimulate antitumor immunity in the tumor microenvironment. Immunotherapies are being intensively investigated in new HNSCC clinical trials, with the goal of optimizing the therapeutic potential of this new class of anticancer agent. Copyright © 2018 Elsevier Inc. All rights reserved.

Targeting myeloid-derived suppressor cells for cancer immunotherapy.

PubMed

Liu, Yijun; Wei, Guowei; Cheng, Wesley A; Dong, Zhenyuan; Sun, Han; Lee, Vincent Y; Cha, Soung-Chul; Smith, D Lynne; Kwak, Larry W; Qin, Hong

2018-05-31

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with an immune suppressive phenotype. They represent a critical component of the immune suppressive niche described in cancer, where they support immune escape and tumor progression through direct effects on both the innate and adaptive immune responses, largely by contributing to maintenance of a high oxidative stress environment. The number of MDSCs positively correlates with protumoral activity, and often diminishes the effectiveness of immunotherapies, which is particularly problematic with the emergence of personalized medicine. Approaches targeting MDSCs showed promising results in preclinical studies and are under active investigation in clinical trials in combination with various immune checkpoint inhibitors. In this review, we discuss MDSC targets and therapeutic approaches targeting MDSC that have the aim of enhancing the existing tumor therapies.

Development of InCVAX as a novel in situ autologous vaccine for metastatic cancers (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hode, Tomas; Alleruzzo, Luciano; Raker, Joseph; Lam, Samuel Siu Kit; Nordquist, Robert E.; Chen, Wei R.

2016-03-01

A novel method, an in situ autologous whole-cell cancer vaccine (inCVAX), is being developed by Immunophotonics, Inc., for the treatment of metastatic cancers. inCVAX combines phototherapy and immunotherapy to potentially induce a systemic anti-tumor immune response in the hosts. Immunophotonics and its academic partners have spent years conducting nonclinical research, developing CMC techniques and conducting clinical research. In 2015 the company initiated a late-stage (II/III) clinical trial in South America for advanced breast cancer patients. The process of developing the inCVAX approach from a laboratory setting into clinical trials requires significant efforts from a group of dedicated engineers, scientists, and physicians. The growth of the company and its business advances demonstrated the determination of a group of visionary investors, entrepreneurs, and business leaders. This talk will chronicle the milestones of the scientific achievement, medical progress, and business development of Immunophotonics.

Low-dose radiation potentiates the therapeutic efficacy of folate receptor-targeted hapten therapy.

PubMed

Sega, Emanuela I; Lu, Yingjuan; Ringor, Michael; Leamon, Christopher P; Low, Philip S

2008-06-01

Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm(3) before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy. Mice bearing 300-mm(3) subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon alpha) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm(3). More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.

Effect on quality of life of the mixed house dust mite/weed pollen extract immunotherapy.

PubMed

Li, Lisha; Guan, Kai

2016-07-01

Although many patients with allergic rhinitis have symptoms due to sensitization to more than one kind of allergens, and mixed allergen extracts are widely used for immunotherapy, there are few published trials. Our study aimed to evaluate the effect of multiple-allergen immunotherapy on improving the symptoms and quality of life of allergic rhinitis patients. We performed a 1-year single-center observation study of subcutaneous immunotherapy using house dust mite extract (n = 12), weed pollen extract (n = 21), or mixed house dust mite/weed pollen extract (n = 11) in 44 allergic rhinitis patients. All the allergens responsible for the symptom of each patient were included in his immunotherapy. Symptom score, medication score, and quality of life of the patients were evaluated before and after 1-year immunotherapy. Quality of life was evaluated with the Rhinoconjunctivitis Quality of Life Questionnaire. In all 3 groups receiving subcutaneous immunotherapy, significant improvement of symptom score, medication score, and quality of life was found vs. baseline at 1 year, irrespective of the allergen used. In the weed pollen season, the changes of quality of life questionnaire score after 1-year treatment were not significantly different between the weed pollen group (1.55 ± 1.24) and the mixed house dust mite/weed pollen group (1.14 ± 1.01). The same happened in the nonpollen seasons, during which dust mite immunotherapy (1.23 ± 1.63) and mixed immunotherapy (0.60 ± 0.47) did not show significantly different effect on the quality of life. The multiple-allergen immunotherapy might be effective in polysensitized allergic rhinitis patients, and could improve their quality of life. Our result did not show significant difference between the effects of multiple-allergen immunotherapy and mono-allergen immunotherapy.

Specific immunotherapy in grass pollen allergy

PubMed Central

Mailhol, Claire; Didier, Alain

2012-01-01

Since its description by Noon in 1911, desensitization, or allergen specific immunotherapy (SIT), has been largely used in respiratory allergic diseases treatment. It remains the only etiologic treatment for allergic diseases. The development of the sublingual route and new forms of medication, as an alternative to subcutaneous injection, has led to large scale clinical trials. Many of them had been performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing all respiratory allergic symptoms. Data on long-term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on natural history of allergic disease, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this therapeutic method in the future. The sublingual route appears to be safer with a better safety profile. This may lead to an extension of allergen specific immunotherapy indications in patients with respiratory allergic diseases. PMID:23095875

Allergy immunotherapy across the life cycle to promote active and healthy ageing: from research to policies: An AIRWAYS Integrated Care Pathways (ICPs) programme item (Action Plan B3 of the European Innovation Partnership on active and healthy ageing) and the Global Alliance against Chronic Respiratory Diseases (GARD), a World Health Organization GARD research demonstration project.

PubMed

Calderon, M A; Demoly, P; Casale, T; Akdis, C A; Bachert, C; Bewick, M; Bilò, B M; Bohle, B; Bonini, S; Bush, A; Caimmi, D P; Canonica, G W; Cardona, V; Chiriac, A M; Cox, L; Custovic, A; De Blay, F; Devillier, P; Didier, A; Di Lorenzo, G; Du Toit, G; Durham, S R; Eng, P; Fiocchi, A; Fox, A T; van Wijk, R Gerth; Gomez, R M; Haathela, T; Halken, S; Hellings, P W; Jacobsen, L; Just, J; Tanno, L K; Kleine-Tebbe, J; Klimek, L; Knol, E F; Kuna, P; Larenas-Linnemann, D E; Linneberg, A; Matricardi, M; Malling, H J; Moesges, R; Mullol, J; Muraro, A; Papadopoulos, N; Passalacqua, G; Pastorello, E; Pfaar, O; Price, D; Del Rio, P Rodriguez; Ruëff, R; Samolinski, B; Scadding, G K; Senti, G; Shamji, M H; Sheikh, A; Sisul, J C; Sole, D; Sturm, G J; Tabar, A; Van Ree, R; Ventura, M T; Vidal, C; Varga, E M; Worm, M; Zuberbier, T; Bousquet, J

2016-01-01

Allergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a working group of AIRWAYS integrated care pathways for airways diseases, the model of chronic respiratory diseases of the European Innovation Partnership on active and healthy ageing (DG CONNECT and DG Santé). It considered (1) the political background, (2) the rationale for allergen immunotherapy across the life cycle, (3) the unmet needs for the treatment, in particular in preschool children and old age adults, (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunotherapy, its mechanisms and the concept of active and healthy ageing.

Immunotherapy for Prostate Cancer: Lessons from Responses to Tumor-Associated Antigens

PubMed Central

Westdorp, Harm; Sköld, Annette E.; Snijer, Berit A.; Franik, Sebastian; Mulder, Sasja F.; Major, Pierre P.; Foley, Ronan; Gerritsen, Winald R.; de Vries, I. Jolanda M.

2014-01-01

Prostate cancer (PCa) is the most common cancer in men and the second most common cause of cancer-related death in men. In recent years, novel therapeutic options for PCa have been developed and studied extensively in clinical trials. Sipuleucel-T is the first cell-based immunotherapeutic vaccine for treatment of cancer. This vaccine consists of autologous mononuclear cells stimulated and loaded with an immunostimulatory fusion protein containing the prostate tumor antigen prostate acid posphatase. The choice of antigen might be key for the efficiency of cell-based immunotherapy. Depending on the treatment strategy, target antigens should be immunogenic, abundantly expressed by tumor cells, and preferably functionally important for the tumor to prevent loss of antigen expression. Autoimmune responses have been reported against several antigens expressed in the prostate, indicating that PCa is a suitable target for immunotherapy. In this review, we will discuss PCa antigens that exhibit immunogenic features and/or have been targeted in immunotherapeutic settings with promising results, and we highlight the hurdles and opportunities for cancer immunotherapy. PMID:24834066

Immunotherapeutic strategies for the treatment of renal cell carcinoma: Where will we go?

PubMed

Anselmo Da Costa, Inês; Rausch, Steffen; Kruck, Stephan; Todenhöfer, Tilman; Stenzl, Arnulf; Bedke, Jens

2017-04-01

Historically, renal cell carcinoma (RCC) is considered a chemotherapy-resistant tumor. The cornerstone of systemic therapy included mammalian target of rapamycin (mTOR) inhibitors, endothelial growth factor receptor (VEGFR) and tyrosine kinase inhibitors (TKIs). Currently, a new era is enteres with promising immunotherapeutic treatments, which are becoming commercially available. Areas covered: We provide a comprehensive review using PubMed and ClinicalTrials.gov about the following immunotherapies in RCC: i) vaccine therapy, ii) adoptive T Cell Transfer and CAR T cells, iii) nonspecific immunotherapy - IL-2 (new formulations), iv) Checkpoint inhibitors, v) other checkpoint-molecules. We will also discuss their mechanism of action and toxicity, the importance of developing new patient selection algorithms (immunoprofiling, guidelines updates) and new biomarkers such as PD-1 expression. Expert commentary: Immunotherapy shows promise, and the current tools used in clinical practice, including guidelines, staging-classification and algorithms should be revised and adapted to the new immunotherapeutic drugs. Although immunotherapy in RCC show promising results, more research is needed in parallel to discover biomarkers that enable the prediction of a treatment response and therefore lead to better patient selection.

Molecular biomarkers for grass pollen immunotherapy

PubMed Central

Popescu, Florin-Dan

2014-01-01

Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines. PMID:25237628

Greater Real-Life Diagnostic Efficacy of Allergen Molecule-Based Diagnosis for Prescription of Immunotherapy in an Area with Multiple Pollen Exposure

PubMed Central

Saltabayeva, Ulbosin; Garib, Victoria; Morenko, Marina; Rosenson, Rafail; Ispayeva, Zhanat; Gatauova, Madina; Zulus, Loreta; Karaulov, Alexander; Gastager, Felix; Valenta, Rudolf

2017-01-01

Background Allergen molecule-based diagnosis has been suggested to facilitate the identification of disease-causing allergen sources and the prescription of allergen-specific immunotherapy (AIT). The aim of the current study was to compare allergen molecule-based IgE serology with allergen extract-based skin testing for the identification of the disease-causing allergen sources. The study was conducted in an area where patients are exposed to pollen from multiple sources (trees, grasses, and weeds) at the same time to compare the diagnostic efficiency of the 2 forms of diagnosis. Methods Patients from Astana, Kazakhstan, who suffered from pollen-induced allergy (n = 95) were subjected to skin prick testing (SPT) with a local panel of tree pollen, grass pollen, and weed pollen allergen extracts and IgE antibodies specific for marker allergen molecules (nArt v 1, nArt v 3, rAmb a 1, rPhl p 1, rPhl p 5, rBet v 1) were measured by ImmunoCAP. Direct and indirect costs for diagnosis based on SPT and marker allergen-based IgE serology as well as direct costs for immunotherapy depending on SPT and serological test results were calculated. Results The costs for SPT-based diagnosis per patient were lower than the costs for allergen molecule-based IgE serology. However, allergen molecule-based serology was more precise in detecting the disease-causing allergen sources. A lower number of immunotherapy treatments (n = 119) was needed according to molecular diagnosis as compared to extract-based diagnosis (n = 275), which considerably reduced the total costs for diagnosis and for a 3-year treatment from EUR 1,112.30 to 521.77 per patient. Conclusions The results from this real-life study show that SPT is less expensive than allergen molecule-based diagnostic testing, but molecular diagnosis allowed more precise prescription of immunotherapy which substantially reduced treatment costs and combined costs for diagnosis and treatment. PMID:28654920

Factors influencing the quality of Myrmecia pilosula (Jack Jumper) ant venom for use in in vitro and in vivo diagnoses of allergen sensitization and in allergen immunotherapy.

PubMed

Wanandy, T; Dwyer, H E; McLean, L; Davies, N W; Nichols, D; Gueven, N; Brown, S G A; Wiese, M D

2017-11-01

Allergen immunotherapy uses pharmaceutical preparations derived from naturally occurring source materials, which contain water-soluble allergenic components responsible for allergic reactions. The success of in vivo and in vitro diagnoses in allergen sensitization and allergen immunotherapy largely depends on the quality, composition and uniformity of allergenic materials used to produce the active ingredients, and the formulation employed to prepare finished products. We aimed to examine the factors influencing batch-to-batch consistency of Jack Jumper (Myrmecia pilosula) ant venom (JJAV) in the form of active pharmaceutical ingredient (AI) and informed whether factors such as temperature, artificial light and container materials influence the quality of JJAV AIs. We also aimed to establish handling and storage requirements of JJAV AIs to ensure preservation of allergenic activities during usage in the diagnosis of allergen sensitization and in allergen immunotherapy. The quality and consistency of JJAV AIs were analysed using a combination of bicinchoninic acid assay for total protein quantification, HPLC-UV for JJAV allergen peptides quantification, ELISA inhibition for total allergenic potency, SDS-PAGE, AU-PAGE and immunoblot for qualitative assessment of JJAV components, and Limulus Amebocyte Lysate assay for the quantification of endotoxin concentration. API-ZYM and Zymogram assays were used to probe the presence of enzymatic activities in JJAV. Pharmaceutical-grade JJAV for allergen immunotherapy has good batch-to-batch consistency. Temporary storage at 4°C and light exposure do not affect the quality of JJAV. Exposure to temperature above 40°C degrades high MW allergens in JJAV. Vials containing JJAV must be stored frozen and in upright position during long-term storage. We have identified factors, which can influence the quality and consistency of JJAV AIs, and provided a framework for appropriate handling, transporting and storage of JJAV to be used for the diagnosis of allergen sensitization and in AIT. © 2017 John Wiley & Sons Ltd.

In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.

PubMed

Manguso, Robert T; Pope, Hans W; Zimmer, Margaret D; Brown, Flavian D; Yates, Kathleen B; Miller, Brian C; Collins, Natalie B; Bi, Kevin; LaFleur, Martin W; Juneja, Vikram R; Weiss, Sarah A; Lo, Jennifer; Fisher, David E; Miao, Diana; Van Allen, Eliezer; Root, David E; Sharpe, Arlene H; Doench, John G; Haining, W Nicholas

2017-07-27

Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

Passive antibody-mediated immunotherapy for the treatment of malignant gliomas.

PubMed

Mitra, Siddhartha; Li, Gordon; Harsh, Griffith R

2010-01-01

Despite advances in understanding the molecular mechanisms of brain cancer, the outcome of patients with malignant gliomas treated according to the current standard of care remains poor. Novel therapies are needed, and immunotherapy has emerged with great promise. The diffuse infiltration of malignant gliomas is a major challenge to effective treatment; immunotherapy has the advantage of accessing the entire brain with specificity for tumor cells. Therapeutic immune approaches include cytokine therapy, passive immunotherapy, and active immunotherapy. Cytokine therapy involves the administration of immunomodulatory cytokines to activate the immune system. Active immunotherapy is the generation or augmentation of an immune response, typically by vaccination against tumor antigens. Passive immunotherapy connotes either adoptive therapy, in which tumor-specific immune cells are expanded ex vivo and reintroduced into the patient, or passive antibody-mediated therapy. In this article, the authors discuss the preclinical and clinical studies that have used passive antibody-mediated immunotherapy, otherwise known as serotherapy, for the treatment of malignant gliomas.

Evaluation of the Immunologic Impact of RAF Inhibitors to Guide Optimal Combination of RAF Inhibitors and Immunotherapy for the Treatment of Advanced Melanoma

DTIC Science & Technology

2013-10-01

Association  for  Cancer  Research  2012.   4.   Koya  RC,  Mok  S,  Otte  N,  et  al.  BRAF  inhibitor   vemurafenib ...Hodi  FS,  Callahan  M,  Konto  C,  Wolchok  J.  Hepatotoxicity  with  combination   of   vemurafenib  and  ipilimumab

Novel immunotherapy and treatment modality for severe food allergies.

PubMed

Nagakura, Ken-Ichi; Sato, Sakura; Yanagida, Noriyuki; Ebisawa, Motohiro

2017-06-01

In recent years, many studies on oral immunotherapy (OIT) have been conducted; however, few have focused on severe food allergies. The purpose of this review was to assess the efficacy and safety of oral immunotherapies for patients with severe food allergy. We reviewed multiple immunotherapy reports published within a few years or reports focusing on severe food allergies. We also investigated recent studies on OIT and novel food allergy management. Immunotherapies targeting low-dose antigen exposure and oral food challenges using low-dose target volumes may be safer than conventional OIT. It is necessary to consider which immunotherapy regimen is appropriate based on allergy severity of the patient.

Chemotherapy remains an essential element of personalized care for persons with lung cancers

PubMed Central

Hellmann, M. D.; Li, B. T.; Chaft, J. E.; Kris, M. G.

2016-01-01

Molecularly targeted and immunotherapies have improved the care of patients with lung cancers. These successes have rallied calls to replace or avoid chemotherapy. Yet, even in this era of precision medicine and exciting advances, cytotoxic chemotherapies remain an essential component of lung cancer treatment. In the setting of locoregional disease, chemotherapy is the only systemic therapy thus far proven to enhance curability when combined with surgery or radiation. In the metastatic setting, chemotherapy can improve the length and quality of life in many patients. Chemotherapy remains the mainstay of care for individuals whose cancers with oncogenic drivers have acquired resistance to targeted agents. Chemotherapy also has the potential to modulate the immune system to enhance the effectiveness of immune checkpoint inhibitors. In this context, chemotherapy should be framed as a critical component of the armamentarium available for optimizing cancer care rather than an unfortunate anachronism. We examine the role of chemotherapy with precision medicine in the current care of patients with lung cancers, as well as opportunities for future integration in combinations with targeted agents, angiogenesis inhibitors, immunotherapies, and antibody drug conjugates. PMID:27456296

[Secondary and tertiary prevention of allergic asthma in children].

PubMed

Rancé, F; Deschildre, A; Bidat, E; Just, J; Couderc, L; Wanin, S; Weiss, L

2010-12-01

Asthma is a disease of the lung epithelial barrier, most often associated with allergy in children. Asthma and allergy are two distinct diseases, but the phenotypic expression of asthma depends on atopic status. A better definition of phenotypes of asthma would result in better targeting of prevention and treatment modalities. Secondary prevention aims to prevent the onset of asthma and the acquisition of new sensitizations in sensitized children. Studies concerning allergen avoidance are insufficient to reach a definitive conclusion and antihistamines have not been shown to be effective. The results for specific immunotherapy suggest a benefit to prevent transition from allergic rhinitis to asthma and the onset of new sensitizations. Tertiary prevention aims to reduce symptoms in children with an existing allergic asthma diagnosis. The avoidance of known respiratory allergens will only be effective in combination with management of the whole environment. Specific immunotherapy has a real place, in combination with background therapy. It should be used according to guidelines in appropriately treated patients. Copyright © 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Allergen-specific sublingual immunotherapy in the treatment of migraines: a prospective study.

PubMed

Theodoropoulos, D S; Katzenberger, D R; Jones, W M; Morris, D L; Her, C; Cullen, N A M; Morrisa, D L

2011-10-01

Inflammation is a cardinal feature of migraines. A number of observations point to the possibility that an allergic component of a type I (IgE-mediated) nature may be involved in at least some migraineurs. Not only are migraines frequent among patients with allergic rhinitis but quite frequently the same medical approaches are beneficial in both diseases: anti-inflammatories, adrenergic tone modifiers, immune suppressants. The effect that immunotherapy for allergic rhinitis has upon migraines is studied. Patients were recruited who suffered from typical migraines but were not treated with regular migraine controllers (beta blockers, antiepileptics, tricyclics, etc.). They underwent allergen-specific, sublingual immunotherapy with physician-formulated, individually-prepared airborne allergen extracts. Response to treatment was assessed with serum C-reactive protein level changes and symptom scores. Serum C-reactive protein (CRP), an acute phase reactant, was chosen as a marker because its usefulness has already been assessed in interictal migraine activity. Interictal serum CRP levels decline was observed in the course of sublingual immunotherapy. Concurrent improvement in symptom scores for both rhinitis and migraines was also observed. In patients with allergic rhinitis, migraine development and course may have a significant allergic component. Assessment of migraineurs for the possibility of coexisting allergic rhinitis is justified. Treatment of allergic rhinitis by immune response modifiers, such as immunotherapy, may have a place in the management of migraines for these patients.

Beyond immune checkpoint blockade: new approaches to targeting host-tumor interactions in prostate cancer: report from the 2014 Coffey-Holden prostate cancer academy meeting.

PubMed

Miyahira, Andrea K; Kissick, Haydn T; Bishop, Jennifer L; Takeda, David Y; Barbieri, Christopher E; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2015-03-01

The 2014 Coffey-Holden Prostate Cancer Academy Meeting, held in La Jolla, CA from June 26 to 29, 2014, was themed: "Beyond Immune Checkpoint Blockade: New Approaches to Targeting Host-Tumor Interactions in Prostate Cancer." Sponsored by the Prostate Cancer Foundation (PCF), this annual, invitation-only meeting is structured as an action-tank, and brought together 72 investigators with diverse academic backgrounds to discuss the most relevant topics in the fields of prostate cancer immunotherapy and the tumor microenvironment. The questions addressed at the meeting included: mechanisms underlying the successes and failures of prostate cancer immunotherapies, how to trigger an effective immune response against prostate cancer, the tumor microenvironment and its role in therapy resistance and tumor metastasis, clinically relevant prostate cancer mouse models, how host-tumor interactions affect current therapies and tumor phenotypes, application of principles of precision medicine to prostate cancer immunotherapy, optimizing immunotherapy clinical trial design, and complex multi-system interactions that affect prostate cancer and immune responses including the effects of obesity and the potential role of the host microbiome. This article highlights the most significant recent progress and unmet needs that were discussed at the meeting toward the goal of speeding the development of optimal immunotherapies for the treatment of prostate cancer. © 2014 Wiley Periodicals, Inc.

WITHDRAWN: Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma.

PubMed

Sasse, Andre D; Sasse, Emma C; Clark, Luciana Go; Clark, Otavio Augusto Camara

2018-02-06

Malignant melanoma, one of the most aggressive of all skin cancers, is increasing in incidence throughout the world. Surgery remains the cornerstone of curative treatment in earlier stages. Metastatic disease is incurable in most affected people, because melanoma does not respond to most systemic treatments. A number of novel approaches are under evaluation and have shown promising results, but they are usually associated with increased toxicity and cost. The combination of chemotherapy and immunotherapy has been reported to improve treatment results, but it is still unclear whether evidence exists to support this choice, compared with chemotherapy alone. No language restrictions were imposed. To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in people with metastatic malignant melanoma. We searched the Cochrane Skin Group Specialised Register (14 February 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to 30 January 2006 ), EMBASE (2003 to 20 July 2005) and LILACS (1982 to 20 February 2006). References, conference proceedings, and databases of ongoing trials were also used to locate trials. All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age, diagnosed with metastatic melanoma. Two authors independently assessed each study to determine whether it met the pre-defined selection criteria, with differences being resolved through discussion with the review team. Two authors independently extracted the data from the articles using data extraction forms. Quality assessment included an evaluation of various components associated with biased estimates of treatment effect. Whenever possible, a meta-analysis was performed on the extracted data, in order to calculate a weighed treatment effect across trials. Eighteen studies met our criteria and were included in the meta-analysis, with a total of 2625 participants. We found evidence of an increase of objective response rates in people treated with chemoimmunotherapy, in comparison with people treated with chemotherapy. Nevertheless, the impact of these increased response rates was not translated into a survival benefit. We found no difference in survival to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma, with a hazard ratio of 0.89 (95% CI 0.72 to 1.11, P = 0.31). Additionally, we found increased hematological and non-hematological toxicities in people treated with chemoimmunotherapy. We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic melanoma. Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials.

Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

PubMed Central

Qi, Xing-Shun

2017-01-01

Specific immunotherapies, including vaccines with autologous tumor cells and tumor antigen-specific monoclonal antibodies, are important treatments for PC patients. To evaluate the clinical outcomes of PC-specific immunotherapy, we performed a systematic review and meta-analysis of the relevant published clinical trials. The effects of specific immunotherapy were compared with those of nonspecific immunotherapy and the meta-analysis was executed with results regarding the overall survival (OS), immune responses data, and serum cancer markers data. The pooled analysis was performed by using the random-effects model. We found that significantly improved OS was noted for PC patients utilizing specific immunotherapy and an improved immune response was also observed. In conclusion, specific immunotherapy was superior in prolonging the survival time and enhancing immunological responses in PC patients. PMID:28265583

Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype.

PubMed

Irani, Sarosh R; Stagg, Charlotte J; Schott, Jonathan M; Rosenthal, Clive R; Schneider, Susanne A; Pettingill, Philippa; Pettingill, Rosemary; Waters, Patrick; Thomas, Adam; Voets, Natalie L; Cardoso, Manuel J; Cash, David M; Manning, Emily N; Lang, Bethan; Smith, Shelagh J M; Vincent, Angela; Johnson, Michael R

2013-10-01

Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346-4515 pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11-200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immunotherapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross-sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n = 13) (P < 0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenotype. Immunotherapy is associated with excellent control of the frequently anti-epileptic drug refractory seizures, hastens time to recovery, and may prevent the subsequent development of cognitive impairment observed in this study.

Specific immunotherapy in hepatocellular cancer: A systematic review.

PubMed

Baradaran Noveiry, Behnoud; Hirbod-Mobarakeh, Armin; Khalili, Nastaran; Hourshad, Niloufar; Greten, Tim F; Abou-Alfa, Ghassan K; Rezaei, Nima

2017-02-01

In recent years, several novel immunotherapeutic approaches were developed and investigated in patients with hepatocellular carcinoma (HCC). We designed this systematic review, to evaluate clinical efficacy of specific immunotherapy in patients with HCC, according to the guidelines of Border of Immune Tolerance Education and Research Network (BITERN) and Cochrane collaboration. We searched Medline, Scopus, CENTRAL, TRIP, DART, OpenGrey, and ProQuest through the 9th of December 2015. One author reviewed and retrieved citations from these seven databases for irrelevant and duplicate studies, and two other authors independently extracted data from the studies and rated their quality. We collated study findings and calculated a weighted treatment effect across studies using Review Manager. We found 12144 references in seven databases of which 21 controlled studies with 1885 HCC patients in different stages were included in this systematic review after the primary and secondary screenings. Overall, patients undergoing specific immunotherapy had significantly higher overall survival than those in control group (HR = 0.59; 95% CI = 0.47-0.76, P < 0.0001). There was a significant difference in recurrence-free survival between patients undergoing specific immunotherapy and patients in control groups and patients in immunotherapy groups overall had less recurrence than control group (HR = 0.54; 95% CI = 0.46-0.63, P < 0.00001). Results of this systematic review based on the available literature suggest that overall specific immunotherapeutic approaches could be beneficiary for the treatment of patients with HCC. This further supports the current and ongoing evaluations of specific immunotherapies in the field. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Rush immunotherapy for wasp venom allergy seems safe and effective in patients with mastocytosis.

PubMed

Verburg, M; Oldhoff, J M; Klemans, R J B; Lahey-de Boer, A; de Bruin-Weller, M S; Röckmann, H; Sanders, C; Bruijnzeel-Koomen, C A F M; Pasmans, S G M A; Knulst, A C

2015-11-01

Patients with mastocytosis and wasp venom allergy (WA) may benefit from venom immunotherapy (VIT). However, fatal insect sting reactions have been described in mastocytosis patients despite previous immunotherapy. We investigated the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. To investigate the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. We describe nine patients with cutaneous mastocytosis and WA who received VIT. Cutaneous mastocytosis was confirmed by histopathology and systemic mastocytosis was diagnosed according to World Health Organization criteria. VIT was given according to a rush protocol. Given the difference in safety and efficacy of VIT in patients with WA and honeybee venom allergy, we reviewed the literature for VIT with the focus on WA patients with mastocytosis and addressed the difference between patients with cutaneous versus systemic mastocytosis. Nine patients had WA and mastocytosis, of whom six had cutaneous mastocytosis, two combined cutaneous and systemic mastocytosis and one systemic mastocytosis. All patients received rush IT with wasp venom. Most patients had only mild local side effects, with no systemic side effects during the course of VIT. One patient had a systemic reaction upon injection on one occasion, during the updosing phase, with dyspnoea and hypotension, but responded well to treatment. Immunotherapy was continued after temporary dose adjustment without problems. Two patients with a previous anaphylactic reaction were re-stung, without any systemic effects. VIT is safe in cutaneous mastocytosis patients with WA, while caution has to be made in case of systemic mastocytosis. VIT was effective in the patients who were re-stung.

[Anti-PD-1 antibody: basics and clinical application].

PubMed

Tanaka, Yoshimasa; Okamura, Haruki

2013-09-01

Although the treatment of cancer with monoclonal antibodies has long been pursued, T cell-directed immunotherapy has met with limited success. Recently, much attention has been devoted to the blockade of PD-1 signaling to activate an immune response to cancer. PD-1, a protein expressed on T cells, is a member of the CD28 superfamily, and it transmits coinhibitory signals upon engagement with its ligands PD-L1 and PD-L2. Accumulating evidence suggests that the PD-1 system plays pivotal roles in the regulation of autoimmunity, transplantation immunity, infectious immunity, and tumor immunity. Because the interaction of PD-1 with its ligands occurs in the effector phase of killer T cell responses in peripheral blood, anti-PD-1 and anti-PD-L1 monoclonal antibodies are ideal as specific agents to augment T cell responses to tumors with fewer adverse events than with the inhibition of CTLA-4, because the interaction of CTLA-4 with its ligands occurs in the priming phase of T cell responses within lymph nodes. In recent phase I clinical trials, objective responses were observed in patients with melanoma, renal cell carcinoma, and non-small cell lung cancer who underwent immunotherapy with an anti-PD-1 monoclonal antibody. In addition, the antitumor activity of an anti-PD-L1 monoclonal antibody was observed in patients with melanoma, renal cell carcinoma, non-small cell lung cancer, and ovarian cancer. The next frontier of immunotherapy targeting the PD-1 axis is to define patient selection criteria and explore combination therapy with other therapeutic manipulations such as adoptive immunotherapies.

Combination therapy with PD-1/PD-L1 blockade: An overview of ongoing clinical trials.

PubMed

Johnson, C Bryce; Win, Shwe Y

2018-01-01

Monoclonal antibodies (mAbs) that block the programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) receptors are the most clinically advanced tumor immunotherapies. Given the broad antitumor efficacy and novel mechanism of action, numerous combinatorial approaches incorporating PD-1/PD-L1 blockade have been suggested; herein we present a comprehensive analysis of these clinical trials. We queried clinicaltrials.gov for all PD-1/PD-L1 mAbs administered for cancer therapy with an end date of 4/30/2017. A total of 1,218 clinical trials met our search criteria. These trials have a planned enrollment of 227,190 patients, and approximately half (493) were initiated in 2016 alone. Of these over 1,200 trials, 916 combine PD-1/PD-L1 blockade with at least one additional therapy, ranging from traditional treatment modalities like surgery and chemoradiation to newer therapies like small molecule inhibitors and other immunotherapies. The staggering proliferation of clinical trials combining PD-1/PD-L1 blockade with disparate treatments necessitates careful accounting to maximize efficiency and highlight areas of unmet needs. We believe our analysis provides this data and expect it will facilitate the design of future clinical trials in this burgeoning area of oncology research.

Treatment of Canine Oral Melanoma with Nanotechnology-Based Immunotherapy and Radiation.

PubMed

Hoopes, P Jack; Wagner, Robert J; Duval, Kayla; Kang, Kevin; Gladstone, David J; Moodie, Karen L; Crary-Burney, Margaret; Ariaspulido, Hugo; Veliz, Frank A; Steinmetz, Nicole F; Fiering, Steven N

2018-04-12

The presence and benefit of a radiation therapy-associated immune reaction is of great interest as the overall interest in cancer immunotherapy expands. The pathological assessment of irradiated tumors rarely demonstrates consistent immune or inflammatory response. More recent information, primarily associated with the "abscopal effect", suggests a subtle radiation-based systemic immune response may be more common and have more therapeutic potential than previously believed. However, to be of consistent value, the immune stimulatory potential of radiation therapy (RT) will clearly need to be supported by combination with other immunotherapy efforts. In this study, using a spontaneous canine oral melanoma model, we have assessed the efficacy and tumor immunopathology of two nanotechnology-based immune adjuvants combined with RT. The immune adjuvants were administered intratumorally, in an approach termed "in situ vaccination", that puts immunostimulatory reagents into a recognized tumor and utilizes the endogenous antigens in the tumor as the antigens in the antigen/adjuvant combination that constitutes a vaccine. The radiation treatment consisted of a local 6 × 6 Gy tumor regimen given over a 12 day period. The immune adjuvants were a plant-based virus-like nanoparticle (VLP) and a 110 nm diameter magnetic iron oxide nanoparticle (mNPH) that was activated with an alternating magnetic field (AMF) to produce moderate heat (43 °C/60 min). The RT was used alone or combined with one or both adjuvants. The VLP (4 × 200 μg) and mNPH (2 × 7.5 mg/gram tumor) were delivered intratumorally respectively during the RT regimen. All patients received a diagnostic biopsy and CT-based 3-D radiation treatment plan prior to initiating therapy. Patients were assessed clinically 14-21 days post-treatment, monthly for 3 months following treatment, and bimonthly, thereafter. Immunohistopathologic assessment of the tumors was performed before and 14-21 days following treatment. Results suggest that addition of VLPs and/or mNPH to a hypofractionated radiation regimen increases the immune cell infiltration in the tumor, extends the tumor control interval, and has important systemic therapeutic potential.

Laser immunotherapy for advanced solid tumors

NASA Astrophysics Data System (ADS)

Naylor, Mark; Li, Xiaosong; Hode, Tomas; Alleruzzo, Lu; Raker, Joseph; Lam, Siu Kit; Zhou, Feifan; Chen, Wei

2017-02-01

Immunologically oriented therapy (immunotherapy) has arguably proved to be the most effective method for treating advanced melanoma, the prototypical chemotherapy-resistant solid tumor. The efficacy and benefit of immunotherapy for other tumors, including those that are at least partly responsive to chemotherapy, is less well established. Breast cancer, one of the most common of the solid tumors in humans, is partially responsive to traditional chemotherapy. We believe that breast cancer patients, like melanoma patients, will benefit from the application of immunotherapy techniques. Here we review the different forms of laser immunotherapy (LIT), a key type of immunologically oriented therapy, discuss its use in melanoma and in breast cancer, and discuss its potentially pivotal role in the immunotherapy armamentarium.

More Haste, Less Speed: Could Public–Private Partnerships Advance Cellular Immunotherapies?

PubMed Central

Bubela, Tania; Bonter, Katherine; Lachance, Silvy; Delisle, Jean-Sébastien; Gold, E. Richard

2017-01-01

Cellular immunotherapies promise to transform cancer care. However, they must overcome serious challenges, including: (1) the need to identify and characterize novel cancer antigens to expand the range of therapeutic targets; (2) the need to develop strategies to minimize serious adverse events, such as cytokine release syndrome and treatment-related toxicities; and (3) the need to develop efficient production/manufacturing processes to reduce costs. Here, we discuss whether these challenges might better be addressed through forms of public–private research collaborations, including public–private partnerships (PPPs), or whether these challenges are best addressed by way of standard market transactions. We reviewed 14 public–private relationships and 25 underlying agreements for the clinical development of cancer cellular immunotherapies in the US. Most were based on bilateral research agreements and pure market transactions in the form of service contracts and technology licenses, which is representative of the commercialization focus of the field. We make the strategic case that multiparty PPPs may better advance cancer antigen discovery and characterization and improved cell processing/manufacturing and related activities. In the rush toward the competitive end of the translational continuum for cancer cellular immunotherapy and the attendant focus on commercialization, many gaps have appeared in our understanding of cellular biology, immunology, and bioengineering. We conclude that the model of bilateral agreements between leading research institutions and the private sector may be inadequate to efficiently harness the interdisciplinary skills and knowledge of the public and private sectors to bring these promising therapies to the clinic for the benefit of cancer patients. PMID:28861415

More Haste, Less Speed: Could Public-Private Partnerships Advance Cellular Immunotherapies?

PubMed

Bubela, Tania; Bonter, Katherine; Lachance, Silvy; Delisle, Jean-Sébastien; Gold, E Richard

2017-01-01

Cellular immunotherapies promise to transform cancer care. However, they must overcome serious challenges, including: (1) the need to identify and characterize novel cancer antigens to expand the range of therapeutic targets; (2) the need to develop strategies to minimize serious adverse events, such as cytokine release syndrome and treatment-related toxicities; and (3) the need to develop efficient production/manufacturing processes to reduce costs. Here, we discuss whether these challenges might better be addressed through forms of public-private research collaborations, including public-private partnerships (PPPs), or whether these challenges are best addressed by way of standard market transactions. We reviewed 14 public-private relationships and 25 underlying agreements for the clinical development of cancer cellular immunotherapies in the US. Most were based on bilateral research agreements and pure market transactions in the form of service contracts and technology licenses, which is representative of the commercialization focus of the field. We make the strategic case that multiparty PPPs may better advance cancer antigen discovery and characterization and improved cell processing/manufacturing and related activities. In the rush toward the competitive end of the translational continuum for cancer cellular immunotherapy and the attendant focus on commercialization, many gaps have appeared in our understanding of cellular biology, immunology, and bioengineering. We conclude that the model of bilateral agreements between leading research institutions and the private sector may be inadequate to efficiently harness the interdisciplinary skills and knowledge of the public and private sectors to bring these promising therapies to the clinic for the benefit of cancer patients.