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Sample records for dendritic cell-based vaccination

  1. Dendritic cell-based cancer therapeutic vaccines

    PubMed Central

    Palucka, Karolina; Banchereau, Jacques

    2013-01-01

    The past decade has seen tremendous developments in novel cancer therapies, through targeting of tumor cell-intrinsic pathways whose activity is linked to genetic alterations, as well as the targeting of tumor cell-extrinsic factors such as growth factors. Furthermore, immunotherapies are entering the clinic at an unprecedented speed following the demonstration that T cells can efficiently reject tumors and that their anti-tumor activity can be enhanced with antibodies against immune regulatory molecules (checkpoints blockade). Current immunotherapy strategies include monoclonal antibodies against tumor cells or immune regulatory molecules, cell-based therapies such as adoptive transfer of ex vivo activated T cells and natural killer (NK) cells, and cancer vaccines. Herein, we discuss the immunological basis for therapeutic cancer vaccines and how the current understanding of dendritic cell (DC) and T cell biology might enable development of next-generation curative therapies for patients with cancer. PMID:23890062

  2. Dendritic cell-based vaccines: barriers and opportunities

    PubMed Central

    Cintolo, Jessica A; Datta, Jashodeep; Mathew, Sarah J; Czerniecki, Brian J

    2014-01-01

    Dendritic cells (DCs) have several characteristics that make them an ideal vehicle for tumor vaccines, and with the first US FDA-approved DC-based vaccine in use for the treatment of prostate cancer, this technology has become a promising new therapeutic option. However, DC-based vaccines face several barriers that have limited their effectiveness in clinical trials. A major barrier includes the activation state of the DC. Both DC lineage and maturation signals must be selected to optimize the antitumor response and overcome immunosuppressive effects of the tumor microenvironment. Another barrier to successful vaccination is the selection of target antigens that will activate both CD8+ and CD4+ T cells in a potent, immune-specific manner. Finally, tumor progression and immune dysfunction limit vaccine efficacy in advanced stages, which may make DC-based vaccines more efficacious in treating early-stage disease. This review underscores the scientific basis and advances in the development of DC-based vaccines, focuses on current barriers to success and highlights new research opportunities to address these obstacles. PMID:23130928

  3. Dendritic cell-based in vitro assays for vaccine immunogenicity

    PubMed Central

    Vandebriel, Rob J.; Hoefnagel, Marcel H.N.

    2012-01-01

    Dendritic cells (DC) are pivotal in the induction of adaptive immune responses because they can activate naive T-cells. Moreover, they steer these adaptive immune responses by integrating various stimuli, such as from different pathogen associated molecular patterns and the cytokine milieu. Immature DC are very well capable of ingesting protein antigens, whereas mature DC are efficient presenters of peptides to naive T cells. Human DC can be readily cultured from peripheral blood mononuclear cells, which are isolated from human blood. There is a strong need to monitor in a high-throughput fashion the immunogenicity of candidate vaccines during the process of vaccine development. Furthermore, regulators require efficacy and safety testing for batch release. For some vaccines, these tests require animal testing, causing pain and discomfort, which cannot be contested because it would interfere with the test results. With the aims of promoting vaccine development and reducing the number of animals for batch release testing, we propose to use more broadly human DC for vaccine immunogenicity testing. In this commentary, this proposition is illustrated by several examples in which the maturation of human DC was successfully used to test for vaccine and adjuvant immunogenicity. PMID:22951585

  4. Dendritic Cell-Based Vaccine Against Fungal Infection.

    PubMed

    Ueno, Keigo; Urai, Makoto; Ohkouchi, Kayo; Miyazaki, Yoshitsugu; Kinjo, Yuki

    2016-01-01

    Several pathogenic fungi, including Cryptococcus gattii, Histoplasma capsulatum, Coccidioides immitis, and Penicillium marneffei, cause serious infectious diseases in immunocompetent humans. However, currently, prophylactic and therapeutic vaccines are not clinically used. In particular, C. gattii is an emerging pathogen and thus far protective immunity against this pathogen has not been well characterized. Experimental vaccines such as component and attenuated live vaccines have been used as tools to study protective immunity against fungal infection. Recently, we developed a dendritic cell (DC)-based vaccine to study protective immunity against pulmonary infection by highly virulent C. gattii strain R265 that was clinically isolated from bronchial washings of infected patients during the Vancouver Island outbreak. In this approach, bone marrow-derived DCs (BMDCs) are pulsed with heat-killed C. gattii and then transferred into mice prior to intratracheal infection. This DC vaccine significantly increases interleukin 17A (IL-17A)-, interferon gamma (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing T cells in the lungs and spleen and ameliorates the pathology, fungal burden, and mortality following C. gattii infection. This approach may result in the development of a new means of controlling lethal fungal infections. In this chapter, we describe the procedures of DC vaccine preparation and murine pulmonary infection model for analysis of immune response against C. gattii. PMID:27076152

  5. Dendritic cell-based vaccine for pancreatic cancer in Japan

    PubMed Central

    Okamoto, Masato; Kobayashi, Masanori; Yonemitsu, Yoshikazu; Koido, Shigeo; Homma, Sadamu

    2016-01-01

    “Vaccell” is a dendritic cell (DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DC-maturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity (DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be “Responders” for the DC vaccine in advanced pancreatic cancer patients. We next conducted a small-scale prospective clinical study. In this trial, we pulsed HLA class II-restricted WT1 peptide (WT1-II) in addition to HLA class I-restricted peptide (WT1-I) into the DCs. Survival of the patients received WT1-I and -II pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-I or WT1-II alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progression-free survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan. PMID:26855819

  6. Dendritic cell-based vaccine for pancreatic cancer in Japan.

    PubMed

    Okamoto, Masato; Kobayashi, Masanori; Yonemitsu, Yoshikazu; Koido, Shigeo; Homma, Sadamu

    2016-02-01

    "Vaccell" is a dendritic cell (DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DC-maturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity (DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be "Responders" for the DC vaccine in advanced pancreatic cancer patients. We next conducted a small-scale prospective clinical study. In this trial, we pulsed HLA class II-restricted WT1 peptide (WT1-II) in addition to HLA class I-restricted peptide (WT1-I) into the DCs. Survival of the patients received WT1-I and -II pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-I or WT1-II alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progression-free survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan. PMID:26855819

  7. Dendritic-Tumor Fusion Cell-Based Cancer Vaccines

    PubMed Central

    Koido, Shigeo

    2016-01-01

    Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells to generate DC-tumor fusion cells (DC-tumor FCs) is an alternative strategy to treat cancer patients. The cell fusion method allows DCs to be exposed to the broad array of TAAs originally expressed by whole tumor cells. DCs then process TAAs endogenously and present them through major histocompatibility complex (MHC) class I and II pathways in the context of costimulatory molecules, resulting in simultaneous activation of both CD4+ and CD8+ T cells. DC-tumor FCs require optimized enhanced immunogenicity of both DCs and whole tumor cells. In this context, an effective fusion strategy also needs to produce immunogenic DC-tumor FCs. We discuss the potential ability of DC-tumor FCs and the recent progress in improving clinical outcomes by DC-tumor FC-based cancer vaccines. PMID:27240347

  8. Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies

    PubMed Central

    Pyzer, Athalia R; Avigan, David E; Rosenblatt, Jacalyn

    2015-01-01

    The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies. PMID:25625926

  9. Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines

    PubMed Central

    de Gruijl, Tanja D.; van den Eertwegh, Alfons J. M.; Pinedo, Herbert M.

    2008-01-01

    The field of tumor vaccination is currently undergoing a shift in focus, from individualized tailor-made vaccines to more generally applicable vaccine formulations. Although primarily predicated by financial and logistic considerations, stemming from a growing awareness that clinical development for wide-scale application can only be achieved through backing from major pharmaceutical companies, these new approaches are also supported by a growing knowledge of the intricacies and minutiae of antigen presentation and effector T-cell activation. Here, the development of whole-cell tumor and dendritic cell (DC)-based vaccines from an individualized autologous set-up to a more widely applicable allogeneic approach will be discussed as reflected by translational studies carried out over the past two decades at our laboratories and clinics in the vrije universiteit medical center (VUmc) in Amsterdam, The Netherlands. PMID:18523771

  10. Combination strategies to enhance the potency of monocyte-derived dendritic cell-based cancer vaccines.

    PubMed

    Fecek, Ronald J; Storkus, Walter J

    2016-10-01

    Dendritic cells (DCs) are potent inducers of adaptive immunity and their clinical use in cancer vaccine formulations remains an area of active translational and clinical investigation. Although cancer vaccines applied as monotherapies have had a modest history of clinical success, there is great enthusiasm for novel therapeutic strategies combining DC-based cancer vaccines with agents that 'normalize' immune function in the tumor microenvironment (TME). Broadly, these combination vaccines are designed to antagonize/remove immunosuppressive networks within the TME that serve to limit the antitumor action of vaccine-induced T cells and/or to condition the TME to facilitate the recruitment and optimal function and durability of vaccine-induced T cells. Such combination regimens are expected to dramatically enhance the clinical potency of DC-based cancer vaccine platforms. PMID:27605069

  11. Dendritic cell-based therapeutic cancer vaccines: what we have and what we need

    PubMed Central

    Kalinski, Pawel; Urban, Julie; Narang, Rahul; Berk, Erik; Wieckowski, Ewa; Muthuswamy, Ravikumar

    2009-01-01

    Therapeutic cancer vaccines rely on the immune system to eliminate tumor cells. In contrast to chemotherapy or passive (adoptive) immunotherapies with antibodies or ex vivo-expanded T cells, therapeutic vaccines do not have a direct anti-tumor activity, but aim to reset patients’ immune systems to achieve this goal. Recent identification of effective ways of enhancing immunogenicity of tumor-associated antigens, including the use of dendritic cells and other potent vectors of cancer vaccines, provide effective tools to induce high numbers of circulating tumor-specific T cells. However, despite indications that some of the new cancer vaccines may be able to delay tumor recurrence or prolong the survival of cancer patients, their ability to induce cancer regression remains low. Recent reports help to identify and prospectively remove the remaining obstacles towards effective therapeutic vaccination of cancer patients. They indicate that the successful induction of tumor-specific T cells by cancer vaccines is not necessarily associated with the induction of functional cytotoxic T lymphocytes, and that current cancer vaccines may promote undesirable expansion of Treg cells. Furthermore, recent studies also identify the tools to counteract such phenomena, in order to assure the desirable induction of Th1-cytotoxic T lymphocytes, NK-mediated type-1 immunity and appropriate homing of effector cells to tumors. PMID:19374544

  12. Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma.

    PubMed

    Markov, Oleg V; Mironova, Nadezhda L; Sennikov, Sergey V; Vlassov, Valentin V; Zenkova, Marina A

    2015-01-01

    Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless

  13. Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma

    PubMed Central

    Sennikov, Sergey V.; Vlassov, Valentin V.; Zenkova, Marina A.

    2015-01-01

    Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless

  14. Dendritic Cell-Based Vaccination in Cancer: Therapeutic Implications Emerging from Murine Models

    PubMed Central

    Mac Keon, Soledad; Ruiz, María Sol; Gazzaniga, Silvina; Wainstok, Rosa

    2015-01-01

    Dendritic cells (DCs) play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel-T), there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts toward an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment. PMID:26042126

  15. Immune Evasion Pathways and the Design of Dendritic Cell-based Cancer Vaccines

    PubMed Central

    Hanks, Brent A.

    2016-01-01

    Emerging data is suggesting that the process of dendritic cell (DC) tolerization is an important step in tumorigenesis. Our understanding of the networks within the tumor microenvironment that functionally tolerize DC function is evolving while methods for genetically manipulating DC populations in situ continue to develop. A more intimate understanding of the paracrine signaling pathways which mediate immune evasion by subverting DC function promises to provide novel strategies for improving the clinical efficacy of DC-based cancer vaccines. This will likely require a better understanding of both the antigen expression profile and the immune evasion network of the tumor and its associated stromal tissues. PMID:27011049

  16. Use of Cell-Penetrating Peptides in Dendritic Cell-Based Vaccination

    PubMed Central

    Lim, Sangho; Koo, Ja-Hyun

    2016-01-01

    Cell-penetrating peptides (CPPs) are short amino acids that have been widely used to deliver macromolecules such as proteins, peptides, DNA, or RNA, to control cellular behavior for therapeutic purposes. CPPs have been used to treat immunological diseases through the delivery of immune modulatory molecules in vivo. Their intracellular delivery efficiency is highly synergistic with the cellular characteristics of the dendritic cells (DCs), which actively uptake foreign antigens. DC-based vaccines are primarily generated by pulsing DCs ex vivo with various immunomodulatory antigens. CPP conjugation to antigens would increase DC uptake as well as antigen processing and presentation on both MHC class II and MHC class I molecules, leading to antigen specific CD4+ and CD8+ T cell responses. CPP-antigen based DC vaccination is considered a promising tool for cancer immunotherapy due to the enhanced CTL response. In this review, we discuss the various applications of CPPs in immune modulation and DC vaccination, and highlight the advantages and limitations of the current CPP-based DC vaccination. PMID:26937230

  17. Comparative evaluation of techniques for the manufacturing of dendritic cell-based cancer vaccines

    PubMed Central

    Dohnal, Alexander Michael; Graffi, Sebastian; Witt, Volker; Eichstill, Christina; Wagner, Dagmar; Ul-Haq, Sidrah; Wimmer, Doris; Felzmann, Thomas

    2009-01-01

    Abstract Manufacturing procedures for cellular therapies are continuously improved with particular emphasis on product safety. We previously developed a dendritic cell (DC) cancer vaccine technology platform that uses clinical grade lipopolysaccharide (LPS) and interferon (IFN)-y for the maturation of monocyte derived DCs. DCs are frozen after 6 hrs exposure at a semi-mature stage (smDCs) retaining the capacity to secret interleukin (IL)-12 and thus support cytolytic T-cell responses, which is lost at full maturation. We compared closed systems for monocyte enrichment from leucocyte apheresis products from healthy individuals using plastic adherence, CD14 selection, or CD2/19 depletion with magnetic beads, or counter flow centrifugation (elutriation) using a clinical grade in comparison to a research grade culture medium for the following DC generation. We found that elutriation was superior compared to the other methods showing 36 ± 4% recovery, which was approximately 5-fold higher as the most frequently used adherence protocol (8 ± 1%), and a very good purity (92 ± 5%) of smDCs. Immune phenotype and IL-12 secretion (adherence: 1.4 ± 0.4; selection: 20 ± 0.6; depletion: 1 ±0.5; elutriation: 3.6 ± 1.5 ng/ml) as well as the potency of all DCs to stimulate T cells in an allogeneic mixed leucocyte reaction did not show statistically significant differences. Research grade and clinical grade DC culture media were equally potent and freezing did not impair the functions of smDCs. Finally, we assessed the functional capacity of DC cancer vaccines manufactured for three patients using this optimized procedure thereby demonstrating the feasibility of manufacturing DC cancer vaccines that secret IL-12 (9.4 ± 6.4 ng/ml). We conclude that significant steps were taken here towards clinical grade DC cancer vaccine manufacturing. PMID:18363835

  18. Evaluation of an α synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease.

    PubMed

    Ugen, Kenneth E; Lin, Xiaoyang; Bai, Ge; Liang, Zhanhua; Cai, Jianfeng; Li, Kunyun; Song, Shijie; Cao, Chuanhai; Sanchez-Ramos, Juan

    2015-01-01

    In order to develop a cell-based vaccine against the Parkinson disease (PD) associated protein α-synuclein (α-Syn) 3 peptides were synthesized based upon predicted B cell epitopes within the full length α-Syn protein sequence. These peptide fragments as well as the full length recombinant human α-Syn (rh- α-Syn) protein were used to sensitize mouse bone marrow-derived dendritic cells (DC) ex vivo, followed by intravenous delivery of these sensitized DCs into transgenic (Tg) mice expressing the human A53T variant of α-Syn. ELISA analysis and testing of behavioral locomotor function by rotometry were performed on all mice after the 5th vaccination as well as just prior to euthanasia. The results indicated that vaccination with peptide sensitized DCs (PSDC) as well as DCs sensitized by rh-α-Syn induced specific anti-α-Syn antibodies in all immunized mice. In terms of rotometry performance, a measure of locomotor activity correlated to brain dopamine levels, mice vaccinated with PSDC or rh- α-Syn sensitized DCs performed significantly better than non-vaccinated Tg control mice during the final assessment (i.e. at 17 months of age) before euthanasia. As well, measurement of levels of brain IL-1α, a cytokine hypothesized to be associated with neuroinflammation, demonstrated that this proinflammatory molecule was significantly reduced in the PSDC and rh- α-Syn sensitized DC vaccinated mice compared to the non-vaccinated Tg control group. Overall, α-Syn antigen-sensitized DC vaccination was effective in generating specific anti- α-Syn antibodies and improved locomotor function without eliciting an apparent general inflammatory response, indicating that this strategy may be a safe and effective treatment for PD. PMID:25714663

  19. Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine

    PubMed Central

    Ohshio, Yasuhiko; Teramoto, Koji; Hanaoka, Jun; Tezuka, Noriaki; Itoh, Yasushi; Asai, Tohru; Daigo, Yataro; Ogasawara, Kazumasa

    2015-01-01

    Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME-targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer-associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro-tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor-associated immune responses by CAF-targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti-fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid-derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell-derived factor-1, prostaglandin E2, and transforming growth factor-β. In tumor-draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor-associated antigen-specific CD8+ T cells. In addition, CAF-targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8+ T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell-based vaccines; however, the suppressive effect on tumor growth was not observed in tumor-bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF-targeted therapy, and these effects are enhanced when combined with effector-stimulatory immunotherapy such as dendritic cell-based vaccines. Our mouse model provides a novel rationale with TME-targeted strategy for the development of cell-based cancer immunotherapy. PMID:25483888

  20. Systemic Administration of Interleukin 2 Enhances the Therapeutic Efficacy of Dendritic Cell-Based Tumor Vaccines

    NASA Astrophysics Data System (ADS)

    Shimizu, K.; Fields, R. C.; Giedlin, M.; Mule, J. J.

    1999-03-01

    We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of non-toxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-γ production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.

  1. DNA is an efficient booster of dendritic cell-based vaccine

    PubMed Central

    Li, Jinyao; Valentin, Antonio; Beach, Rachel Kelly; Alicea, Candido; Felber, Barbara K; Pavlakis, George N

    2015-01-01

    DC-based therapeutic vaccines as a promising strategy against chronic infections and cancer have been validated in several clinical trials. However, DC-based vaccines are complex and require many in vitro manipulations, which makes this a personalized and expensive therapeutic approach. In contrast, DNA-based vaccines have many practical advantages including simplicity, low cost of manufacturing and potent immunogenicity already proven in non-human primates and humans. In this study, we explored whether DC-based vaccines can be simplified by the addition of plasmid DNA as prime or boost to achieve robust CD8-mediated immune responses. We compared the cellular immunity induced in BALB/c and C57BL/6 mice by DC vaccines, loaded either with peptides or optimized SIV Env DNA, and plasmid DNA-based vaccines delivered by electroporation (EP). We found that mature DC loaded with peptides (P-mDC) induced the highest CD8+ T cell responses in both strains of mice, but those responses were significantly higher in the C57BL/6 model. A heterologous prime-boost strategy (P-DC prime-DNA boost) induced CD8+ T cell responses similar to those obtained by the P-DC vaccine. Importantly, this strategy elicited robust polyfunctional T cells as well as highest antigen-specific central memory CD8+ T cells in C57BL/6 mice, suggesting long-term memory responses. These results indicate that a DC-based vaccine in combination with DNA in a heterologous DC prime-DNA boost strategy has potential as a repeatedly administered vaccine. PMID:26125100

  2. Exploring dendritic cell based vaccines targeting survivin for the treatment of head and neck cancer patients

    PubMed Central

    2013-01-01

    Background New treatment modalities are needed for the treatment of cancers of the head and neck region (HNSCC). Survivin is important for the survival and proliferation of tumor cells and may therefore provide a target for immunotherapy. Here we focused on the ex vivo presence and in vitro induction of survivin specific T cells. Methods Tetramer staining and ELIspot assays were used to document the presence of survivin specific T cells in patient derived material, and to monitor the presence and persistence of survivin specific T cells after repeated in vitro stimulation with autologous dendritic cells. Results Ex vivo analysis showed the presence of survivin-specific T cells in the peripheral blood (by tetramer analysis) and in the draining lymph node (by ELIspot analysis) in a HNSCC and a locally advanced breast cancer patient respectively. However, we were unable to maintain isolated survivin specific T cells for prolonged periods of time. For the in vitro generation of survivin specific T cells, monocyte derived DC were electroporated with mRNA encoding full length survivin or a survivin mini-gene together with either IL21 or IL12 mRNA. Western blotting and immunohistochemical staining of dendritic cell cytospin preparations confirmed translation of the full length survivin protein. After repeated stimulation we observed an increase, followed by a decrease, of the number of survivin specific T cells. FACS sorted or limiting dilution cloned survivin specific T cells could not be maintained on feeder mix for prolonged periods of time. Protein expression analysis subsequently showed that activated, but not resting T cells contain survivin protein. Conclusions Here we have shown that survivin specific T cells can be detected ex vivo in patient derived material. Furthermore, survivin specific T cells can be induced in vitro using autologous dendritic cells with enforced expression of survivin and cytokines. However, we were unable to maintain enriched or cloned

  3. A simple in vitro method for evaluating dendritic cell-based vaccinations

    PubMed Central

    Pham, Phuc Van; Nguyen, Nhung Thi; Nguyen, Hoang Minh; Khuat, Lam Tan; Le, Phong Minh; Pham, Viet Quoc; Nguyen, Sinh Truong; Phan, Ngoc Kim

    2014-01-01

    Background Dendritic cell (DC) therapy is a promising therapy for cancer-targeting treatments. Recently, DCs have been used for treatment of some cancers. We aimed to develop an in vitro assay to evaluate DC therapy in cancer treatment using a breast cancer model. Methods DCs were induced from murine bone marrow mononuclear cells in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with GM-CSF (20 ng/mL) and IL-4 (20 ng/mL). Immature DCs were primed with breast cancer stem cell (BCSC)-derived antigens. BCSCs were sorted from 4T1 cell lines based on aldehyde dehydrogenase expression. A mixture of DCs and cytotoxic T lymphocytes (CTLs) were used to evaluate the inhibitory effect of antigen-primed DCs on BCSCs. BCSC proliferation and doubling time were recorded based on impedance-based cell analysis using the xCELLigence system. The specification of inhibitory effects of DCs and CTLs was also evaluated using the same system. Results The results showed that impedance-based analysis of BCSCs reflected cytotoxicity and inhibitory effects of DCs and CTLs at 72 hours. Differences in ratios of DC:CTL changed the cytotoxicity of DCs and CTLs. Conclusion This study successfully used impedance-based cell analysis as a new in vitro assay to evaluate DC efficacy in cancer immunotherapy. We hope this technique will contribute to the development and improvement of immunotherapies in the near future. PMID:25170272

  4. PD-L1 peptide co-stimulation increases immunogenicity of a dendritic cell-based cancer vaccine.

    PubMed

    Munir Ahmad, Shamaila; Martinenaite, Evelina; Hansen, Morten; Junker, Niels; Borch, Troels Holz; Met, Özcan; Donia, Marco; Svane, Inge Marie; Andersen, Mads Hald

    2016-08-01

    We recently described naturally occurring PD-L1-specific T cells that recognize PD-L1-expressing immune cells as well as malignant cells. In the present study, we investigated whether the immunogenicity of a dendritic cell (DC)-based vaccine could be influenced by co-stimulation with a known PD-L1-derived epitope. We incubated a PD-L1-derived peptide epitope (19 amino acids long) or a control peptide (an irrelevant HIV epitope) with peripheral blood mononuclear cells from patients with malignant melanoma who had received a DC-based vaccine. We observed a significantly higher number of T cells that reacted to the vaccine in cultures that had been co-stimulated with the PD-L1 peptide epitope compared to cultures incubated with control peptide. Next, we characterized a novel PD-L1-derived epitope (23 amino acids long) and found that co-stimulation with both PD-L1 epitopes boosted the immune response elicited by the DC vaccine even further. Consequently, we observed a significant increase in the number of vaccine-reacting T cells in vitro. In conclusion, activation of PD-L1-specific T cells may directly modulate immunogenicity of DC vaccines. Addition of PD-L1 epitopes may thus be an easily applicable and attractive option to augment the effectiveness of cancer vaccines and other immunotherapeutic agents. PMID:27622072

  5. Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine

    PubMed Central

    Lin, Tien-Jen; Liang, Wen-Miin; Hsiao, Pei-Wen; M. S, Pradeep; Wei, Wen-Chi; Lin, Hsin-Ting; Yin, Shu-Yi; Yang, Ning-Sun

    2015-01-01

    Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan’s National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine. PMID:26426423

  6. Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine.

    PubMed

    Lin, Tien-Jen; Liang, Wen-Miin; Hsiao, Pei-Wen; M S, Pradeep; Wei, Wen-Chi; Lin, Hsin-Ting; Yin, Shu-Yi; Yang, Ning-Sun

    2015-01-01

    Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine. PMID:26426423

  7. Antitumor dendritic cell-based vaccines: lessons from 20 years of clinical trials and future perspectives.

    PubMed

    Constantino, João; Gomes, Célia; Falcão, Amílcar; Cruz, Maria T; Neves, Bruno M

    2016-02-01

    Dendritic cells (DCs) are versatile elements of the immune system and are best known for their unparalleled ability to initiate and modulate adaptive immune responses. During the past few decades, DCs have been the subject of numerous studies seeking new immunotherapeutic strategies against cancer. Despite the initial enthusiasm, disappointing results from early studies raised some doubts regarding the true clinical value of these approaches. However, our expanding knowledge of DC immunobiology and the definition of the optimal characteristics for antitumor immune responses have allowed a more rational development of DC-based immunotherapies in recent years. Here, after a brief overview of DC immunobiology, we sought to systematize the knowledge provided by 20 years of clinical trials, with a special emphasis on the diversity of approaches used to manipulate DCs and their consequent impact on vaccine effectiveness. We also address how new therapeutic concepts, namely the combination of DC vaccines with other anticancer therapies, are being implemented and are leveraging clinical outcomes. Finally, optimization strategies, new insights, and future perspectives on the field are also highlighted. PMID:26297944

  8. Exploiting the Role of Endogenous Lymphoid-Resident Dendritic Cells in the Priming of NKT Cells and CD8+ T Cells to Dendritic Cell-Based Vaccines

    PubMed Central

    Petersen, Troels R.; Sika-Paotonu, Dianne; Knight, Deborah A.; Simkins, Helen M. A.; Hermans, Ian F.

    2011-01-01

    Transfer of antigen between antigen-presenting cells (APCs) is potentially a physiologically relevant mechanism to spread antigen to cells with specialized stimulatory functions. Here we show that specific CD8+ T cell responses induced in response to intravenous administration of antigen-loaded bone marrow-derived dendritic cells (BM-DCs), were ablated in mice selectively depleted of endogenous lymphoid-resident langerin+ CD8α+ dendritic cells (DCs), suggesting that the antigen is transferred from the injected cells to resident APCs. In contrast, antigen-specific CD4+ T cells were primed predominantly by the injected BM-DCs, with only very weak contribution of resident APCs. Crucially, resident langerin+ CD8α+ DCs only contributed to the priming of CD8+ T cells in the presence of maturation stimuli such as intravenous injection of TLR ligands, or by loading the BM-DCs with the glycolipid α-galactosylceramide (α-GalCer) to recruit the adjuvant activity of activated invariant natural killer-like T (iNKT) cells. In fact, injection of α-GalCer-loaded CD1d−/− BM-DCs resulted in potent iNKT cell activation, suggesting that this glycolipid antigen can also be transferred to resident CD1d+ APCs. While iNKT cell activation per se was independent of langerin+ CD8α+ DCs, some iNKT cell-mediated activities were reduced, notably release of IL-12p70 and transactivation of NK cells. We conclude that both protein and glycolipid antigens can be exchanged between distinct DC species. These data suggest that the efficacy of DC-based vaccination strategies may be improved by the incorporation of a systemic maturation signal aimed to engage resident APCs in CD8+ T cell priming, and α-GalCer may be particularly well suited to this purpose. PMID:21483862

  9. Treatment with cyclophosphamide supported by various dendritic cell-based vaccines induces diversification in CD4⁺ T cell response against MC38 colon carcinoma.

    PubMed

    Wojas-Turek, Justyna; Szczygieł, Agnieszka; Kicielińska, Jagoda; Rossowska, Joanna; Piasecki, Egbert; Pajtasz-Piasecka, Elżbieta

    2016-02-01

    The present study shows that an application of cyclophosphamide (CY) supported by dendritic cell (DC)-based vaccines affected differentiation of the activity of CD4+ T cell subpopulations accompanied by an alteration in CD8+ cell number. Vaccines were composed of bone marrow-derived DCs activated with tumor cell lysate (BM-DC/TAgTNF-α) and/or genetically modified DCs of JAWS II line (JAWS II/Neo or JAWS II/IL-2 cells). Compared to untreated or CY-treated mice, the combined treatment of MC38 colon carcinoma-bearing mice resulted in significant tumor growth inhibition associated with an increase in influx of CD4+ and CD8+ T cells into tumor tissue. Whereas, the division of these cell population in spleen was not observed. Depending on the nature of DC-based vaccines and number of their applications, both tumor infiltrating cells and spleen cells were able to produce various amount of IFN-γ, IL-4 and IL-10 after mitogenic ex vivo stimulation. The administration of CY followed by BM-DC/TAgTNF-α and genetically modified JAWS II cells, increased the percentage of CD4+T-bet+ and CD4+GATA3+ cells and decreased the percentage of CD4+RORγt+ and CD4+FoxP3+ lymphocytes. However, the most intensive response against tumor was noted after the ternary treatment with CY + BM-DC/TAgTNF-α + JAWS II/IL-2 cells. Thus, the administration of various DC-based vaccines was responsible for generation of the diversified antitumor response. These findings demonstrate that the determination of the size of particular CD4+ T cell subpopulations may become a prognostic factor and be the basis for future development of anticancer therapy. PMID:26648160

  10. Treatment with cyclophosphamide supported by various dendritic cell-based vaccines induces diversification in CD4+ T cell response against MC38 colon carcinoma

    PubMed Central

    WOJAS-TUREK, JUSTYNA; SZCZYGIEŁ, AGNIESZKA; KICIELIŃSKA, JAGODA; ROSSOWSKA, JOANNA; PIASECKI, EGBERT; PAJTASZ-PIASECKA, ELŻBIETA

    2016-01-01

    The present study shows that an application of cyclophosphamide (CY) supported by dendritic cell (DC)-based vaccines affected differentiation of the activity of CD4+ T cell subpopulations accompanied by an alteration in CD8+ cell number. Vaccines were composed of bone marrow-derived DCs activated with tumor cell lysate (BM-DC/TAgTNF-α) and/or genetically modified DCs of JAWS II line (JAWS II/ Neo or JAWS II/IL-2 cells). Compared to untreated or CY-treated mice, the combined treatment of MC38 colon carcinoma-bearing mice resulted in significant tumor growth inhibition associated with an increase in influx of CD4+ and CD8+ T cells into tumor tissue. Whereas, the division of these cell population in spleen was not observed. Depending on the nature of DC-based vaccines and number of their applications, both tumor infiltrating cells and spleen cells were able to produce various amount of IFN-γ, IL-4 and IL-10 after mitogenic ex vivo stimulation. The administration of CY followed by BM-DC/TAgTNF-α and genetically modified JAWS II cells, increased the percentage of CD4+T-bet+ and CD4+GATA3+ cells and decreased the percentage of CD4+RORγt+ and CD4+FoxP3+ lymphocytes. However, the most intensive response against tumor was noted after the ternary treatment with CY + BM-DC/TAgTNF-α + JAWS II/IL-2 cells. Thus, the administration of various DC-based vaccines was responsible for generation of the diversified antitumor response. These findings demonstrate that the determination of the size of particular CD4+ T cell subpopulations may become a prognostic factor and be the basis for future development of anticancer therapy. PMID:26648160

  11. SLA-PGN-primed dendritic cell-based vaccination induces Th17-mediated protective immunity against experimental visceral leishmaniasis: a crucial role of PKCβ.

    PubMed

    Jawed, Junaid Jibran; Majumder, Saikat; Bandyopadhyay, Syamdas; Biswas, Satabdi; Parveen, Shabina; Majumdar, Subrata

    2016-07-01

    Emergence of drug resistance during visceral leishmaniasis (VL) is a major obstacle imposed during successful therapy. An effective vaccine strategy against this disease is therefore necessary. Our present study exploited the SLA (soluble leishmanial antigen) and PGN (peptidoglycan) stimulated bone marrow-derived dendritic cells (DCs) as a suitable vaccine candidate during experimental VL. SLA-PGN-stimulated DCs showed a significant decrease in hepatic and splenic parasite burden, which were associated with increased production of nitric oxide and pro-inflammatory cytokines such as IL-12, IFN-γ and IL-17. Elevated level of IL-17 was accompanied with the generation of more Th17 cells. Further studies on DC provided the evidence that these SLA-PGN-stimulated DCs played an important role in providing necessary cytokines such as IL-6, IL-23 and TGF-β for the generation of Th17 cells. Interestingly, inhibition of protein kinase C-β (PKCβ) in DCs led to decreased production of Th17 polarizing cytokines, causing reduction of the Th17 population size. Altogether, our finding highlighted the important role of DC-based PKCβ in regulation of the function and generation of Th17 cells. PMID:27150838

  12. The combination of Pleurotus ferulae water extract and CpG-ODN enhances the immune responses and antitumor efficacy of HPV peptides pulsed dendritic cell-based vaccine.

    PubMed

    Li, Jinyu; Li, Jinyao; Aipire, Adila; Luo, JiaoJiao; Yuan, Pengfei; Zhang, Fuchun

    2016-06-30

    Our previous study reported that the combination of Pleurotus ferulae water extract (PFWE) and CpG (PFWE+CpG) enhanced the maturation and function of dendritic cells (DCs). Here, we investigated the effects of PFWE+CpG on the immune responses and antitumor efficacy of DC-based vaccine. We observed that all of HPV E6 and E7 peptides pulsed DCs (HPV-immature DCs, HPV+PFWE-, +CpG- or +PFWE+CpG-DCs) induced antigen-specific CD8(+) T cell responses and HPV+PFWE+CpG-DCs induced highest level of CD8(+) T cell responses. The antitumor efficacy of HPV-DCs vaccines was evaluated in TC-1 tumor mouse model. The early therapeutic study showed that HPV+PFWE-, +CpG- and +PFWE+CpG-DCs greatly inhibited tumor growth. Moreover, HPV+PFWE+CpG-DCs controlled tumor growth at a faster rate compared to other groups. These three groups induced HPV-specific CD8(+) T cell responses and significantly decreased the frequencies of induced regulatory T cells (iTregs: CD4(+)CD25(-)Fopx3(+)). However, only HPV+PFWE+CpG-DCs significantly decreased the frequency of natural Tregs (nTregs: CD4(+)CD25(+)Fopx3(+)). Furthermore, HPV+PFWE+CpG-DCs also significantly inhibited tumor growth in the late therapeutic study. The results showed that PFWE+CpG enhanced the immune responses and antitumor efficacy of DC-based vaccine, suggesting that PFWE+CpG might be the potential candidate for the generation of clinical-grade mature DCs. PMID:27211038

  13. In vivo immunogenicity of Tax 11-19 epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine

    PubMed Central

    Sagar, Divya; Masih, Shet; Schell, Todd; Jacobson, Steven; Comber, Joseph D.; Philip, Ramila; Wigdahl, Brian; Jain, Pooja; Khan, Zafar K.

    2014-01-01

    Viral oncoprotein Tax plays key roles in transformation of human T-cell leukemia virus (HTLV-1)-infected T cells leading to adult T-cell leukemia (ATL), and is the key antigen recognized during HTLV-associated myelopathy (HAM). In HLA-A2+ asymptomatic carriers as well as ATL and HAM patients, Tax(11-19) epitope exhibits immunodominance. Here, we evaluate CD8 T-cell immune response against this epitope in the presence and absence of dendritic cells (DCs) given the recent encouraging observations made with Phase 1 DC-based vaccine trial for ATL. To facilitate these studies, we first generated an HLA-A2/DTR hybrid mouse strain carrying the HLA-A2.1 and CD11c-DTR genes. We then studied CD8 T-cell immune response against Tax(11-19) epitope delivered in the absence or presence of Freund’s adjuvant and/or DCs. Overall results demonstrate that naturally presented Tax epitope could initiate an antigen-specific CD8 T cell response in vivo but failed to do so upon DC depletion. Presence of adjuvant potentiated Tax(11-19)-specific response. Elevated serum IL-6 levels coincided with depletion of DCs whereas decreased TGF-β was associated with adjuvant use. Thus, Tax(11-19) epitope is a potential candidate for the DC-based anti-HTLV-1 vaccine and the newly hybrid mouse strain could be used for investigating DC involvement in human class-I-restricted immune responses. PMID:24739247

  14. Dendritic cell-based vaccination with lentiviral vectors encoding ubiquitinated hepatitis B core antigen enhances hepatitis B virus-specific immune responses in vivo.

    PubMed

    Dai, Shenglan; Zhuo, Meng; Song, Linlin; Chen, Xiaohua; Yu, Yongsheng; Tang, Zhenghao; Zang, Guoqing

    2015-11-01

    The activity of hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) plays a predominant role in the clearance of HBV. Dendritic cells (DCs) are key antigen-presenting cells and play an important role in the initiation of immune responses. We previously verified that lentiviral vector encoding ubiquitinated hepatitis B core antigen (LV-Ub-HBcAg) effectively transduced DCs to induce maturation, and the mature DCs efficiently induced T cell polarization to Th1 and generated HBcAg-specific CTLs ex vivo. In this study, HBV-specific immune responses of LV-Ub-HBcAg in BALB/c mice (H-2Kd) were evaluated. It was shown that direct injection of LV-Ub-HBcAg increased the production of cytokines IL-2 and IFN-γ, elicited strong antibody responses, and remarkably generated a high percentage of IFN-γ+CD8+ T cells with HBV-specific CTL responses in BALB/c mice. In addition, direct injection of LV-Ub-HBcAg induced potent anti-HBV immune responses, similar to those elicited by in vitro-transduced DCs. In conclusion, the DC-based therapeutic vaccine LV-Ub-HBcAg elicited specific antibody immune responses and induced robust specific CTL activity in vivo. PMID:26373843

  15. Dendritic Cell-Targeted Vaccines

    PubMed Central

    Cohn, Lillian; Delamarre, Lélia

    2014-01-01

    Despite significant effort, the development of effective vaccines inducing strong and durable T-cell responses against intracellular pathogens and cancer cells has remained a challenge. The initiation of effector CD8+ T-cell responses requires the presentation of peptides derived from internalized antigen on class I major histocompatibility complex molecules by dendritic cells (DCs) in a process called cross-presentation. A current strategy to enhance the effectiveness of vaccination is to deliver antigens directly to DCs. This is done via selective targeting of antigen using monoclonal antibodies directed against endocytic receptors on the surface of the DCs. In this review, we will discuss considerations relevant to the design of such vaccines: the existence of DC subsets with specialized functions, the impact of the antigen intracellular trafficking on cross-presentation, and the influence of maturation signals received by DCs on the outcome of the immune response. PMID:24910635

  16. Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection.

    PubMed

    Akbar, Sk Md Fazle; Horiike, Norio; Onji, Morikazu

    2006-05-14

    Hepatitis B virus (HBV) infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects. Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection: (1) These influence acquisition of chronic HBV carrier state, (2) They are important in the context of liver damages, (3) Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses. However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult. During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach (vaccine therapy). The present regimen of vaccine therapy is safe and cheap, but not so effective. A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV-specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection. PMID:16718812

  17. Dendritic cell-based cancer immunotherapy for colorectal cancer

    PubMed Central

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-01-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients. PMID:27158196

  18. Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy

    PubMed Central

    Datta, Jashodeep; Terhune, Julia H.; Lowenfeld, Lea; Cintolo, Jessica A.; Xu, Shuwen; Roses, Robert E.; Czerniecki, Brian J.

    2014-01-01

    Dendritic cells (DC) are professional antigen-presenting cells uniquely suited for cancer immunotherapy. They induce primary immune responses, potentiate the effector functions of previously primed T-lymphocytes, and orchestrate communication between innate and adaptive immunity. The remarkable diversity of cytokine activation regimens, DC maturation states, and antigen-loading strategies employed in current DC-based vaccine design reflect an evolving, but incomplete, understanding of optimal DC immunobiology. In the clinical realm, existing DC-based cancer immunotherapy efforts have yielded encouraging but inconsistent results. Despite recent U.S. Federal and Drug Administration (FDA) approval of DC-based sipuleucel-T for metastatic castration-resistant prostate cancer, clinically effective DC immunotherapy as monotherapy for a majority of tumors remains a distant goal. Recent work has identified strategies that may allow for more potent “next-generation” DC vaccines. Additionally, multimodality approaches incorporating DC-based immunotherapy may improve clinical outcomes. PMID:25506283

  19. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer

    PubMed Central

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Matsumoto, Yoshihiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-01-01

    The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients. PMID:27182156

  20. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer.

    PubMed

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Matsumoto, Yoshihiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-05-14

    The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients. PMID:27182156

  1. Dendritic Cell-Based Immunotherapy Treatment for Glioblastoma Multiforme

    PubMed Central

    Yang, Liu; Guo, Geng; Niu, Xiao-yuan; Liu, Jing

    2015-01-01

    Glioblastoma multiforme (GBM) is the most malignant glioma and patients diagnosed with this disease had poor outcomes even treated with the combination of conventional treatment (surgery, chemotherapy, and radiation). Dendritic cells (DCs) are the most powerful antigen presenting cells and DC-based vaccination has the potential to target and eliminate GBM cells and enhance the responses of these cells to the existing therapies with minimal damage to the healthy tissues around them. It can enhance recognition of GBM cells by the patients' immune system and activate vast, potent, and long-lasting immune reactions to eliminate them. Therefore, this therapy can prolong the survival of GBM patients and has wide and bright future in the treatment of GBM. Also, the efficacy of this therapy can be strengthened in several ways at some degree: the manipulation of immune regulatory components or costimulatory molecules on DCs; the appropriate choices of antigens for loading to enhance the effectiveness of the therapy; regulation of positive regulators or negative regulators in GBM microenvironment. PMID:26167495

  2. Dendritic Cell Cancer Vaccines: From the Bench to the Bedside

    PubMed Central

    Katz, Tamar; Avivi, Irit; Benyamini, Noam; Rosenblatt, Jacalyn; Avigan, David

    2014-01-01

    The recognition that the development of cancer is associated with acquired immunodeficiency, mostly against cancer cells themselves, and understanding pathways inducing this immunosuppression, has led to a tremendous development of new immunological approaches, both vaccines and drugs, which overcome this inhibition. Both “passive” (e.g. strategies relying on the administration of specific T cells) and “active” vaccines (e.g. peptide-directed or whole-cell vaccines) have become attractive immunological approaches, inducing cell death by targeting tumor-associated antigens. Whereas peptide-targeted vaccines are usually directed against a single antigen, whole-cell vaccines (e.g. dendritic cell vaccines) are aimed to induce robust responsiveness by targeting several tumor-related antigens simultaneously. The combination of vaccines with new immuno-stimulating agents which target “immunosuppressive checkpoints” (anti-CTLA-4, PD-1, etc.) is likely to improve and maintain immune response induced by vaccination. PMID:25386340

  3. A multifunctional core-shell nanoparticle for dendritic cell-based cancer immunotherapy

    NASA Astrophysics Data System (ADS)

    Cho, Nam-Hyuk; Cheong, Taek-Chin; Min, Ji Hyun; Wu, Jun Hua; Lee, Sang Jin; Kim, Daehong; Yang, Jae-Seong; Kim, Sanguk; Kim, Young Keun; Seong, Seung-Yong

    2011-10-01

    Dendritic cell-based cancer immunotherapy requires tumour antigens to be delivered efficiently into dendritic cells and their migration to be monitored in vivo. Nanoparticles have been explored as carriers for antigen delivery, but applications have been limited by the toxicity of the solvents used to make nanoparticles, and by the need to use transfection agents to deliver nanoparticles into cells. Here we show that an iron oxide-zinc oxide core-shell nanoparticle can deliver carcinoembryonic antigen into dendritic cells while simultaneously acting as an imaging agent. The nanoparticle-antigen complex is efficiently taken up by dendritic cells within one hour and can be detected in vitro by confocal microscopy and in vivo by magnetic resonance imaging. Mice immunized with dendritic cells containing the nanoparticle-antigen complex showed enhanced tumour antigen specific T-cell responses, delayed tumour growth and better survival than controls.

  4. Dendritic cell vaccination in glioblastoma after fluorescence-guided resection

    PubMed Central

    Valle, Ricardo Diez; de Cerio, Ascension Lopez-Diaz; Inoges, Susana; Tejada, Sonia; Pastor, Fernando; Villanueva, Helena; Gallego, Jaime; Espinos, Jaime; Aristu, Javier; Idoate, Miguel Angel; Andreu, Enrique; Bendandi, Maurizio

    2012-01-01

    AIM: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. METHODS: Preliminary to our ongoing, phase-II clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patients were class V and one was class IV. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations. RESULTS: Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years. CONCLUSION: Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results. PMID:23293753

  5. Dendritic cell-based therapy for mantle cell lymphoma.

    PubMed

    Munger, Corey M; Vose, Julie M; Joshi, Shantaram S

    2006-06-01

    Mantle cell lymphoma (MCL) is a B cell malignancy that is resistant to conventional therapies. High-dose therapy (HDT) followed by stem cell transplantation is effective in inducing remission. However, residual lymphoma cells are eventually responsible for the subsequent relapse. Effective therapeutic strategies to eliminate the residual lymphoma is required. In this study, we have examined the in vitro and in vivo anti-lymphoma effects of MCL-specific cytotoxic T lymphocytes (CTLs) that were generated using dendritic cells (DCs) fused with MCL cells for immunostimulation. Dendritic cells were generated in vitro using dendritic cell-specific medium, cytomorphology, immunophenotypes and functional capabilities of the generated DCs were studied. Such DCs were then used for the preparation of DC-MCL hybrids and the DC-MCL hybrids were used to generate CTLs against MCL cells and tested for their MCL-specific cytotoxicity in vitro and in vivo. The CTLs demonstrated MCL-specific cytotoxicity in vitro against GRANT-519, a human MCL cell line. These CTLs did not show significant effect against an irrelevant target. To test the in vivo therapeutic effect of DC-MCL hybrid-stimulated CTLs, a preclinical model consisting of NOD-SCID mice bearing Granta 519 was developed. The NOD-SCID mice bearing Granta-519 MCL tumors were treated with DC-MCL hybrids and the same donor T lymphocytes. There was an increase in survival (60% in mice treated with DC-MCL hybrid approach compared to 20% in the untreated group). Histological analysis of liver from control and treated mice displayed a decrease in the number of the tumor nodules in the treatment group. These results indicate the potential of DC-based therapy for the treatment of MCL. PMID:16685434

  6. Trial watch: Dendritic cell-based anticancer therapy

    PubMed Central

    Bloy, Norma; Pol, Jonathan; Aranda, Fernando; Eggermont, Alexander; Cremer, Isabelle; Fridman, Wolf Hervé; Fučíková, Jitka; Galon, Jérôme; Tartour, Eric; Spisek, Radek; Dhodapkar, Madhav V.; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    The use of patient-derived dendritic cells (DCs) as a means to elicit therapeutically relevant immune responses in cancer patients has been extensively investigated throughout the past decade. In this context, DCs are generally expanded, exposed to autologous tumor cell lysates or loaded with specific tumor-associated antigens (TAAs), and then reintroduced into patients, often in combination with one or more immunostimulatory agents. As an alternative, TAAs are targeted to DCs in vivo by means of monoclonal antibodies, carbohydrate moieties or viral vectors specific for DC receptors. All these approaches have been shown to (re)activate tumor-specific immune responses in mice, often mediating robust therapeutic effects. In 2010, the first DC-based preparation (sipuleucel-T, also known as Provenge®) has been approved by the US Food and Drug Administration (FDA) for use in humans. Reflecting the central position occupied by DCs in the regulation of immunological tolerance and adaptive immunity, the interest in harnessing them for the development of novel immunotherapeutic anticancer regimens remains high. Here, we summarize recent advances in the preclinical and clinical development of DC-based anticancer therapeutics. PMID:25941593

  7. Natural Killer Cells as Helper Cells in Dendritic Cell Cancer Vaccines

    PubMed Central

    Pampena, María Betina; Levy, Estrella Mariel

    2015-01-01

    Vaccine-based cancer immunotherapy has generated highly variable clinical results due to differing methods of vaccine preparation and variation in patient populations among other lesser factors. Moreover, these clinical responses do not necessarily correspond with the induction of tumor-specific cytotoxic lymphocytes. Here, we review the participation of natural killer (NK) cells as alternative immune components that could cooperate in successful vaccination treatment. NK cells have been described as helper cells in dendritic cell-based cancer vaccines, but the role in other kinds of vaccination strategies (whole cells, peptide, or DNA-based vaccines) is poorly understood. In this article, we address the following issues regarding the role of NK cells in cancer vaccines: NK cell anti-tumor action sites, and the loci of NK cell interaction with other immune cells; descriptions of new data on the memory characteristics of NK cells described in infectious diseases; and finally phenotypical and functional changes after vaccination measured by immunomonitoring in preclinical and clinical settings. PMID:25674087

  8. Targeting dendritic cells for improved HIV-1 vaccines.

    PubMed

    Smed-Sörensen, Anna; Loré, Karin

    2013-01-01

    As dendritic cells (DCs) have the unique capacity to activate antigen-naive T cells they likely play a critical role in eliciting immune responses to vaccines. DCs are therefore being explored as attractive targets for vaccines, but understanding the interaction of DCs and clinically relevant vaccine antigens and adjuvants is a prerequisite. The HIV-1/AIDS epidemic continues to be a significant health problem, and despite intense research efforts over the past 30 years a protective vaccine has not yet been developed. A common challenge in vaccine design is to find a vaccine formulation that best shapes the immune response to protect against and/or control the given pathogen. Here, we discuss the importance of understanding the diversity, anatomical location and function of different human DC subsets in order to identify the optimal target cells for an HIV-1 vaccine. We review human DC interactions with some of the HIV-1 vaccine antigen delivery vehicles and adjuvants currently utilized in preclinical and clinical studies. Specifically, the effects of distinctly different vaccine adjuvants in terms of activation of DCs and improving DC function and vaccine efficacy are discussed. The susceptibility and responses of DCs to recombinant adenovirus vectors are reviewed, as well as the strategy of directly targeting DCs by using DC marker-specific monoclonal antibodies coupled to an antigen. PMID:22975879

  9. Topical vaccination with functionalized particles targeting dendritic cells.

    PubMed

    Baleeiro, Renato B; Wiesmüller, Karl-Heinz; Reiter, Yoran; Baude, Barbara; Dähne, Lars; Patzelt, Alexa; Lademann, Jürgen; Barbuto, José A; Walden, Peter

    2013-08-01

    Needle-free vaccination, for reasons of safety, economy, and convenience, is a central goal in vaccine development, but it also needs to meet the immunological requirements for efficient induction of prophylactic and therapeutic immune responses. Combining the principles of noninvasive delivery to dendritic cells (DCs) through skin and the immunological principles of cell-mediated immunity, we developed microparticle-based topical vaccines. We show here that the microparticles are efficient carriers for coordinated delivery of the essential vaccine constituents to DCs for cross-presentation of the antigens and stimulation of T-cell responses. When applied to the skin, the microparticles penetrate into hair follicles and target the resident DCs, the immunologically most potent cells and site for induction of efficient immune responses. The microparticle vaccine principle can be applied to different antigen formats such as peptides and proteins, or nucleic acids coding for the antigens. PMID:23426134

  10. In Situ Modulation of Dendritic Cells by Injectable Thermosensitive Hydrogels for Cancer Vaccines in Mice

    PubMed Central

    2014-01-01

    Attempts to develop cell-based cancer vaccines have shown limited efficacy, partly because transplanted dendritic cells (DCs) do not survive long enough to reach the lymph nodes. The development of biomaterials capable of modulating DCs in situ to enhance antigen uptake and presentation has emerged as a novel method toward developing more efficient cancer vaccines. Here, we propose a two-step hybrid strategy to produce a more robust cell-based cancer vaccine in situ. First, a significant number of DCs are recruited to an injectable thermosensitive mPEG–PLGA hydrogel through sustained release of chemoattractants, in particular, granulocyte-macrophage colony-stimulating factor (GM-CSF). Then, these resident DCs can be loaded with cancer antigens through the use of viral or nonviral vectors. We demonstrate that GM-CSF-releasing mPEG–PLGA hydrogels successfully recruit and house DCs and macrophages, allowing the subsequent introduction of antigens by vectors to activate the resident cells, thus, initiating antigen presentation and triggering immune response. Moreover, this two-step hybrid strategy generates a high level of tumor-specific immunity, as demonstrated in both prophylactic and therapeutic models of murine melanoma. This injectable thermosensitive hydrogel shows great promise as an adjuvant for cancer vaccines, potentially providing a new approach for cell therapies through in situ modulation of cells. PMID:25207465

  11. A cell-based microarray to investigate combinatorial effects of microparticle-encapsulated adjuvants on dendritic cell activation

    PubMed Central

    Acharya, Abhinav P.; Carstens, Matthew R.; Lewis, Jamal S.; Dolgova, Natalia; Xia, C. Q.; Clare-Salzler, Michael J.

    2016-01-01

    Experimental vaccine adjuvants are being designed to target specific toll-like receptors (TLRs) alone or in combination, expressed by antigen presenting cells, notably dendritic cells (DCs). There is a need for high-content screening (HCS) platforms to explore how DC activation is affected by adjuvant combinations. Presented is a cell-based microarray approach, “immunoarray”, exposing DCs to a large number of adjuvant combinations. Microparticles encapsulating TLR ligands are printed onto arrays in a range of doses for each ligand, in all possible dose combinations. Dendritic cells are then co-localized with physisorbed microparticles on the immunoarray, adherent to isolated islands surrounded by a non-fouling background, and DC activation is quantified. Delivery of individual TLR ligands was capable of eliciting high levels of specific DC activation markers. For example, either TLR9 ligand, CpG, or TLR3 ligand, poly I:C, was capable of inducing among the highest 10% expression levels of CD86. In contrast, MHC-II expression in response to TLR4 agonist MPLA was among the highest, whereas either MPLA or poly I:C, was capable of producing among the highest levels of CCR7 expression, as well as inflammatory cytokine IL-12. However, in order to produce robust responses across all activation markers, adjuvant combinations were required, and combinations were more represented among the high responders. The immunoarray also enables investigation of interactions between adjuvants, and each TLR ligand suggested antagonism to other ligands, for various markers. Altogether, this work demonstrates feasibility of the immunoarray platform to screen microparticle-encapsulated adjuvant combinations for the development of improved and personalized vaccines. PMID:26985393

  12. Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

    PubMed Central

    Van Acker, Heleen H; Anguille, Sébastien; Van Tendeloo, Viggo F; Lion, Eva

    2015-01-01

    Gamma delta (γδ) T cells are the all-rounders of our immune-system with their major histocompatibility complex-unrestricted cytotoxicity, capacity to secrete immunosti-mulatory cytokines and ability to promote the generation of tumor antigen-specific CD8+ and CD4+ T cell responses. Dendritic cell (DC)-based vaccine therapy has the prospective to harness these unique features of the γδ T cells in the fight against cancer. In this review, we will discuss our current knowledge on DC-mediated γδ T cell activation and related opportunities for tumor immunologists. PMID:26405575

  13. Dendritic-cell-based technology landscape: Insights from patents and citation networks

    PubMed Central

    Kong, Xiangjun; Hu, Yuanjia; Cai, Zhifang; Yang, Fengqing; Zhang, Qianru

    2015-01-01

    As the most potent antigen-presenting cells, dendritic cells (DCs) are pivotal players in regulating immune responses. DC-based technologies have generated a series of typical and promising therapeutic options, especially after the first DC-based cancer vaccine was approved by US. Food and Drug Administration (US. FDA). In this context, this paper employs patents and citation networks to conduct a fundamental analysis in order to show overall landscape of DC-based technologies. The results in this research can be used as references for decision-making in developing efficacious DC therapeutic products. PMID:25714961

  14. Dendritic-cell-based technology landscape: Insights from patents and citation networks.

    PubMed

    Kong, Xiangjun; Hu, Yuanjia; Cai, Zhifang; Yang, Fengqing; Zhang, Qianru

    2015-01-01

    As the most potent antigen-presenting cells, dendritic cells (DCs) are pivotal players in regulating immune responses. DC-based technologies have generated a series of typical and promising therapeutic options, especially after the first DC-based cancer vaccine was approved by US. Food and Drug Administration (US. FDA). In this context, this paper employs patents and citation networks to conduct a fundamental analysis in order to show overall landscape of DC-based technologies. The results in this research can be used as references for decision-making in developing efficacious DC therapeutic products. PMID:25714961

  15. Targeting dendritic cells: a promising strategy to improve vaccine effectiveness

    PubMed Central

    Macri, Christophe; Dumont, Claire; Johnston, Angus PR; Mintern, Justine D

    2016-01-01

    Dendritic cell (DC) targeting is a novel strategy to enhance vaccination efficacy. This approach is based on the in situ delivery of antigen via antibodies that are specific for endocytic receptors expressed at the surface of DCs. Here we review the complexity of the DC subsets and the antigen presentation pathways that need to be considered in the settings of DC targeting. We also summarize current knowledge about antigen delivery to DCs via DEC-205, Clec9A and Clec12A, receptor targets that strongly enhance cellular and humoral immune responses. Finally, we discuss the intracellular trafficking criteria of the targeted receptors that may impact their effectiveness as DC targets. PMID:27217957

  16. Dendritic cell based immunotherapy using tumor stem cells mediates potent antitumor immune responses.

    PubMed

    Dashti, Amir; Ebrahimi, Marzieh; Hadjati, Jamshid; Memarnejadian, Arash; Moazzeni, Seyed Mohammad

    2016-04-28

    Cancer stem cells (CSCs) are demonstrated to be usually less sensitive to conventional methods of cancer therapies, resulting in tumor relapse. It is well-known that an ideal treatment would be able to selectively target and kill CSCs, so as to avoid the tumor reversion. The aim of our present study was to evaluate the effectiveness of a dendritic cell (DC) based vaccine against CSCs in a mouse model of malignant melanoma. C57BL/6 mouse bone marrow derived DCs pulsed with a murine melanoma cell line (B16F10) or CSC lysates were used as a vaccine. Immunization of mice with CSC lysate-pulsed DCs was able to induce a significant prophylactic effect by a higher increase in lifespan and obvious depression of tumor growth in tumor bearing mice. The mice vaccinated with DCs loaded with CSC-lysate were revealed to produce specific cytotoxic responses to CSCs. The proliferation assay and cytokine (IFN-γ and IL-4) secretion of mice vaccinated with CSC lysate-pulsed DCs also showed more favorable results, when compared to those receiving B16F10 lysate-pulsed DCs. These findings suggest a potential strategy to improve the efficacy of DC-based immunotherapy of cancers. PMID:26803056

  17. Dendritic cell-based immunotherapy in myeloid leukaemia: translating fundamental mechanisms into clinical applications.

    PubMed

    van de Loosdrecht, A A; van den Ancker, W; Houtenbos, I; Ossenkoppele, G J; Westers, T M

    2009-01-01

    Immunotherapy for leukaemia patients, aiming at the generation of anti-leukaemic T cell responses, could provide a new therapeutic approach to eliminate minimal residual disease (MRD) cells in acute myeloid leukaemia (AML). Leukaemic blasts harbour several ways to escape the immune system including deficient MHC class II expression, low levels of co-stimulatory molecules and suppressive cytokines. Therapeutic vaccination with dendritic cells (DC) is now recognized as an important investigational therapy. Due to their unique antigen presenting capacity, immunosuppressive features of the leukaemic blasts can be circumvented. DC can be successfully cultured from leukaemic blasts in 60-70% of patients and show functional potential in vivo. Alternatively, monocyte derived DC obtained at time of complete remission loaded with leukaemia-specific antigens can be used as vaccine. Several sources of leukaemia-associated antigen and different methods of loading antigen onto DC have been used in an attempt to optimize antitumour responses including apoptotic cells, necrotic cell lysates and tumour-associated pep-tides. Currently, the AML-derived cell line MUTZ-3, an immortalized equivalent of CD34(+) DC precursor cells, is under investigation for vaccination purposes. For effective DC vaccination the intrinsic tolerant state of the patient must be overcome. Therefore, the development of efficient and safe adjuvants in antigen specific immunotherapeutic programs should be encouraged. PMID:19031033

  18. Targeting Skin Dendritic Cells to Improve Intradermal Vaccination

    PubMed Central

    Romani, N.; Flacher, V.; Tripp, C. H.; Sparber, F.; Ebner, S.; Stoitzner, P.

    2014-01-01

    Vaccinations in medicine are typically administered into the muscle beneath the skin or into the subcutaneous fat. As a consequence, the vaccine is immunologically processed by antigen-presenting cells of the skin or the muscle. Recent evidence suggests that the clinically seldom used intradermal route is effective and possibly even superior to the conventional subcutaneous or intramuscular route. Several types of professional antigen-presenting cells inhabit the healthy skin. Epidermal Langerhans cells (CD207/langerin+), dermal langerinneg, and dermal langerin+ dendritic cells (DC) have been described, the latter subset so far only in mouse skin. In human skin langerinneg dermal DC can be further classified based on their reciprocal expression of CD1a and CD14. The relative contributions of these subsets to the generation of immunity or tolerance are still unclear. Yet, specializations of these different populations have become apparent. Langerhans cells in human skin appear to be specialized for induction of cytotoxic T lymphocytes; human CD14+ dermal DC can promote antibody production by B cells. It is currently attempted to rationally devise and improve vaccines by harnessing such specific properties of skin DC. This could be achieved by specifically targeting functionally diverse skin DC subsets. We discuss here advances in our knowledge on the immunological properties of skin DC and strategies to significantly improve the outcome of vaccinations by applying this knowledge. PMID:21253784

  19. Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

    PubMed Central

    Ueno, Keigo; Okubo, Yoichiro; Aki, Kyoko; Urai, Makoto; Kaneko, Yukihiro; Shimizu, Kiminori; Wang, Dan-Ni; Okawara, Akiko; Nara, Takuya; Ohkouchi, Kayo; Mizuguchi, Yuki; Kawamoto, Susumu; Kamei, Katsuhiko; Ohno, Hideaki; Niki, Yoshihito; Shibuya, Kazutoshi; Miyazaki, Yoshitsugu

    2015-01-01

    Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection. PMID:25644007

  20. Dendritic cell-based immunization ameliorates pulmonary infection with highly virulent Cryptococcus gattii.

    PubMed

    Ueno, Keigo; Kinjo, Yuki; Okubo, Yoichiro; Aki, Kyoko; Urai, Makoto; Kaneko, Yukihiro; Shimizu, Kiminori; Wang, Dan-Ni; Okawara, Akiko; Nara, Takuya; Ohkouchi, Kayo; Mizuguchi, Yuki; Kawamoto, Susumu; Kamei, Katsuhiko; Ohno, Hideaki; Niki, Yoshihito; Shibuya, Kazutoshi; Miyazaki, Yoshitsugu

    2015-04-01

    Cryptococcosis due to a highly virulent fungus, Cryptococcus gattii, emerged as an infectious disease on Vancouver Island in Canada and surrounding areas in 1999, causing deaths among immunocompetent individuals. Previous studies indicated that C. gattii strain R265 isolated from the Canadian outbreak had immune avoidance or immune suppression capabilities. However, protective immunity against C. gattii has not been identified. In this study, we used a gain-of-function approach to investigate the protective immunity against C. gattii infection using a dendritic cell (DC)-based vaccine. Bone marrow-derived dendritic cells (BMDCs) efficiently engulfed acapsular C. gattii (Δcap60 strain), which resulted in their expression of costimulatory molecules and inflammatory cytokines. This was not observed for BMDCs that were cultured with encapsulated strains. When Δcap60 strain-pulsed BMDCs were transferred to mice prior to intratracheal R265 infection, significant amelioration of pathology, fungal burden, and the survival rate resulted compared with those in controls. Multinucleated giant cells (MGCs) that engulfed fungal cells were significantly increased in the lungs of immunized mice. Interleukin 17A (IL-17A)-, gamma interferon (IFN-γ)-, and tumor necrosis factor alpha (TNF-α)-producing lymphocytes were significantly increased in the spleens and lungs of immunized mice. The protective effect of this DC vaccine was significantly reduced in IFN-γ knockout mice. These results demonstrated that an increase in cytokine-producing lymphocytes and the development of MGCs that engulfed fungal cells were associated with the protection against pulmonary infection with highly virulent C. gattii and suggested that IFN-γ may have been an important mediator for this vaccine-induced protection. PMID:25644007

  1. Enhancing dendritic cell activation and HIV vaccine effectiveness through nanoparticle vaccination.

    PubMed

    Glass, Joshua J; Kent, Stephen J; De Rose, Robert

    2016-06-01

    Novel vaccination approaches are needed to prevent and control human immunodeficiency virus (HIV) infection. A growing body of literature demonstrates the potential of nanotechnology to modulate the human immune system and generate targeted, controlled immune responses. In this Review, we summarize important advances in how 'nanovaccinology' can be used to develop safe and effective vaccines for HIV. We highlight the central role of dendritic cells in the immune response to vaccination and describe how nanotechnology can be used to enhance delivery to and activation of these important antigen-presenting cells. Strategies employed to improve biodistribution are discussed, including improved lymph node delivery and mucosal penetration concepts, before detailing methods to enhance the humoral and/or cellular immune response to vaccines. We conclude with a commentary on the current state of nanovaccinology. PMID:26783186

  2. Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

    PubMed Central

    Apostolopoulos, Vasso; Thalhammer, Theresia; Tzakos, Andreas G.

    2013-01-01

    Dendritic cells (DCs) are highly specialized antigen presenting cells of the immune system which play a key role in regulating immune responses. Depending on the method of antigen delivery, DCs stimulate immune responses or induce tolerance. As a consequence of the dual function of DCs, DCs are studied in the context of immunotherapy for both cancer and autoimmune diseases. In vaccine development, a major aim is to induce strong, specific T-cell responses. This is achieved by targeting antigen to cell surface molecules on DCs that efficiently channel the antigen into endocytic compartments for loading onto MHC molecules and stimulation of T-cell responses. The most attractive cell surface receptors, expressed on DCs used as targets for antigen delivery for cancer and other diseases, are discussed. PMID:24228179

  3. Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

    PubMed Central

    Larregina, Adriana T.

    2010-01-01

    One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation. PMID:20140521

  4. Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy.

    PubMed

    Datta, Jashodeep; Berk, Erik; Cintolo, Jessica A; Xu, Shuwen; Roses, Robert E; Czerniecki, Brian J

    2015-01-01

    Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications - such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer - clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of "precision" cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted - and personalized - approach combining DC-based vaccination with adjunctive strategies. PMID:26082780

  5. Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy

    PubMed Central

    Datta, Jashodeep; Berk, Erik; Cintolo, Jessica A.; Xu, Shuwen; Roses, Robert E.; Czerniecki, Brian J.

    2015-01-01

    Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies. PMID:26082780

  6. Preconditioning Vaccine Sites for mRNA-Transfected Dendritic Cell Therapy and Antitumor Efficacy.

    PubMed

    Batich, Kristen A; Swartz, Adam M; Sampson, John H

    2016-01-01

    Messenger RNA (mRNA)-transfected dendritic cell (DC) vaccines have been shown to be a powerful modality for eliciting antitumor immune responses in mice and humans; however, their application has not been fully optimized since many of the factors that contribute to their efficacy remain poorly understood. Work stemming from our laboratory has recently demonstrated that preconditioning the vaccine site with a recall antigen prior to the administration of a dendritic cell vaccine creates systemic recall responses and resultantly enhances dendritic cell migration to the lymph nodes with improved antitumor efficacy. This chapter describes the generation of murine mRNA-transfected DC vaccines, as well as a method for vaccine site preconditioning with protein antigen formulations that create potent recall responses. PMID:27076169

  7. Dendritic cell targeted vaccines: Recent progresses and challenges.

    PubMed

    Chen, Pengfei; Liu, Xinsheng; Sun, Yuefeng; Zhou, Peng; Wang, Yonglu; Zhang, Yongguang

    2016-03-01

    Dendritic cells (DCs) are known to be a set of morphology, structure and function of heterogeneous professional antigen presenting cells (APCs), as well as the strongest functional antigen presenting cells, which can absorb, process and present antigens. As the key regulators of innate and adaptive immune responses, DCs are at the center of the immune system and capable of interacting with both B cells and T cells, thereby manipulating the humoral and cellular immune responses. DCs provide an essential link between the innate and adaptive immunity, and the strong immune activation function of DCs and their properties of natural adjuvants, make them a valuable target for antigen delivery. Targeting antigens to DC-specific endocytic receptors in combination with the relevant antibodies or ligands along with immunostimulatory adjuvants has been recently recognized as a promising strategy for designing an effective vaccine that elicits a strong and durable T cell response against intracellular pathogens and cancer. This opinion article provides a brief summary of the rationales, superiorities and challenges of existing DC-targeting approaches. PMID:26513200

  8. Dendrimer-like alpha-d-glucan nanoparticles activate dendritic cells and are effective vaccine adjuvants.

    PubMed

    Lu, Fangjia; Mencia, Alejandra; Bi, Lin; Taylor, Aaron; Yao, Yuan; HogenEsch, Harm

    2015-04-28

    The use of nanoparticles for delivery of vaccine antigens and as vaccine adjuvants is appealing because their size allows efficient uptake by dendritic cells and their biological properties can be tailored to the desired function. Here, we report the effect of chemically modified phytoglycogen, a dendrimer-like α-d-glucan nanoparticle, on dendritic cells in vitro, and the utility of this type of nanoparticle as a vaccine adjuvant in vivo. The modified phytoglycogen nanoparticle, termed Nano-11, has a positive surface charge which enabled electrostatic adsorption of negatively charged protein antigens. The Nano-11-antigen complexes were efficiently phagocytized by dendritic cells. Nano-11 induced increased expression of costimulatory molecules and the secretion of IL-1β and IL-12p40 by dendritic cells. Intramuscular injection of Nano-11-antigen formulations induced a significantly enhanced immune response to two different protein antigens. Examination of the injection site revealed numerous monocytes and relatively few neutrophils at one day after injection. The inflammation had nearly completely disappeared by 2 weeks after injection. These studies indicate that Nano-11 is an effective vaccine delivery vehicle that significantly enhances the immune response. This type of plant based nanoparticle is considered highly cost-effective compared with fully synthetic nanoparticles and appears to have an excellent safety profile making them an attractive adjuvant candidate for prophylactic vaccines. PMID:25747143

  9. Maturation of dendritic cells with lipopeptides that represent vaccine candidates for hepatitis C virus.

    PubMed

    Chua, Brendon Y; Healy, Anne; Cameron, Paul U; Stock, Owen; Rizkalla, Michael; Zeng, Weiguang; Torresi, Joseph; Brown, Lorena E; Fowler, Nina L; Gowans, Eric J; Jackson, David C

    2003-02-01

    The ability of antigens to elicit immune responses depends upon their initial recognition, uptake, processing and presentation by dendritic cells. This fact has been recognized by many workers and dendritic cells are now regarded as natural 'adjuvants' in the business of vaccine design. One way of persuading dendritic cells to become interested in foreign material is to decorate it with lipid moieties found in bacteria. This approach has been used in the context of synthetic peptide-based immunogens and depending on the nature of the epitopes included, can provide highly immunogenic structures capable of eliciting antibody or cytotoxic T cell responses. In this paper we describe the results of experiments in which the stimulatory effects of peptide-based vaccine candidates on human dendritic cells are examined. Our findings indicate that lipidated structures comprising vaccine target sequences of viral origin coupled to the synthetic lipid groups of bacteria are able to induce the maturation of dendritic cells, as measured by the expression of cell surface MHC class II molecules. PMID:12534949

  10. Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

    PubMed Central

    Cicchelero, Laetitia; Denies, Sofie; Devriendt, Bert; de Rooster, Hilde; Sanders, Niek N

    2015-01-01

    Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID:26587315

  11. Vaccines, adjuvants and dendritic cell activators – Current Status and Future Challenges

    PubMed Central

    Obeid, Joseph M.; Hu, Yinin; Slingluff, Craig L.

    2015-01-01

    Cancer vaccines offer a low-toxicity approach to induce anticancer immune responses. They have shown promise for clinical benefit with one cancer vaccine approved in the U.S. for advanced prostate cancer. As other immune therapies are now clearly effective for treatment of advanced cancers of many histologies, there is renewed enthusiasm for optimizing cancer vaccines for use to prevent recurrence in early stage cancers and/or to combine with other immune therapies for therapy of advanced cancers. Future advancements in vaccine therapy will involve the identification and selection of effective antigen formulations, optimization of adjuvants, dendritic cell activation, and combination therapies. In this summary we present the current practice, the broad collection of challenges, and the promising future directions of vaccine therapy for cancer. PMID:26320060

  12. High-throughput identification and dendritic cell-based functional validation of MHC class I-restricted Mycobacterium tuberculosis epitopes

    PubMed Central

    Nair, Smita K.; Tomaras, Georgia D.; Sales, Ana Paula; Boczkowski, David; Chan, Cliburn; Plonk, Kelly; Cai, Yongting; Dannull, Jens; Kepler, Thomas B.; Pruitt, Scott K.; Weinhold, Kent J.

    2014-01-01

    Emergence of drug-resistant strains of the pathogen Mycobacterium tuberculosis (Mtb) and the ineffectiveness of BCG in curtailing Mtb infection makes vaccine development for tuberculosis an important objective. Identifying immunogenic CD8+ T cell peptide epitopes is necessary for peptide-based vaccine strategies. We present a three-tiered strategy for identifying and validating immunogenic peptides: first, identify peptides that form stable complexes with class I MHC molecules; second, determine whether cytotoxic T lymphocytes (CTLs) raised against the whole protein antigen recognize and lyse target cells pulsed with peptides that passed step 1; third, determine whether peptides that passed step 2, when administered in vivo as a vaccine in HLA-A2 transgenic mice, elicit CTLs that lyse target cells expressing the whole protein antigen. Our innovative approach uses dendritic cells transfected with Mtb antigen-encoding mRNA to drive antigen expression. Using this strategy, we have identified five novel peptide epitopes from the Mtb proteins Apa, Mtb8.4 and Mtb19. PMID:24755960

  13. High-throughput identification and dendritic cell-based functional validation of MHC class I-restricted Mycobacterium tuberculosis epitopes.

    PubMed

    Nair, Smita K; Tomaras, Georgia D; Sales, Ana Paula; Boczkowski, David; Chan, Cliburn; Plonk, Kelly; Cai, Yongting; Dannull, Jens; Kepler, Thomas B; Pruitt, Scott K; Weinhold, Kent J

    2014-01-01

    Emergence of drug-resistant strains of the pathogen Mycobacterium tuberculosis (Mtb) and the ineffectiveness of BCG in curtailing Mtb infection makes vaccine development for tuberculosis an important objective. Identifying immunogenic CD8+ T cell peptide epitopes is necessary for peptide-based vaccine strategies. We present a three-tiered strategy for identifying and validating immunogenic peptides: first, identify peptides that form stable complexes with class I MHC molecules; second, determine whether cytotoxic T lymphocytes (CTLs) raised against the whole protein antigen recognize and lyse target cells pulsed with peptides that passed step 1; third, determine whether peptides that passed step 2, when administered in vivo as a vaccine in HLA-A2 transgenic mice, elicit CTLs that lyse target cells expressing the whole protein antigen. Our innovative approach uses dendritic cells transfected with Mtb antigen-encoding mRNA to drive antigen expression. Using this strategy, we have identified five novel peptide epitopes from the Mtb proteins Apa, Mtb8.4 and Mtb19. PMID:24755960

  14. Dendritic Cell-Based Cancer Immunotherapy against Multiple Myeloma: From Bench to Clinic

    PubMed Central

    Hoang, My-Dung; Jung, Sung-Hoon; Lee, Hyun-Ju; Lee, Youn-Kyung; Nguyen-Pham, Thanh-Nhan; Choi, Nu-Ri; Vo, Manh-Cuong; Lee, Seung-Shin; Ahn, Jae-Sook; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon

    2015-01-01

    Although the introduction of stem cell transplantation and novel agents has improved survival, multiple myeloma (MM) is still difficult to cure. Alternative approaches are clearly needed to prolong the survival of patients with MM. Dendritic cell (DC) therapy is a very promising tool immunologically in MM. We developed a method to generate potent DCs with increased Th1 polarization and migration ability for inducing strong myeloma-specific cytotoxic T lymphocytes. In this review, we discuss how the efficacy of cancer immunotherapy using DCs can be improved in MM. PMID:25914874

  15. Expansion of a BDCA1+CD14+ Myeloid Cell Population in Melanoma Patients May Attenuate the Efficacy of Dendritic Cell Vaccines.

    PubMed

    Bakdash, Ghaith; Buschow, Sonja I; Gorris, Mark A J; Halilovic, Altuna; Hato, Stanleyson V; Sköld, Annette E; Schreibelt, Gerty; Sittig, Simone P; Torensma, Ruurd; Duiveman-de Boer, Tjitske; Schröder, Christoph; Smits, Evelien L; Figdor, Carl G; de Vries, I Jolanda M

    2016-08-01

    The tumor microenvironment is characterized by regulatory T cells, type II macrophages, myeloid-derived suppressor cells, and other immunosuppressive cells that promote malignant progression. Here we report the identification of a novel BDCA1(+)CD14(+) population of immunosuppressive myeloid cells that are expanded in melanoma patients and are present in dendritic cell-based vaccines, where they suppress CD4(+) T cells in an antigen-specific manner. Mechanistic investigations showed that BDCA1(+)CD14(+) cells expressed high levels of the immune checkpoint molecule PD-L1 to hinder T-cell proliferation. While this BDCA1(+)CD14(+) cell population expressed markers of both BDCA1(+) dendritic cells and monocytes, analyses of function, transcriptome, and proteome established their unique nature as exploited by tumors for immune escape. We propose that targeting these cells may improve the efficacy of cancer immunotherapy. Cancer Res; 76(15); 4332-46. ©2016 AACR. PMID:27325645

  16. Dendritic cell-targeting DNA-based mucosal adjuvants for the development of mucosal vaccines

    PubMed Central

    Kataoka, Kosuke; Fujihashi, Kohtaro

    2009-01-01

    In order to establish effective mucosal immunity against various mucosal pathogens, vaccines must be delivered via the mucosal route and contain effective adjuvant(s). Since mucosal adjuvants can simply mix with the antigen, it is relatively easy to adapt them for different types of vaccine development. Even in simple admixture vaccines, the adjuvant itself must be prepared without any complications. Thus, CpG oligodeoxynucleotides or plasmids encoding certain cDNA(s) would be potent mucosal adjuvant candidates when compared with other substances that can be used as mucosal adjuvants. The strategy of a DNA-based mucosal adjuvant facilitates the targeting of mucosal dendritic cells, and thus is an effective and safe approach. It would also provide great flexibility for the development of effective vaccines for various mucosal pathogens. PMID:19722892

  17. Self-Amplifying Replicon RNA Vaccine Delivery to Dendritic Cells by Synthetic Nanoparticles

    PubMed Central

    McCullough, Kenneth C.; Milona, Panagiota; Thomann-Harwood, Lisa; Démoulins, Thomas; Englezou, Pavlos; Suter, Rolf; Ruggli, Nicolas

    2014-01-01

    Dendritic cells (DC) play essential roles determining efficacy of vaccine delivery with respect to immune defence development and regulation. This renders DCs important targets for vaccine delivery, particularly RNA vaccines. While delivery of interfering RNA oligonucleotides to the appropriate intracellular sites for RNA-interference has proven successful, the methodologies are identical for RNA vaccines, which require delivery to RNA translation sites. Delivery of mRNA has benefitted from application of cationic entities; these offer value following endocytosis of RNA, when cationic or amphipathic properties can promote endocytic vesicle membrane perturbation to facilitate cytosolic translocation. The present review presents how such advances are being applied to the delivery of a new form of RNA vaccine, replicons (RepRNA) carrying inserted foreign genes of interest encoding vaccine antigens. Approaches have been developed for delivery to DCs, leading to the translation of the RepRNA and encoded vaccine antigens both in vitro and in vivo. Potential mechanisms favouring efficient delivery leading to translation are discussed with respect to the DC endocytic machinery, showing the importance of cytosolic translocation from acidifying endocytic structures. The review relates the DC endocytic pathways to immune response induction, and the potential advantages for these self-replicating RNA vaccines in the near future. PMID:26344889

  18. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation.

    PubMed

    Ravindran, Rajesh; Khan, Nooruddin; Nakaya, Helder I; Li, Shuzhao; Loebbermann, Jens; Maddur, Mohan S; Park, Youngja; Jones, Dean P; Chappert, Pascal; Davoust, Jean; Weiss, David S; Virgin, Herbert W; Ron, David; Pulendran, Bali

    2014-01-17

    The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8(+) T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4(+) and CD8(+) T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response. PMID:24310610

  19. Ipilimumab administered to metastatic melanoma patients who progressed after dendritic cell vaccination

    PubMed Central

    Boudewijns, Steve; Koornstra, Rutger H. T.; Westdorp, Harm; Schreibelt, Gerty; van den Eertwegh, Alfons J. M.; Geukes Foppen, Marnix H.; Haanen, John B.; de Vries, I. Jolanda M.; Figdor, Carl G.; Bol, Kalijn F.; Gerritsen, Winald R.

    2016-01-01

    ABSTRACT Background: Ipilimumab has proven to be effective in metastatic melanoma patients. The purpose of this study was to determine the efficacy of ipilimumab in advanced melanoma patients who showed progressive disease upon experimental dendritic cell (DC) vaccination. Methods: Retrospective analysis of 48 stage IV melanoma patients treated with ipilimumab after progression upon DC vaccination earlier in their treatment. DC vaccination was given either as adjuvant treatment for stage III disease (n = 18) or for stage IV disease (n = 30). Ipilimumab (3 mg/kg) was administered every 3 weeks for up to 4 cycles. Results: Median time between progression upon DC vaccination and first gift of ipilimumab was 5.4 mo. Progression-free survival (PFS) rates for patients that received ipilimumab after adjuvant DC vaccination, and patients that received DC vaccination for stage IV melanoma, were 35% and 7% at 1 y and 35% and 3% at 2 y, while the median PFS was 2.9 mo and 3.1 mo, respectively. Median overall survival of patients pre-treated with adjuvant DC vaccination for stage III melanoma was not reached versus 8.0 mo (95% CI, 5.2–10.9) in the group pre-treated with DC vaccination for stage IV disease (HR of death, 0.36; p = 0.017). Grade 3 immune-related adverse events occurred in 19% of patients and one death (2%) was related to ipilimumab. Conclusions: Clinical responses to ipilimumab were found in a considerable number of advanced melanoma patients with progression after adjuvant DC vaccination for stage III disease, while the effect was very limited in patients who showed progression after DC vaccination for stage IV disease. PMID:27622070

  20. Dendritic Cell-based Immunotherapy for Rheumatoid Arthritis: from Bench to Bedside

    PubMed Central

    Ahmed, Md. Selim

    2016-01-01

    Dendritic cells (DCs) are professional antigen presenting cells, and play an important role in the induction of antigen-specific adaptive immunity. However, some DC populations are involved in immune regulation and immune tolerance. These DC populations are believed to take part in the control of immune exaggeration and immune disorder, and maintain immune homeostasis in the body. Tolerogenic DCs (tolDCs) can be generated in vitro by genetic or pharmacological modification or by controlling the maturation stages of cytokine-derived DCs. These tolDCs have been investigated for the treatment of rheumatoid arthritis (RA) in experimental animal models. In the last decade, several in vitro and in vivo approaches have been translated into clinical trials. As of 2015, three tolDC trials for RA are on the list of ClinicalTrial.gov (www.clinicaltrials.gov). Other trials for RA are in progress and will be listed soon. In this review, we discuss the evolution of tolDC-based immunotherapy for RA and its limitations and future prospects. PMID:26937231

  1. Anti-Tumor Effects From Dendritic Cell-Based Cancer Immunotherapy Using Liposomal Bubbles and Ultrasound

    NASA Astrophysics Data System (ADS)

    Oda, Yusuke; Suzuki, Ryo; Hirata, Keiichi; Nomura, Tetsuya; Utoguchi, Naoki; Maruyama, Kazuo

    2011-09-01

    Dendritic cell (DC)-based cancer immunotherapy has the potential to be a minimally invasive therapy that could prevent cancer metastasis and recurrence. Recently, in order to induce effective anti-tumor immunity, we developed a novel antigen delivery system for DCs by the combination of ultrasound (US) and liposomal bubbles (Bubble Liposomes: BLs) with entrapped perfluoropropane gas. In this study, we investigated the induction of antigen specific immune responses in vivo and the anti-tumor effect caused by immunization of DCs treated with BLs and US. For the immunization of DCs which had delivered antigen, using BLs and US, the mice induced antigen specific cytotoxic T lymphocytes (CTLs) were found to be the main effector cells in DC-based cancer immunotherapy. In addition, immunization with DCs that had been pulsed with antigen using BLs and US completely suppressed tumor growth Therefore, immunization of DCs with this antigen delivery system has promise for the efficient induction of anti-tumor immune responses.

  2. Mahaley Clinical Research Award: chemosensitization of glioma through dendritic cell vaccination.

    PubMed

    Yu, John S; Luptrawan, Anne; Black, Keith L; Liu, Gentao

    2006-01-01

    A major reason chemotherapy fails in cancer treatment is drug resistance. New targets against chemotherapy resistance have been developed with the identification of molecular pathways in drug resistance. These targets are proteins that are highly expressed in human gliomas and are known to be tumor antigens. The immune system produces specialized white blood cells called dendritic cells (DCs). DCs are the most potent antigen-presenting cell of the immune system. DCs have demonstrated the ability to stimulate antibodies and cell-mediated immune responses against tumor antigens. Immunotherapy has emerged as a novel treatment strategy for gliomas with tumor antigens serving as the driving force. Clinical immunotherapy trials for glioma patients using vaccinations made of tumor antigens combined with dendritic cells ex vivo have shown promising results. DC vaccinations may increase sensitivity to chemotherapy, as demonstrated by a significant increase in 2-year survival rates in patients with malignant gliomas who received chemotherapy after immunotherapy (51). The use of DC vaccinations to increase sensitivity of tumor cells to chemotherapy can be rationalized as a novel strategy. Hence, this review will focus on the recent advances in the identification of tumor-associated antigens in gliomas, as well as their biological function related to drug resistance. The current research status and the future direction of DC vaccines to treat glioma in animal models and clinical trials will also be discussed. PMID:17380773

  3. Experimental production of clinical-grade dendritic cell vaccine for acute myeloid leukemia.

    PubMed

    Tan, Yuen-Fen; Sim, Geok-Choo; Habsah, Aziz; Leong, Chooi-Fun; Cheong, Soon-Keng

    2008-12-01

    Dendritic cells (DC) are professional antigen presenting cells of the immune system. Through the use of DC vaccines (DC after exposure to tumour antigens), cryopreserved in single-use aliquots, an attractive and novel immunotherapeutic strategy is available as an option for treatment. In this paper we describe an in vitro attempt to scale-up production of clinical-grade DC vaccines from leukemic cells. Blast cells of two relapsed AML patients were harvested for DC generation in serum-free culture medium containing clinical-grade cytokines GM-CSF, IL-4 and TNF-alpha. Cells from patient 1 were cultured in a bag and those from patient 2 were cultured in a flask. The numbers of seeding cells were 2.24 x 10(8) and 0.8 x 10(8), respectively. DC yields were 10 x 10(6) and 29.8 x 10(6) cells, giving a conversion rate of 4.7% and 37%, respectively. These DC vaccines were then cryopreserved in approximately one million cells per vial with 20% fresh frozen group AB plasma and 10% DMSO. At 12 months and 21 months post cryopreservation, these DC vaccines were thawed, and their sterility, viability, phenotype and functionality were studied. DC vaccines remained sterile up to 21 months of storage. Viability of the cryopreserved DC in the culture bag and flask was found to be 50% and 70% at 12 months post cryopreservation respectively; and 48% and 67% at 21 months post cryopreservation respectively. These DC vaccines exhibited mature DC surface phenotypic markers of CD83, CD86 and HLA-DR, and negative for haemopoietic markers. Mixed lymphocyte reaction (MLR) study showed functional DC vaccines. These experiments demonstrated that it is possible to produce clinical-grade DC vaccines in vitro from blast cells of leukemic patients, which could be cryopreserved up to 21 months for use if repeated vaccinations are required in the course of therapy. PMID:19291915

  4. Duality at the gate: Skin dendritic cells as mediators of vaccine immunity and tolerance.

    PubMed

    Nirschl, Christopher J; Anandasabapathy, Niroshana

    2016-01-01

    Since Edward Jenner's discovery that intentional exposure to cowpox could provide lifelong protection from smallpox, vaccinations have been a major focus of medical research. However, while the protective benefits of many vaccines have been successfully translated into the clinic, the cellular and molecular mechanisms that differentiate effective vaccines from sub-optimal ones are not well understood. Dendritic cells (DCs) are the gatekeepers of the immune system, and are ultimately responsible for the generation of adaptive immunity and lifelong protective memory through interactions with T cells. In addition to lymph node and spleen resident DCs, a number of tissue resident DC populations have been identified at barrier tissues, such as the skin, which migrate to the local lymph node (migDC). These populations have unique characteristics, and play a key role in the function of cutaneous vaccinations by shuttling antigen from the vaccination site to the draining lymph node, rapidly capturing freely draining antigens in the lymph node, and providing key stimuli to T cells. However, while migDCs are responsible for the generation of immunity following exposure to certain pathogens and vaccines, recent work has identified a tolerogenic role for migDCs in the steady state as well as during protein immunization. Here, we examine the roles and functions of skin DC populations in the generation of protective immunity, as well as their role as regulators of the immune system. PMID:26836327

  5. Phase I dendritic cell p53 peptide vaccine for head and neck cancer

    PubMed Central

    Schuler, Patrick J.; Harasymczuk, Malgorzata; Visus, Carmen; DeLeo, Albert; Trivedi, Sumita; Lei, Yu; Argiris, Athanassios; Gooding, William; Butterfield, Lisa H.; Whiteside, Theresa L.; Ferris, Robert L.

    2014-01-01

    Background p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)-based vaccination against p53 was tested in a phase I clinical trial. Methods Monocyte-derived DC from 16 patients were loaded with two modified HLA-class I p53 peptides (Arm 1); additional T-helper(Th) tetanus toxoid peptide (Arm 2) or additional Th wt p53-specific peptide (Arm 3). Vaccine DC (vDC) were delivered to inguinal lymph nodes at 3 time points. Vaccine (vDC) phenotype, circulating p53-specific T-cells and regulatory T-cells (Treg) were serially monitored by flow cytometry and cytokine production by Luminex. vDC properties were compared to those of DC1 generated with an alternative maturation regimen. Results No grade II-IV adverse events were observed. Two-year disease-free survival (DFS) of 88% was favorable. p53-specific T-cell frequencies were increased post vaccination in 11/16 patients (69%), with IFN-γ secretion detected in 4/16 patients. Treg frequencies were consistently decreased (p=0.006) relative to pre-vaccination values. The phenotype and function of DC1 were improved relative to vDC. Conclusion Adjuvant p53-specific vaccination of HNSCC patients was safe and associated with promising clinical outcome, decreased Treg levels, and modest vaccine-specific immunity. HNSCC patients’ DC required stronger maturation stimuli to reverse immune suppression and improve vaccine efficacy. PMID:24583792

  6. Induction of Indoleamine 2, 3-Dioxygenase in Human Dendritic Cells by a Cholera Toxin B Subunit—Proinsulin Vaccine

    PubMed Central

    Mbongue, Jacques C.; Nicholas, Dequina A.; Zhang, Kangling; Kim, Nan-Sun; Hamilton, Brittany N.; Larios, Marco; Zhang, Guangyu; Umezawa, Kazuo; Firek, Anthony F.; Langridge, William H. R.

    2015-01-01

    Dendritic cells (DC) interact with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this study, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1). Increased biosynthesis of the immunosuppressive enzyme was detected in DCs inoculated with the CTB-INS fusion protein but not in DCs inoculated with proinsulin, CTB, or an unlinked combination of the two proteins. Immunoblot and PCR analyses of vaccine treated DCs detected IDO1mRNA by 3 hours and IDO1 protein synthesis by 6 hours after vaccine inoculation. Determination of IDO1 activity in vaccinated DCs by measurement of tryptophan degradation products (kynurenines) showed increased tryptophan cleavage into N-formyl kynurenine. Vaccination did not interfere with monocytes differentiation into DC, suggesting the vaccine can function safely in the human immune system. Treatment of vaccinated DCs with pharmacological NF-κB inhibitors ACHP or DHMEQ significantly inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in vaccine up-regulation of dendritic cell IDO1. Heat map analysis of the proteomic data revealed an overall down-regulation of vaccinated DC functions, suggesting vaccine suppression of DC maturation. Together, our experimental data indicate that CTB-INS vaccine induction of IDO1 biosynthesis in human DCs may result in the inhibition of DC maturation generating a durable state of immunological tolerance. Understanding how CTB-INS modulates IDO1 activity in human DCs will facilitate vaccine efficacy and safety, moving this immunosuppressive strategy closer to clinical applications for prevention of type 1

  7. Induction of indoleamine 2, 3-dioxygenase in human dendritic cells by a cholera toxin B subunit-proinsulin vaccine.

    PubMed

    Mbongue, Jacques C; Nicholas, Dequina A; Zhang, Kangling; Kim, Nan-Sun; Hamilton, Brittany N; Larios, Marco; Zhang, Guangyu; Umezawa, Kazuo; Firek, Anthony F; Langridge, William H R

    2015-01-01

    Dendritic cells (DC) interact with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this study, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1). Increased biosynthesis of the immunosuppressive enzyme was detected in DCs inoculated with the CTB-INS fusion protein but not in DCs inoculated with proinsulin, CTB, or an unlinked combination of the two proteins. Immunoblot and PCR analyses of vaccine treated DCs detected IDO1mRNA by 3 hours and IDO1 protein synthesis by 6 hours after vaccine inoculation. Determination of IDO1 activity in vaccinated DCs by measurement of tryptophan degradation products (kynurenines) showed increased tryptophan cleavage into N-formyl kynurenine. Vaccination did not interfere with monocytes differentiation into DC, suggesting the vaccine can function safely in the human immune system. Treatment of vaccinated DCs with pharmacological NF-κB inhibitors ACHP or DHMEQ significantly inhibited IDO1 biosynthesis, suggesting a role for NF-κB signaling in vaccine up-regulation of dendritic cell IDO1. Heat map analysis of the proteomic data revealed an overall down-regulation of vaccinated DC functions, suggesting vaccine suppression of DC maturation. Together, our experimental data indicate that CTB-INS vaccine induction of IDO1 biosynthesis in human DCs may result in the inhibition of DC maturation generating a durable state of immunological tolerance. Understanding how CTB-INS modulates IDO1 activity in human DCs will facilitate vaccine efficacy and safety, moving this immunosuppressive strategy closer to clinical applications for prevention of type 1

  8. Cell-free tumor microparticle vaccines stimulate dendritic cells via cGAS/STING signaling.

    PubMed

    Zhang, Huafeng; Tang, Ke; Zhang, Yi; Ma, Ruihua; Ma, Jingwei; Li, Yong; Luo, Shunqun; Liang, Xiaoyu; Ji, Tiantian; Gu, Zhichao; Lu, Jinzhi; He, Wei; Cao, Xuetao; Wan, Yonghong; Huang, Bo

    2015-02-01

    Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell-derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP-loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications. PMID:25477253

  9. Early Transcriptome Signatures from Immunized Mouse Dendritic Cells Predict Late Vaccine-Induced T-Cell Responses

    PubMed Central

    Dérian, Nicolas; Bellier, Bertrand; Pham, Hang Phuong; Tsitoura, Eliza; Kazazi, Dorothea; Huret, Christophe; Mavromara, Penelope; Klatzmann, David; Six, Adrien

    2016-01-01

    Systems biology offers promising approaches for identifying response-specific signatures to vaccination and assessing their predictive value. Here, we designed a modelling strategy aiming to predict the quality of late T-cell responses after vaccination from early transcriptome analysis of dendritic cells. Using standardized staining with tetramer, we first quantified antigen-specific T-cell expansion 5 to 10 days after vaccination with one of a set of 41 different vaccine vectors all expressing the same antigen. Hierarchical clustering of the responses defined sets of high and low T cell response inducers. We then compared these responses with the transcriptome of splenic dendritic cells obtained 6 hours after vaccination with the same vectors and produced a random forest model capable of predicting the quality of the later antigen-specific T-cell expansion. The model also successfully predicted vector classification as low or strong T-cell response inducers of a novel set of vaccine vectors, based on the early transcriptome results obtained from spleen dendritic cells, whole spleen and even peripheral blood mononuclear cells. Finally, our model developed with mouse datasets also accurately predicted vaccine efficacy from literature-mined human datasets. PMID:26998760

  10. A Novel Cancer Vaccine Strategy Based on HLA-A*0201 Matched Allogeneic Plasmacytoid Dendritic Cells

    PubMed Central

    Aspord, Caroline; Charles, Julie; Leccia, Marie-Therese; Laurin, David; Richard, Marie-Jeanne; Chaperot, Laurence; Plumas, Joel

    2010-01-01

    Background The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy. Methods and Findings Stimulation of PBMC from HLA-A*0201+ donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels of antigen-specific and functional cytotoxic T cell responses (up to 98% tetramer+ CD8 T cells). The pDC vaccine demonstrated strong anti-tumor therapeutic in vivo efficacy as shown by the inhibition of tumor growth in a humanized mouse model. It also elicited highly functional tumor-specific T cells ex-vivo from PBMC and TIL of stage I-IV melanoma patients. Responses against MelA, GP100, tyrosinase and MAGE-3 antigens reached tetramer levels up to 62%, 24%, 85% and 4.3% respectively. pDC vaccine-primed T cells specifically killed patients' own autologous melanoma tumor cells. This semi-allogeneic pDC vaccine was more effective than conventional myeloid DC-based vaccines. Furthermore, the pDC vaccine design endows it with a strong potential for clinical application in cancer treatment. Conclusions These findings highlight HLA-A*0201 matched allogeneic pDCs as potent inducers of tumor immunity and provide a promising immunotherapeutic strategy to fight cancer. PMID:20454561

  11. Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer.

    PubMed

    Xi, Hai-Bo; Wang, Gong-Xian; Fu, Bin; Liu, Wei-Peng; Li, Yu

    2015-01-01

    Dendritic cell (DC)-based vaccines are a promising therapeutic modality for cancer. Results from recent trials and approval of the first DC vaccine by the U.S. Food and Drugs Administration for prostate cancer have paved the way for DC-based vaccines. A total of 21 hormone refractory prostate cancer (HRPC) patients with a life expectancy >3 months were randomised into two groups. DC loaded with recombinant Prostate Specific Membrane Antigen (rPSMA) and recombinant Survivin (rSurvivin) peptides was administered as an subcutaneous (s.c.) injection (5×10(6) cells). Docetaxel (75 mg/m(2) intravenous (i.v.)) and prednisone (5 mg, bis in die (b.i.d.)) served as control. Clinical and immunological responses were evaluated. Primary endpoints were safety and feasibility; secondary endpoint was overall survival. Responses were evaluated on day 15, day 30, day 60, and day 90. DC vaccination was well tolerated with no signs of grade 2 toxicity. DC vaccination induced delayed-type hypersensitivity reactivity and an immune response in all patients. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumours (RECIST) was 72.7% (8/11) versus 45.4 (5/11) in the docetaxel arm and immune related response criteria (irRC) was 54.5% (6/11) compared with 27.2% (3/11) in the control arm. The DC arm showed stable disease (SD) in 6 patients, progressive disease (PD) in 3 patients, and partial remission (PR) in two patients compared to SD in 5 patients, PD in 6 patients, and PR in none in the docetaxel arm. There was a cellular response, disease stabilization, no adverse events, and partial remission with the rPSMA and rSurvivin primed DC vaccine. PMID:25787895

  12. Progress on the development of human in vitro dendritic cell based assays for assessment of the sensitizing potential of a compound

    SciTech Connect

    Galvao dos Santos, G.; Reinders, J.; Ouwehand, K.; Rustemeyer, T.; Scheper, R.J.; Gibbs, S.

    2009-05-01

    Allergic contact dermatitis is the result of an adaptive immune response of the skin to direct exposure to an allergen. Since many chemicals are also allergens, European regulations require strict screening of all ingredients in consumer products. Until recently, identifying a potential allergen has completely relied on animal testing (e.g.: Local Lymph Node Assay). In addition to the ethical problems, both the 7th Amendment to the Cosmetics Directive and REACH have stimulated the development of alternative tests for the assessment of potential sensitizers. This review is aimed at summarising the progress on cell based assays, in particular dendritic cell based assays, being developed as animal alternatives. Primary cells (CD34{sup +} derived dendritic cells, monocyte derived dendritic cells) as well as dendritic cell-like cell lines (THP-1, U-937, MUTZ-3, KG-1, HL-60, and K562) are extensively described along with biomarkers such as cell surface markers, cytokines, chemokines and kinases. From this review, it can be concluded that no single cell based assay nor single marker is yet able to distinguish all sensitizers from non-sensitizers in a test panel of chemicals, nor is it possible to rank the sensitizing potential of the test chemicals. This suggests that sensitivity and specificity may be increased by a tiered assay approach. Only a limited number of genomic and proteomic studies have been completed until now. Such studies have the potential to identify novel biomarkers for inclusion in future assay development. Although progress is promising, this review suggests that it may be difficult to meet the up and coming European regulatory deadlines.

  13. Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines

    PubMed Central

    Vandenberk, Lien; Belmans, Jochen; Van Woensel, Matthias; Riva, Matteo; Van Gool, Stefaan W.

    2016-01-01

    Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings. PMID:26834740

  14. ERK1 as a Therapeutic Target for Dendritic Cell Vaccination against High-Grade Gliomas.

    PubMed

    Ku, Min-Chi; Edes, Inan; Bendix, Ivo; Pohlmann, Andreas; Waiczies, Helmar; Prozorovski, Tim; Günther, Martin; Martin, Conrad; Pagès, Gilles; Wolf, Susanne A; Kettenmann, Helmut; Uckert, Wolfgang; Niendorf, Thoralf; Waiczies, Sonia

    2016-08-01

    Glioma regression requires the recruitment of potent antitumor immune cells into the tumor microenvironment. Dendritic cells (DC) play a role in immune responses to these tumors. The fact that DC vaccines do not effectively combat high-grade gliomas, however, suggests that DCs need to be genetically modified specifically to promote their migration to tumor relevant sites. Previously, we identified extracellular signal-regulated kinase (ERK1) as a regulator of DC immunogenicity and brain autoimmunity. In the current study, we made use of modern magnetic resonance methods to study the role of ERK1 in regulating DC migration and tumor progression in a model of high-grade glioma. We found that ERK1-deficient mice are more resistant to the development of gliomas, and tumor growth in these mice is accompanied by a higher infiltration of leukocytes. ERK1-deficient DCs exhibit an increase in migration that is associated with sustained Cdc42 activation and increased expression of actin-associated cytoskeleton-organizing proteins. We also demonstrated that ERK1 deletion potentiates DC vaccination and provides a survival advantage in high-grade gliomas. Considering the therapeutic significance of these results, we propose ERK1-deleted DC vaccines as an additional means of eradicating resilient tumor cells and preventing tumor recurrence. Mol Cancer Ther; 15(8); 1975-87. ©2016 AACR. PMID:27256374

  15. Dendritic cell vaccination for glioblastoma multiforme: review with focus on predictive factors for treatment response

    PubMed Central

    Dejaegher, Joost; Van Gool, Stefaan; De Vleeschouwer, Steven

    2014-01-01

    Glioblastoma multiforme (GBM) is the most common and most aggressive type of primary brain cancer. Since median overall survival with multimodal standard therapy is only 15 months, there is a clear need for additional effective and long-lasting treatments. Dendritic cell (DC) vaccination is an experimental immunotherapy being tested in several Phase I and Phase II clinical trials. In these trials, safety and feasibility have been proven, and promising clinical results have been reported. On the other hand, it is becoming clear that not every GBM patient will benefit from this highly personalized treatment. Defining the subgroup of patients likely to respond to DC vaccination will position this option correctly amongst other new GBM treatment modalities, and pave the way to incorporation in standard therapy. This review provides an overview of GBM treatment options and focuses on the currently known prognostic and predictive factors for response to DC vaccination. In this way, it will provide the clinician with the theoretical background to refer patients who might benefit from this treatment.

  16. A Cell-Based Systems Biology Assessment of Human Blood to Monitor Immune Responses after Influenza Vaccination

    PubMed Central

    Hoek, Kristen L.; Samir, Parimal; Howard, Leigh M.; Niu, Xinnan; Prasad, Nripesh; Galassie, Allison; Liu, Qi; Allos, Tara M.; Floyd, Kyle A.; Guo, Yan; Shyr, Yu; Levy, Shawn E.; Joyce, Sebastian; Edwards, Kathryn M.; Link, Andrew J.

    2015-01-01

    Systems biology is an approach to comprehensively study complex interactions within a biological system. Most published systems vaccinology studies have utilized whole blood or peripheral blood mononuclear cells (PBMC) to monitor the immune response after vaccination. Because human blood is comprised of multiple hematopoietic cell types, the potential for masking responses of under-represented cell populations is increased when analyzing whole blood or PBMC. To investigate the contribution of individual cell types to the immune response after vaccination, we established a rapid and efficient method to purify human T and B cells, natural killer (NK) cells, myeloid dendritic cells (mDC), monocytes, and neutrophils from fresh venous blood. Purified cells were fractionated and processed in a single day. RNA-Seq and quantitative shotgun proteomics were performed to determine expression profiles for each cell type prior to and after inactivated seasonal influenza vaccination. Our results show that transcriptomic and proteomic profiles generated from purified immune cells differ significantly from PBMC. Differential expression analysis for each immune cell type also shows unique transcriptomic and proteomic expression profiles as well as changing biological networks at early time points after vaccination. This cell type-specific information provides a more comprehensive approach to monitor vaccine responses. PMID:25706537

  17. Polypropylene Sulfide Nanoparticle p24 Vaccine Promotes Dendritic Cell-Mediated Specific Immune Responses against HIV-1.

    PubMed

    Caucheteux, Stephan M; Mitchell, John P; Ivory, Matthew O; Hirosue, Sachiko; Hakobyan, Svetlana; Dolton, Garry; Ladell, Kristin; Miners, Kelly; Price, David A; Kan-Mitchell, June; Sewell, Andrew K; Nestle, Frank; Moris, Arnaud; Karoo, Richard O; Birchall, James C; Swartz, Melody A; Hubbel, Jeffrey A; Blanchet, Fabien P; Piguet, Vincent

    2016-06-01

    Delivery of vaccine formulations into the dermis using antigen-coated microneedle patches is a promising and safe approach because of efficient antigen delivery and safety. We evaluated an intradermal vaccine using HIV-1 p24 Gag peptide-conjugated polypropylene sulfide nanoparticles to induce immunity against HIV-1. This peptide-conjugated polypropylene sulfide nanoparticle formulation did not accelerate the maturation of blood- or skin-derived subsets of dendritic cells, either generated in vitro or purified ex vivo, despite efficient uptake in the absence of adjuvant. Moreover, dendritic cell-mediated capture of particulate antigen in this form induced potent HIV-1-specific CD4(+) T-cell responses, as well as B-cell-mediated antibody production. Nanoparticle-based intradermal antigen delivery may therefore provide a new option in the global effort to develop an effective vaccine against HIV-1. PMID:26896775

  18. Immune Monitoring Using mRNA-Transfected Dendritic Cells.

    PubMed

    Borch, Troels Holz; Svane, Inge Marie; Met, Özcan

    2016-01-01

    Dendritic cells are known to be the most potent antigen presenting cell in the immune system and are used as cellular adjuvants in therapeutic anticancer vaccines using various tumor-associated antigens or their derivatives. One way of loading antigen into the dendritic cells is by mRNA electroporation, ensuring presentation of antigen through major histocompatibility complex I and potentially activating T cells, enabling them to kill the tumor cells. Despite extensive research in the field, only one dendritic cell-based vaccine has been approved. There is therefore a great need to elucidate and understand the immunological impact of dendritic cell vaccination in order to improve clinical benefit. In this chapter, we describe a method for performing immune monitoring using peripheral blood mononuclear cells and autologous dendritic cells transfected with tumor-associated antigen-encoding mRNA. PMID:27236804

  19. New approaches to the development of adenoviral dendritic cell vaccines in melanoma

    PubMed Central

    Vujanovic, Lazar

    2013-01-01

    Considerable research in the field of immunotherapy for melanoma has demonstrated that this tumor type can be responsive to therapeutic immune activation strategies. In early clinical trials, vaccine strategies using dendritic cells (DCs) and adenovirus (Ad) vectors (AdVs) were safe and immunogenic, and induced clinical responses in a minority of patients. Research from the past several years has yielded an improved mechanistic understanding of DC biology, AdV effects on DCs and the crosstalk that occurs between antigen-loaded DCs and specific lymphocyte subsets. This knowledge base is being combined with technological advances in cytokine delivery, AdV design and in vivo DC targeting. These developments are leading to novel AdV-transduced DC-based therapeutic modalities that may further advance melanoma immunotherapy. Interactions between AdVs and DCs, initial clinical trial results, and new developments in DC engineering and in AdV biology are reviewed. PMID:21154122

  20. Paradigm Shift in Dendritic Cell-Based Immunotherapy: From in vitro Generated Monocyte-Derived DCs to Naturally Circulating DC Subsets

    PubMed Central

    Wimmers, Florian; Schreibelt, Gerty; Sköld, Annette E.; Figdor, Carl G.; De Vries, I. Jolanda M.

    2014-01-01

    Dendritic cell (DC)-based immunotherapy employs the patients’ immune system to fight neoplastic lesions spread over the entire body. This makes it an important therapy option for patients suffering from metastatic melanoma, which is often resistant to chemotherapy. However, conventional cellular vaccination approaches, based on monocyte-derived DCs (moDCs), only achieved modest response rates despite continued optimization of various vaccination parameters. In addition, the generation of moDCs requires extensive ex vivo culturing conceivably hampering the immunogenicity of the vaccine. Recent studies, thus, focused on vaccines that make use of primary DCs. Though rare in the blood, these naturally circulating DCs can be readily isolated and activated thereby circumventing lengthy ex vivo culture periods. The first clinical trials not only showed increased survival rates but also the induction of diversified anti-cancer immune responses. Upcoming treatment paradigms aim to include several primary DC subsets in a single vaccine as pre-clinical studies identified synergistic effects between various antigen-presenting cells. PMID:24782868

  1. Development of a dendritic cell vaccine encoding multiple cytotoxic T lymphocyte epitopes targeting hepatitis C virus.

    PubMed

    Zhou, Yun; Zhao, Futao; Chen, Lin; Ma, Li; Wang, Yu; He, Yu; Ma, Zhiyuan; Liu, Haili; Guo, Yonghong; Zhang, Ying; Yao, Zhiqiang; Hao, Chunqiu; Jia, Zhansheng

    2013-10-01

    The aim of the present study was to develop a dendritic cell (DC) vaccine encoding hepatitis C virus (HCV) multiple cytotoxic T lymphocyte (CTL) epitopes that can stimulate T cell responses in vitro, and can be used for immunization in vivo. DCs were infected with recombinant replication-defective adenoviruses (Ads) expressing 2 HCV sequences fused with green fluorescent protein (GFP) and FLAG tags. One sequence (sequence 1) contained the HCV CTL epitopes, NS4B 1793-1801 and P7 774-782, as well as the HCV Th epitope, NS3 1248-1261. A second sequence (sequence 2) was the positive epitope control which contained HCV core 35-44, core 132-140 and NS3 1248-1261. The efficiency of infection was detected by flow cytometry and the expression of HCV epitopes in the DCs was confirmed by RT-PCR and western blot analysis. Ad infection significantly enhanced DC maturation and interleukin (IL)-12p70 production, resulting in T cell proliferation and increased interferon-γ secretion. The CTLs stimulated by Ad-infected DCs specifically killed Huh7.5 human hepatoma cells. The recombinant Ad-expressing multiple CTL HCV epitopes effectively infected the DCs in vitro and promoted T cell antiviral immune responses, thereby laying the foundation for the development of anti-HCV DC vaccines. PMID:23934073

  2. Immunogenic Properties of a BCG Adjuvanted Chitosan Nanoparticle-Based Dengue Vaccine in Human Dendritic Cells.

    PubMed

    Hunsawong, Taweewun; Sunintaboon, Panya; Warit, Saradee; Thaisomboonsuk, Butsaya; Jarman, Richard G; Yoon, In-Kyu; Ubol, Sukathida; Fernandez, Stefan

    2015-09-01

    Dengue viruses (DENVs) are among the most rapidly and efficiently spreading arboviruses. WHO recently estimated that about half of the world's population is now at risk for DENV infection. There is no specific treatment or vaccine available to treat or prevent DENV infections. Here, we report the development of a novel dengue nanovaccine (DNV) composed of UV-inactivated DENV-2 (UVI-DENV) and Mycobacterium bovis Bacillus Calmette-Guerin cell wall components (BCG-CWCs) loaded into chitosan nanoparticles (CS-NPs). CS-NPs were prepared by an emulsion polymerization method prior to loading of the BCG-CWCs and UVI-DENV components. Using a scanning electron microscope and a zetasizer, DNV was determined to be of spherical shape with a diameter of 372.0 ± 11.2 nm in average and cationic surface properties. The loading efficacies of BCG-CWCs and UVI-DENV into the CS-NPs and BCG-CS-NPs were up to 97.2 and 98.4%, respectively. THP-1 cellular uptake of UVI-DENV present in the DNV was higher than soluble UVI-DENV alone. DNV stimulation of immature dendritic cells (iDCs) resulted in a significantly higher expression of DCs maturation markers (CD80, CD86 and HLA-DR) and induction of various cytokine and chemokine productions than in UVI-DENV-treated iDCs, suggesting a potential use of BCG- CS-NPs as adjuvant and delivery system for dengue vaccines. PMID:26394138

  3. Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.

    PubMed

    Osada, Takuya; Nagaoka, Koji; Takahara, Masashi; Yang, Xiao Yi; Liu, Cong-Xiao; Guo, Hongtao; Roy Choudhury, Kingshuk; Hobeika, Amy; Hartman, Zachary; Morse, Michael A; Lyerly, H Kim

    2015-05-01

    Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy. PMID:25839441

  4. Mechanism of Ad5 Vaccine Immunity and Toxicity: Fiber Shaft Targeting of Dendritic Cells

    PubMed Central

    Kong, Wing-pui; Sheets, Rebecca L; Gomez, Phillip L; King, C. Richter; Nabel, Gary J

    2007-01-01

    Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs) was independent of the coxsackievirus and adenovirus receptor (CAR), its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines. PMID:17319743

  5. A generic RNA-pulsed dendritic cell vaccine strategy for renal cell carcinoma

    PubMed Central

    Geiger, Christiane; Regn, Sybille; Weinzierl, Andreas; Noessner, Elfriede; Schendel, Dolores J

    2005-01-01

    We present a generic dendritic cell (DC) vaccine strategy for patients with renal cell carcinoma (RCC) based on the use of RNA as a source of multiplex tumor-associated antigens (TAAs). Instead of preparing RNA from tumor tissue of each individual RCC patient, we propose to substitute RNA prepared from a well characterized highly immunogenic RCC cell line (RCC-26 tumor cells) as a generic source of TAAs for loading of DCs. We demonstrate here that efficient RNA transfer can be achieved using lipofection of immature DCs, which are subsequently matured with a cytokine cocktail to express high levels of MHC and costimulatory molecules as well as the chemokine receptor CCR7. Neither RNA itself nor the lipid component impacted on the phenotype or the cytokine secretion of mature DCs. Following RNA loading, DCs derived from HLA-A2-positive donors were able to activate effector-memory cytotoxic T lymphocytes (CTLs) specific for a TAA ligand expressed by the RCC-26 cell line. CTL responses to RNA-loaded DCs reached levels comparable to those stimulated directly by the RCC-26 tumor cells. Furthermore, DCs expressing tumor cell RNA primed naïve T cells, yielding T cell lines with cytotoxicity and cytokine secretion after contact with RCC tumor cells. RCC-26 cell lines are available as good manufacturing practice (GMP)-certified reagents enabling this source of RNA to be easily standardized and adapted for clinical testing. In addition, well defined immune monitoring tools, including the use of RNA expressing B cell lines, are available. Thus, this DC vaccine strategy can be directly compared with an ongoing gene therapy trial using genetically-engineered variants of the RCC-26 cell line as vaccines for RCC patients with metastatic disease. PMID:16045799

  6. Pathogen-Associated Molecular Patterns Induced Crosstalk between Dendritic Cells, T Helper Cells, and Natural Killer Helper Cells Can Improve Dendritic Cell Vaccination

    PubMed Central

    Oth, Tammy; Vanderlocht, Joris; Van Elssen, Catharina H. M. J.; Bos, Gerard M. J.; Germeraad, Wilfred T. V.

    2016-01-01

    A coordinated cellular interplay is of crucial importance in both host defense against pathogens and malignantly transformed cells. The various interactions of Dendritic Cells (DC), Natural Killer (NK) cells, and T helper (Th) cells can be influenced by a variety of pathogen-associated molecular patterns (PAMPs) and will lead to enhanced CD8+ effector T cell responses. Specific Pattern Recognition Receptor (PRR) triggering during maturation enables DC to enhance Th1 as well as NK helper cell responses. This effect is correlated with the amount of IL-12p70 released by DC. Activated NK cells are able to amplify the proinflammatory cytokine profile of DC via the release of IFN-γ. The knowledge on how PAMP recognition can modulate the DC is of importance for the design and definition of appropriate therapeutic cancer vaccines. In this review we will discuss the potential role of specific PAMP-matured DC in optimizing therapeutic DC-based vaccines, as some of these DC are efficiently activating Th1, NK cells, and cytotoxic T cells. Moreover, to optimize these vaccines, also the inhibitory effects of tumor-derived suppressive factors, for example, on the NK-DC crosstalk, should be taken into account. Finally, the suppressive role of the tumor microenvironment in vaccination efficacy and some proposals to overcome this by using combination therapies will be described. PMID:26980946

  7. Exceptional antineoplastic activity of a dendritic-cell-targeted vaccine loaded with a Listeria peptide proposed against metastatic melanoma

    PubMed Central

    Calderon-Gonzalez, Ricardo; Bronchalo-Vicente, Lucia; Freire, Javier; Frande-Cabanes, Elisabet; Alaez-Alvarez, Lidia; Gomez-Roman, Javier; Yañez-Diaz, Sonsóles; Alvarez-Dominguez, Carmen

    2016-01-01

    Vaccination with dendritic cells (DCs) is proposed to induce lasting responses against melanoma but its survival benefit in patients needs to be demonstrated. We propose a DC-targeted vaccine loaded with a Listeria peptide with exceptional anti-tumour activity to prevent metastasis of melanoma. Mice vaccinated with vaccines based on DCs loaded with listeriolysin O peptide (91–99) (LLO91–99) showed clear reduction of metastatic B16OVA melanoma size and adhesion, prevention of lung metastasis, enhanced survival, and reversion of immune tolerance. Robust innate and specific immune responses explained the efficiency of DC-LLO91–99 vaccines against B16OVA melanoma. The noTable features of this vaccine related to melanoma reduction were: expansion of immune-dominant LLO91–99-specific CD8 T cells that helped to expand melanoma-specific CD8+ T cells; high numbers of tumour-infiltrating lymphocytes with a cytotoxic phenotype; and a decrease in CD4+CD25high regulatory T cells. This vaccine might be a useful alternative treatment for advanced melanoma, alone or in combination with other therapies. PMID:26942874

  8. A novel adjuvant Ling Zhi-8 enhances the efficacy of DNA cancer vaccine by activating dendritic cells.

    PubMed

    Lin, Chi-Chen; Yu, Yen-Ling; Shih, Chia-Chiao; Liu, Ko-Jiunn; Ou, Keng-Liang; Hong, Ling-Zong; Chen, Jody D C; Chu, Ching-Liang

    2011-07-01

    DNA vaccine has been suggested to use in cancer therapy, but the efficacy remains to be improved. The immunostimulatory effect of a fungal immunomodulatory protein Ling Zhi-8 (LZ-8) isolated from Ganoderma lucidum has been reported. In this study, we tested the adjuvanticity of LZ-8 for HER-2/neu DNA vaccine against p185(neu) expressing tumor MBT-2 in mice. We found that recombinant LZ-8 stimulated mouse bone marrow-derived dendritic cells (DCs) via TLR4 and its stimulatory effect was not due to any microbe contaminant. In addition, LZ-8 enhanced the ability of DCs to induce antigen-specific T cell activation in vitro and in a subunit vaccine model in vivo. Surprisingly, LZ-8 cotreatment strongly improved the therapeutic effect of DNA vaccine against MBT-2 tumor in mice. This increase in antitumor activity was attributed to the enhancement of vaccine-induced Th1 and CTL responses. Consistent with the results from DCs, the promoting effect of LZ-8 on DNA vaccine was diminished when the MBT-2 tumor cells were grown in TLR4 mutant mice. Thus, we concluded that LZ-8 may be a promising adjuvant to enhance the efficacy of DNA vaccine by activating DCs via TLR4. PMID:21499904

  9. Immunogenic Properties of a BCG Adjuvanted Chitosan Nanoparticle-Based Dengue Vaccine in Human Dendritic Cells

    PubMed Central

    Hunsawong, Taweewun; Sunintaboon, Panya; Warit, Saradee; Thaisomboonsuk, Butsaya; Jarman, Richard G.; Yoon, In-Kyu; Ubol, Sukathida; Fernandez, Stefan

    2015-01-01

    Dengue viruses (DENVs) are among the most rapidly and efficiently spreading arboviruses. WHO recently estimated that about half of the world’s population is now at risk for DENV infection. There is no specific treatment or vaccine available to treat or prevent DENV infections. Here, we report the development of a novel dengue nanovaccine (DNV) composed of UV-inactivated DENV-2 (UVI-DENV) and Mycobacterium bovis Bacillus Calmette-Guerin cell wall components (BCG-CWCs) loaded into chitosan nanoparticles (CS-NPs). CS-NPs were prepared by an emulsion polymerization method prior to loading of the BCG-CWCs and UVI-DENV components. Using a scanning electron microscope and a zetasizer, DNV was determined to be of spherical shape with a diameter of 372.0 ± 11.2 nm in average and cationic surface properties. The loading efficacies of BCG-CWCs and UVI-DENV into the CS-NPs and BCG-CS-NPs were up to 97.2 and 98.4%, respectively. THP-1 cellular uptake of UVI-DENV present in the DNV was higher than soluble UVI-DENV alone. DNV stimulation of immature dendritic cells (iDCs) resulted in a significantly higher expression of DCs maturation markers (CD80, CD86 and HLA-DR) and induction of various cytokine and chemokine productions than in UVI-DENV-treated iDCs, suggesting a potential use of BCG- CS-NPs as adjuvant and delivery system for dengue vaccines. PMID:26394138

  10. Therapeutic vaccine generated by electrofusion of dendritic cells and tumour cells.

    PubMed

    Kuriyama, H; Shimizu, K; Lee, W; Kjaergaard, J; Parkhurst, M R; Cohen, P A; Shu, S

    2004-01-01

    Immunotherapy with fusion of dendritic cells (DCs) and tumour cells potentially confers the advantages of DC antigen-presenting functionality and a continuous source of unaltered tumour antigens. However, fusion using chemical or viral fusogens has been inefficient. We have recently developed a high throughput electrofusion technique with which very efficient fusion rates (15-54%) were observed in over 300 experiments, using a variety of murine and human tumour cell lines. The fused cells display a mature DC phenotype and express tumour-associated antigens. In two pre-clinical animal models (B16 melanoma transduced with the LacZ gene and the MCA 205 fibrosarcoma), a single vaccination of mice bearing tumours established in the lung, brain and skin resulted in tumour regression and prolongation of life. However, therapeutic efficacy required the administration of adjuvants such as IL-12 and OX-40R mAbs. Effective immunotherapy also required the delivery of fusion cells directly into lymphoid organs (spleen or lymph nodes). Using five defined human T cell lines derived from melanoma patients, allogeneic DCs of HLA-A2, HLA-DR4 and HLA-DR7 haplotypes fused with MART-1, gp100, tyrosinase and TRP-2 expressing 888 mel melanoma cells were analysed for their ability to stimulate specific cytokine (IFN-gamma and GM-CSF) secretion. DC-888 mel hybrids presented all tumour-associated epitopes to both CD4 and CD8 T cell lines in the context of MHC class II and I molecules, respectively. The therapeutic efficacy of a DC-tumour fusion vaccine is now being evaluated for the treatment of metastatic melanoma. PMID:15603192

  11. Vaccine delivery by penetratin: mechanism of antigen presentation by dendritic cells.

    PubMed

    Pouniotis, Dodie; Tang, Choon-Kit; Apostolopoulos, Vasso; Pietersz, Geoffrey

    2016-08-01

    Cell-penetrating peptides (CPP) or membrane-translocating peptides such as penetratin from Antennapedia homeodomain or TAT from human immunodeficiency virus are useful vectors for the delivery of protein antigens or their cytotoxic (Tc) or helper (Th) T cell epitopes to antigen-presenting cells. Mice immunized with CPP containing immunogens elicit antigen-specific Tc and/or Th responses and could be protected from tumor challenges. In the present paper, we investigate the mechanism of class I and class II antigen presentation of ovalbumin covalently linked to penetratin (AntpOVA) by bone marrow-derived dendritic cells with the use of biochemical inhibitors of various pathways of antigen processing and presentation. Results from our study suggested that uptake of AntpOVA is via a combination of energy-independent (membrane fusion) and energy-dependent pathways (endocytosis). Once internalized by either mechanism, multiple tap-dependent or independent antigen presentation pathways are accessed while not completely dependent on proteasomal processing but involving proteolytic trimming in the ER and Golgi compartments. Our study provides an understanding on the mechanism of antigen presentation mediated by CPP and leads to greater insights into future development of vaccine formulations. PMID:27138940

  12. Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens

    PubMed Central

    Young, Louise J.; Wilson, Nicholas S.; Schnorrer, Petra; Mount, Adele; Lundie, Rachel J.; La Gruta, Nicole L.; Crabb, Brendan S.; Belz, Gabrielle T.; Heath, William R.; Villadangos, Jose A.

    2007-01-01

    When dendritic cells (DCs) encounter signals associated with infection or inflammation, they become activated and undergo maturation. Mature DCs are very efficient at presenting antigens captured in association with their activating signal but fail to present subsequently encountered antigens, at least in vitro. Such impairment of MHC class II (MHC II) antigen presentation has generally been thought to be a consequence of down-regulation of endocytosis, so it might be expected that antigens synthesized by the DCs themselves (for instance, viral antigens) would still be presented by mature DCs. Here, we show that DCs matured in vivo could still capture and process soluble antigens, but were unable to present peptides derived from these antigens. Furthermore, presentation of viral antigens synthesized by the DCs themselves was also severely impaired. Indeed, i.v. injection of pathogen mimics, which caused systemic DC activation in vivo, impaired the induction of CD4 T cell responses against subsequently encountered protein antigens. This immunosuppressed state could be reversed by adoptive transfer of DCs loaded exogenously with antigens, demonstrating that impairment of CD4 T cell responses was due to lack of antigen presentation rather than to overt suppression of T cell activation. The biochemical mechanism underlying this phenomenon was the down-regulation of MHC II–peptide complex formation that accompanied DC maturation. These observations have important implications for the design of prophylactic and therapeutic DC vaccines and contribute to the understanding of the mechanisms causing immunosuppression during systemic blood infections. PMID:17978177

  13. High-yield production of a stable Vero cell-based vaccine candidate against the highly pathogenic avian influenza virus H5N1

    SciTech Connect

    Zhou, Fangye; Zhou, Jian; Ma, Lei; Song, Shaohui; Zhang, Xinwen; Li, Weidong; Jiang, Shude; Wang, Yue; Liao, Guoyang

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer Vero cell-based HPAI H5N1 vaccine with stable high yield. Black-Right-Pointing-Pointer Stable high yield derived from the YNVa H3N2 backbone. Black-Right-Pointing-Pointer H5N1/YNVa has a similar safety and immunogenicity to H5N1delta. -- Abstract: Highly pathogenic avian influenza (HPAI) viruses pose a global pandemic threat, for which rapid large-scale vaccine production technology is critical for prevention and control. Because chickens are highly susceptible to HPAI viruses, the supply of chicken embryos for vaccine production might be depleted during a virus outbreak. Therefore, developing HPAI virus vaccines using other technologies is critical. Meeting vaccine demand using the Vero cell-based fermentation process has been hindered by low stability and yield. In this study, a Vero cell-based HPAI H5N1 vaccine candidate (H5N1/YNVa) with stable high yield was achieved by reassortment of the Vero-adapted (Va) high growth A/Yunnan/1/2005(H3N2) (YNVa) virus with the A/Anhui/1/2005(H5N1) attenuated influenza vaccine strain (H5N1delta) using the 6/2 method. The reassorted H5N1/YNVa vaccine maintained a high hemagglutination (HA) titer of 1024. Furthermore, H5N1/YNVa displayed low pathogenicity and uniform immunogenicity compared to that of the parent virus.

  14. Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine

    PubMed Central

    Woodruff, Matthew C.; Heesters, Balthasar A.; Herndon, Caroline N.; Groom, Joanna R.; Thomas, Paul G.; Luster, Andrew D.; Turley, Shannon J.

    2014-01-01

    Dendritic cells (DCs) are well established as potent antigen-presenting cells critical to adaptive immunity. In vaccination approaches, appropriately stimulating lymph node–resident DCs (LNDCs) is highly relevant to effective immunization. Although LNDCs have been implicated in immune response, their ability to directly drive effective immunity to lymph-borne antigen remains unclear. Using an inactive influenza vaccine model and whole node imaging approaches, we observed surprising responsiveness of LNDC populations to vaccine arrival resulting in a transnodal repositioning into specific antigen collection sites within minutes after immunization. Once there, LNDCs acquired viral antigen and initiated activation of viral specific CD4+ T cells, resulting in germinal center formation and B cell memory in the absence of skin migratory DCs. Together, these results demonstrate an unexpected stimulatory role for LNDCs where they are capable of rapidly locating viral antigen, driving early activation of T cell populations, and independently establishing functional immune response. PMID:25049334

  15. HPV vaccine stimulates cytotoxic activity of killer dendritic cells and natural killer cells against HPV-positive tumour cells

    PubMed Central

    Van den Bergh, Johan M J; Guerti, Khadija; Willemen, Yannick; Lion, Eva; Cools, Nathalie; Goossens, Herman; Vorsters, Alex; Van Tendeloo, Viggo F I; Anguille, Sébastien; Van Damme, Pierre; Smits, Evelien L J M

    2014-01-01

    Cervarix™ is approved as a preventive vaccine against infection with the human papillomavirus (HPV) strains 16 and 18, which are causally related to the development of cervical cancer. We are the first to investigate in vitro the effects of this HPV vaccine on interleukin (IL)-15 dendritic cells (DC) as proxy of a naturally occurring subset of blood DC, and natural killer (NK) cells, two innate immune cell types that play an important role in antitumour immunity. Our results show that exposure of IL-15 DC to the HPV vaccine results in increased expression of phenotypic maturation markers, pro-inflammatory cytokine production and cytotoxic activity against HPV-positive tumour cells. These effects are mediated by the vaccine adjuvant, partly through Toll-like receptor 4 activation. Next, we demonstrate that vaccine-exposed IL-15 DC in turn induce phenotypic activation of NK cells, resulting in a synergistic cytotoxic action against HPV-infected tumour cells. Our study thus identifies a novel mode of action of the HPV vaccine in boosting innate immunity, including killing of HPV-infected cells by DC and NK cells. PMID:24979331

  16. Phase I/II study of vaccination with dendritic-like leukaemia cells for the immunotherapy of acute myeloid leukaemia.

    PubMed

    Roddie, H; Klammer, M; Thomas, C; Thomson, R; Atkinson, A; Sproul, A; Waterfall, M; Samuel, K; Yin, J; Johnson, P; Turner, M

    2006-04-01

    Twenty-two patients with acute myeloid leukaemia were recruited into a phase I/II clinical trial investigating the vaccination of patients in complete remission (CR) with autologous dendritic-like leukaemia cells (DLLC). At trial entry, leukaemia cells were harvested and tested for their ability to undergo cytokine-induced dendritic cell differentiation. Patients were then treated with intensive chemotherapy. Five patients achieved both CR and had leukaemia cells that successfully underwent differentiation and therefore proceeded to vaccination. Four escalating doses of DLLC were administered weekly by subcutaneous injection. Vaccination was generally well tolerated although one patient developed extensive eczema and an increased antinuclear factor titre possibly indicating induction of autoimmunity. Development of anti-leukaemic T-cell responses was assessed by enzyme-linked immunospot analysis of gamma-interferon secreting T lymphocytes and by human leucocyte antigen tetramer analysis for WT1-specific T cells. Increases in anti-leukaemic T-cell responses were demonstrated in four patients, but only two of the five remained in remission more than 12 months postvaccination. The study has demonstrated that generation of DLLC is feasible in only a subgroup of patients and is currently neither broadly applicable or clinically effective. PMID:16611305

  17. Effect of HSV-IL12 Loaded Tumor Cell-Based Vaccination in a Mouse Model of High-Grade Neuroblastoma

    PubMed Central

    Pereboeva, Larisa; Gillespie, G. Yancey; Cloud, Gretchen A.; Langford, Catherine

    2016-01-01

    We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor. The syngeneic but unrelated H6 hepatocellular tumor cell line grew unrestricted in vaccinated mice, indicative of vaccine-mediated specific immunity to Neuro 2a tumors. Longitudinal analyses of tumor-infiltrating lymphocytes revealed a primary adaptive T cell response involving both CD4+ and CD8+ T cell subsets. Spleen cell mononuclear preparations from vaccinated mice were significantly more cytotoxic to Neuro 2a tumor cells than spleen cells from control mice as demonstrated in a four-hour in vitro cytotoxicity assay. These results strongly suggest that an irradiated whole cell tumor vaccine incorporating IL-12-expressing M002 HSV can produce a durable, specific immunization in a murine model of intracranial tumor. PMID:27610392

  18. Effect of HSV-IL12 Loaded Tumor Cell-Based Vaccination in a Mouse Model of High-Grade Neuroblastoma.

    PubMed

    Bauer, David F; Pereboeva, Larisa; Gillespie, G Yancey; Cloud, Gretchen A; Elzafarany, Osama; Langford, Catherine; Markert, James M; Jr, Lawrence S Lamb

    2016-01-01

    We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor. The syngeneic but unrelated H6 hepatocellular tumor cell line grew unrestricted in vaccinated mice, indicative of vaccine-mediated specific immunity to Neuro 2a tumors. Longitudinal analyses of tumor-infiltrating lymphocytes revealed a primary adaptive T cell response involving both CD4+ and CD8+ T cell subsets. Spleen cell mononuclear preparations from vaccinated mice were significantly more cytotoxic to Neuro 2a tumor cells than spleen cells from control mice as demonstrated in a four-hour in vitro cytotoxicity assay. These results strongly suggest that an irradiated whole cell tumor vaccine incorporating IL-12-expressing M002 HSV can produce a durable, specific immunization in a murine model of intracranial tumor. PMID:27610392

  19. Xenogeneic cell-based vaccine therapy for stage III melanoma: safety, immune-mediated responses and survival benefits.

    PubMed

    Seledtsova, Galina V; Shishkov, Alexey A; Kaschenko, Erika A; Goncharov, Andrey G; Gazatova, Natalya D; Seledtsov, Victor I

    2016-04-01

    New therapies for melanoma have yielded promising results, but their application is limited because of serious side-effects and only moderate impact on patient survival. Vaccine therapies may offer some hope by targeting tumor-specific responses, considering the immunogenic nature of melanomas. To investigate the safety profile and efficiency of a xenogeneic cell-based vaccine therapy in stage III melanoma patients and evaluate the survival rate in treated patients. Twenty-seven stage III melanoma patients were immunized with a lyophilized xenogeneic polyantigenic vaccine (XPV) prepared from murine melanoma B16 and carcinoma LLC cells. Neither grade III/IV toxicities, nor clinically significant changes in blood and biochemical parameters were noted after an induction course of 10 XPV subcutaneous immunizations. No laboratory or clinical signs of systemic autoimmunity were documented. Following 10 vaccinations, a relative increase in the numbers of circulating memory CD4+CD45RO+ T cells (but not CD8+ CD45RO+ T cells) was observed. Peripheral blood mononuclear cells obtained from XPV-treated patients demonstrated increased proliferative responses to human BRO melanoma-associated antigens and marked increases in serum levels of IFN-γ and IL-8. Serum levels of TNF-α, IL-4 and IL-6 were not affected. The overall five-year survival rate in the treated patients was significantly higher than that in 27 control patients with matched clinical and prognostic characteristics (55% vs 18%). XPV-based immunotherapy could be maximally effective when started as early as possible before or after surgical excision of the primary tumor and local metastases, i.e. when tumor-mediated suppressive effects on immunity are minimal. PMID:27026566

  20. A dendritic cell targeted vaccine induces long-term HIV-specific immunity within the gastrointestinal tract.

    PubMed

    Ruane, D; Do, Y; Brane, L; Garg, A; Bozzacco, L; Kraus, T; Caskey, M; Salazar, A; Trumpheller, C; Mehandru, S

    2016-09-01

    Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4(+) T cells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered α-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while α-CD205-p24 prime-boost immunization generated CD4(+) T-cell responses, heterologous prime-boost immunization with α-CD205-p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4(+) and CD8(+) T cells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infections. PMID:26732678

  1. A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer

    PubMed Central

    2013-01-01

    Purpose Ovarian cancer, like most solid tumors, is in dire need of effective therapies. The significance of this trial lies in its promise to spearhead the development of combination immunotherapy and to introduce novel approaches to therapeutic immunomodulation, which could enable otherwise ineffective vaccines to achieve clinical efficacy. Rationale Tumor-infiltrating T cells have been associated with improved outcome in ovarian cancer, suggesting that activation of antitumor immunity will improve survival. However, molecularly defined vaccines have been generally disappointing. Cancer vaccines elicit a modest frequency of low-to-moderate avidity tumor-specific T-cells, but powerful tumor barriers dampen the engraftment, expansion and function of these effector T-cells in the tumor, thus preventing them from reaching their full therapeutic potential. Our work has identified two important barriers in the tumor microenvironment: the blood-tumor barrier, which prevents homing of effector T cells, and T regulatory cells, which inactivate effector T cells. We hypothesize that cancer vaccine therapy will benefit from combinations that attenuate these two barrier mechanisms. Design We propose a three-cohort sequential study to investigate a combinatorial approach of a new dendritic cell (DC) vaccine pulsed with autologous whole tumor oxidized lysate, in combination with antiangiogenesis therapy (bevacizumab) and metronomic cyclophosphamide, which impacts Treg cells. Innovation This study uses a novel autologous tumor vaccine developed with 4-day DCs pulsed with oxidized lysate to elicit antitumor response. Furthermore, the combination of bevacizumab with a whole tumor antigen vaccine has not been tested in the clinic. Finally the combination of bevacizumab and metronomic cyclophosphamide in immunotherapy is novel. PMID:23777306

  2. Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell-based Anti-tumor Immunotherapy

    PubMed Central

    Son, Keum-joo; Choi, Ki ryung; Lee, Seog Jae

    2016-01-01

    Cancer is one of the leading causes of morbidity and mortality worldwide; therefore there is a need to discover new therapeutic modules with improved efficacy and safety. Immune-(cell) therapy is a promising therapeutic strategy for the treatment of intractable cancers. The effectiveness of certain chemotherapeutics in inducing immunogenic tumor cell death thus promoting cancer eradication has been reported. Ginsenoside Rg3 is a ginseng saponin that has antitumor and immunomodulatory activity. In this study, we treated tumor cells with Rg3 to verify the significance of inducing immunogenic tumor cell death in antitumor therapy, especially in DC-based immunotherapy. Rg3 killed the both immunogenic (B16F10 melanoma cells) and non-immunogenic (LLC: Lewis Lung Carcinoma cells) tumor cells by inducing apoptosis. Surface expression of immunogenic death markers including calreticulin and heat shock proteins and the transcription of relevant genes were increased in the Rg3-dying tumor. Increased calreticulin expression was directly related to the uptake of dying tumor cells by dendritic cells (DCs): the proportion of CRT+ CD11c+ cells was increased in the Rg3-treated group. Interestingly, tumor cells dying by immunogenic cell death secreted IFN-γ, an effector molecule for antitumor activity in T cells. Along with the Rg3-induced suppression of pro-angiogenic (TNF-α) and immunosuppressive cytokine (TGF-β) secretion, IFN-γ production from the Rg3-treated tumor cells may also indicate Rg3 as an effective anticancer immunotherapeutic strategy. The data clearly suggests that Rg3-induced immunogenic tumor cell death due its cytotoxic effect and its ability to induce DC function. This indicates that Rg3 may be an effective immunotherapeutic strategy. PMID:26937234

  3. Closely Related Mycobacterial Strains Demonstrate Contrasting Levels of Efficacy as Antitumor Vaccines and Are Processed for Major Histocompatibility Complex Class I Presentation by Multiple Routes in Dendritic Cells

    PubMed Central

    Cheadle, Eleanor J.; O'Donnell, Dearbhaile; Selby, Peter J.; Jackson, Andrew M.

    2005-01-01

    Mycobacteria expressing recombinant antigens are already being developed as vaccines against both infections and tumors. Little is known about how dendritic cells might process such antigens. Two different mycobacterial species, the fast-growing Mycobacterium smegmatis and the slow-growing M. bovis M. bovis BCG, were engineered to express a model tumor antigen, the Kb-restricted dominant cytotoxic T-lymphocyte epitope OVA257-264. Recombinant M. bovis BCG but not recombinant M. smegmatis conferred protection to mice challenged with the B16-OVA tumor cell line. We went on to investigate whether the contrast in antitumor efficacy could be due to differences in how dendritic cells process antigen from the two mycobacterial strains for class I presentation. Both strains of mycobacteria caused phenotypic maturation of dendritic cells, but recombinant M. smegmatis infection led to a greater degree of dendritic cell maturation than recombinant M. bovis BCG infection. Antigen from recombinant M. smegmatis was processed and presented as OVA257-264 on Kb molecules by the dendritic cell line DC2.4 but not by bone marrow-derived dendritic cells (BMDC) or splenic dendritic cells. In contrast, antigen from recombinant M. bovis BCG was presented by all three dendritic cell types as long as the mycobacteria were viable. Such presentation was dependent on proteasome function and nascent major histocompatibility complex (MHC) class I molecules in DC2.4 cells but independent of the proteasome and transporter associated with antigen processings (TAP) in BMDC and splenic dendritic cells. These data demonstrate for the first time that antigen vectored by the slow-growing M. bovis BCG but not that vectored by fast-growing, readily destroyed M. smegmatis is processed and presented on MHC class I by in vitro-generated dendritic cells, which has implications for recombinant microbial vaccine development. PMID:15664917

  4. A Mammalian Cell Based FACS-Panning Platform for the Selection of HIV-1 Envelopes for Vaccine Development

    PubMed Central

    Bruun, Tim-Henrik; Mühlbauer, Katharina; Benen, Thomas; Kliche, Alexander; Wagner, Ralf

    2014-01-01

    An increasing number of broadly neutralizing monoclonal antibodies (bnMAb) against the HIV-1 envelope (Env) protein has been discovered recently. Despite this progress, vaccination efforts with the aim to re-elicit bnMAbs that provide protective immunity have failed so far. Herein, we describe the development of a mammalian cell based FACS-panning method in which bnMAbs are used as tools to select surface-exposed envelope variants according to their binding affinity. For that purpose, an HIV-1 derived lentiviral vector was developed to infect HEK293T cells at low multiplicity of infection (MOI) in order to link Env phenotype and genotype. For proof of principle, a gp145 Env model-library was established in which the complete V3 domain was substituted by five strain specific V3 loop sequences with known binding affinities to nMAb 447-52D, respectively. Env genes were recovered from selected cells by PCR, subcloned into a lentiviral vector (i) to determine and quantify the enrichment nMAb binders and (ii) to generate a new batch of transduction competent particles. After 2 selection cycles the Env variant with highest affinity was enriched 20-fold and represented 80% of the remaining Env population. Exploiting the recently described bnMAbs, this procedure might prove useful in selecting Env proteins from large Env libraries with the potential to elicit bnMAbs when used as vaccine candidates. PMID:25279768

  5. A Double-Blind Randomized Phase I Clinical Trial Targeting ALVAC-HIV Vaccine to Human Dendritic Cells

    PubMed Central

    Cox, Josephine H.; Lesho, Emil; Wang, Zhining; Currier, Jeffrey R.; Darden, Janice M.; Polonis, Victoria R.; Vahey, Maryanne T.; Peel, Sheila; Robb, Merlin L.; Michael, Nelson L.; Marovich, Mary A.

    2011-01-01

    Background We conducted a novel pilot study comparing different delivery routes of ALVAC-HIV (vCP205), a canarypox vaccine containing HIV gene inserts: env, gag and pol. We explored the concept that direct ex vivo targeting of human dendritic cells (DC) would enhance the immune response compared to either conventional intramuscular or intradermal injections of the vaccine alone. Methodology/Principal Findings Healthy HIV-1 uninfected volunteers were administered ALVAC-HIV or placebo by intramuscular injection (IM), intradermal injection (ID) or subcutaneous injection (SQ) of autologous ex vivo transfected DC at months 0, 1, 3 and 6. All vaccine delivery routes were well tolerated. Binding antibodies were observed to both the ALVAC vector and HIV-1 gp160 proteins. Modest cellular responses were observed in 2/7 individuals in the DC arm and 1/8 in the IM arm as determined by IFN-γ ELISPOT. Proliferative responses were most frequent in the DC arm where 4/7 individuals had measurable responses to multiple HIV-1 antigens. Loading DC after maturation resulted in lower gene expression, but overall better responses to both HIV-1 and control antigens, and were associated with better IL-2, TNF-α and IFN-γ production. Conclusions/Significance ALVAC-HIV delivered IM, ID or SQ with autologous ex vivo transfected DC proved to be safe. The DC arm was most immunogenic. Proliferative immune responses were readily detected with only modest cytotoxic CD8 T cell responses. Loading mature DC with the live viral vaccine induced stronger immune responses than loading immature DC, despite increased transgene expression with the latter approach. Volunteers who received the autologous vaccine loaded mature DC developed a broader and durable immune response compared to those vaccinated by conventional routes. Trial Registration ClinicalTrials.gov NCT00013572 PMID:21949699

  6. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma

    PubMed Central

    Shimizu, Koichi; Kotera, Yoshihito; Aruga, Atsushi; Takeshita, Nobuhiro; Katagiri, Satoshi; Ariizumi, Shun-ichi; Takahashi, Yutaka; Yoshitoshi, Kenji; Takasaki, Ken; Yamamoto, Masakazu

    2014-01-01

    The recurrence rate after surgery in patients with hepatocellular carcinoma (HCC) is very high, while prognosis is quite poor. However, there is no standard treatment to prevent recurrence of HCC after a curative operation. In this study, we investigated the clinical utilization of an autologous tumor lysate-pulsed dendritic cell vaccine plus ex vivo activated T cell transfer (ATVAC) in an adjuvant setting for postoperative HCC as a non-randomized controlled trial. Ninety-four patients with invasive HCC received informed consent information regarding the study, and 42 opted to have the ATVAC after surgery. Their recurrence-free survival (RFS) and overall survival (OS) were measured after 5 years and compared with those of 52 patients who selected to have the curative operation alone. The median RFS and OS were 24.5 months and 97.7 months in the patients receiving adjuvant ATVAC and 12.6 months and 41.0 months in the group receiving surgery alone (P = 0.011 and 0.029). In the treated group, patients with positive delayed-type hypersensitivity (DTH) had a better prognosis (RFS P = 0.019, OS P = 0.025). No adverse events of grade 3 or more were observed. A postoperative dendritic cell vaccine plus activated T cell transfer would be a feasible and effective treatment for preventing recurrence in HCC patients and achieving long-term survival especially in DTH positive patients. PMID:24419174

  7. Immune responses in patients with esophageal cancer treated with SART1 peptide-pulsed dendritic cell vaccine.

    PubMed

    Narita, Miwako; Kanda, Tatsuo; Abe, Takashi; Uchiyama, Takayoshi; Iwafuchi, Minami; Zheng, Zhiyin; Liu, Aichun; Kaifu, Tsutomu; Kosugi, Shinichi; Minagawa, Masahiro; Itoh, Kyogo; Takahashi, Masuhiro

    2015-04-01

    Patients with advanced stage of squamous cell carcinoma of esophagus have a poor prognosis with a lethal outcome. In order to explore the feasibility and effectiveness of dendritic cell (DC)-based immunotherapy for squamous cell carcinoma of esophagus, we performed a phase I/II clinical trial of monocyte-derived dendritic cells (moDCs) pulsed with SART1 peptide in seven patients with advanced stage of this disease. Although the feasibility of this therapy was definite, the effectiveness was not clearly confirmed in advanced stage of squamous cell carcinoma of esophagus. However, in vitro study revealed that moDCs generated for this therapy possessed a potent ability of inducing SART1 peptide-specific cytotoxic T lymphocytes (CTLs). In addition, these moDCs were demonstrated to be able to produce exosomes with an antigen presenting ability for inducing SART1 peptide-specific CTLs. ELISPOT assay using cryopreserved patient's lymphocytes demonstrated that IFN-γ ELISPOTs were increased after four times of SART1 peptide-pulsed moDC vaccinations compared with before the vaccination in a patient. The present study demonstrated that moDCs prepared from advanced stage of squamous cell carcinoma of esophagus possess a good immune function and in vivo immune responses (detected by ELISPOT assay) were evoked by the infusion of these moDCs. These findings suggest that DC-based immunotherapy could be one of the modalities applicable for squamous cell carcinoma of esophagus. PMID:25625346

  8. Identification and characterisation of T-cell epitopes for incorporation into dendritic cell-delivered Listeria vaccines.

    PubMed

    Calderon-Gonzalez, Ricardo; Tobes, Raquel; Pareja, Eduardo; Frande-Cabanes, Elisabet; Petrovsky, Nikolai; Alvarez-Dominguez, Carmen

    2015-09-01

    Dendritic cells loaded with antigenic peptides, because of their safety and robust immune stimulation, would be ideal for induction of immunity to protect against listeriosis. However, there is no currently accepted method to predict which peptides derived from the Listeria proteome might confer protection. While elution of peptides from MHC molecules after Listeria infection yields high-affinity immune-dominant epitopes, these individual epitopes did not reliably confer Listeria protection. Instead we applied bioinformatic predictions of MHC class I and II epitopes to generate antigenic peptides that were then formulated with Advax™, a novel polysaccharide particulate adjuvant able to enhance cross-presentation prior to being screened for their ability to induce protective T-cell responses. A combination of at least four intermediate strength MHC-I binding epitopes and one weak MHC-II binding epitope when expressed in a single peptide sequence and formulated with Advax adjuvant induced a potent T-cell response and high TNF-α and IL-12 production by dendritic cells resulting in robust listeriosis protection in susceptible mice. This T-cell vaccine approach might be useful for the design of vaccines to protect against listeriosis or other intracellular infections. PMID:26031451

  9. Transcriptional specialization of human dendritic cell subsets in response to microbial vaccines

    PubMed Central

    Banchereau, Romain; Baldwin, Nicole; Cepika, Alma-Martina; Athale, Shruti; Xue, Yaming; Yu, Chun I; Metang, Patrick; Cheruku, Abhilasha; Berthier, Isabelle; Gayet, Ingrid; Wang, Yuanyuan; Ohouo, Marina; Snipes, LuAnn; Xu, Hui; Obermoser, Gerlinde; Blankenship, Derek; Oh, Sangkon; Ramilo, Octavio; Chaussabel, Damien; Banchereau, Jacques; Palucka, Karolina; Pascual, Virginia

    2014-01-01

    The mechanisms by which microbial vaccines interact with human APCs remain elusive. Herein, we describe the transcriptional programs induced in human DCs by pathogens, innate receptor ligands and vaccines. Exposure of DCs to influenza, Salmonella enterica and Staphylococcus aureus allows us to build a modular framework containing 204 transcript clusters. We use this framework to characterize the responses of human monocytes, monocyte-derived DCs and blood DC subsets to 13 vaccines. Different vaccines induce distinct transcriptional programs based on pathogen type, adjuvant formulation and APC targeted. Fluzone, Pneumovax and Gardasil, respectively, activate monocyte-derived DCs, monocytes and CD1c+ blood DCs, highlighting APC specialization in response to vaccines. Finally, the blood signatures from individuals vaccinated with Fluzone or infected with influenza reveal a signature of adaptive immunity activation following vaccination and symptomatic infections, but not asymptomatic infections. These data, offered with a web interface, may guide the development of improved vaccines. PMID:25335753

  10. Chimeric Vaccine Stimulation of Human Dendritic Cell Indoleamine 2, 3-Dioxygenase Occurs via the Non-Canonical NF-κB Pathway

    PubMed Central

    Kim, Nan-Sun; Mbongue, Jacques C.; Nicholas, Dequina A.; Esebanmen, Grace E.; Unternaehrer, Juli J.; Firek, Anthony F.; Langridge, William H. R.

    2016-01-01

    A chimeric protein vaccine composed of the cholera toxin B subunit fused to proinsulin (CTB-INS) was shown to suppress type 1 diabetes onset in NOD mice and upregulate biosynthesis of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) in human dendritic cells (DCs). Here we demonstrate siRNA inhibition of the NF-κB-inducing kinase (NIK) suppresses vaccine-induced IDO1 biosynthesis as well as IKKα phosphorylation. Chromatin immunoprecipitation (ChIP) analysis of CTB-INS inoculated DCs showed that RelB bound to NF-κB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-κB pathway activates IDO1 expression in vivo. The addition of Tumor Necrosis Factor Associated Factors (TRAF) TRAF 2, 3 and TRAF6 blocking peptides to vaccine inoculated DCs was shown to inhibit IDO1 biosynthesis. This experimental outcome suggests vaccine activation of the TNFR super-family receptor pathway leads to upregulation of IDO1 biosynthesis in CTB-INS inoculated dendritic cells. Together, our experimental data suggest the CTB-INS vaccine uses a TNFR-dependent signaling pathway of the non-canonical NF-κB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimmunity. PMID:26881431

  11. Chimeric Vaccine Stimulation of Human Dendritic Cell Indoleamine 2, 3-Dioxygenase Occurs via the Non-Canonical NF-κB Pathway.

    PubMed

    Kim, Nan-Sun; Mbongue, Jacques C; Nicholas, Dequina A; Esebanmen, Grace E; Unternaehrer, Juli J; Firek, Anthony F; Langridge, William H R

    2016-01-01

    A chimeric protein vaccine composed of the cholera toxin B subunit fused to proinsulin (CTB-INS) was shown to suppress type 1 diabetes onset in NOD mice and upregulate biosynthesis of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) in human dendritic cells (DCs). Here we demonstrate siRNA inhibition of the NF-κB-inducing kinase (NIK) suppresses vaccine-induced IDO1 biosynthesis as well as IKKα phosphorylation. Chromatin immunoprecipitation (ChIP) analysis of CTB-INS inoculated DCs showed that RelB bound to NF-κB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-κB pathway activates IDO1 expression in vivo. The addition of Tumor Necrosis Factor Associated Factors (TRAF) TRAF 2, 3 and TRAF6 blocking peptides to vaccine inoculated DCs was shown to inhibit IDO1 biosynthesis. This experimental outcome suggests vaccine activation of the TNFR super-family receptor pathway leads to upregulation of IDO1 biosynthesis in CTB-INS inoculated dendritic cells. Together, our experimental data suggest the CTB-INS vaccine uses a TNFR-dependent signaling pathway of the non-canonical NF-κB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimmunity. PMID:26881431

  12. Signal transduction profile of chemical sensitisers in dendritic cells: An endpoint to be included in a cell-based in vitro alternative approach to hazard identification?

    SciTech Connect

    Neves, Bruno Miguel; Goncalo, Margarida; Figueiredo, Americo; Duarte, Carlos B.; Lopes, Maria Celeste; Cruz, Maria Teresa

    2011-01-15

    The development of non-animal testing methods for the assessment of skin sensitisation potential is an urgent challenge within the framework of existing and forthcoming legislation. Efforts have been made to replace current animal tests, but so far no alternative methods have been developed. It is widely recognised that alternatives to animal testing cannot be accomplished with a single approach, but rather will require the integration of results obtained from different in vitro and in silico assays. The argument subjacent to the development of in vitro dendritic cell (DC)-based assays is that sensitiser-induced changes in the DC phenotype can be differentiated from those induced by irritants. This assumption is derived from the unique capacity of DC to convert environmental signals encountered at the skin into a receptor expression pattern (MHC class II molecules, co-stimulatory molecules, chemokine receptors) and a soluble mediator release profile that will stimulate T lymphocytes. Since signal transduction cascades precede changes in surface marker expression and cytokine/chemokine secretion, these phenotypic modifications are a consequence of a signal transduction profile that is specifically triggered by sensitisers and not by irritants. A limited number of studies have addressed this subject and the present review attempts to summarise and highlight all of the signalling pathways modulated by skin sensitisers and irritants. Furthermore, we conclude this review by focusing on the most promising strategies suitable for inclusion into a cell-based in vitro alternative approach to hazard identification.

  13. Dendritic cell vaccine modified by Ag85A gene enhances anti-tumor immunity against bladder cancer.

    PubMed

    Zhang, Pei; Wang, Jinyan; Wang, Danan; Wang, Huan; Shan, Fengping; Chen, Liudan; Hou, Ying; Wang, Enhua; Lu, Chang-Long

    2012-11-01

    The ability of dendritic cells to provide all the signals required for T-cell activation makes them an ideal cancer vaccine platform. With the use of established DC2.4 cell line, originated from C57BL/6 mice and developed by superinfecting GM-CSF transduced bone marrow cells with myc and raf oncogenes, we investigated whether the DC 2.4 cell line transfected with Ag85A gene could enhance immunity against bladder cancer. Both phenotypic and functional analyses of Ag85A-DCs were done with use of FCM and T cell proliferation test. The cytotoxicity of Ag85A-DCs loaded with tumor cell lysate was verified by LDH. Finally, the production of interferon gamma was assayed by both ELISA and FCM. The immunotherapeutic effect of DC vaccine on murine bladder cancer was assessed pharmacologically and pathologically. Our results showed that Ag85A gene transfected DCs expressed high levels of key surface markers such as CD80, CD86 and MHC-II. The CTL primed with MB49 lysate-pulsed Ag85A-DCs elicits higher activity against MB49 tumor cells and upregulated level of IFN-γ production. Furthermore, the significant inhibitive effect on tumor growth in mice was found in the group of Ag85A-DC vaccine. The infiltration of CD4(+) or CD8(+) T cell within established tumor treated by Ag85A-DC vaccine significantly increased as compared with control groups. It is therefore concluded that DCs engineered by Ag85A gene exerts enhanced anti-tumor immunity against bladder cancer and this study might provide a meaningful mode of action with the use of Ag85A engineered DC vaccination in anti-cancer immunotherapy. PMID:22884511

  14. Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

    PubMed Central

    Boudewijns, Steve; Bol, Kalijn F.; Schreibelt, Gerty; Westdorp, Harm; Textor, Johannes C.; van Rossum, Michelle M.; Scharenborg, Nicole M.; de Boer, Annemiek J.; van de Rakt, Mandy W. M. M.; Pots, Jeanne M.; van Oorschot, Tom G. M.; Duiveman-de Boer, Tjitske; Olde Nordkamp, Michel A.; van Meeteren, Wilmy S. E. C.; van der Graaf, Winette T. A.; Bonenkamp, Johannes J.; de Wilt, Johannes H. W.; Aarntzen, Erik H. J. G.; Punt, Cornelis J. A.; Gerritsen, Winald R.; Figdor, Carl G.; de Vries, I. Jolanda M.

    2016-01-01

    ABSTRACT Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. Experimental design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8+ T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. Results: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8+ T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154–162, gp100:280–288, and tyrosinase:369–377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154–162, gp100:280–288, and tyrosinase:369–377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. Conclusions: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response. PMID:27622047

  15. Clinical outcome of immunotherapy with dendritic cell vaccine and cytokine-induced killer cell therapy in hepatobiliary and pancreatic cancer

    PubMed Central

    ZHANG, LIHONG; ZHU, WEI; LI, JIALI; YANG, XUEJING; REN, YANJIE; NIU, JINGXIU; PANG, YAN

    2016-01-01

    The aim of this study was to determine the therapeutic effects of adoptive immunotherapy following dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell therapy and evaluate its cytotoxicity, survival benefits and quality of life (QOL) changes in patients with hepatobiliary and pancreatic cancer (HPC). We performed a retrospective analysis of 407 clinical cases, including 77 patients with HPC who received immunotherapy with DC vaccine and CIK cells (I group) and 330 patients with similar characteristics who underwent baseline treatment but did not receive immunotherapy [non-immunotherapy (NI) group)] as the control group. After a follow-up period of 294±207.5 days, the median survival time (MST) of the two groups was compared using the Kaplan-Meier method. In the I group, 61% of the patients developed a positive, delayed-type hypersensitivity response and 65% of the patients exhibited an improvement in QOL. The most notable adverse events included fever (28%), insomnia (25%), anorexia (17%), skin rash (12%) and arthralgia (31%). No severe toxicities were observed in patients in the I group; in addition, the MST was significantly longer in the I group compared with that in the NI group (P=0.014). Thus, the DC vaccine and CIK cell therapy was associated with mild adverse effects, but was able to induce an immune response and effectively eliminate tumor cells, thereby improving the QOL and prolonging the MST of the patients. PMID:26870371

  16. Dendritic cell vaccination with a toll-like receptor agonist derived from mycobacteria enhances anti-tumor immunity.

    PubMed

    Vo, Manh-Cuong; Lee, Hyun-Ju; Kim, Jong-Seok; Hoang, My-Dung; Choi, Nu-Ri; Rhee, Joon Haeng; Lakshmanan, Vinoth-Kumar; Shin, Sung-Jae; Lee, Je-Jung

    2015-10-20

    Dendritic cell (DC)-based vaccines are considered useful in cancer immunotherapy, and the interaction of DC and adjuvants is important in the design of the next generation vaccines. In this study, whether DC combined with Rv2299c derived from mycobacteria could improve anti-tumor immune responses in a colon cancer mouse model was evaluated. MC38 cell lines were injected subcutaneously to establish colon-cancer-bearing mice and the following four groups were evaluated: PBS control, tumor antigen (TA) loaded-DC, Rv2299c, and a combination of TA-loaded-DC and Rv2299c. The combination treatment with TA-loaded-DC and Rv2299c exhibited greater inhibition of tumor growth compared to other groups. These effects were associated with the reduction of suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, and the induction of effector cells, such as CD4+ T cells and CD8+ T cells, in spleen, and with the activation of cytotoxic T Lymphocytes and NK cells. These results suggest that TA-loaded-DC vaccination with Rv2299c derived from mycobacteria enhanced anti-tumor immunity in a mouse colon cancer model by inhibiting the generation of immune-suppressive cells and recovering numbers of effector cells, and demonstrated superior polarization of the Th1/Th2 balance in favor of the Th1 immune response. PMID:26418952

  17. Dendritic cell vaccination with a toll-like receptor agonist derived from mycobacteria enhances anti-tumor immunity

    PubMed Central

    Vo, Manh-Cuong; Lee, Hyun-Ju; Kim, Jong-Seok; Hoang, My-Dung; Choi, Nu-Ri; Rhee, Joon Haeng; Lakshmanan, Vinoth-Kumar; Shin, Sung-Jae; Lee, Je-Jung

    2015-01-01

    Dendritic cell (DC)-based vaccines are considered useful in cancer immunotherapy, and the interaction of DC and adjuvants is important in the design of the next generation vaccines. In this study, whether DC combined with Rv2299c derived from mycobacteria could improve anti-tumor immune responses in a colon cancer mouse model was evaluated. MC38 cell lines were injected subcutaneously to establish colon-cancer-bearing mice and the following four groups were evaluated: PBS control, tumor antigen (TA) loaded-DC, Rv2299c, and a combination of TA-loaded-DC and Rv2299c. The combination treatment with TA-loaded-DC and Rv2299c exhibited greater inhibition of tumor growth compared to other groups. These effects were associated with the reduction of suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, and the induction of effector cells, such as CD4+ T cells and CD8+ T cells, in spleen, and with the activation of cytotoxic T Lymphocytes and NK cells. These results suggest that TA-loaded-DC vaccination with Rv2299c derived from mycobacteria enhanced anti-tumor immunity in a mouse colon cancer model by inhibiting the generation of immune-suppressive cells and recovering numbers of effector cells, and demonstrated superior polarization of the Th1/Th2 balance in favor of the Th1 immune response. PMID:26418952

  18. Whole tumor antigen vaccination using dendritic cells: comparison of RNA electroporation and pulsing with UV-irradiated tumor cells.

    PubMed

    Benencia, Fabian; Courrèges, Maria C; Coukos, George

    2008-01-01

    Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC) based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV) B radiation using a convenient tumor model expressing human papilloma virus (HPV) E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions. PMID:18445282

  19. Poly(2-aminoethyl methacrylate) with well-defined chain-length for DNA vaccine delivery to dendritic cells

    PubMed Central

    Ji, Weihang; Panus, David; Palumbo, R. Noelle; Tang, Rupei; Wang, Chun

    2011-01-01

    Poly(2-aminoethyl methacrylate) (PAEM) homopolymers with defined chain-length and narrow molecular weight distribution were synthesized using atom transfer radical polymerization (ATRP), and a comprehensive study was conducted to evaluate the colloidal properties of PAEM/plasmid DNA polyplexes, the uptake and subcellular trafficking of polyplexes in antigen-presenting dendritic cells (DCs), and the biological performance of PAEM as a potential DNA vaccine carrier. PAEM of different chain-length (45, 75 and 150 repeating units) showed varying strength in condensing plasmid DNA into narrowly dispersed nanoparticles with very low cytotoxicity. Longer polymer chain-length resulted in higher levels of overall cellular uptake and nuclear uptake of plasmid DNA, but shorter polymer chains favored intracellular and intra-nuclear release of free plasmid from the polyplexes. Despite its simple chemical structure, PAEM transfected DCs very efficiently in vitro in media with or without serum and led to phenotypic maturation of DCs. When a model antigen-encoding ovalbumin plasmid was used, transfected DCs stimulated the activation of naïve CD8+ T cells to produce high levels of interferon-γ. The efficiency of transfection, DC maturation, and CD8+ T cell activation showed varying degrees of polymer chain-length dependence. These structurally defined cationic polymers may have much potential as efficient DNA vaccine carriers and immunostimulatory adjuvants. They may also serve as a model material system for elucidating structural and intracellular mechanisms of polymer-mediated DNA vaccine delivery. PMID:22082257

  20. Generation and Cryopreservation of Clinical Grade Wilms' Tumor 1 mRNA-Loaded Dendritic Cell Vaccines for Cancer Immunotherapy.

    PubMed

    Smits, Evelien L J M; Stein, Barbara; Nijs, Griet; Lion, Eva; Van Tendeloo, Viggo F; Willemen, Yannick; Anguille, Sébastien; Berneman, Zwi N

    2016-01-01

    First described in the 1970s, dendritic cells (DC) are currently subjects of intense investigation to exploit their unique antigen-presenting and immunoregulatory capacities. In cancer, DC show promise to elicit or amplify immune responses directed against cancer cells by activating natural killer (NK) cells and tumor antigen-specific T cells. Wilms' tumor 1 (WT1) protein is a tumor-associated antigen that is expressed in a majority of cancer types and has been designated as an antigen of major interest to be targeted in clinical cancer immunotherapy trials. In this chapter, we describe the generation, cryopreservation, and thawing of clinical grade autologous monocyte-derived DC vaccines that are loaded with WT1 by messenger RNA (mRNA) electroporation. This in-house-developed transfection method gives rise to presentation of multiple antigen epitopes and can be used for all patients without restriction of human leukocyte antigen (HLA) type. PMID:27033213

  1. Vaccines delivered by integration-deficient lentiviral vectors targeting dendritic cells induces strong antigen-specific immunity

    PubMed Central

    Hu, Biliang; Dai, Bingbing; Wang, Pin

    2010-01-01

    We report a study of an integration-deficient lentiviral vector (IDLV) enveloped with a Sindbis virus glycoprotein mutant (SVGmu) capable of selectively binding to dendritic cells (DCs) for its potential as a vaccine carrier. The in vitro assays showed that the D64V point mutation in the catalytic domain of HIV-1 integrase efficiently inhibited the integration of the transgene upon vector transduction, while the targeting specificity of the vector to preferentially transduce and mediate durable expression in DCs was maintained. Substantial immune responses in C57BL/6 mice and complete protection against a challenge with the C57BL/6 thymoma EG.7 tumor expressing a delivered ovalbumin (OVA) antigen in mice have been achieved through the direct injection of the DC-directed IDLV encoding OVA. Thus, this DC-directed IDLV system represents a promising and efficient vector platform with remarkably improved safety for the future development of DC-based immunotherapy. PMID:20709004

  2. Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study

    PubMed Central

    2011-01-01

    Background Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. Methods Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5 × 107 DC cells administered subcutaneous and intravenously two times at two week intervals. The immunologic response, safety and tolerability to the vaccine were evaluated by the lymphoproliferation assay and clinical and laboratorial evolution, respectively. Results The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.005). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. Conclusion Despite the small sample size, the results on the immune response, safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment. Trial Registration Current Controlled Trials: ISRCTN45563569 PMID:21682877

  3. A novel recombinant protein of ephrinA1-PE38/GM-CSF activate dendritic cells vaccine in rats with glioma.

    PubMed

    Li, Ming; Wang, Bin; Wu, Zhonghua; Zhang, Jiadong; Shi, Xiwen; Cheng, Wenlan; Han, Shuangyin

    2015-07-01

    Dendritic cells loaded with tumor-associated antigens can effectively stimulate the antitumor immune response of cytotoxic T lymphocytes in the body, which facilitates the development of novel and effective treatments for cancer. In this study, the adenovirus-mediated ephrinA1-PE38/GM-CSF was successfully constructed using the overlap extension method, and verified with sequencing analysis. HEK293 cells were infected with the adenovirus and the cellular expression of ephrinA1-PE38/GM-CSF was measured with an enzyme-linked immunosorbent assay. The recombinant adenovirus was then delivered into the tumor-bearing rats and the results showed that such treatment significantly reduced the volumes of gliomas and improved the survival of the transplanted rats. The results from immunohistochemistry and flow cytometry suggested that this immunomodulatory agent cause activation of dendritic cells. The findings that ephrinA1-PE38/GM-CSF had a high efficacy in the activation of the dendritic cells would facilitate the development of in vivo dendritic-cell vaccines for the treatment of gliomas in rats. Our new method of DC vaccine production induces not only a specific local antitumor immune response but also a systemic immunotherapeutic effect. In addition, this method completely circumvents the risk of contamination related to the in vitro culture of DCs, thus greatly improving the safety and feasibility of clinical application of the DC vaccines in glioma. PMID:25677907

  4. Cytokine-enhanced maturation and migration to the lymph nodes of a human dying melanoma cell-loaded dendritic cell vaccine.

    PubMed

    Pizzurro, Gabriela A; Tapia, Ivana J; Sganga, Leonardo; Podhajcer, Osvaldo L; Mordoh, José; Barrio, María M

    2015-11-01

    Dendritic cells (DCs) are professional APCs used for the development of cancer vaccines because of their ability to activate adaptive immune responses. Previously, we designed the DC/Apo-Nec vaccine using human DCs loaded with dying melanoma cells that primed Ag-specific cytotoxic T cells. Here, we evaluate the effect of a standard pro-inflammatory cytokine cocktail (CC) and adjuvants on DC/Apo-Nec maturation and migration. CC addition to the vaccine coculture allowed efficient Ag uptake while attaining strong vaccine maturation with an immunostimulatory profile. The use of CC not only increased CCR7 expression and the vaccine chemokine responsiveness but also upregulated matrix metalloproteinase-9 secretion, which regulated its invasive migration in vitro. Neither IL-6 nor prostaglandin E2 had a negative effect on vaccine preparation. In fact, all CC components were necessary for complete vaccine maturation. Subcutaneously injected DC/Apo-Nec vaccine migrated rapidly to draining LNs in nude mice, accumulating regionally after 48 h. The migrating cells of the CC-matured vaccine augmented in proportion and range of distribution, an effect that increased further with the topical administration of imiquimod cream. The migrating proportion of human DCs was detected in draining LNs for at least 9 days after injection. The addition of CC during DC/Apo-Nec preparation enhanced vaccine performance by improving maturation and response to LN signals and by conferring a motile and invasive vaccine phenotype both in vitro and in vivo. More importantly, the vaccine could be combined with different adjuvants. Therefore, this DC-based vaccine design shows great potential value for clinical translation. PMID:26197849

  5. The role of surface charge density in cationic liposome-promoted dendritic cell maturation and vaccine-induced immune responses

    NASA Astrophysics Data System (ADS)

    Ma, Yifan; Zhuang, Yan; Xie, Xiaofang; Wang, Ce; Wang, Fei; Zhou, Dongmei; Zeng, Jianqiang; Cai, Lintao

    2011-05-01

    Cationic liposomes have emerged as a novel adjuvant and antigen delivery system to enhance vaccine efficacy. However, the role of surface charge density in cationic liposome-regulated immune responses has not yet been elucidated. In the present study, we prepared a series of DOTAP/DOPC cationic liposomes with different surface densities by incorporating varying amounts of DOPC (a neutral lipid) into DOTAP (a cationic lipid). The results showed that DOTAP/DOPC cationic liposome-regulated immune responses relied on the surface charge density, and might occur through ROS signaling. The liposomes with a relatively high charge density, such as DOTAP/DOPC 5 : 0 and 4 : 1 liposomes, potently enhanced dendritic cell maturation, ROS generaion, antigen uptake, as well as the production of OVA-specific IgG2a and IFN-γ. In contrast, low-charge liposomes, such as DOTAP/DOPC 1 : 4 liposome, failed to promote immune responses even at high concentrations, confirming that the immunoregulatory effect of cationic liposomes is mostly attributable to their surface charge density. Moreover, the DOTAP/DOPC 1 : 4 liposome suppressed anti-OVA antibody responses in vivo. Overall, maintaining an appropriate surface charge is crucial for optimizing the adjuvant effect of cationic liposomes and enhancing the efficacy of liposome-based vaccines.

  6. Dendritic cell targeted liposomes-protamine-DNA complexes mediated by synthetic mannosylated cholestrol as a potential carrier for DNA vaccine

    NASA Astrophysics Data System (ADS)

    Li, Pan; Chen, Simu; Jiang, Yuhong; Jiang, Jiayu; Zhang, Zhirong; Sun, Xun

    2013-07-01

    To construct mannosylated liposomes/protamine/DNA (LPD) carriers for DNA vaccine targeting to dendritic cells (DCs), a mannosylated cholesterol derivative (Man-C6-Chol) was synthesized via simple ester linkage and amide bonds. Then, the Man-C6-Chol was applied to LPD formulation as a synthetic ligand. The physicochemical properties of mannosylated LPD (Man-LPD) were first evaluated, including the size and zeta potential, morphology and the ability to protect DNA against DNase I degradation. Man-LPD showed a small size with a stable viral-like structure. In comparison to non-mannose liposomes/LPD (Man-free liposomes/LPD), mannosylated liposomes/LPD (Man-liposomes/Man-LPD) exhibited higher efficiency in both intracellular uptake (2.3-fold) and transfection (4.5-fold) in vitro. Subsequent MTT assays indicated that the LPD carriers had low toxicity on the tested cells. Afterwards, the investigation into the maturation activation on primary bone marrow-derived DCs (BMDCs) showed that both Man-LPD and Man-free LPD induced remarkable up-regulation of CD80, CD86 and CD40 on BMDCs. Inspired by these studies, we can conclude that the synthetic mannosylated LPD targeting to DCs was a potential carrier for DNA vaccine.

  7. DNA vaccination strategy targets epidermal dendritic cells, initiating their migration and induction of a host immune response.

    PubMed

    Smith, Trevor Rf; Schultheis, Katherine; Kiosses, William B; Amante, Dinah H; Mendoza, Janess M; Stone, John C; McCoy, Jay R; Sardesai, Niranjan Y; Broderick, Kate E

    2014-01-01

    The immunocompetence and clinical accessibility of dermal tissue offers an appropriate and attractive target for vaccination. We previously demonstrated that pDNA injection into the skin in combination with surface electroporation (SEP), results in rapid and robust expression of the encoded antigen in the epidermis. Here, we demonstrate that intradermally EP-enhanced pDNA vaccination results in the rapid induction of a host humoral immune response. In the dermally relevant guinea pig model, we used high-resolution laser scanning confocal microscopy to observe direct dendritic cell (DC) transfections in the epidermis, to determine the migration kinetics of these cells from the epidermal layer into the dermis, and to follow them sequentially to the immediate draining lymph nodes. Furthermore, we delineate the relationship between the migration of directly transfected epidermal DCs and the generation of the host immune response. In summary, these data indicate that direct presentation of antigen to the immune system by DCs through SEP-based in vivo transfection in the epidermis, is related to the generation of a humoral immune response. PMID:26052522

  8. Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results

    PubMed Central

    Pham, Phuc Van; Le, Hanh Thi; Vu, Binh Thanh; Pham, Viet Quoc; Le, Phong Minh; Phan, Nhan Lu-Chinh; Trinh, Ngu Van; Nguyen, Huyen Thi-Lam; Nguyen, Sinh Truong; Nguyen, Toan Linh; Phan, Ngoc Kim

    2016-01-01

    Background Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. Materials and methods NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 106 cells/mice, and the survival percentage was monitored in both treated and untreated groups. Results The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. Conclusion These results suggested that targeting BCSCs with DCs is a promising therapy for BC. PMID:27499638

  9. DNA vaccination strategy targets epidermal dendritic cells, initiating their migration and induction of a host immune response

    PubMed Central

    Smith, Trevor RF; Schultheis, Katherine; Kiosses, William B; Amante, Dinah H; Mendoza, Janess M; Stone, John C; McCoy, Jay R; Sardesai, Niranjan Y; Broderick, Kate E

    2014-01-01

    The immunocompetence and clinical accessibility of dermal tissue offers an appropriate and attractive target for vaccination. We previously demonstrated that pDNA injection into the skin in combination with surface electroporation (SEP), results in rapid and robust expression of the encoded antigen in the epidermis. Here, we demonstrate that intradermally EP-enhanced pDNA vaccination results in the rapid induction of a host humoral immune response. In the dermally relevant guinea pig model, we used high-resolution laser scanning confocal microscopy to observe direct dendritic cell (DC) transfections in the epidermis, to determine the migration kinetics of these cells from the epidermal layer into the dermis, and to follow them sequentially to the immediate draining lymph nodes. Furthermore, we delineate the relationship between the migration of directly transfected epidermal DCs and the generation of the host immune response. In summary, these data indicate that direct presentation of antigen to the immune system by DCs through SEP-based in vivo transfection in the epidermis, is related to the generation of a humoral immune response. PMID:26052522

  10. High-density sub-100-nm peptide-gold nanoparticle complexes improve vaccine presentation by dendritic cells in vitro

    NASA Astrophysics Data System (ADS)

    Lin, Adam Yuh; Lunsford, Jessica; Bear, Adham Sean; Young, Joseph Keith; Eckels, Phillip; Luo, Laureen; Foster, Aaron Edward; Drezek, Rebekah Anna

    2013-02-01

    Nanocarriers have been explored to improve the delivery of tumor antigens to dendritic cells (DCs). Gold nanoparticles are attractive nanocarriers because they are inert, non-toxic, and can be readily endocytosed by DCs. Here, we designed novel gold-based nanovaccines (AuNVs) using a simple self-assembling bottom-up conjugation method to generate high-peptide density delivery and effective immune responses with limited toxicity. AuNVs were synthesized using a self-assembling conjugation method and optimized using DC-to-splenocyte interferon-γ enzyme-linked immunosorbent spot assays. The AuNV design has shown successful peptide conjugation with approximately 90% yield while remaining smaller than 80 nm in diameter. DCs uptake AuNVs with minimal toxicity and are able to process the vaccine peptides on the particles to stimulate cytotoxic T lymphocytes (CTLs). These high-peptide density AuNVs can stimulate CTLs better than free peptides and have great potential as carriers for various vaccine types.

  11. In vitro innate immune cell based models to assess whole cell Bordetella pertussis vaccine quality: a proof of principle.

    PubMed

    Hoonakker, M E; Verhagen, L M; Hendriksen, C F M; van Els, C A C M; Vandebriel, R J; Sloots, A; Han, W G H

    2015-03-01

    Lot release testing of vaccines is primarily based on animal models that are costly, time-consuming and sometimes of questionable relevance. In order to reduce animal use, functional in vitro assays are being explored as an alternative approach for the current lot release testing paradigm. In this study, we present an evaluation of APC platforms assessing innate immune activation by whole cell Bordetella pertussis (wP) vaccines. Primary monocytes, monocyte-derived DC (moDC) and human monocyte/DC cell lines (MonoMac6 and MUTZ-3) were compared for their capacity to respond to wP vaccines of varying quality. To produce such vaccines, the production process of wP was manipulated, resulting in wP vaccines covering a range of in vivo potencies. The responses of MUTZ-3 cells and primary monocytes to these vaccines were marginal and these models were therefore considered inappropriate. Importantly, moDC and MonoMac6 cells responded to the wP vaccines and discriminated between vaccines of varying quality, although slight variations in the responses to wP vaccines of similar quality were also observed. This study provides a proof of principle for the use of in vitro APC platforms as part of a new strategy to assess wP vaccine lot consistency, though careful standardisation of assay conditions is necessary. PMID:25633359

  12. T-cell-based diagnosis of tuberculosis infection in children in Lithuania: a country of high incidence despite a high coverage with bacille Calmette-Guerin vaccination

    PubMed Central

    Hansted, Edita; Andriuskeviciene, Angele; Sakalauskas, Raimundas; Kevalas, Rimantas; Sitkauskiene, Brigita

    2009-01-01

    Background Lithuania is a country with a high incidence of tuberculosis (TB), despite a high coverage with bacille Calmette-Guerin (BCG) vaccination. Until now the only method used to detect latent TB infection was the tuberculin skin test (TST). However, TST may have a cross reactivity to the BCG vaccine and to environmental mycobacteria. The aim of this study was to conduct assessments of the diagnostic accuracy of the T-cell based test (T SPOT TB) for TB in children who had previously been BCG vaccinated and compare these with the results of the TST. Methods Between January 2005 and February 2007, children with bacteriologically confirmed TB, children having contacts with a case of infectious pulmonary TB and children without any known risk for TB were tested with both the TST and T SPOT TB. Results The TST and T SPOT TB tests were positive for all patients in the „culture-confirmed TB“ group. Whereas, in the „high risk for TB“ group, the TST was positive for 60%, but the T SPOT TB test, only for 17.8%. Meanwhile the results for the „low risk for TB“ group were 65.4% and 9.6%, respectively. A correlation between the TST and T SPOT TB was obtained in the "culture-confirmed TB" group where the TST ≥15 mm (r = 0.35, p < 0.001). Conclusion The T-cell based method is more objective than the TST for identifying latent TB infection in children who had been previously BCG vaccinated. This method could be useful in countries like Lithuania where there is a high incidence of TB despite a high coverage with BCG vaccination. It may also help to avoid unnecessary chemoprophylaxis when TST reactions are false-positive. PMID:19689817

  13. Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide

    PubMed Central

    Mitchell, Duane A.; Sayour, Elias J.; Reap, Elizabeth; Schmittling, Robert; De Leon, Gabriel; Norberg, Pamela; Desjardins, Annick; Friedman, Allan H.; Friedman, Henry S.; Archer, Gary; Sampson, John H.

    2015-01-01

    Therapeutic vaccination of patients with cancer-targeting tumor-associated antigens is a promising strategy for the specific eradication of invasive malignancies with minimal toxicity to normal tissues. However, as increasingly potent modalities for stimulating immunologic responses are developed for clinical evaluation, the risk of inflammatory and autoimmune toxicities also may be exacerbated. In this report, we describe the induction of a severe (Grade 3) immunologic reaction in a patient with newly-diagnosed glioblastoma (GBM) receiving autologous RNA-pulsed dendritic cell (DC) vaccines admixed with GM-CSF and administered coordinately with cycles of dose-intensified temozolomide (diTMZ). Shortly after the eighth administration of the admixed intradermal vaccine, the patient experienced dizziness, flushing, conjunctivitis, headache, and the outbreak of a disseminated macular/papular rash and bilateral indurated injection sites. Immunologic work-up of patient reactivity revealed sensitization to the GM-CSF component of the vaccine and the production of high levels of anti-GM-CSF autoantibodies during vaccination. Removal of GM-CSF from the DC vaccine allowed continued vaccination without incident. Despite the known lymphodepletive and immunosuppressive effects of TMZ, these observations demonstrate the capacity for the generation of severe immunologic reactivity in patients with GBM receiving DC-based therapy during adjuvant diTMZ. PMID:25387895

  14. Immune Reactions against Gene Gun Vaccines Are Differentially Modulated by Distinct Dendritic Cell Subsets in the Skin

    PubMed Central

    Deressa, Tekalign; Strandt, Helen; Florindo Pinheiro, Douglas; Mittermair, Roberta; Pizarro Pesado, Jennifer; Thalhamer, Josef; Hammerl, Peter; Stoecklinger, Angelika

    2015-01-01

    The skin accommodates multiple dendritic cell (DC) subsets with remarkable functional diversity. Immune reactions are initiated and modulated by the triggering of DC by pathogen-associated or endogenous danger signals. In contrast to these processes, the influence of intrinsic features of protein antigens on the strength and type of immune responses is much less understood. Therefore, we investigated the involvement of distinct DC subsets in immune reactions against two structurally different model antigens, E. coli beta-galactosidase (betaGal) and chicken ovalbumin (OVA) under otherwise identical conditions. After epicutaneous administration of the respective DNA vaccines with a gene gun, wild type mice induced robust immune responses against both antigens. However, ablation of langerin+ DC almost abolished IgG1 and cytotoxic T lymphocytes against betaGal but enhanced T cell and antibody responses against OVA. We identified epidermal Langerhans cells (LC) as the subset responsible for the suppression of anti-OVA reactions and found regulatory T cells critically involved in this process. In contrast, reactions against betaGal were not affected by the selective elimination of LC, indicating that this antigen required a different langerin+ DC subset. The opposing findings obtained with OVA and betaGal vaccines were not due to immune-modulating activities of either the plasmid DNA or the antigen gene products, nor did the differential cellular localization, size or dose of the two proteins account for the opposite effects. Thus, skin-borne protein antigens may be differentially handled by distinct DC subsets, and, in this way, intrinsic features of the antigen can participate in immune modulation. PMID:26030383

  15. Immune Reactions against Gene Gun Vaccines Are Differentially Modulated by Distinct Dendritic Cell Subsets in the Skin.

    PubMed

    Weber, Corinna Stefanie; Hainz, Katrina; Deressa, Tekalign; Strandt, Helen; Florindo Pinheiro, Douglas; Mittermair, Roberta; Pizarro Pesado, Jennifer; Thalhamer, Josef; Hammerl, Peter; Stoecklinger, Angelika

    2015-01-01

    The skin accommodates multiple dendritic cell (DC) subsets with remarkable functional diversity. Immune reactions are initiated and modulated by the triggering of DC by pathogen-associated or endogenous danger signals. In contrast to these processes, the influence of intrinsic features of protein antigens on the strength and type of immune responses is much less understood. Therefore, we investigated the involvement of distinct DC subsets in immune reactions against two structurally different model antigens, E. coli beta-galactosidase (betaGal) and chicken ovalbumin (OVA) under otherwise identical conditions. After epicutaneous administration of the respective DNA vaccines with a gene gun, wild type mice induced robust immune responses against both antigens. However, ablation of langerin+ DC almost abolished IgG1 and cytotoxic T lymphocytes against betaGal but enhanced T cell and antibody responses against OVA. We identified epidermal Langerhans cells (LC) as the subset responsible for the suppression of anti-OVA reactions and found regulatory T cells critically involved in this process. In contrast, reactions against betaGal were not affected by the selective elimination of LC, indicating that this antigen required a different langerin+ DC subset. The opposing findings obtained with OVA and betaGal vaccines were not due to immune-modulating activities of either the plasmid DNA or the antigen gene products, nor did the differential cellular localization, size or dose of the two proteins account for the opposite effects. Thus, skin-borne protein antigens may be differentially handled by distinct DC subsets, and, in this way, intrinsic features of the antigen can participate in immune modulation. PMID:26030383

  16. Ex vivo generation of interstitial and Langerhans cell-like dendritic cell subset-based vaccines for hematological malignancies.

    PubMed

    Hutten, Tim; Thordardottir, Soley; Hobo, Willemijn; Hübel, Jessica; van der Waart, Anniek B; Cany, Jeannette; Dolstra, Harry; Hangalapura, Basav N

    2014-06-01

    Autologous, patient-specific, monocyte-derived dendritic cell (MoDC) vaccines have been successfully applied in the clinical studies so far. However, the routine application of this strategy has been hampered by the difficulties in generating sufficient numbers of DC and the poor DC vaccine quality because of pathology or prior treatment received by the patients. The immunotherapeutic potential of other subsets of DC has not been thoroughly investigated because of their rarity in tissues and difficulties associated with their ex vivo generation. The high expansion and differentiation potential of CD34 hematopoietic progenitor cells (HPC), isolated from umbilical cord blood (UCB), into different DC subsets make them an attractive alternative DC source for cancer immunotherapy. Therefore, the aim of this study was to generate a large number of different DC subsets from CD34 HPC and evaluate their functionality in comparison with MoDC. Our culture protocol generated a clinically relevant number of mature CD1a myeloid DC and CD207 Langerhans cells (LC)-like DC subsets from CD34 HPC with >95% purity. Both DC subsets exhibited a cytokine profile that favors cytotoxic T-cell responses. Furthermore, UCB-DC and UCB-LC demonstrated superior induction of proliferation of both allogeneic as well as viral antigen-specific CD8 T cells, both in vitro and in vivo. Additional studies revealed that UCC-DC and UCB-LC can efficiently expand minor histocompatibility antigen (MiHA) HA-1-specific cytotoxic T cells in the peripheral blood of leukemia patients and prime MiHA HA-1-specific and HA-2-specific cytotoxic T cells in vitro. These preclinical findings support the pharmaceutical development of the described culture protocol for clinical evaluation. PMID:24810638

  17. Polarized Dendritic Cells as Cancer Vaccines: Directing Effector-type T Cells to Tumors

    PubMed Central

    Kalinski, Pawel; Okada, Hideho

    2010-01-01

    Ex-vivo-generation and antigen loading of dendritic cells (DCs) from cancer patients helps to bypass the dysfunction of endogenous DCs. It also allows to control the process of DC maturation and to imprint in maturing DCs several functions essential for induction of effective forms of cancer immunity. Recent reports from several groups including ours demonstrate that distinct conditions of DC generation and maturation can prime DCs for preferential interaction with different (effector versus regulatory) subsets of immune cells. Moreover, differentially-generated DCs have been shown to imprint different effector mechanisms in CD4+ and CD8+ T cells (delivery of “signal three”) and to induce their different homing properties (delivery of “signal four”). These developments allow for selective induction of tumor-specific T cells with desirable effector functions and tumor-relevant homing properties and to direct the desirable types of immune cells to tumors. PMID:20409732

  18. Infection of Nonhost Species Dendritic Cells In Vitro with an Attenuated Myxoma Virus Induces Gene Expression That Predicts Its Efficacy as a Vaccine Vector ▿ †

    PubMed Central

    Top, S.; Foulon, E.; Pignolet, B.; Deplanche, M.; Caubet, C.; Tasca, C.; Bertagnoli, S.; Meyer, G.; Foucras, G.

    2011-01-01

    Recombinant myxoma virus (MYXV) can be produced without a loss of infectivity, and its highly specific host range makes it an ideal vaccine vector candidate, although careful examination of its interaction with the immune system is necessary. Similar to rabbit bone marrow-derived dendritic cells (BM-DCs), ovine dendritic cells can be infected by SG33, a MYXV vaccine strain, and support recombinant antigen expression. The frequency of infected cells in the nonhost was lower and the virus cycle was abortive in these cell types. Among BM-DC subpopulations, Langerhans cell-like DCs were preferentially infected at low multiplicities of infection. Interestingly, ovine BM-DCs remained susceptible to MYXV after maturation, although apoptosis occurred shortly after infection as a function of the virus titer. When gene expression was assessed in infected BM-DC cultures, type I interferon (IFN)-related and inflammatory genes were strongly upregulated. DC gene expression profiles were compared with the profiles produced by other poxviruses in interaction with DCs, but very few commonalities were found, although genes that were previously shown to predict vaccine efficacy were present. Collectively, these data support the idea that MYXV permits efficient priming of adaptive immune responses and should be considered a promising vaccine vector along with other poxviruses. PMID:21835800

  19. Toll-like receptor activation enhances cell-mediated immunity induced by an antibody vaccine targeting human dendritic cells

    PubMed Central

    Ramakrishna, Venky; Vasilakos, John P; Tario, Joseph D; Berger, Marc A; Wallace, Paul K; Keler, Tibor

    2007-01-01

    Previously, we have successfully targeted the mannose receptor (MR) expressed on monocyte-derived dendritic cells (DCs) using a fully human MR-specific antibody, B11, as a vehicle to deliver whole protein tumor antigens such as the human chorionic gonadotropin hormone (hCGβ). Since MRs play a role in bridging innate immunity with adaptive immunity we have explored several toll-like receptor (TLR)-specific ligands that may synergize with MR targeting and be applicable as adjuvants in the clinic. We demonstrate that antigen-specific helper and cytolytic T cells from both healthy donors and cancer patients were effectively primed with B11-hCGβ-treated autologous DCs when a combination of one or several TLR ligands is used. Specifically, concomitant signaling of DCs via TLR3 with dsRNA (poly I:C) and DC TLR 7/8 with Resiquimod (R-848), respectively, elicited efficient antigen presentation-mediated by MR-targeting. We demonstrate that MR and TLRs contribute towards maturation and activation of DCs by a mechanism that may be driven by a combination of adjuvant and antibody vaccines that specifically deliver antigenic targets to DCs. PMID:17254349

  20. Clinically feasible approaches to potentiating cancer cell-based immunotherapies

    PubMed Central

    Seledtsov, VI; Goncharov, AG; Seledtsova, GV

    2015-01-01

    The immune system exerts both tumor-destructive and tumor-protective functions. Mature dendritic cells (DCs), classically activated macrophages (M1), granulocytes, B lymphocytes, aβ and ɣδ T lymphocytes, natural killer T (NKT) cells, and natural killer (NK) cells may be implicated in antitumor immunoprotection. Conversely, tolerogenic DCs, alternatively activated macrophages (M2), myeloid-derived suppressor cells (MDSCs), and regulatory T (Tregs) and B cells (Bregs) are capable of suppressing antitumor immune responses. Anti-cancer vaccination is a useful strategy to elicit antitumor immune responses, while overcoming immunosuppressive mechanisms. Whole tumor cells or lysates derived thereof hold more promise as cancer vaccines than individual tumor-associated antigens (TAAs), because vaccinal cells can elicit immune responses to multiple TAAs. Cancer cell-based vaccines can be autologous, allogeneic or xenogeneic. Clinical use of xenogeneic vaccines is advantageous in that they can be most effective in breaking the preexisting immune tolerance to TAAs. To potentiate immunotherapy, vaccinations can be combined with other modalities that target different immune pathways. These modalities include 1) genetic or chemical modification of cell-based vaccines; 2) cross-priming TAAs to T cells by engaging dendritic cells; 3) T-cell adoptive therapy; 4) stimulation of cytotoxic inflammation by non-specific immunomodulators, toll-like receptor (TLR) agonists, cytokines, chemokines or hormones; 5) reduction of immunosuppression and/or stimulation of antitumor effector cells using antibodies, small molecules; and 6) various cytoreductive modalities. The authors envisage that combined immunotherapeutic strategies will allow for substantial improvements in clinical outcomes in the near future. PMID:25933181

  1. Clinically feasible approaches to potentiating cancer cell-based immunotherapies.

    PubMed

    Seledtsov, V I; Goncharov, A G; Seledtsova, G V

    2015-01-01

    The immune system exerts both tumor-destructive and tumor-protective functions. Mature dendritic cells (DCs), classically activated macrophages (M1), granulocytes, B lymphocytes, aβ and ɣδ T lymphocytes, natural killer T (NKT) cells, and natural killer (NK) cells may be implicated in antitumor immunoprotection. Conversely, tolerogenic DCs, alternatively activated macrophages (M2), myeloid-derived suppressor cells (MDSCs), and regulatory T (Tregs) and B cells (Bregs) are capable of suppressing antitumor immune responses. Anti-cancer vaccination is a useful strategy to elicit antitumor immune responses, while overcoming immunosuppressive mechanisms. Whole tumor cells or lysates derived thereof hold more promise as cancer vaccines than individual tumor-associated antigens (TAAs), because vaccinal cells can elicit immune responses to multiple TAAs. Cancer cell-based vaccines can be autologous, allogeneic or xenogeneic. Clinical use of xenogeneic vaccines is advantageous in that they can be most effective in breaking the preexisting immune tolerance to TAAs. To potentiate immunotherapy, vaccinations can be combined with other modalities that target different immune pathways. These modalities include 1) genetic or chemical modification of cell-based vaccines; 2) cross-priming TAAs to T cells by engaging dendritic cells; 3) T-cell adoptive therapy; 4) stimulation of cytotoxic inflammation by non-specific immunomodulators, toll-like receptor (TLR) agonists, cytokines, chemokines or hormones; 5) reduction of immunosuppression and/or stimulation of antitumor effector cells using antibodies, small molecules; and 6) various cytoreductive modalities. The authors envisage that combined immunotherapeutic strategies will allow for substantial improvements in clinical outcomes in the near future. PMID:25933181

  2. Inhibitory effects of a dendritic cell vaccine loaded with radiation-induced apoptotic tumor cells on tumor cell antigens in mouse bladder cancer.

    PubMed

    Xie, X F; Ding, Q; Hou, J G; Chen, G

    2015-01-01

    Herein, the preparation of a dendritic cell (DC) vaccine with radiation-induced apoptotic tumor cells and its immunological effects on bladder cancer in C57BL/6 mice was investigated. We used radiation to obtain a MB49 cell antigen that was sensitive to bone marrow-derived DCs to prepare a DC vaccine. An animal model of tumor-bearing mice was established with the MB49 mouse bladder cancer cell line. Animals were randomly allocated to an experimental group or control group. DC vaccine or phosphate-buffered saline was given 7 days before inoculation with tumor cells. Each group consisted of 2 subgroups in which tumor volume and the survival of tumor-bearing mice were recorded. Tumor volumes and average tumor masses of mice administered DC vaccine loaded with radiation-induced apoptotic cells were significantly lower than those in the control group (P < 0.01). Survival in the experimental group was also longer than that in the control group, and 2 mice survived without tumor formation. In the DC vaccine group, 2 mice were alive without tumor growth after 30 days, and no tumor was observed at 30 days after subcutaneous inoculation of MB49 cells. The DC vaccine loaded with radiation-induced apoptotic tumor cells had an anti-tumor effect and was associated with increased survival in a bladder cancer model in mice. PMID:26214433

  3. Incorporation of CpG into a liposomal vaccine formulation increases the maturation of antigen-loaded dendritic cells and monocytes to improve local and systemic immunity.

    PubMed

    Neeland, Melanie R; Elhay, Martin J; Nathanielsz, Jackie; Meeusen, Els N T; de Veer, Michael J

    2014-04-15

    Liposomal vaccine formulations incorporating stimulants that target innate immune receptors have been shown to significantly increase vaccine immunity. Following vaccination, innate cell populations respond to immune stimuli, phagocytose and process Ag, and migrate from the injection site, via the afferent lymphatic vessels, into the local lymph node. In this study, the signals received in the periphery promote and sculpt the adaptive immune response. Effector lymphocytes then leave the lymph node via the efferent lymphatic vessel to perform their systemic function. We have directly cannulated the ovine lymphatic vessels to detail the in vivo innate and adaptive immune responses occurring in the local draining lymphatic network following vaccination with a liposome-based delivery system incorporating CpG. We show that CpG induces the rapid recruitment of neutrophils, enhances dendritic cell-associated Ag transport, and influences the maturation of innate cells entering the afferent lymph. This translated into an extended period of lymph node shutdown, the induction of IFN-γ-positive T cells, and enhanced production of Ag-specific Abs. Taken together, the results of this study quantify the real-time in vivo kinetics of the immune response in a large animal model after vaccination of a dose comparable to that administered to humans. This study details enhancement of numerous immune mechanisms that provide an explanation for the immunogenic function of CpG when employed as an adjuvant within vaccines. PMID:24646740

  4. Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.

    PubMed

    Bol, Kalijn F; Aarntzen, Erik H J G; Pots, Jeanette M; Olde Nordkamp, Michel A M; van de Rakt, Mandy W M M; Scharenborg, Nicole M; de Boer, Annemiek J; van Oorschot, Tom G M; Croockewit, Sandra A J; Blokx, Willeke A M; Oyen, Wim J G; Boerman, Otto C; Mus, Roel D M; van Rossum, Michelle M; van der Graaf, Chantal A A; Punt, Cornelis J A; Adema, Gosse J; Figdor, Carl G; de Vries, I Jolanda M; Schreibelt, Gerty

    2016-03-01

    Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail. PMID:26861670

  5. Classical Flt3L-dependent dendritic cells control immunity to protein vaccine

    PubMed Central

    Feder, Rachel; Mollah, Shamim; Tse, Sze-Wah; Longhi, Maria Paula; Mehandru, Saurabh; Matos, Ines; Cheong, Cheolho; Ruane, Darren; Brane, Lucas; Teixeira, Angela; Dobrin, Joseph; Mizenina, Olga; Park, Chae Gyu; Meredith, Matthew; Clausen, Björn E.; Nussenzweig, Michel C.; Steinman, Ralph M.

    2014-01-01

    DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin+ DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs. PMID:25135299

  6. A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients

    PubMed Central

    Rahma, Osama E.; Ashtar, Ed; Czystowska, Malgorzata; Szajnik, Marta E.; Wieckowski, Eva; Bernstein, Sarah; Herrin, Vincent E.; Shams, Mortada A.; Steinberg, Seth M.; Merino, Maria; Gooding, William; Visus, Carmen; DeLeo, Albert B.; Wolf, Judith K.; Bell, Jeffrey G.; Berzofsky, Jay A.; Whiteside, Theresa L.; Khleif, Samir N.

    2013-01-01

    Purpose Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine. Experimental design Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer over-expressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles. Results Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively. Conclusion We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials. PMID:21927947

  7. Dendritic cells primed with a chimeric plasmid containing HIV-1-gag associated with lysosomal-associated protein-1 (LAMP/gag) is a potential therapeutic vaccine against HIV.

    PubMed

    Lucas, Carolina G D O; Matassoli, Flavio L; Peçanha, Ligia M T; Santillo, Bruna Tereso; Oliveira, Luanda Mara da Silva; Oshiro, Telma Miyuki; Marques, Ernesto T D A; Oxenius, Annette; de Arruda, Luciana B

    2016-08-01

    The decline in number and function of T cells is a hallmark of HIV infection, and preservation or restoration of HIV-specific cellular immune response is a major goal of AIDS treatment. Dendritic cells (DCs) play a key role in the initiation and maintenance of the immune response, and their use as a vaccine vehicle is a promising strategy for enhancing vaccine efficacy. We evaluated the potential of DC-mediated immunization with a DNA vaccine consisting of HIV-1-p55gag (gag, group-specific antigen) associated to lysosomal associated protein (LAMP) sequence (LAMP/gag vaccine). Immunization of mice with mouse DCs transfected with LAMP/gag (Lg-mDCs) stimulated more potent B- and T-cell responses than naked DNA or DCs pulsed with inactivated HIV. Anti-Gag antibody levels were sustained for at least 3 mo after immunization, and recall T-cell responses were also strongly detected at this time point. Human DCs transfected with LAMP/gag (Lg-hDCs) were also activated and able to stimulate greater T-cell response than native gag-transfected DCs. Coculture between Lg-hDCs and T lymphocytes obtained from patients with HIV resulted in upregulation of CD38, CD69, HLA-DR, and granzyme B by CD4(+) and CD8(+) T cells, and increased IFN-γ and TNF-α production. These results indicate that the use of LAMP/gag-DC may be an efficient strategy for enhancing immune function in patients with HIV.-Lucas, C. G. D. O., Matassoli, F. L., Peçanha, L. M. T., Santillo, B. T., Oliveira, L. M. D. S., Oshiro, T. M., Marques, E. T. D. A., Jr., Oxenius, A., de Arruda, L. B. Dendritic cells primed with a chimeric plasmid containing HIV-1-gag associated with lysosomal-associated protein-1 (LAMP/gag) is a potential therapeutic vaccine against HIV. PMID:27199296

  8. The Adjuvant Effects of High-Molecule-Weight Polysaccharides Purified from Antrodia cinnamomea on Dendritic Cell Function and DNA Vaccines

    PubMed Central

    Lin, Chi-Chen; Pan, I-Hong; Li, Yi-Rong; Pan, Yi-Gen; Lin, Ming-Kuem; Lu, Yi-Huang; Wu, Hsin-Chieh; Chu, Ching-Liang

    2015-01-01

    The biological activity of the edible basidiomycete Antrodia cinnamomea (AC) has been studied extensively. Many effects, such as anti-cancer, anti-inflammatory, and antioxidant activities, have been reported from either crude extracts or compounds isolated from AC. However, research addressing the function of AC in enhancing immunity is rare. The aim of the present study is to investigate the active components and the mechanism involved in the immunostimulatory effect of AC. We found that polysaccharides (PS) in the water extract of AC played a major role in dendritic cell (DC) activation, which is a critical leukocyte in initiating immune responses. We further size purified and identified that the high-molecular weight PS fraction (greater than 100 kDa) exhibited the activating effect. The AC high-molecular weight PSs (AC hmwPSs) promoted pro-inflammatory cytokine production by DCs and the maturation of DCs. In addition, DC-induced antigen-specific T cell activation and Th1 differentiation were increased by AC hmwPSs. In studying the molecular mechanism, we confirmed the activation of the MAPK and NF-κB pathways in DCs after AC hmwPSs treatment. Furthermore, we demonstrated that TLR2 and TLR4 are required for the stimulatory activity of AC hmwPSs on DCs. In a mouse tumor model, we demonstrated that AC hmwPSs enhanced the anti-tumor efficacy of the HER-2/neu DNA vaccine by facilitating specific Th1 responses. Thus, we conclude that hmwPSs are the major components of AC that stimulate DCs via the TLR2/TLR4 and NF-κB/MAPK signaling pathways. The AC hmwPSs have potential to be applied as adjuvants. PMID:25723174

  9. Carthamus tinctorius Enhances the Antitumor Activity of Dendritic Cell Vaccines via Polarization toward Th1 Cytokines and Increase of Cytotoxic T Lymphocytes

    PubMed Central

    Chang, Jia-Ming; Hung, Le-Mei; Chyan, Yau-Jan; Cheng, Chun-Ming; Wu, Rey-Yuh

    2011-01-01

    Carthamus tinctorius (CT), also named safflower, is a traditional Chinese medicine widely used to improve blood circulation. CT also has been studied for its antitumor activity in certain cancers. To investigate the effects of CT on the dendritic cell (DC)-based vaccine in cancer treatment, cytokine secretion of mouse splenic T lymphocytes and the maturation of DCs in response to CT were analyzed. To assess the antitumor activity of CT extract on mouse CD117+ (c-kit)-derived DCs pulsed with JC mammal tumor antigens, the JC tumor was challenged by the CT-treated DC vaccine in vivo. CT stimulated IFN-γ and IL-10 secretion of splenic T lymphocytes and enhanced the maturation of DCs by enhancing immunological molecule expression. When DC vaccine was pulsed with tumor antigens along with CT extract, the levels of TNF-α and IL-1β were dramatically increased with a dose-dependent response and more immunologic and co-stimulatory molecules were expressed on the DC surface. In addition, CT-treated tumor lysate-pulsed DC vaccine reduced the tumor weight in tumor-bearing mice by 15.3% more than tumor lysate-pulsed DC vaccine without CT treatment. CT polarized cytokine secretion toward the Th1 pathway and also increased the population of cytotoxic T lymphocytes ex vivo. In conclusion, CT activates DCs might promote the recognition of antigens and facilitate antigen presentation to Th1 immune responses. PMID:19001481

  10. TLR-3 stimulation improves anti-tumor immunity elicited by dendritic cell exosome-based vaccines in a murine model of melanoma

    PubMed Central

    Damo, Martina; Wilson, David S.; Simeoni, Eleonora; Hubbell, Jeffrey A.

    2015-01-01

    Dendritic cell (DC)-derived exosomes (Dexo) contain the machinery necessary to activate potent antigen-specific immune responses. As promising cell-free immunogens, Dexo have been tested in previous clinical trials for cancer vaccine immunotherapy, yet resulted in limited therapeutic benefit. Here, we explore a novel Dexo vaccine formulation composed of Dexo purified from DCs loaded with antigens and matured with either the TLR-3 ligand poly(I:C), the TLR-4 ligand LPS or the TLR-9 ligand CpG-B. When poly(I:C) was used to produce exosomes together with ovalbumin (OVA), the resulting Dexo vaccine strongly stimulated OVA-specific CD8+ and CD4+ T cells to proliferate and acquire effector functions. When a B16F10 melanoma cell lysate was used to load DCs with tumor antigens during exosome production together with poly(I:C), we obtained a Dexo vaccine capable of inducing robust activation of melanoma-specific CD8+ T cells and the recruitment of cytotoxic CD8+ T cells, NK and NK-T cells to the tumor site, resulting in significantly reduced tumor growth and enhanced survival as compared to a Dexo vaccine formulation similar to the one previously tested on human patients. Our results indicate that poly(I:C) is a particularly favorable TLR agonist for DC maturation during antigen loading and exosome production for cancer immunotherapy. PMID:26631690

  11. Vaccination with liposomal poly(I:C) induces discordant maturation of migratory dendritic cell subsets and anti-viral gene signatures in afferent lymph cells.

    PubMed

    Neeland, Melanie R; Elhay, Martin J; Meeusen, Els N T; de Veer, Michael J

    2014-10-29

    Vaccine formulations administered in the periphery must activate naive immune cells within the lymph node. In this study, we have directly cannulated the ovine lymphatic vessels to investigate the cellular and molecular mechanisms that transfer information from the periphery into the local draining lymph node via the afferent lymph. Inclusion of poly(I:C) into a liposomal vaccine formulation enhances the neutrophil-associated inflammatory immune response in afferent lymph and increases antigen uptake by migratory dendritic cells (DCs). Interestingly, antigen positive migratory DCs undergo discordant maturation, with peak expression of CD86 at 4 h and CD80 at 48-72 h post vaccination. Afferent lymph monocytes up-regulate expression of genes related to inflammatory and anti-viral immune phenotypes following vaccination however show no differentiation into APCs prior to their migration to the local lymph node as measured by surface MHC II expression. Finally, this study reveals the addition of poly(I:C) increases systemic antigen-specific humoral immunity. These findings provide a detailed understanding of the real time in vivo immune response induced by liposomes incorporating the innate immune agonist poly(I:C) utilising a vaccination setting comparable to that administered in humans. PMID:25280435

  12. Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.

    PubMed

    Suehiro, Youko; Hasegawa, Atsuhiko; Iino, Tadafumi; Sasada, Amane; Watanabe, Nobukazu; Matsuoka, Masao; Takamori, Ayako; Tanosaki, Ryuji; Utsunomiya, Atae; Choi, Ilseung; Fukuda, Tetsuya; Miura, Osamu; Takaishi, Shigeo; Teshima, Takanori; Akashi, Koichi; Kannagi, Mari; Uike, Naokuni; Okamura, Jun

    2015-05-01

    Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL. PMID:25612920

  13. Synthetic virus seeds for improved vaccine safety: Genetic reconstruction of poliovirus seeds for a PER.C6 cell based inactivated poliovirus vaccine.

    PubMed

    Sanders, Barbara P; Edo-Matas, Diana; Papic, Natasa; Schuitemaker, Hanneke; Custers, Jerome H H V

    2015-10-13

    Safety of vaccines can be compromised by contamination with adventitious agents. One potential source of adventitious agents is a vaccine seed, typically derived from historic clinical isolates with poorly defined origins. Here we generated synthetic poliovirus seeds derived from chemically synthesized DNA plasmids encoding the sequence of wild-type poliovirus strains used in marketed inactivated poliovirus vaccines. The synthetic strains were phenotypically identical to wild-type polioviruses as shown by equivalent infectious titers in culture supernatant and antigenic content, even when infection cultures are scaled up to 10-25L bioreactors. Moreover, the synthetic seeds were genetically stable upon extended passaging on the PER.C6 cell culture platform. Use of synthetic seeds produced on the serum-free PER.C6 cell platform ensures a perfectly documented seed history and maximum control over starting materials. It provides an opportunity to maximize vaccine safety which increases the prospect of a vaccine end product that is free from adventitious agents. PMID:26362098

  14. Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA–Transfected Dendritic Cells

    PubMed Central

    Van Craenenbroeck, Amaryllis H.; Smits, Evelien L.J.; Anguille, Sébastien; Van de Velde, Ann; Stein, Barbara; Braeckman, Tessa; Van Camp, Kirsten; Nijs, Griet; Ieven, Margareta; Goossens, Herman; Berneman, Zwi N.; Van Tendeloo, Viggo F.I.; Verpooten, Gert A.; Van Damme, Pierre; Cools, Nathalie

    2015-01-01

    Background Infection with human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ and hematopoietic stem cell transplant (HSCT) recipients. Methods The present study explored the safety, feasibility, and immunogenicity of CMV pp65 messenger RNA–loaded autologous monocyte-derived dendritic cells (DC) as a cellular vaccine for active immunization in healthy volunteers and allogeneic HSCT recipients. Four CMV-seronegative healthy volunteers and three allogeneic HSCT recipients were included in the study. Four clinical-grade autologous monocyte-derived DC vaccines were prepared after a single leukapheresis procedure and administered intradermally at a weekly interval. Results De novo induction of CMV-specific T-cell responses was detected in three of four healthy volunteers without serious adverse events. Of the HSCT recipients, none developed CMV disease and one of two patients displayed a remarkable threefold increase in CMV pp65-specific T cells on completion of the DC vaccination trial. Conclusion In conclusion, our DC vaccination strategy induced or expanded a CMV-specific cellular response in four of six efficacy-evaluable study subjects, providing a base for its further exploration in larger cohorts. PMID:25050468

  15. Langerin negative dendritic cells promote potent CD8+ T-cell priming by skin delivery of live adenovirus vaccine microneedle arrays

    PubMed Central

    Bachy, Veronique; Hervouet, Catherine; Becker, Pablo D.; Chorro, Laurent; Carlin, Leo M.; Herath, Shanthi; Papagatsias, Timos; Barbaroux, Jean-Baptiste; Oh, Sea-Jin; Benlahrech, Adel; Athanasopoulos, Takis; Dickson, George; Patterson, Steven; Kwon, Sung-Yun; Geissmann, Frederic; Klavinskis, Linda S.

    2013-01-01

    Stabilization of virus protein structure and nucleic acid integrity is challenging yet essential to preserve the transcriptional competence of live recombinant viral vaccine vectors in the absence of a cold chain. When coupled with needle-free skin delivery, such a platform would address an unmet need in global vaccine coverage against HIV and other global pathogens. Herein, we show that a simple dissolvable microneedle array (MA) delivery system preserves the immunogenicity of vaccines encoded by live recombinant human adenovirus type 5 (rAdHu5). Specifically, dried rAdHu5 MA immunization induced CD8+ T-cell expansion and multifunctional cytokine responses equipotent with conventional injectable routes of immunization. Intravital imaging demonstrated MA cargo distributed both in the epidermis and dermis, with acquisition by CD11c+ dendritic cells (DCs) in the dermis. The MA immunizing properties were attributable to CD11c+ MHCIIhi CD8αneg epithelial cell adhesion molecule (EpCAMneg) CD11b+ langerin (Lang; CD207)neg DCs, but neither Langerhans cells nor Lang+ DCs were required for CD8+ T-cell priming. This study demonstrates an important technical advance for viral vaccine vectors progressing to the clinic and provides insights into the mechanism of CD8+ T-cell priming by live rAdHu5 MAs. PMID:23386724

  16. Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma

    PubMed Central

    Vandenberk, Lien; Garg, Abhishek D.; Verschuere, Tina; Koks, Carolien; Belmans, Jochen; Beullens, Monique; Agostinis, Patrizia; De Vleeschouwer, Steven; Van Gool, Stefaan W.

    2016-01-01

    ABSTRACT Dendritic cell (DC)-based immunotherapy has yielded promising results against high-grade glioma (HGG). However, the efficacy of DC vaccines is abated by HGG-induced immunosuppression and lack of attention toward the immunogenicity of the tumor lysate/cells used for pulsing DCs. A literature analysis of DC vaccination clinical trials in HGG patients delineated the following two most predominantly applied methods for tumor lysate preparation: freeze-thaw (FT)-induced necrosis or FT-necrosis followed by X-ray irradiation. However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. Using an orthotopic HGG murine model (GL261-C57BL/6), we observed that prophylactic vaccination with DCs pulsed with irradiated FT-necrotic cells (compared to FT-necrotic cells only) prolonged overall survival by increasing tumor rejection in glioma-challenged mice. This was associated, both in prophylactic and curative vaccination setups, with an increase in brain-infiltrating Th1 cells and cytotoxic T lymphocytes (CTL), paralleled by a reduced accumulation of regulatory T cells, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC). Further analysis showed that irradiation treatment of FT-necrotic cells considerably increased the levels of carbonylated proteins — a surrogate-marker of oxidation-associated molecular patterns (OAMPs). Through further application of antioxidants and hydrogen peroxide, we found a striking correlation between the amount of lysate-associated protein carbonylation/OAMPs and DC vaccine-mediated tumor rejection capacity thereby suggesting for the first time a role for protein carbonylation/OAMPs in at least partially mediating antitumor immunity. Together, these data strongly advocate the use of protein oxidation-inducing modalities like irradiation for increasing the immunogenicity of tumor lysate/cells used for pulsing DC vaccines. PMID:27057467

  17. Microparticulate β-glucan vaccine conjugates phagocytized by dendritic cells activate both naïve CD4 and CD8 T cells in vitro.

    PubMed

    Berner, Vanessa K; duPre, Sally A; Redelman, Doug; Hunter, Kenneth W

    2015-01-01

    Microparticulate β-glucan (MG) conjugated to vaccine antigen has been shown to serve as an effective adjuvant in vivo. To further study antigen presentation by MG:vaccine conjugates, bone marrow-derived dendritic cells (BMDC) were treated with MG conjugated to ovalbumin (OVA), then interacted with splenocytes from DO11.10 transgenic mice expressing an OVA peptide-specific T cell receptor. BMDC treated with MG:OVA induced significantly higher numbers of activated (CD25+CD69+) OVA-specific CD4+ T cells than BMDC treated with OVA alone. BMDC treated with MG:OVA upregulated CD86 and CD40 expression as well as MG alone, indicating that conjugation of OVA does not alter the immunostimulatory capacity of MG. Activation of CD8+ OVA-specific OT-1 cells showed that MG:OVA is also capable of enhancing cross-presentation by BMDC to CD8+ cytotoxic T cells. These results show that MG acts as an adjuvant to enhance antigen presentation by dendritic cells to naïve, antigen-specific CD4 and CD8 T cells. PMID:26549577

  18. Vaccinations

    MedlinePlus

    ... vaccinated? For many years, a set of annual vaccinations was considered normal and necessary for dogs and ... to protect for a full year. Consequently, one vaccination schedule will not work well for all pets. ...

  19. A Dendritic Cell Vaccine Pulsed with Autologous Hypochlorous Acid-Oxidized Ovarian Cancer Lysate Primes Effective Broad Antitumor Immunity: From Bench to Bedside

    PubMed Central

    Chiang, Cheryl Lai-Lai; Kandalaft, Lana E.; Tanyi, Janos; Hagemann, Andrea R.; Motz, Gregory T.; Svoronos, Nikolaos; Montone, Kathleen; Mantia-Smaldone, Gina M.; Nisenbaum, Harvey L.; Levine, Bruce L.; Kalos, Michael; Czerniecki, Brian J.; Torigian, Drew A.; Powell, Daniel J.; Mick, Rosemarie; Smith, Lori; Coukos, George

    2013-01-01

    Purpose Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy for they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB-irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl)-oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. Experimental Design We compared DCs’ ability to engulf three different tumor lysate preparations, produce Th1-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo. Results We demonstrated that DCs engulfed HOCl-oxidized lysate most efficiently, stimulated robust MLRs and elicited strong tumor-specific IFN-γ secretions in autologous T-cells. These DCs produced the highest levels of Th1-priming cytokines and chemokines, including IL-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy and progression free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating T regulatory cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of ≥24 months after OCDC. Conclusions This is the first study demonstrating the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. PMID:23838316

  20. Type I Interferon Signals in Macrophages and Dendritic Cells Control Dengue Virus Infection: Implications for a New Mouse Model To Test Dengue Vaccines

    PubMed Central

    Toh, Ying-Xiu; Valdés, Iris; Cerny, Daniela; Heinrich, Julia; Hermida, Lisset; Marcos, Ernesto; Guillén, Gerardo; Kalinke, Ulrich; Shi, Pei-Yong; Fink, Katja

    2014-01-01

    ABSTRACT Dengue virus (DENV) infects an estimated 400 million people every year, causing prolonged morbidity and sometimes mortality. Development of an effective vaccine has been hampered by the lack of appropriate small animal models; mice are naturally not susceptible to DENV and only become infected if highly immunocompromised. Mouse models lacking both type I and type II interferon (IFN) receptors (AG129 mice) or the type I IFN receptor (IFNAR−/− mice) are susceptible to infection with mouse-adapted DENV strains but are severely impaired in mounting functional immune responses to the virus and thus are of limited use for study. Here we used conditional deletion of the type I IFN receptor (IFNAR) on individual immune cell subtypes to generate a minimally manipulated mouse model that is susceptible to DENV while retaining global immune competence. Mice lacking IFNAR expression on CD11c+ dendritic cells and LysM+ macrophages succumbed completely to DENV infection, while mice deficient in the receptor on either CD11c+ or LysM+ cells were susceptible to infection but often resolved viremia and recovered fully from infection. Conditional IFNAR mice responded with a swift and strong CD8+ T-cell response to viral infection, compared to a weak response in IFNAR−/− mice. Furthermore, mice lacking IFNAR on either CD11c+ or LysM+ cells were also sufficiently immunocompetent to raise a protective immune response to a candidate subunit vaccine against DENV-2. These data demonstrate that mice with conditional deficiencies in expression of the IFNAR represent improved models for the study of DENV immunology and screening of vaccine candidates. IMPORTANCE Dengue virus infects 400 million people every year worldwide, causing 100 million clinically apparent infections, which can be fatal if untreated. Despite many years of research, there are no effective vaccine and no antiviral treatment available for dengue. Development of vaccines has been hampered in particular by

  1. Heat shock protein X purified from Mycobacterium tuberculosis enhances the efficacy of dendritic cells-based immunotherapy for the treatment of allergic asthma.

    PubMed

    Kim, Hye-Young; Kang, Hyun Kyu; Cho, Joon; Jung, In Duk; Yoon, Gun Young; Lee, Min-Goo; Shin, Sung Jae; Park, Won Sun; Park, Jong-Hwan; Ryu, Seung-Wook; Park, Yeong-Min; You, Ji Chang

    2015-03-01

    Dendritic cells play an important role in determining whether naïve T cells mature into either Th1 or Th2 cells. We determined whether heat-shock protein X (HspX) purified from Mycobacterium tuberculosis regulates the Th1/Th2 immune response in an ovalbumin (OVA)-induced murine model of asthma. HspX increased interferon-gamma, IL-17A, -12 and transforming growth factor (TGF)-β production and T-bet gene expression but reduced IL-13 production and GATA-3 gene expression. HspX also inhibited asthmatic reactions as demonstrated by an increase in the number of eosinophils in bronchoalveolar lavage fluid, inflammatory cell infiltration in lung tissues, airway luminal narrowing, and airway hyper-responsiveness. Furthermore, HspX enhanced OVA-induced decrease of regulatory T cells in the mediastinal lymph nodes. This study provides evidence that HspX plays critical roles in the amelioration of asthmatic inflammation in mice. These findings provide new insights into the immunotherapeutic role of HspX with respect to its effects on a murine model of asthma. PMID:25560695

  2. Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation.

    PubMed

    De Keersmaecker, Brenda; Fostier, Karel; Corthals, Jurgen; Wilgenhof, Sofie; Heirman, Carlo; Aerts, Joeri L; Thielemans, Kris; Schots, Rik

    2014-10-01

    Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4(+) and CD8(+) T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8(+) T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM. PMID:24947180

  3. The clinical effects of dendritic cell vaccines combined with cytokine-induced killer cells intraperitoneal injected on patients with malignant ascites

    PubMed Central

    Ai, Yue-Qin; Cai, Kai; Hu, Jian-Hua; Jiang, Long-Wei; Gao, Yan-Rong; Zhao, Hua; Jia, Shao-Chang

    2014-01-01

    Malignant ascites (MA) is a pathological condition due to a variety of primary abdominal and extra-abdominal neoplasms. It is a primary cause of morbidity and presents many difficulties in evaluation and treatment. In this study we used dendritic cell vaccines combined with cytokine-induced killer (CIK) cells intraperitoneal injected in patients with MA, and evaluated the safety and efficacy of this treatment. The results showed that the percentage of CD3+ CD56+ CIK cells after treatment increased significantly while the percentage of CD4+ CD25+ Treg cells decreased (P < 0.05). The clinical response rate (RR) was 40.9% and disease control rate (DCR) was 77.3%. We then studied and identified the mechanisms of the anti-tumor effects of the vaccines by analyzing a series of cytokines that are commonly involved in tumor progression and ascitic development including granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-10 (IL-10), interferon-γ (IFN-γ), tumor necrosis factor-α (TGF-α), tumor necrosis factor-β (TGF-β), Vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1). These data demonstrated that intraperitoneal injection with DC vaccines combined with CIK cells in patients with malignant peritoneal effusion is safe and feasible. This therapy modality can achieve a certain clinical benefit even in patients resistant to conventional treatments. PMID:25550942

  4. Induction of CML28-specific cytotoxic T cell responses using co-transfected dendritic cells with CML28 DNA vaccine and SOCS1 small interfering RNA expression vector

    SciTech Connect

    Zhou Hongsheng; Zhang Donghua . E-mail: hanson2008@gmail.com; Wang Yaya; Dai Ming; Zhang Lu; Liu Wenli; Liu Dan; Tan Huo; Huang Zhenqian

    2006-08-18

    CML28 is an attractive target for antigen-specific immunotherapy. SOCS1 represents an inhibitory control mechanism for DC antigen presentation and the magnitude of adaptive immunity. In this study, we evaluated the potential for inducing CML28-specific cytotoxic T lymphocytes (CTL) responses by dendritic cells (DCs)-based vaccination. We constructed a CML28 DNA vaccine and a SOCS1 siRNA vector and then cotransfect monocyte-derived DCs. Flow cytometry analysis showed gene silencing of SOCS1 resulted in higher expressions of costimulative moleculars in DCs. Mixed lymphocyte reaction (MLR) indicated downregulation of SOCS1 stronger capability to stimulate proliferation of responder cell in DCs. The CTL assay revealed transfected DCs effectively induced autologous CML28-specific CTL responses and the lytic activities induced by SOCS1-silenced DCs were significantly higher compared with those induced by SOCS1-expressing DCs. These results in our study indicates gene silencing of SOCS1 remarkably enhanced the cytotoxicity efficiency of CML28 DNA vaccine in DCs.

  5. Generation of a cord blood-derived Wilms Tumor 1 dendritic cell vaccine for AML patients treated with allogeneic cord blood transplantation

    PubMed Central

    de Haar, Colin; Plantinga, Maud; Blokland, Nina JG; van Til, Niek P; Flinsenberg, Thijs WH; Van Tendeloo, Viggo F; Smits, Evelien L; Boon, Louis; Spel, Lotte; Boes, Marianne; Boelens, Jaap Jan; Nierkens, Stefan

    2015-01-01

    The poor survival rates of refractory/relapsed acute myeloid leukemia (AML) patients after haematopoietic cell transplantation (HCT) requires the development of additional immune therapeutic strategies. As the elicitation of tumor-antigen specific cytotoxic T lymphocytes (CTLs) is associated with reduced relapses and enhanced survival, enhanced priming of these CTLs using an anti-AML vaccine may result in long-term immunity against AML. Cord blood (CB), as allogeneic HCT source, may provide a unique setting for such post-HCT vaccination, considering its enhanced graft-versus-leukemia (GvL) effects and population of highly responsive naïve T cells. It is our goal to develop a powerful and safe immune therapeutic strategy composed of CB-HCT followed by vaccination with CB CD34+-derived dendritic cells (DCs) presenting the oncoprotein Wilms Tumor-1 (WT1), which is expressed in AML-blasts in the majority of patients. Here, we describe the optimization of a clinically applicable DC culture protocol. This two-step protocol consisting of an expansion phase followed by the differentiation toward DCs, enables us to generate sufficient cord blood-derived DCs (CBDCs) in the clinical setting. At the end of the culture, the CBDCs exhibit a mature surface phenotype, are able to migrate, express tumor antigen (WT1) after electroporation with mRNA encoding the full-length WT1 protein, and stimulate WT1-specific T cells. PMID:26451309

  6. A novel cancer immunotherapy based on the combination of a synthetic carbohydrate-pulsed dendritic cell vaccine and glycoengineered cancer cells

    PubMed Central

    Yu, Shichong; Wang, Qianli; Li, Yinghua; Hu, Zhenlin; Wu, Qiuye; Guo, Zhongwu; Zhang, Junping

    2015-01-01

    Immune tolerance to tumor-associated carbohydrate antigens (TACAs) has severely restricted the usefulness of most TACAs. To overcome this problem, we selected a sialylated trisaccharide TACA, GM3, as a target antigen, and tested a new immunotherapeutic strategy by combining metabolic bioengineering with dendritic cell (DC) vaccination. We engineered cancer cells to express an artificial structure, N-phenylacetyl-D-neuraminic acid, in place of the natural N-acetyl-D-neuraminic acid of GM3 by using N-phenylacetyl-D-mannosamine (ManNPhAc) as a biosynthetic precursor. Next, we selectively targeted the bioengineered cancer cells by vaccination with DCs pulsed with the GM3 N-phenylacetyl derivative. Vaccination with GM3NPhAc-KLH-loaded DCs elicited robust GM3NPhAc-specific T cell-dependent immunity. The results showed that this strategy could significantly inhibit FBL3 tumor growth and prolong the survival of tumor-bearing mice; B16F10 lung metastases could also be reduced. These findings lay out a new strategy for overcoming immune tolerance to TACAs, such as GM3, for the development of effective tumor immunotherapies. PMID:25760071

  7. A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer

    PubMed Central

    Koski, Gary K.; Koldovsky, Ursula; Xu, Shuwen; Mick, Rosemarie; Sharma, Anupama; Fitzpatrick, Elizabeth; Weinstein, Susan; Nisenbaum, Harvey; Levine, Bruce L; Fox, Kevin; Zhang, Paul; Czerniecki, Brian J

    2011-01-01

    Twenty-seven subjects with HER-2/neu over-expressing ductal carcinoma in situ of the breast were enrolled in a neoadjuvant immunization trial for safety and immunogenicity of DC1-polarized dendritic cells (DC1) pulsed with six HER-2/neu promiscuous MHC class II-binding peptides, plus two additional HLA-A2.1 class I-binding peptides. DC1 were generated with IFN-γ plus a special clinical-grade bacterial endotoxin (LPS) and administered directly into groin lymph nodes four times at weekly intervals prior to scheduled surgical resection of DCIS. Subjects were monitored for the induction of new or enhanced anti-peptide reactivity by IFN-γ ELIspot and ELISA assays performed on Th cells obtained from peripheral blood or excised sentinel lymph nodes. Responses by CTL against HLA-A2.1-binding peptides were measured using peptide-pulsed T2 target cells or HER-2/neu-expressing or non-expressing tumor cell lines. DC1 showed surface phenotype indistinct from “gold standard” inflammatory cocktail-activated DC, but displayed a number of distinguishing functional characteristics including the secretion of soluble factors and enhanced “killer DC” capacity against tumor cells in vitro. Post-immunization, we observed sensitization of Th cells to at least 1 class II peptide in 22 of 25 (88%, 95% exact CI 68.8 – 97.5%) evaluable subjects, while eleven of 13 (84.6%, 95% exact CI 64 – 99.8%) HLA-A2.1 subjects were successfully sensitized to class I peptides. Perhaps most importantly, anti-HER-2/neu peptide responses were observed up to 52 months post-immunization. These data show even in the presence of early breast cancer such DC1 are potent inducers of durable type I-polarized immunity, suggesting potential clinical value for development of cancer immunotherapy. PMID:22130160

  8. T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines.

    PubMed

    Vasaturo, Angela; Halilovic, Altuna; Bol, Kalijn F; Verweij, Dagmar I; Blokx, Willeke A M; Punt, Cornelis J A; Groenen, Patricia J T A; van Krieken, J Han J M; Textor, Johannes; de Vries, I Jolanda M; Figdor, Carl G

    2016-06-15

    Tumor-infiltrating lymphocytes appear to be a predictor of survival in many cancers, including cutaneous melanoma. We applied automated multispectral imaging to determine whether density and distribution of T cells within primary cutaneous melanoma tissue correlate with survival of metastatic melanoma patients after dendritic cell (DC) vaccination. CD3(+) T cell infiltration in primary tumors from 77 metastatic melanoma patients was quantified using the ratio of intratumoral versus peritumoral T-cell densities (I/P ratio). Patients with longer survival after DC vaccination had stronger T-cell infiltration than patients with shorter survival in a discovery cohort of 19 patients (P = 0.000026) and a validation cohort of 39 patients (P = 0.000016). I/P ratio was the strongest predictor of survival in a multivariate analysis including M substage and serum lactate dehydrogenase level. To evaluate I/P ratio as a predictive biomarker, we analyzed 19 chemotherapy-treated patients. Longer survival times of DC-vaccinated compared with chemotherapy-treated patients was observed for high (P = 0.000566), but not low (P = 0.154) I/P ratios. In conclusion, T-cell infiltration into primary melanoma is a strong predictor of survival after DC vaccination in metastatic melanoma patients who, on average, started this therapy several years after primary tumor resection. The infiltration remains predictive even after adjustment for late-stage prognostic markers. Our findings suggest that the I/P ratio is a potential predictive biomarker for treatment selection. Cancer Res; 76(12); 3496-506. ©2016 AACR. PMID:27197179

  9. Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients

    PubMed Central

    2013-01-01

    Background In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion. Methods Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2. Results Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells. Conclusions Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome. PMID:23725550

  10. Increasing the efficacy of tumor cell vaccines by enhancing cross priming

    PubMed Central

    Andersen, Brian M.; Ohlfest, John R.

    2012-01-01

    Cancer immunotherapy has been attempted for more than a century, and investment has intensified in the last 20 years. The complexity of the immune system is exemplified by the myriad of immunotherapeutic approaches under investigation. While anti-tumor immunity has been achieved experimentally with multiple effector cells and molecules, particular promise is shown for harnessing the CD8 T cell response. Tumor cell-based vaccines have been employed in hundreds of clinical trials to date and offer several advantages over subunit and peptide vaccines. However, tumor cell-based vaccines, often aimed at cross priming tumor-reactive CD8 T cells, have shown modest success in clinical trials. Here we review the mechanisms of cross priming and discuss strategies to increase the efficacy of tumor cell-based vaccines. A synthesis of recent findings on tissue culture conditions, cell death, and dendritic cell activation reveals promising new avenues for clinical investigation. PMID:22809568

  11. Diversification of Antitumour Immunity in a Patient with Metastatic Melanoma Treated with Ipilimumab and an IDO-Silenced Dendritic Cell Vaccine

    PubMed Central

    Nyakas, Marta; Sæbøe-Larssen, Stein; Mobergslien, Anne; Aamdal, Steinar; Kvalheim, Gunnar

    2016-01-01

    Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) inhibits T-cell activation and promotes T-cell differentiation into regulatory T-cells. Moreover, IDO expression promotes resistance to immunotherapies targeting immune checkpoints such as the cytotoxic T lymphocyte antigen-4 (CTLA-4). Here, a patient with metastatic melanoma pretreated with ipilimumab, an anti-CTLA-4 blocking antibody, was vaccinated with IDO-silenced DCs cotransfected with mRNA for survivin or hTERT tumour antigens. During vaccination, T-cell responses to survivin and hTERT tumour antigens were generated, and a certain degree of clinical benefit was achieved, with a significant reduction in lung, liver, and skin metastases, along with a better performance status. T-cell responses against MART-1 and NY-ESO-1 tumour antigens were also detected in the peripheral blood. The patient also mounted an antibody response to several melanoma proteins, indicating diversification of the antitumour immunity in this patient. The identification of such serum antibody-reacting proteins could facilitate the discovery of tumour neoantigens. PMID:27504122

  12. Diversification of Antitumour Immunity in a Patient with Metastatic Melanoma Treated with Ipilimumab and an IDO-Silenced Dendritic Cell Vaccine.

    PubMed

    Sioud, Mouldy; Nyakas, Marta; Sæbøe-Larssen, Stein; Mobergslien, Anne; Aamdal, Steinar; Kvalheim, Gunnar

    2016-01-01

    Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) inhibits T-cell activation and promotes T-cell differentiation into regulatory T-cells. Moreover, IDO expression promotes resistance to immunotherapies targeting immune checkpoints such as the cytotoxic T lymphocyte antigen-4 (CTLA-4). Here, a patient with metastatic melanoma pretreated with ipilimumab, an anti-CTLA-4 blocking antibody, was vaccinated with IDO-silenced DCs cotransfected with mRNA for survivin or hTERT tumour antigens. During vaccination, T-cell responses to survivin and hTERT tumour antigens were generated, and a certain degree of clinical benefit was achieved, with a significant reduction in lung, liver, and skin metastases, along with a better performance status. T-cell responses against MART-1 and NY-ESO-1 tumour antigens were also detected in the peripheral blood. The patient also mounted an antibody response to several melanoma proteins, indicating diversification of the antitumour immunity in this patient. The identification of such serum antibody-reacting proteins could facilitate the discovery of tumour neoantigens. PMID:27504122

  13. Restoring anti-oncodriver Th1 responses with dendritic cell vaccines in HER2/neu-positive breast cancer: progress and potential.

    PubMed

    De La Cruz, Lucy M; Nocera, Nadia F; Czerniecki, Brian J

    2016-10-01

    HER2/neu is expressed in the majority of in situ breast cancers, but maintained in 20-30% of invasive breast cancer (IBC). During breast tumorigenesis, there is a progressive loss of anti-HER2 CD4(pos) Th1 (anti-HER2Th1) from benign to ductal carcinoma in situ, with almost complete loss in IBC. This anti-HER2Th1 response can predict response to neoadjuvant therapy, risk of recurrence and disease-free survival. Vaccines consisting of HER2-pulsed type I polarized dendritic cells (DC1) administered during ductal carcinoma in situ and early IBC can efficiently correct anti-HER2Th1 response and have clinical impact on the disease. In this review, we will discuss the role of anti-HER2Th1 response in the three phases of immunoediting during HER2 breast cancer development and opportunities for reversing these processes using DC1 vaccines alone or in combination with standard therapies. Correcting the anti-HER2Th1 response may represent an opportunity for improving outcomes and providing a path to eliminate escape variants. PMID:27605070

  14. Vaccines

    MedlinePlus Videos and Cool Tools

    Vaccinations are injections of antigens into the body. Once the antigens enter the blood, they circulate along ... suppressor T cells stop the attack. After a vaccination, the body will have a memory of an ...

  15. Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients

    PubMed Central

    Boudewijns, Steve; Westdorp, Harm; Koornstra, Rutger H.T.; Aarntzen, Erik H.J.G.; Schreibelt, Gerty; Creemers, Jeroen H.A.; Punt, Cornelis J.A.; Figdor, Carl G.; Gerritsen, Winald R.; Bol, Kalijn F.

    2016-01-01

    The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8+ T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune-related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome. PMID:27227325

  16. Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients.

    PubMed

    Boudewijns, Steve; Westdorp, Harm; Koornstra, Rutger H T; Aarntzen, Erik H J G; Schreibelt, Gerty; Creemers, Jeroen H A; Punt, Cornelis J A; Figdor, Carl G; de Vries, I Jolanda M; Gerritsen, Winald R; Bol, Kalijn F

    2016-01-01

    The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8 T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune-related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome. PMID:27227325

  17. Safety and tolerability of allogeneic dendritic cell vaccination with induction of Wilms tumor 1-specific T cells in a pediatric donor and pediatric patient with relapsed leukemia: a case report and review of the literature.

    PubMed

    Saito, Shoji; Yanagisawa, Ryu; Yoshikawa, Kentaro; Higuchi, Yumiko; Koya, Terutsugu; Yoshizawa, Kiyoshi; Tanaka, Miyuki; Sakashita, Kazuo; Kobayashi, Takashi; Kurata, Takashi; Hirabayashi, Koichi; Nakazawa, Yozo; Shiohara, Masaaki; Yonemitsu, Yoshikazu; Okamoto, Masato; Sugiyama, Haruo; Koike, Kenichi; Shimodaira, Shigetaka

    2015-03-01

    A 15-year-old girl with acute lymphoblastic leukemia received allogeneic dendritic cell vaccination, pulsed with Wilms tumor 1 (WT1) peptide, after her third hematopoietic stem cell transplantation (HSCT). The vaccines were generated from the third HSCT donor, who was her younger sister, age 12 years. The patient received 14 vaccines and had no graft-versus-host disease or systemic adverse effect, aside from grade 2 skin reaction at the injection site. WT1-specific immune responses were detected after vaccination by both WT1-tetramer analysis and enzyme-linked immunosorbent spot assay. This strategy may be safe, tolerable and even feasible for patients with a relapse after HSCT. PMID:25484308

  18. Understanding MHC Class I Presentation of Viral Antigens by Human Dendritic Cells as a Basis for Rational Design of Therapeutic Vaccines

    PubMed Central

    van Montfoort, Nadine; van der Aa, Evelyn; Woltman, Andrea M.

    2014-01-01

    Effective viral clearance requires the induction of virus-specific CD8+ cytotoxic T lymphocytes (CTL). Since dendritic cells (DC) have a central role in initiating and shaping virus-specific CTL responses, it is important to understand how DC initiate virus-specific CTL responses. Some viruses can directly infect DC, which theoretically allow direct presentation of viral antigens to CTL, but many viruses target other cells than DC and thus the host depends on the cross-presentation of viral antigens by DC to activate virus-specific CTL. Research in mouse models has highly enhanced our understanding of the mechanisms underlying cross-presentation and the dendritic cells (DC) subsets involved, however, these results cannot be readily translated toward the role of human DC in MHC class I-antigen presentation of human viruses. Here, we summarize the insights gained in the past 20 years on MHC class I presentation of viral antigen by human DC and add to the current debate on the capacities of different human DC subsets herein. Furthermore, possible sources of viral antigens and essential DC characteristics for effective induction of virus-specific CTL are evaluated. We conclude that cross-presentation is not only an efficient mechanism exploited by DC to initiate immunity to viruses that do not infect DC but also to viruses that do infect DC, because cross-presentation has many conceptual advantages and bypasses direct immune modulatory effects of the virus on its infected target cells. Since knowledge on the mechanism of viral antigen presentation and the preferred DC subsets is crucial for rational vaccine design, the obtained insights are very instrumental for the development of effective anti-viral immunotherapy. PMID:24795724

  19. Design and evaluation of surface and adjuvant modified PLGA microspheres for uptake by dendritic cells to improve vaccine responses.

    PubMed

    Salvador, Aiala; Sandgren, Kerrie J; Liang, Frank; Thompson, Elizabeth A; Koup, Richard A; Pedraz, José Luis; Hernandez, Rosa Maria; Loré, Karin; Igartua, Manoli

    2015-12-30

    Designing strategies for targeting antigens to dendritic cells is a major goal in vaccinology. Here, PLGA (poly lactic-co-glycolic acid) microspheres and with several surface modifications that affect to their uptake by human blood primary dendritic cells and monocytes have been evaluated. Higher uptake was found by all the cell types when cationic microspheres (PLGA modified with polyethylene imine) were used. These cationic particles were in vivo evaluated in mice. In addition, MPLA(1) or poly(I:C)(2) and α-GalCer(3) were also encapsulated to address their adjuvant effect. All the microspheres were able to produce humoral immune responses, albeit they were higher for cationic microspheres. Moreover, surface charge seemed to have a role on biasing the immune response; cationic microspheres induced higher IFN-γ levels, indicative of Th1 activation, while unmodified ones mainly triggered IL4 and IL17A release, showing Th2 activation. Thus, we have shown here the potential and versatility of these MS, which may be tailored to needs. PMID:26475970

  20. Virus-Like Particle Vaccine Containing the F Protein of Respiratory Syncytial Virus Confers Protection without Pulmonary Disease by Modulating Specific Subsets of Dendritic Cells and Effector T Cells

    PubMed Central

    Kim, Ki-Hye; Lee, Young-Tae; Hwang, Hye Suk; Kwon, Young-Man; Kim, Min-Chul; Ko, Eun-Ju; Lee, Jong Seok; Lee, Youri

    2015-01-01

    ABSTRACT There is no licensed vaccine against respiratory syncytial virus (RSV) since the failure of formalin-inactivated RSV (FI-RSV) due to its vaccine-enhanced disease. We investigated immune correlates conferring protection without causing disease after intranasal immunization with virus-like particle vaccine containing the RSV fusion protein (F VLP) in comparison to FI-RSV and live RSV. Upon RSV challenge, FI-RSV immune mice showed severe weight loss, eosinophilia, and histopathology, and RSV reinfection also caused substantial RSV disease despite their viral clearance. In contrast, F VLP immune mice showed least weight loss and no sign of histopathology and eosinophilia. High levels of interleukin-4-positive (IL-4+) and tumor necrosis factor alpha-positive (TNF-α+) CD4+ T cells were found in FI-RSV immune mice, whereas gamma interferon-positive (IFN-γ+) and TNF-α+ CD4+ T cells were predominantly detected in live RSV-infected mice. More importantly, in contrast to FI-RSV and live RSV that induced higher levels of CD11b+ dendritic cells, F VLP immunization induced CD8α+ and CD103+ dendritic cells, as well as F-specific IFN-γ+ and TNF-α+ CD8+ T cells. These results suggest that F VLP can induce protection without causing pulmonary RSV disease by inducing RSV neutralizing antibodies, as well as modulating specific subsets of dendritic cells and CD8 T cell immunity. IMPORTANCE It has been a difficult challenge to develop an effective and safe vaccine against respiratory syncytial virus (RSV), a leading cause of respiratory disease. Immune correlates conferring protection but preventing vaccine-enhanced disease remain poorly understood. RSV F virus-like particle (VLP) would be an efficient vaccine platform conferring protection. Here, we investigated the protective immune correlates without causing disease after intranasal immunization with RSV F VLP in comparison to FI-RSV and live RSV. In addition to inducing RSV neutralizing antibodies responsible for

  1. A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination

    PubMed Central

    Collignon, Aurélie; Perles-Barbacaru, Adriana Teodora; Robert, Stéphane; Silvy, Françoise; Martinez, Emmanuelle; Crenon, Isabelle; Germain, Sébastien; Garcia, Stéphane; Viola, Angèle; Lombardo, Dominique

    2015-01-01

    Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC. PMID:26405163

  2. A pancreatic tumor-specific biomarker characterized in humans and mice as an immunogenic onco-glycoprotein is efficient in dendritic cell vaccination.

    PubMed

    Collignon, Aurélie; Perles-Barbacaru, Adriana Teodora; Robert, Stéphane; Silvy, Françoise; Martinez, Emmanuelle; Crenon, Isabelle; Germain, Sébastien; Garcia, Stéphane; Viola, Angèle; Lombardo, Dominique; Mas, Eric; Béraud, Evelyne

    2015-09-15

    Oncofetal fucose-rich glycovariants of the pathological bile salt-dependent lipase (pBSDL) appear during human pancreatic oncogenesis and are detected by themonoclonal antibody J28 (mAbJ28). We aimed to identify murine counterparts onpancreatic ductal adenocarcinoma (PDAC) cells and tissue and investigate the potential of dendritic cells (DC) loaded with this unique pancreatic tumor antigen to promote immunotherapy in preclinical trials. Pathological BSDLs purified from pancreatic juices of patients with PDAC were cleaved to generate glycosylated C-terminal moieties (C-ter) containing mAbJ28-reactive glycoepitopes. Immunoreactivity of the murine PDAC line Panc02 and tumor tissue to mAbJ28 was detected by immunohistochemistry and flow cytometry. C-ter-J28+ immunization promoted Th1-dominated immune responses. In vitro C-ter-J28+-loaded DCskewed CD3+ T-cells toward Th1 polarization. C-ter-J28+-DC-vaccinations selectively enhanced cell immunoreactivity to Panc02, as demonstrated by CD4+- and CD8+-T-cell activation, increased percentages of CD4+- and CD8+-T-cells and NK1.1+ cells expressing granzyme B, and T-cell cytotoxicity. Prophylactic and therapeutic C-ter-J28+-DC-vaccinations reduced ectopic Panc02-tumor growth, provided long-lasting protection from Panc02-tumor development in 100% of micebut not from melanoma, and attenuated progression of orthotopic tumors as revealed by MRI. Thusmurine DC loaded with pancreatic tumor-specific glycoepitope C-ter-J28+ induce efficient anticancer adaptive immunity and represent a potential adjuvant therapy for patients afflicted with PDAC. PMID:26405163

  3. Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.

    PubMed

    Mayanagi, Shuhei; Kitago, Minoru; Sakurai, Toshiharu; Matsuda, Tatsuo; Fujita, Tomonobu; Higuchi, Hajime; Taguchi, Junichi; Takeuchi, Hiroya; Itano, Osamu; Aiura, Koichi; Hamamoto, Yasuo; Takaishi, Hiromasa; Okamoto, Masato; Sunamura, Makoto; Kawakami, Yutaka; Kitagawa, Yuko

    2015-04-01

    This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855). PMID:25614082

  4. Vaccination with collagen-pulsed dendritic cells prevents the onset and reduces the disease severity in the mouse model of spontaneous polychondritis

    PubMed Central

    Sidhu, M; Griffiths, M M; Bradley, D S

    2009-01-01

    Immature dendritic cells (iDCs) have a tolerogenic potential due to low expression of important co-stimulatory cell surface molecules required for antigen presentation and induction of an effective immune response. We report here that injection of iDCs pulsed with chick type II collagen (CII) delayed the onset significantly and suppressed the severity of spontaneous polychondritis (SP) in the human leucocyte antigen (HLA)-DQ6αβ8αβ transgenic mouse model. Bone marrow-derived iDCs were pulsed in vitro with CII and transferred into 6-week-old HLA-DQ6αβ8αβ transgenic mice. Mice receiving CII-pulsed iDCs did not display any clinical signs of disease until 5·5 months of age, indicating the ability of the DC vaccine to delay significantly the onset of SP. Control groups receiving unpulsed iDCs or phosphate-buffered saline (PBS) developed polyarthritis at 3·5 months, as we have reported previously. The severity and incidence of disease was reduced in mice injected with CII-pulsed iDCs. Proinflammatory cytokines were in low to undetectable levels in the serum and tissue in the CII-pulsed iDC mice, correlating with the protection. This is the first evidence of iDC therapy controlling SP and suggests that iDC vaccination may provide a tool to reducing clinical manifestations in human inflammatory autoimmune disease such as relapsing polychondritis and rheumatoid arthritis. PMID:19664142

  5. [VACCINES].

    PubMed

    Bellver Capella, Vincente

    2015-10-01

    Vaccines are an extraordinary instrument of immunization of the population against infectious diseases. Around them there are many ethical issues. One of the most debated is what to do with certain groups opposition to vaccination of their children. States have managed in different ways the conflict between the duty of vaccination and the refusal to use vaccines: some impose the vaccination and others simply promote it. In this article we deal with which of these two approaches is the most suitable from an ethical and legal point of view. We stand up for the second option, which is the current one in Spain, and we propose some measures which should be kept in mind to improve immunization programs. PMID:26685562

  6. Superparamagnetic iron oxide labeling limits the efficacy of rabbit immature dendritic cell vaccination by decreasing their antigen uptake ability in a lysosome-dependent manner.

    PubMed

    Zhang, Min; Zhou, Jing; Wang, Jingchun; Zhou, Quan; Fang, Jin; Zhou, Chengqian; Chen, WenLi

    2015-02-01

    Immature dendritic cells (iDCs) are for cell transplantation; however, no method has yet been developed for in vivo monitoring the transplanted iDCs. We have explored the feasibility of using superparamagnetic iron oxide (SPIO) labeling and magnetic resonance imaging for in vivo tracking of transplanted iDCs and determined the effects of SPIO labeling on iDC vaccination. With up to 50 μg Fe/ml, SPIO effectively labeled the iDCs without affecting their growth. At or above 100 μg Fe/ml, SPIO caused considerable damage to iDCs. SPIO labeling resulted in autophagosome formation and decreased the uptake of oxidized low density lipoprotein (ox-LDL), an exogenous antigen, by iDCs. SPIO and ox-LDL both localized to the lysosomes, and this competition for lysosomes could be partially responsible for the decreased ox-LDL phagocytic capacity of iDCs due to SPIO labeling. PMID:25257596

  7. Dendritic Cell Activity Driven by Recombinant Mycobacterium bovis BCG Producing Human IL-18, in Healthy BCG Vaccinated Adults

    PubMed Central

    Szpakowski, Piotr; Biet, Franck; Locht, Camille; Paszkiewicz, Małgorzata; Rudnicka, Wiesława; Druszczyńska, Magdalena; Allain, Fabrice; Fol, Marek; Pestel, Joël; Kowalewicz-Kulbat, Magdalena

    2015-01-01

    Tuberculosis remains an enormous global burden, despite wide vaccination coverage with the Bacillus Calmette-Guérin (BCG), the only vaccine available against this disease, indicating that BCG-driven immunity is insufficient to protect the human population against tuberculosis. In this study we constructed recombinant BCG producing human IL-18 (rBCGhIL-18) and investigated whether human IL-18 produced by rBCGhIL-18 modulates DC functions and enhances Th1 responses to mycobacterial antigens in humans. We found that the costimulatory CD86 and CD80 molecules were significantly upregulated on rBCGhIL-18-infected DCs, whereas the stimulation of DCs with nonrecombinant BCG was less effective. In contrast, both BCG strains decreased the DC-SIGN expression on human DCs. The rBCGhIL-18 increased IL-23, IL-10, and IP-10 production by DCs to a greater extent than nonrecombinant BCG. In a coculture system of CD4+ T cells and loaded DCs, rBCGhIL-18 favoured strong IFN-γ but also IL-10 production by naive T cells but not by memory T cells. This was much less the case for nonrecombinant BCG. Thus the expression of IL-18 by recombinant BCG increases IL-23, IP-10, and IL-10 expression by human DCs and enhances their ability to induce IFN-γ and IL-10 expression by naive T cells, without affecting the maturation phenotype of the DCs. PMID:26339658

  8. Vaccines

    MedlinePlus Videos and Cool Tools

    ... help the body defend itself against foreign invaders. As the antigens invade the body's tissues, they attract ... the suppressor T cells stop the attack. After a vaccination, the body will have a memory of ...

  9. Therapeutic cancer vaccines and combination immunotherapies involving vaccination

    PubMed Central

    Nguyen, Trang; Urban, Julie; Kalinski, Pawel

    2014-01-01

    Recent US Food and Drug Administration approvals of Provenge® (sipuleucel-T) as the first cell-based cancer therapeutic factor and ipilimumab (Yervoy®/anticytotoxic T-lymphocyte antigen-4) as the first “checkpoint blocker” highlight recent advances in cancer immunotherapy. Positive results of the clinical trials evaluating additional checkpoint blocking agents (blockade of programmed death [PD]-1, and its ligands, PD-1 ligand 1 and 2) and of several types of cancer vaccines suggest that cancer immunotherapy may soon enter the center stage of comprehensive cancer care, supplementing surgery, radiation, and chemotherapy. This review discusses the current status of the clinical evaluation of different classes of therapeutic cancer vaccines and possible avenues for future development, focusing on enhancing the magnitude and quality of cancer-specific immunity by either the functional reprogramming of patients’ endogenous dendritic cells or the use of ex vivo-manipulated dendritic cells as autologous cellular transplants. This review further discusses the available strategies aimed at promoting the entry of vaccination-induced T-cells into tumor tissues and prolonging their local antitumor activity. Finally, the recent improvements to the above three modalities for cancer immunotherapy (inducing tumor-specific T-cells, prolonging their persistence and functionality, and enhancing tumor homing of effector T-cells) and rationale for their combined application in order to achieve clinically effective anticancer responses are addressed. PMID:27471705

  10. Colocalization of a CD1d-Binding Glycolipid with a Radiation-Attenuated Sporozoite Vaccine in Lymph Node-Resident Dendritic Cells for a Robust Adjuvant Effect.

    PubMed

    Li, Xiangming; Kawamura, Akira; Andrews, Chasity D; Miller, Jessica L; Wu, Douglass; Tsao, Tiffany; Zhang, Min; Oren, Deena; Padte, Neal N; Porcelli, Steven A; Wong, Chi-Huey; Kappe, Stefan H I; Ho, David D; Tsuji, Moriya

    2015-09-15

    A CD1d-binding glycolipid, α-Galactosylceramide (αGalCer), activates invariant NK T cells and acts as an adjuvant. We previously identified a fluorinated phenyl ring-modified αGalCer analog, 7DW8-5, displaying nearly 100-fold stronger CD1d binding affinity. In the current study, 7DW8-5 was found to exert a more potent adjuvant effect than αGalCer for a vaccine based on radiation-attenuated sporozoites of a rodent malaria parasite, Plasmodium yoelii, also referred to as irradiated P. yoelii sporozoites (IrPySpz). 7DW8-5 had a superb adjuvant effect only when the glycolipid and IrPySpz were conjointly administered i.m. Therefore, we evaluated the effect of distinctly different biodistribution patterns of αGalCer and 7DW8-5 on their respective adjuvant activities. Although both glycolipids induce a similar cytokine response in sera of mice injected i.v., after i.m. injection, αGalCer induces a systemic cytokine response, whereas 7DW8-5 is locally trapped by CD1d expressed by dendritic cells (DCs) in draining lymph nodes (dLNs). Moreover, the i.m. coadministration of 7DW8-5 with IrPySpz results in the recruitment of DCs to dLNs and the activation and maturation of DCs. These events cause the potent adjuvant effect of 7DW8-5, resulting in the enhancement of the CD8(+) T cell response induced by IrPySpz and, ultimately, improved protection against malaria. Our study is the first to show that the colocalization of a CD1d-binding invariant NK T cell-stimulatory glycolipid and a vaccine, like radiation-attenuated sporozoites, in dLN-resident DCs upon i.m. conjoint administration governs the potency of the adjuvant effect of the glycolipid. PMID:26254338

  11. Dendritic cell vaccine and cytokine-induced killer cell therapy for the treatment of advanced non-small cell lung cancer

    PubMed Central

    ZHANG, LIHONG; YANG, XUEJING; SUN, ZHEN; LI, JIALI; ZHU, HUI; LI, JING; PANG, YAN

    2016-01-01

    The present study aimed to evaluate the survival time, immune response and safety of a dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell therapy (DC-CIK) in advanced non-small cell lung cancer (NSCLC). The present retrospective study enrolled 507 patients with advanced NSCLC; 99 patients received DC-CIK [immunotherapy group (group I)] and 408 matched patients did not receive DC-CIK, and acted as the control [non-immunotherapy group (group NI)]. Delayed-type hypersensitivity (DTH), quality of life (QOL) and safety were analyzed in group I. The follow-up period for the two groups was 489.2±160.4 days. The overall survival (OS) time was calculated using the Kaplan-Meier method. DTH was observed in 59 out of 97 evaluated patients (60.8%) and 67 out of 98 evaluated patients (68.4%) possessed an improved QOL. Fever and a skin rash occurred in 36 out of 98 patients (36.7%) and 7 out of 98 patients (7.1%) in group I. DTH occurred more frequently in patients with squamous cell carcinoma compared with patients with adenocarcinoma (77.1 vs. 40.4%; P=0.0013). Radiotherapy was not associated with DC-CIK-induced DTH (72.7 vs. 79.6%; P=0.18), but chemotherapy significantly reduced the rate of DTH (18.2 vs. 79.6%; P=0.00). The OS time was significantly increased in group I compared with group NI (P=0.03). In conclusion, DC-CIK may induce an immune response against NSCLC, improve the QOL, and prolong the OS time of patients, without adverse effects. Therefore, the present study recommends DC-CIK for the treatment of patients with advanced NSCLC. PMID:27073525

  12. Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised “proof-of-principle” phase II study

    PubMed Central

    2014-01-01

    Background Vaccination with dendritic cells (DC) loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side-effects. Patients with advanced melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed. Methods/Design This is a phase II, “proof-of-principle”, randomized, open-label trial of vaccination with autologous DC loaded with tumor lysate or homogenate in metastatic melanoma patients combined with immunomodulating RT and/or preleukapheresis IFN-α. All patients will receive four bi-weekly doses of the vaccine during the induction phase and monthly doses thereafter for up to a maximum of 14 vaccinations or until confirmed progression. Patients will be randomized to receive: (1.) three daily doses of 8 Gy up to 12 Gy radiotherapy delivered to one non-index metastatic field between vaccine doses 1 and 2 and, optionally, between doses 7 and 8, using IMRT-IMAT techniques; (2.) daily 3 MU subcutaneous IFN-α for 7 days before leukapheresis; (3.) both 1 and 2; (4.) neither 1 nor 2. At least six patients eligible for treatment will be enrolled per arm. Daily 3 MU IL-2 will be administered subcutaneously for 5 days starting from the second day after each vaccine dose. Serial DTH testing and blood sampling to evaluate treatment-induced immune response will be performed. Objective response will be evaluated according to immune-related response criteria (irRC). Discussion Based upon the emerging role of

  13. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy

    PubMed Central

    Duncan, Brynn B.; Highfill, Steven L.; Qin, Haiying; Bouchkouj, Najat; Larabee, Shannon; Zhao, Peng; Woznica, Iwona; Liu, Yuxin; Li, Youhua; Wu, Wengen; Lai, Jack H.; Jones, Barry; Mackall, Crystal L.; Bachovchin, William W.; Fry, Terry J.

    2013-01-01

    Current multimodality therapy consisting of surgery, chemotherapy and radiation will fail in approximately 40% of patients with pediatric sarcomas and results in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (Dipeptidyl peptidase IV activity and/or structural homologues) enzymes can mediate tumor regression via immune-mediated mechanisms. Here we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma (RMS) cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b+) cells, particularly myeloid dendritic cells (DCs), to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11b+Ly6-ChiLy6-Glo) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1-/-) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared to either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies particularly as an adjuvant to tumor vaccines and ACT. PMID:23994886

  14. Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO.

    PubMed

    Basu, Gargi D; Tinder, Teresa L; Bradley, Judy M; Tu, Tony; Hattrup, Christine L; Pockaj, Barbara A; Mukherjee, Pinku

    2006-08-15

    We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines. PMID:16888001

  15. Priming with two DNA vaccines expressing hepatitis C virus NS3 protein targeting dendritic cells elicits superior heterologous protective potential in mice.

    PubMed

    Guan, Jie; Deng, Yao; Chen, Hong; Yin, Xiao; Yang, Yang; Tan, Wenjie

    2015-10-01

    Development an effective vaccine may offer an alternative preventive and therapeutic strategy against HCV infection. DNA vaccination has been shown to induce robust humoral and cellular immunity and overcome many problems associated with conventional vaccines. In this study, mice were primed with either conventional pVRC-based or suicidal pSC-based DNA vaccines carrying DEC-205-targeted NS3 antigen (DEC-NS3) and boosted with type 5 adenoviral vectors encoding the partial NS3 and core antigens (C44P). The prime boost regimen induced a marked increase in antigen-specific humoral and T-cell responses in comparison with either rAd5-based vaccines or DEC-205-targeted DNA immunization in isolation. The protective effect against heterogeneous challenge was correlated with high levels of anti-NS3 IgG and T-cell-mediated immunity against NS3 peptides. Moreover, priming with a suicidal DNA vaccine (pSC-DEC-NS3), which elicited increased TNF-α-producing CD4+ and CD8+ T-cells against NS3-2 peptides (aa 1245-1461), after boosting, showed increased heterogeneous protective potential compared with priming with a conventional DNA vaccine (pVRC-DEC-NS3). In conclusion, a suicidal DNA vector (pSC-DEC-NS3) expressing DEC-205-targeted NS3 combined with boosting using an rAd5-based HCV vaccine (rAd5-C44P) is a good candidate for a safe and effective vaccine against HCV infection. PMID:26215441

  16. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy.

    PubMed

    Duncan, Brynn B; Highfill, Steven L; Qin, Haiying; Bouchkouj, Najat; Larabee, Shannon; Zhao, Peng; Woznica, Iwona; Liu, Yuxin; Li, Youhua; Wu, Wengen; Lai, Jack H; Jones, Barry; Mackall, Crystal L; Bachovchin, William W; Fry, Terry J

    2013-10-01

    Multimodality therapy consisting of surgery, chemotherapy, and radiation will fail in approximately 40% of patients with pediatric sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (dipeptidyl peptidase IV activity and/or structural homologs) enzymes can mediate tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies, particularly as an adjuvant to tumor vaccines and ACT. PMID:23994886

  17. Dendrite inhibitor

    DOEpatents

    Miller, William E.

    1989-01-01

    An apparatus for removing dendrites or other crystalline matter from the surface of a liquid in a matter transport process, and an electrolytic cell including such an apparatus. A notch may be provided to allow continuous exposure of the liquid surface, and a bore may be further provided to permit access to the liquid.

  18. Dendrite inhibitor

    DOEpatents

    Miller, W.E.

    1988-06-07

    An apparatus for removing dendrites or other crystalline matter from the surface of a liquid in a matter transport process, and an electrolytic cell including such an apparatus. A notch may be provided to allow continuous exposure of the liquid surface, and a bore may be further provided to permit access to the liquid. 2 figs.

  19. Dendrite Model

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Donald Gilles, the Discipline Scientist for Materials Science in NASA's Microgravity Materials Science and Applications Department, demonstrates to Carl Dohrman a model of dendrites, the branch-like structures found in many metals and alloys. Dohrman was recently selected by the American Society for Metals International as their 1999 ASM International Foundation National Merit Scholar. The University of Illinois at Urbana-Champaign freshman recently toured NASA's materials science facilities at the Marshall Space Flight Center.

  20. β-glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses.

    PubMed

    Ning, Yongling; Xu, Dongqin; Zhang, Xiaohang; Bai, Yu; Ding, Jun; Feng, Tongbao; Wang, Shizhong; Xu, Ning; Qian, Keqing; Wang, Yong; Qi, Chunjian

    2016-06-01

    Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell-based cancer vaccines can initiate antitumor immune responses, tumor-educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of β-glucan on TEDCs and found that β-glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with β-glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T-lymphocyte responses and led to a delay in tumor progression. These findings reveal that β-glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for β-glucan in immunotherapy and suggesting its potential clinical benefit. β-Glucan directly abrogated tumor-educated dendritic cells-associated immune suppression, promoted Th1 differentiation and cytotoxic T-lymphocyte priming and improved antitumor responses. PMID:26773960

  1. Dendritic Cell (DC) Vaccine in Mouse Lung Cancer Minimal Residual Model; Comparison of Monocyte-derived DC vs. Hematopoietic Stem Cell Derived-DC.

    PubMed

    Baek, Soyoung; Lee, Seog Jae; Kim, Myoung Joo; Lee, Hyunah

    2012-12-01

    The anti-tumor effect of monocyte-derived DC (MoDC) vaccine was studied in lung cancer model with feasible but weak Ag-specific immune response and incomplete blocking of tumor growth. To overcome this limitation, the hematopoietic stem cell-derived DC (SDC) was cultured and the anti-tumor effect of MoDC & SDC was compared in mouse lung cancer minimal residual model (MRD). Therapeutic DCs were cultured from either CD34(+) hematopoietic stem cells with GM-CSF, SCF and IL-4 for 14 days (SDC) or monocytes with GM-CSF and IL-4 for 7 days (MoDC). DCs were injected twice by one week interval into the peritoneum of mice that are inoculated with Lewis Lung Carcinoma cells (LLC) one day before the DC injection. Anti-tumor responses and the immune modulation were observed 3 weeks after the final DC injection. CD11c expression, IL-12 and TGF-β secretion were higher in SDC but CCR7 expression, IFN-γ and IL-10 secretion were higher in MoDC. The proportion of CD11c(+)CD8a(+) cells was similar in both DC cultures. Although both DC reduced the tumor burden, histological anti-tumor effect and the frequencies of IFN-γ secreting CD8(+) T cells were higher in SDC treated group than in MoDC. Conclusively, although both MoDC and SDC can induce the anti-tumor immunity, SDC may be better module as anti-tumor vaccine than MoDC in mouse lung cancer. PMID:23396889

  2. Mucin 1 and poly I:C activates dendritic cells and effectively eradicates pituitary tumors as a prophylactic vaccine.

    PubMed

    Sui, Dehua; Ma, Lixin; Li, Meng; Shao, Wei; Du, Hongpeng; Li, Ke; Li, Zhenzhu; Li, Zefu

    2016-04-01

    Pituitary tumors are the most common type of cancer within the central nervous system. In the present study, the expression levels of mucin 1 (Muc1) were examined in invasive and non‑invasive pituitary tumor samples, and the results of immunohistochemical staining and Western blot analysis demonstrated marked positive expression of Muc1. In addition, Muc1 + polyinosinic:polycytidylic acid (poly I:C) was found to stimulate the expression levels of the surface molecules cluster of differentiation (CD)40, CD83 and CD80, and HLA‑DRm and decreased the expression of CD14 in the dendritic cells, determined using fluorescence‑activated cell sorting. The secretions of interleukin (IL)‑6, tumor necrosis factor‑α and IL‑1β cytokines were also significantly induced, in a dose‑dependent manner. In in vivo experiments, a higher percentage of CD3+CD4+ T lymphocytes was detected, and the levels of interferon‑γ and IL‑2 in the splenocytes were also upregulated. Furthermore, the combination treatment of Muc1 with poly I:C increased anti‑Muc1 IgM and anti‑Muc1 IgG titers, and altered the balance of IgG2a and IgG1, all of which increased the T helper (Th)1 polarized immune response. Thus, the tumor antigen, Muc1, with poly I:C may produce potent protective effects, which polarize immune responses towards Th1, and elicit antitumor immunity to inhibit the progression of pituitary tumors. PMID:26935338

  3. [Regulatory requirements regarding cell-based medicinal products for human and veterinary use - a comparison].

    PubMed

    Kuhlmann-Gottke, Johanna; Duchow, Karin

    2015-11-01

    At present, there is no separate regulatory framework for cell-based medicinal products (CBMP) for veterinary use at the European or German level. Current European and national regulations exclusively apply to the corresponding medicinal products for human use. An increasing number of requests for the regulatory classification of CBMP for veterinary use, such as allogeneic stem cell preparations and dendritic cell-based autologous tumour vaccines, and a rise in scientific advice for companies developing these products, illustrate the need for adequate legislation. Currently, advice is given and decisions are made on a case-by-case basis regarding the regulatory classification and authorisation requirements.Since some of the CBMP - in particular in the area of stem-cell products - are developed in parallel for human and veterinary use, there is an urgent need to create specific legal definitions, regulations, and guidelines for these complex innovative products in the veterinary sector as well. Otherwise, there is a risk that that the current legal grey area regarding veterinary medicinal products will impede therapeutic innovations in the long run. A harmonised EU-wide approach is desirable. Currently the European legislation on veterinary medicinal products is under revision. In this context, veterinary therapeutics based on allogeneic cells and tissues will be defined and regulated. Certainly, the legal framework does not have to be as comprehensive as for human CBMP; a leaner solution is conceivable, similar to the special provisions for advanced-therapy medicinal products laid down in the German Medicines Act. PMID:26369765

  4. Cell-based Immunotherapy for Colorectal Cancer with Cytokine-induced Killer Cells

    PubMed Central

    Kim, Ji Sung; Kim, Yong Guk; Park, Eun Jae; Kim, Boyeong; Lee, Hong Kyung; Hong, Jin Tae; Kim, Youngsoo

    2016-01-01

    Colorectal cancer is the third leading cancer worldwide. Although incidence and mortality of colorectal cancer are gradually decreasing in the US, patients with metastatic colorectal cancer have poor prognosis with an estimated 5-year survival rate of less than 10%. Over the past decade, advances in combination chemotherapy regimens for colorectal cancer have led to significant improvement in progression-free and overall survival. However, patients with metastatic disease gain little clinical benefit from conventional therapy, which is associated with grade 3~4 toxicity with negative effects on quality of life. In previous clinical studies, cell-based immunotherapy using dendritic cell vaccines and sentinel lymph node T cell therapy showed promising therapeutic results for metastatic colorectal cancer. In our preclinical and previous clinical studies, cytokine-induced killer (CIK) cells treatment for colorectal cancer showed favorable responses without toxicities. Here, we review current treatment options for colorectal cancer and summarize available clinical studies utilizing cell-based immunotherapy. Based on these studies, we recommend the use CIK cell therapy as a promising therapeutic strategy for patients with metastatic colorectal cancer. PMID:27162526

  5. Re-irradiation or re-operation followed by dendritic cell vaccination? Comparison of two different salvage strategies for relapsed high-grade gliomas by means of a new prognostic model.

    PubMed

    Müller, Klaus; Henke, Guido; Pietschmann, Sophie; van Gool, Stefaan; De Vleeschouwer, Steven; von Bueren, André O; Compter, Inge; Friedrich, Carsten; Matuschek, Christiane; Klautke, Gunther; Kortmann, Rolf-Dieter; Hundsberger, Thomas; Baumert, Brigitta G

    2015-09-01

    We aimed to compare two different salvage treatment strategies for relapsed high-grade glioma (HGG) patients by means of a new prognostic model. A simplified version of the so-called HGG-Immuno RPA model estimates the prognosis of relapsed HGG patients and distinguishes three different prognostic classes (I = good, II = intermediate, III = poor). The model has been constructed with a cohort of 117 patients whose salvage treatment consisted of re-operation followed by dendritic cell vaccination (ReOP + DCV). However, using only the predictors histology, age and performance status, the simplified HGG-Immuno RPA model is basically independent from treatment. In the present study we applied the simplified model to the cohort used to construct the original HGG-Immuno RPA model and another cohort of 165 patients who underwent re-irradiation (ReRT) at relapse. Then, we compared the outcomes achieved by the two different salvage treatments in each prognostic class. The model predicted good, intermediate and poor prognosis for 11, 31 and 75 patients of the ReOP + DCV cohort and for 20, 39 and 106 patients of the ReRT cohort, respectively. Neither of the two strategies was superior to the other. In the groups with good, intermediate and poor prognosis 12-months survival rates were 73, 59 and 25 % after ReOP + DCV and 72, 36 and 23 % after ReRT, respectively. Being easy to handle and independent from treatment, the aforementioned model is useful for therapeutic decisions. ReRT and ReOP + DVC seem to be equally effective. The choice of salvage treatment should be based on the expected side effects. PMID:26070556

  6. Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regression in a vaccine therapy.

    PubMed

    Azuma, Masahiro; Takeda, Yohei; Nakajima, Hiroko; Sugiyama, Haruo; Ebihara, Takashi; Oshiumi, Hiroyuki; Matsumoto, Misako; Seya, Tsukasa

    2016-08-01

    Successful cancer immunotherapy necessitates T cell proliferation and infiltration into tumor without exhaustion, a process closely links optimal maturation of dendritic cells (DC), and adjuvant promotes this process as an essential prerequisite. Poly(I:C) has contributed to adjuvant immunotherapy that evokes an antitumor response through the Toll-loke receptor 3 (TLR3)/TICAM-1 pathway in DC. However, the mechanism whereby Poly(I:C) acts on DC for T cell proliferation and migration remains undetermined. Subcutaneous injection of Poly(I:C) regressed implant tumors (WT1-C1498 or OVA-EG7) in C57BL/6 mice, which coincided with tumor-infiltration of CD8(+) T cells. Epitope-specific cytotoxic T lymphocytes (CTLs) were increased in spleen by challenge with Poly(I:C)+Db126 WT-1 peptide but not Poly(I:C) alone, suggesting the need of an exogenous Ag density for cross-priming. In tumor, CXCR3 ligands were upregulated by Poly(I:C), which facilitated recruitment of CTL to the tumor. Thus, Poly(I:C) acts on splenic CD8α(+) DC to cross-prime T cells and on intratumor cells to attract CTLs. Besides CD8(+) T cell cross-priming, T cell recruitment into tumor was significantly dampened in Batf3 (-/-) mice, reflecting the importance of tumor Batf3-dependent DC rather than macrophages in T cell recruitment. Poly(I:C)-induced XCR1(hi) CD8α(+) DC with high TLR3 levels were markedly decreased in Batf3 (-/-) mice, which hampered the production of IL-12 and IL-12-mediated CD4(+)/CD8(+) T cell proliferation. Subcutaneous administration of Poly(I:C) and adoptive transfer of wild-type CD8α(+) DC largely recovered antitumor response in those Batf3 (-/-) mice. Collectively, Poly(I:C) tunes up proper maturation of CD8α(+) DC to establish TLR3-mediated IL-12 function and cross-presentation in spleen and lymphocyte-attractive antitumor microenvironment in tumor. PMID:27622060

  7. Isothermal Dendritic Growth Experiment - PVA Dendrites

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Isothermal Dendritic Growth Experiment (IDGE), flown on three Space Shuttle missions, is yielding new insights into virtually all industrially relevant metal and alloy forming operations. IDGE used transparent organic liquids that form dendrites (treelike structures) similar to those inside metal alloys. Comparing Earth-based and space-based dendrite growth velocity, tip size and shape provides a better understanding of the fundamentals of dentritic growth, including gravity's effects. Shalowgraphic images of pivalic acid (PVA) dendrites forming from the melt show the subtle but distinct effects of gravity-driven heat convection on dentritic growth. In orbit, the dendrite grows as its latent heat is liberated by heat conduction. This yields a blunt dendrite tip. On Earth, heat is carried away by both conduction and gravity-driven convection. This yields a sharper dendrite tip. In addition, under terrestrial conditions, the sidebranches growing in the direction of gravity are augmented as gravity helps carry heat out of the way of the growing sidebranches as opposed to microgravity conditions where no augmentation takes place. IDGE was developed by Rensselaer Polytechnic Institute and NASA/Glenn Research Center. Advanced follow-on experiments are being developed for flight on the International Space Station. Photo Credit: NASA/Glenn Research Center

  8. The protein moiety of Brucella abortus outer membrane protein 16 is a new bacterial pathogen-associated molecular pattern that activates dendritic cells in vivo, induces a Th1 immune response, and is a promising self-adjuvanting vaccine against systemic and oral acquired brucellosis.

    PubMed

    Pasquevich, Karina A; García Samartino, Clara; Coria, Lorena M; Estein, Silvia M; Zwerdling, Astrid; Ibañez, Andrés E; Barrionuevo, Paula; Oliveira, Fernanda Souza de; Carvalho, Natalia Barbosa; Borkowski, Julia; Oliveira, Sergio Costa; Warzecha, Heribert; Giambartolomei, Guillermo H; Cassataro, Juliana

    2010-05-01

    Knowing the inherent stimulatory properties of the lipid moiety of bacterial lipoproteins, we first hypothesized that Brucella abortus outer membrane protein (Omp)16 lipoprotein would be able to elicit a protective immune response without the need of external adjuvants. In this study, we demonstrate that Omp16 administered by the i.p. route confers significant protection against B. abortus infection and that the protective response evoked is independent of the protein lipidation. To date, Omp16 is the first Brucella protein that without the requirement of external adjuvants is able to induce similar protection levels to the control live vaccine S19. Moreover, the protein portion of Omp16 (unlipidated Omp16 [U-Omp16]) elicits a protective response when administered by the oral route. Either systemic or oral immunization with U-Omp16 elicits a Th1-specific response. These abilities of U-Omp16 indicate that it is endowed with self-adjuvanting properties. The adjuvanticity of U-Omp16 could be explained, at least in part, by its capacity to activate dendritic cells in vivo. U-Omp16 is also able to stimulate dendritic cells and macrophages in vitro. The latter property and its ability to induce a protective Th1 immune response against B. abortus infection have been found to be TLR4 dependent. The facts that U-Omp16 is an oral protective Ag and possesses a mucosal self-adjuvanting property led us to develop a plant-made vaccine expressing U-Omp16. Our results indicate that plant-expressed recombinant U-Omp16 is able to confer protective immunity, when given orally, indicating that a plant-based oral vaccine expressing U-Omp16 could be a valuable approach to controlling this disease. PMID:20351187

  9. Free dendritic growth

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.

    1984-01-01

    Free dendritic growth refers to the unconstrained development of crystals within a supercooled melt, which is the classical 'dendrite problem'. Great strides have been taken in recent years in both the theoretical understanding of dendritic growth and its experimental status. The development of this field will be sketched, showing that transport theory and interfacial thermodynamics (capillarity theory) were sufficient ingredients to develop a truly predictive model of dendrite formation. The convenient, but incorrect, notion of 'maximum velocity' was used for many years to estimate the behavior of dendritic transformations until supplanted by modern dynamic stability theory. The proper combinations of transport theory and morphological stability seem to able to predict the salient aspects of dendritic growth, especially in the neighborhood of the tip. The overall development of cast microstructures, such as equiaxed zone formation, rapidly solidified microstructures, etc., also seems to contain additional non-deterministic features which lie outside the current theories discussed here.

  10. Direct Transfection of Dendritic Cells in the Epidermis After Plasmid Delivery Enhanced by Surface Electroporation

    PubMed Central

    Amante, Dinah H.; Smith, Trevor R.F.; Kiosses, Bill B.; Sardesai, Niranjan Y.; Humeau, Laurent M.P.F.

    2014-01-01

    Abstract The skin is rich in antigen-presenting cells and as such is an excellent target tissue for vaccination strategies. Electroporation is a physical delivery method that potentiates the uptake of DNA vaccines into target cells. Intradermal electroporation offers a minimally invasive solution to DNA delivery in the clinic. Here we describe the direct transfection of dendritic cells in the epidermis, using a surface dermal electroporation device, and specifically show a dendritic cell transfected with plasmid expressing green fluorescent protein. The dendritic cell has used its motile capabilities after transfection to move from the epidermis into the dermis, making its way to the lymphatic system. PMID:25470335

  11. Direct transfection of dendritic cells in the epidermis after plasmid delivery enhanced by surface electroporation.

    PubMed

    Amante, Dinah H; Smith, Trevor R F; Kiosses, Bill B; Sardesai, Niranjan Y; Humeau, Laurent M P F; Broderick, Kate E

    2014-12-01

    The skin is rich in antigen-presenting cells and as such is an excellent target tissue for vaccination strategies. Electroporation is a physical delivery method that potentiates the uptake of DNA vaccines into target cells. Intradermal electroporation offers a minimally invasive solution to DNA delivery in the clinic. Here we describe the direct transfection of dendritic cells in the epidermis, using a surface dermal electroporation device, and specifically show a dendritic cell transfected with plasmid expressing green fluorescent protein. The dendritic cell has used its motile capabilities after transfection to move from the epidermis into the dermis, making its way to the lymphatic system. PMID:25470335

  12. Vaccine therapy for pancreatic cancer

    PubMed Central

    Salman, Bulent; Zhou, Donger; Jaffee, Elizabeth M; Edil, Barish H; Zheng, Lei

    2013-01-01

    Pancreatic cancer is a lethal disease and currently available therapies have significant limitations. Pancreatic cancer is thus an ideal setting for the development of novel treatment modalities such as immunotherapy. However, relevant obstacles must be overcome for immunotherapeutic regimens against pancreatic cancer to be successful. Vaccine therapy relies on the administration of biological preparations that include an antigen that (at least ideally) is specifically expressed by malignant cells, boosting the natural ability of the immune system to react against neoplastic cells. There are a number of ways to deliver anticancer vaccines. Potent vaccines stimulate antigen presentation by dendritic cells, hence driving the expansion of antigen-specific effector and memory T cells. Unlike vaccines given as a prophylaxis against infectious diseases, anticancer vaccines require the concurrent administration of agents that interfere with the natural predisposition of tumors to drive immunosuppression. The safety and efficacy of vaccines against pancreatic cancer are nowadays being tested in early phase clinical trials. PMID:24498551

  13. Vaccine Therapy, Oncolytic Viruses, and Gliomas.

    PubMed

    Desjardins, Annick; Vlahovic, Gordana; Friedman, Henry S

    2016-03-01

    After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary. PMID:26984213

  14. Partial Protection against Porcine Influenza A Virus by a Hemagglutinin-Expressing Virus Replicon Particle Vaccine in the Absence of Neutralizing Antibodies.

    PubMed

    Ricklin, Meret E; Vielle, Nathalie J; Python, Sylvie; Brechbühl, Daniel; Zumkehr, Beatrice; Posthaus, Horst; Zimmer, Gert; Summerfield, Artur

    2016-01-01

    This work was initiated by previous reports demonstrating that mismatched influenza A virus (IAV) vaccines can induce enhanced disease, probably mediated by antibodies. Our aim was, therefore, to investigate if a vaccine inducing opsonizing but not neutralizing antibodies against the hemagglutinin (HA) of a selected heterologous challenge virus would enhance disease or induce protective immune responses in the pig model. To this end, we immunized pigs with either whole inactivated virus (WIV)-vaccine or HA-expressing virus replicon particles (VRP) vaccine based on recombinant vesicular stomatitis virus (VSV). Both types of vaccines induced virus neutralizing and opsonizing antibodies against homologous virus as shown by a highly sensitive plasmacytoid dendritic cell-based opsonization assay. Opsonizing antibodies showed a broader reactivity against heterologous IAV compared with neutralizing antibodies. Pigs immunized with HA-recombinant VRP vaccine were partially protected from infection with a mismatched IAV, which was not neutralized but opsonized by the immune sera. The VRP vaccine reduced lung lesions, lung inflammatory cytokine responses, serum IFN-α responses, and viral loads in the airways. Only the VRP vaccine was able to prime IAV-specific IFNγ/TNFα dual secreting CD4(+) T cells detectable in the peripheral blood. In summary, this work demonstrates that with the virus pair selected, a WIV vaccine inducing opsonizing antibodies against HA which lack neutralizing activity, is neither protective nor does it induce enhanced disease in pigs. In contrast, VRP-expressing HA is efficacious vaccines in swine as they induced both potent antibodies and T-cell immunity resulting in a broader protective value. PMID:27446083

  15. Partial Protection against Porcine Influenza A Virus by a Hemagglutinin-Expressing Virus Replicon Particle Vaccine in the Absence of Neutralizing Antibodies

    PubMed Central

    Ricklin, Meret E.; Vielle, Nathalie J.; Python, Sylvie; Brechbühl, Daniel; Zumkehr, Beatrice; Posthaus, Horst; Zimmer, Gert; Summerfield, Artur

    2016-01-01

    This work was initiated by previous reports demonstrating that mismatched influenza A virus (IAV) vaccines can induce enhanced disease, probably mediated by antibodies. Our aim was, therefore, to investigate if a vaccine inducing opsonizing but not neutralizing antibodies against the hemagglutinin (HA) of a selected heterologous challenge virus would enhance disease or induce protective immune responses in the pig model. To this end, we immunized pigs with either whole inactivated virus (WIV)-vaccine or HA-expressing virus replicon particles (VRP) vaccine based on recombinant vesicular stomatitis virus (VSV). Both types of vaccines induced virus neutralizing and opsonizing antibodies against homologous virus as shown by a highly sensitive plasmacytoid dendritic cell-based opsonization assay. Opsonizing antibodies showed a broader reactivity against heterologous IAV compared with neutralizing antibodies. Pigs immunized with HA-recombinant VRP vaccine were partially protected from infection with a mismatched IAV, which was not neutralized but opsonized by the immune sera. The VRP vaccine reduced lung lesions, lung inflammatory cytokine responses, serum IFN-α responses, and viral loads in the airways. Only the VRP vaccine was able to prime IAV-specific IFNγ/TNFα dual secreting CD4+ T cells detectable in the peripheral blood. In summary, this work demonstrates that with the virus pair selected, a WIV vaccine inducing opsonizing antibodies against HA which lack neutralizing activity, is neither protective nor does it induce enhanced disease in pigs. In contrast, VRP-expressing HA is efficacious vaccines in swine as they induced both potent antibodies and T-cell immunity resulting in a broader protective value. PMID:27446083

  16. Polyvalent AIDS Vaccines

    PubMed Central

    Lu, Shan; Grimes Serrano, Jill M.; Wang, Shixia

    2013-01-01

    A major hurdle in the development of a global HIV-1 vaccine is viral diversity. For close to three decades, HIV vaccine development has focused on either the induction of T cell immune responses or antibody responses, and only rarely on both components. After the failure of the STEP trial, the scientific community concluded that a T cell-based vaccine would likely not be protective if the T cell immune responses were elicited against only a few dominant epitopes. Similarly, for vaccines focusing on antibody responses, one of the main criticisms after VaxGen’s failed Phase III trials was on the limited antigen breadth included in the two formulations used. The successes of polyvalent vaccine approaches against other antigenically variable pathogens encourage implementation of the same approach for the design of HIV-1 vaccines. A review of the existing HIV-1 vaccination approaches based on the polyvalent principle is included here to provide a historical perspective for the current effort of developing a polyvalent HIV-1 vaccine. Results summarized in this review provide a clear indication that the polyvalent approach is a viable one for the future development of an effective HIV vaccine. PMID:21054250

  17. Nanoparticle Drug Delivery Systems Designed to Improve Cancer Vaccines and Immunotherapy

    PubMed Central

    Fan, Yuchen; Moon, James J.

    2015-01-01

    Recent studies have demonstrated great therapeutic potential of educating and unleashing our own immune system for cancer treatment. However, there are still major challenges in cancer immunotherapy, including poor immunogenicity of cancer vaccines, off-target side effects of immunotherapeutics, as well as suboptimal outcomes of adoptive T cell transfer-based therapies. Nanomaterials with defined physico-biochemical properties are versatile drug delivery platforms that may address these key technical challenges facing cancer vaccines and immunotherapy. Nanoparticle systems have been shown to improve targeted delivery of tumor antigens and therapeutics against immune checkpoint molecules, amplify immune activation via the use of new stimuli-responsive or immunostimulatory materials, and augment the efficacy of adoptive cell therapies. Here, we review the current state-of-the-art in nanoparticle-based strategies designed to potentiate cancer immunotherapies, including cancer vaccines with subunit antigens (e.g., oncoproteins, mutated neo-antigens, DNA and mRNA antigens) and whole-cell tumor antigens, dendritic cell-based vaccines, artificial antigen-presenting cells, and immunotherapeutics based on immunogenic cell death, immune checkpoint blockade, and adoptive T-cell therapy. PMID:26350600

  18. Laser vaccine adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C

    2014-01-01

    Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines. The development of new adjuvants with the potential to be both efficacious and safe constitutes a significant need in modern vaccine practice. The use of non-damaging laser light represents a markedly different approach to enhancing immune responses to a vaccine antigen, particularly with intradermal vaccination. This approach, which was initially explored in Russia and further developed in the US, appears to significantly improve responses to both prophylactic and therapeutic vaccines administered to the laser-exposed tissue, particularly the skin. Although different types of lasers have been used for this purpose and the precise molecular mechanism(s) of action remain unknown, several approaches appear to modulate dendritic cell trafficking and/or activation at the irradiation site via the release of specific signaling molecules from epithelial cells. The most recent study, performed by the authors of this review, utilized a continuous wave near-infrared laser that may open the path for the development of a safe, effective, low-cost, simple-to-use laser vaccine adjuvant that could be used in lieu of conventional adjuvants, particularly with intradermal vaccines. In this review, we summarize the initial Russian studies that have given rise to this approach and comment upon recent advances in the use of non-tissue damaging lasers as novel physical adjuvants for vaccines. PMID:25424797

  19. Vaccine Therapies in Malignant Glioma

    PubMed Central

    Oh, Taemin; Sayegh, Eli T.; Fakurnejad, Shayan; Oyon, Daniel; Lamano, Jonathan Balquiedra; DiDomenico, Joseph David; Bloch, Orin; Parsa, Andrew T.

    2015-01-01

    Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal and, even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered. PMID:25431096

  20. Mucosal dendritic cells shape mucosal immunity

    PubMed Central

    Chang, Sun-Young; Ko, Hyun-Jeong; Kweon, Mi-Na

    2014-01-01

    Dendritic cells (DCs) are key modulators that shape the immune system. In mucosal tissues, DCs act as surveillance systems to sense infection and also function as professional antigen-presenting cells that stimulate the differentiation of naive T and B cells. On the basis of their molecular expression, DCs can be divided into several subsets with unique functions. In this review, we focus on intestinal DC subsets and their function in bridging the innate signaling and adaptive immune systems to maintain the homeostasis of the intestinal immune environment. We also review the current strategies for manipulating mucosal DCs for the development of efficient mucosal vaccines to protect against infectious diseases. PMID:24626170

  1. Strategies to reduce dendritic cell activation through functional biomaterial design

    PubMed Central

    Hume, Patrick S.; He, Jing; Haskins, Kathryn; Anseth, Kristi S.

    2012-01-01

    Dendritic cells play a key role in determining adaptive immunity, and there is growing interest in characterizing and manipulating the interactions between dendritic cells and biomaterial surfaces. Contact with several common biomaterials can induce the maturation of immature dendritic cells, but substrates that reduce dendritic cell maturation are of particular interest within the field of cell-based therapeutics where the goal is to reduce the immune response to cell-laden material carriers. In this study, we use a materials-based strategy to functionalize poly(ethylene glycol) hydrogels with immobilized immunosuppressive factors (TGF-β1 and IL-10) to reduce the maturation of immature dendritic cells. TGF-β1 and IL-10 are commonly employed as soluble factors to program dendritic cells in vitro, and we demonstrate that these proteins retain bioactivity towards dendritic cells when immobilized on hydrogel surfaces. Following stimulation with lipopolysaccharide (LPS) and/or cytokines, a dendritic cell line interacting with the surfaces of immunosuppressive hydrogels expressed reduced markers of maturation, including IL-12 and MHCII. The bioactivity of these immunomodulatory hydrogels was further confirmed with primary bone marrow dendritic cells (BMDCs) isolated from non-obese diabetic (NOD) mice, as quantified by a decrease in activation markers and a significantly reduced capacity to activate T cells. Furthermore, by introducing a second signal to promote BMDC-material interactions combined with the presentation of tolerizing signals, the mulitfunctional PEG hydrogels were found to further increase signaling towards BMDCs, as evidenced by greater reductions in maturation markers. PMID:22361099

  2. Dendritic Growth Investigators

    NASA Technical Reports Server (NTRS)

    2000-01-01

    Representatives of NASA materials science experiments supported the NASA exhibit at the Rernselaer Polytechnic Institute's Space Week activities, April 5 through 11, 1999. From left to right are: Angie Jackman, project manager at NASA's Marshall Space Flight Center for dendritic growth experiments; Dr. Martin Glicksman of Rennselaer Polytechnic Instutute, Troy, NY, principal investigator on the Isothermal Dendritic Growth Experiment (IDGE) that flew three times on the Space Shuttle; and Dr. Matthew Koss of College of the Holy Cross in Worcester, MA, a co-investigator on the IDGE and now principal investigator on the Transient Dendritic Solidification Experiment being developed for the International Space Station (ISS). The image at far left is a dendrite grown in Glicksman's IDGE tests aboard the Shuttle. Glicksman is also principal investigator for the Evolution of Local Microstructures: Spatial Instabilities of Coarsening Clusters.

  3. CD40-Activated B Cell Cancer Vaccine Improves Second Clinical Remission and Survival in Privately Owned Dogs with Non-Hodgkin's Lymphoma

    PubMed Central

    Krick, Erika; Coughlin, Christina M.; Overley, Beth; Gregor, Thomas P.

    2011-01-01

    Cell-based active immunotherapy for cancer is a promising novel strategy, with the first dendritic cell (DC) vaccine achieving regulatory approval for clinical use last year. Manufacturing remains arduous, especially for DC vaccines, and the prospect of using cell-based immunotherapy in the adjuvant setting or in combination with chemotherapy remains largely untested. Here, we used a comparative oncology approach to test the safety and potential efficacy of tumor RNA-loaded, CD40-activated B cells in privately owned dogs presenting with non-Hodgkin's lymphoma (NHL), a clinical scenario that represents not only a major problem in veterinary medicine but also a bona fide spontaneous animal model for the human condition. When administered to NHL dogs in remission after induction chemotherapy, CD40-B cells electroporated ex vivo with autologous tumor RNA safely stimulated immunity in vivo. Although chemotherapy plus CD40-B vaccination did not improve time-to-progression or lymphoma-specific survival compared to dogs treated with chemotherapy alone, vaccination potentiated the effects of salvage therapy and improved the rate of durable second remissions as well as subsequent lymphoma-specific survival following salvage therapy. Several of these relapsed dogs are now long-term survivors and free of disease for more than a year. Overall, these clinical and immunological results suggest that cell-based CD40 cancer vaccination is safe and synergizes with chemotherapy to improve clinical outcome in canine NHL. More broadly, our findings underscore the unique value of clinical investigations in tumor-bearing companion animals. PMID:21904611

  4. Polio Vaccination

    MedlinePlus

    ... inactive polio vaccine OPV=oral polio vaccine Polio Vaccination Pronounced [PO-lee-oh] Recommend on Facebook Tweet ... handling and storage Related Pages Global Vaccines and Immunization Global Polio Also Known As & Abbreviations Polio=poliomyelitis ...

  5. On the dendrites and dendritic transitions in undercooled germanium

    SciTech Connect

    Lau, C.F.; Kui, H.W. . Dept. of Physics)

    1993-07-01

    Undercooled molten Ge was allowed to solidify at initial bulk undercoolings, [Delta]T, from 10 to 200C under dehydrated boron oxide flux. It turned out that in addition to the (211) twin dendrite found by Billig and the (100) twin-free dendrite discovered by Devaud and Turnbill, there is a third novel twin dendrite, the (110) twin dendrite. The twin planes in a (110) dendrite always appear in multiple numbers and the orientation is (111). These different kinds of dendrites exist at different initial interfacial undercoolings and the transition temperatures for (110) to (211), (211) to (100) are [Delta]T = 61 and 93C, respectively.

  6. Isothermal Dendritic Growth Experiment - SCN Dendrites

    NASA Technical Reports Server (NTRS)

    1995-01-01

    The Isothermal Dendritic Growth Experiment (IDGE), flown on three Space Shuttle missions, is yielding new insights into virtually all industrially relevant metal and alloy forming operations. IDGE used transparent organic liquids that form dendrites (treelike structures) similar to the crystals that form inside metal alloys. Comparing Earth-based and space-based dentrite growth velocity, tip size and shape provid a better understanding of the fundamentals of dentritic growth, including gravity's effects. These shadowgraphic images show succinonitrile (SCN) dentrites growing in a melt (liquid). The space-grown crystals also have cleaner, better defined sidebranches. IDGE was developed by Rensselaer Polytechnic Institude (RPI) and NASA/ Glenn Research Center(GRC). Advanced follow-on experiments are being developed for flight on the International Space Station. Photo gredit: NASA/Glenn Research Center

  7. Vaccine hesitancy

    PubMed Central

    Dubé, Eve; Laberge, Caroline; Guay, Maryse; Bramadat, Paul; Roy, Réal; Bettinger, Julie A.

    2013-01-01

    Despite being recognized as one of the most successful public health measures, vaccination is perceived as unsafe and unnecessary by a growing number of individuals. Lack of confidence in vaccines is now considered a threat to the success of vaccination programs. Vaccine hesitancy is believed to be responsible for decreasing vaccine coverage and an increasing risk of vaccine-preventable disease outbreaks and epidemics. This review provides an overview of the phenomenon of vaccine hesitancy. First, we will characterize vaccine hesitancy and suggest the possible causes of the apparent increase in vaccine hesitancy in the developed world. Then we will look at determinants of individual decision-making about vaccination. PMID:23584253

  8. Synopsis of the 6th Walker's Cay Colloquium on Cancer Vaccines and Immunotherapy

    PubMed Central

    Kast, W Martin; Levitsky, Hyam; Marincola, Francesco M

    2004-01-01

    The 6th annual Cancer Vaccines and Immunotherapy Colloquium at Walker's Cay was held under the auspices of the Albert B. Sabin Vaccine Institute on March 10–13, 2004. The Colloquium consisted of a select group of 34 scientists representing academia, biotechnology and pharmaceutical industry. The main goal of this gathering was to promote in a peaceful and comfortable environment exchanges between basic and clinical science. The secondary benefit was to inspire novel bench to bedside ventures and at the same time provide feed back about promising and/or disappointing clinical results that could help re-frame some scientific question or guide the design of future trials. Several topics were covered that included tumor antigen discovery and validation, platforms for vaccine development, tolerance, immune suppression and tumor escape mechanisms, adoptive T cell therapy and dendritic cell-based therapies, clinical trials and assessment of response. Here we report salient points raised by speakers or by the audience during animated discussion that followed each individual presentation. PMID:15212694

  9. Dendritic Polymers for Theranostics

    PubMed Central

    Ma, Yuan; Mou, Quanbing; Wang, Dali; Zhu, Xinyuan; Yan, Deyue

    2016-01-01

    Dendritic polymers are highly branched polymers with controllable structures, which possess a large population of terminal functional groups, low solution or melt viscosity, and good solubility. Their size, degree of branching and functionality can be adjusted and controlled through the synthetic procedures. These tunable structures correspond to application-related properties, such as biodegradability, biocompatibility, stimuli-responsiveness and self-assembly ability, which are the key points for theranostic applications, including chemotherapeutic theranostics, biotherapeutic theranostics, phototherapeutic theranostics, radiotherapeutic theranostics and combined therapeutic theranostics. Up to now, significant progress has been made for the dendritic polymers in solving some of the fundamental and technical questions toward their theranostic applications. In this review, we briefly summarize how to control the structures of dendritic polymers, the theranostics-related properties derived from their structures and their theranostics-related applications. PMID:27217829

  10. Lithium Dendrite Formation

    SciTech Connect

    2015-03-06

    Scientists at the Department of Energy’s Oak Ridge National Laboratory have captured the first real-time nanoscale images of lithium dendrite structures known to degrade lithium-ion batteries. The ORNL team’s electron microscopy could help researchers address long-standing issues related to battery performance and safety. Video shows annular dark-field scanning transmission electron microscopy imaging (ADF STEM) of lithium dendrite nucleation and growth from a glassy carbon working electrode and within a 1.2M LiPF6 EC:DM battery electrolyte.