Background Q fever is caused by the intracellular bacterium Coxiella burnetii. Initial infection can present as acute Q fever, while a minority of infected individuals develops chronic Q fever endocarditis or vascular infection months to years after initial infection. Serology is an important diagnostic tool for both acute and chronic Q fever. However, since immunosuppressive drugs may hamper the humoral immune response, diagnosis of Q fever might be blurred when these drugs are used. Case presentation A 71-year-old Caucasian male was diagnosed with symptomatic acute Q fever (based on positive C. burnetii PCR followed by seroconversion) while using anti-tumor necrosis factor-? (anti-TNF?) drugs for rheumatoid arthritis (RA). He was treated for two weeks with moxifloxacin. After 24 months of follow-up, the diagnosis of probable chronic Q fever was established based on increasing anti-C. burnetii phase I IgG antibody titres in a immunocompromised patient combined with clinical suspicion of endocarditis. At the time of chronic Q fever diagnosis, he had been treated with anti B-cell therapy for 16 months. Antibiotic therapy consisting of 1.5 years doxycycline and hydroxychloroquine was started and successfully completed and no signs of relapse were seen after more than one year of follow-up. Conclusion The use of anti-TNF? agents for RA in the acute phase of Q fever did not hamper the C. burnetii-specific serological response as measured by immunofluorescence assay. However, in the presented case, an intact humoral response did not prevent progression to probable chronic C. burnetii infection, most likely because essential cellular immune responses were suppressed during the acute phase of the infection. Despite the start of anti-B-cell therapy with rituximab after the acute Q fever episode, an increase in anti-C. burnetii phase I IgG antibodies was observed, supporting the notion that C. burnetii specific CD20-negative memory B-cells are responsible for this rise in antibody titres.
: A health care system is needed where care is based on the best available evidence and is delivered reliably, efficiently, and less expensively (best care at lower cost). In gastroenterology, anti-tumor necrosis factor agents represent the most effective medical therapeutic option for patients with moderate-to-severe inflammatory bowel disease (IBD), but are very expensive and account for nearly a quarter of the cost of IBD care, representing a major area of present and future impact in direct health care costs. The ImproveCareNow Network, consisting of over 55 pediatric IBD centers, seeks ways to improve the value of care in IBD, curtailing unnecessary costs and promoting better health outcomes through systematic and incremental quality improvement initiatives. This report summarizes the key evidence to facilitate the cost-effective use of anti-tumor necrosis factor agents for patients with IBD. Our review outlines the scientific rationale for initiating cost-reducing measures in anti-tumor necrosis factor use and focuses on 3 implementable strategies and 4 exploratory considerations through practical clinical guidelines, as supported by existing evidence. Implementable strategies can be readily integrated into today's daily practice, whereas exploratory considerations can guide research to support future implementation. PMID:24451222
Park, K T; Crandall, Wallace V; Fridge, Jacqueline; Leibowitz, Ian H; Tsou, Marc; Dykes, Dana M H; Hoffenberg, Edward J; Kappelman, Michael D; Colletti, Richard B
Background: Local reactions (LRs) are a very frequent side effect of specific immunotherapy with allergens and can impair patients’ adherence. Antihistamine pretreatment – originally introduced as a safety measure to reduce anaphylactic side effects – has been the only treatment option for LRs so far, although these swellings usually do not appear immediately but after hours. We were interested whether
Stefan Wöhrl; Simon Gamper; Wolfgang Hemmer; Georg Heinze; Georg Stingl; Tamar Kinaciyan
Autoimmune hepatitis (AIH) is occasionally triggered by drug treatments. Recently, as biological agents are becoming widely used for autoimmune disorders, there have been a growing number of reports of the development of autoimmune processes related to these agents. A 52-year-old Japanese woman with psoriasis developed liver damage two months after initiation of anti-TNF-? therapy with adalimumab. Liver histological findings were compatible with AIH, and positive conversions of ANAs were detected. The patient was treated with prednisolone and had a good response. While some cases of AIH triggered by anti-TNF-? therapies have been reported, the pathogenesis remains unspecified. When elevation of liver enzymes is observed with high IgG levels and seropositivity of ANA during the course of anti-TNF-? therapy, liver biopsy findings may be essential and important to make definitive diagnosis of AIH.
Purpose of review To highlight recent evidence from clinical trials of anti-Tumor necrosis factor (TNF) and non-anti-TNF biologics for rheumatoid arthritis (RA) focused on comparative clinical efficacy including safety outcomes and medication discontinuation. Recent findings Patients with RA are sometimes able to attain low disease activity or remission since the introduction of biologic therapy for RA. Biologics like anti-TNF, anti-interleukin-6 (IL-6), anti-CD20 and those that modulate T-cell co-stimulation have consistently shown good efficacy in patients with RA. Preliminary data from comparative efficacy studies to evaluate potential differences in between anti-TNF and non-anti-TNF biologics have shown little differences among these. There is ongoing work in comparative efficacy to answer this question further. Summary Biologic therapy in RA has significantly changed the course of RA in the last decade. Recently published CTs have been focused on comparative efficacy, cardiovascular safety of biologics and potential anti-TNF therapy discontinuation in patients with RA.
Navarro-Millan, Iris; Curtis, Jeffrey R
Background The overexpression of tumor necrosis factor (TNF)-? leads to systemic as well as local loss of bone and cartilage and is also an important regulator during fracture healing. In this study, we investigate how TNF-? inhibition using a targeted monoclonal antibody affects fracture healing in a TNF-? driven animal model of human rheumatoid arthritis (RA) and elucidate the question whether enduring the anti TNF-? therapy after trauma is beneficial or not. Methods A standardized femur fracture was applied to wild type and human TNF-? transgenic mice (hTNFtg mice), which develop an RA-like chronic polyarthritis. hTNFtg animals were treated with anti-TNF antibody (Infliximab) during the fracture repair. Untreated animals served as controls. Fracture healing was evaluated after 14 and 28 days of treatment by clinical assessment, biomechanical testing and histomorphometry. Results High levels of TNF-? influence fracture healing negatively, lead to reduced cartilage and more soft tissue in the callus as well as decreased biomechanical bone stability. Blocking TNF-? in hTNFtg mice lead to similar biomechanical and histomorphometrical properties as in wild type. Conclusions High levels of TNF-? during chronic inflammation have a negative impact on fracture healing. Our data suggest that TNF-? inhibition by an anti-TNF antibody does not interfere with fracture healing.
TNF-? is a pleiotropic cytokine, which plays a major role in the pathogenesis of numerous autoimmune and/or inflammatory systemic diseases. Systemic vasculitis constitutes a group of rare diseases, characterized by inflammation of the arterial or venous vessel wall, causing stenosis and thrombosis. Treatment of the different type of vasculitis mainly relies on steroids and immunosuppressive drugs. In case of refractory or relapsing diseases, however, a second line of treatment may be required. Anti-TNF-? drugs have been used in this setting during the last 15 years with inconsistent results. We reviewed herein the use of anti-TNF-? therapy in different kind of vasculitis and concluded that, except for Behcet's disease, this therapeutic option has not demonstrated significant improvement in the treatment of vasculitis.
The availability of biologic agents targeting tumor necrosis factor (TNF)-? represents a significant advance in the management\\u000a of rheumatoid arthritis. Anti-TNF-? therapy has been associated with dramatic improvements in the clinical signs and symptoms\\u000a of rheumatoid arthritis and has been shown to greatly retard the destructive process that too often characterizes this condition.\\u000a Although effective and well-tolerated in a substantial
Alan R. Erickson; Ted R. Mikuls
Ankylosing spondylitis (AS) is an inflammatory chronic disease that affects young males and in more than 90% of cases is associated with HLA B27 antigen. Therapeutic options for those patients with spondyloarthropathies have been limited during the last decades. Infliximab and etanercept are both approved for the treatment of patients with active disease that does not respond to conventional therapies. Anti-TNF therapy is very effective in AS, and eventually can be more effective than in rheumatoid arthritis. In 2003 Assessments in Ankylosing Spondylitis Group (ASAS) published international recommendations about the use of these agents in AS, which can be used as guidance in taking decisions and elaborating guidelines. To define their utilization it is necessary more studies about efficacy, toxicity and about ways of use. PMID:17187716
Cravo, Ana Rita; Tavares, Viviana; Da Silva, José Canas
Background A high rate of infection has been reported in patients receiving treatment with anti-tumor necrosis factor (anti-TNF). This study describes the rate of and risk factors for serious infections in patients receiving anti-TNF agents in Jordan. Methods This retrospective observational study was conducted at a large tertiary referral center in the north of Jordan. Between January 2006 and January 2012, 199 patients who received an anti-TNF agent (infliximab, adalimumab, or etanercept) were included. Patients received the anti-TNF treatment for rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, or other conditions. A serious infection was defined as any bacterial, viral, or fungal infection that required hospitalization, administration of appropriate intravenous antimicrobial therapy, and temporary withholding of anti-TNF treatment. Results The mean duration of anti-TNF treatment was 26.2 months. Steroids were used in 29.1% of patients, while 54.8% were given additional immunosuppressant therapy (methotrexate or azathioprine). Only one anti-TNF agent was given in 70.4% of patients, while 29.6% received different anti-TNF agents for the duration of treatment. Serious infections were documented in 39 patients (19.6%), including respiratory tract infections (41%), urinary tract infections (30.8%), and skin infections (20.5%), and extrapulmonary tuberculosis in three patients (7.7%). Exposure to more than one anti-TNF agent was the only factor associated with a significant increase in the rate of infection (relative risk 1.9, 95% confidence interval 1.06–4.0, P=0.03). Conclusion Serious infections, including tuberculosis, were a common problem in patients receiving anti-TNF agents, and exposure to more than one anti-TNF agent increased the risk of serious infection.
Alawneh, Khaldoon M; Ayesh, Mahmoud H; Khassawneh, Basheer Y; Saadeh, Salwa Shihadeh; Smadi, Mahmoud; Bashaireh, Khaldoun
ObjectiveThe British Society for Rheumatology Biologics Register (BSRBR) has collected data on adverse events including pregnancies in patients with rheumatoid arthritis treated with anti-tumour necrosis factor (anti-TNF) therapy. The purpose of this report is to summarise the pregnancy outcomes in women treated with anti-TNF in the BSRBR.MethodsPatients were categorised according to anti-TNF exposure as follows: (1) exposure to anti-TNF and
Suzanne M M Verstappen; Yvonne King; Kath D Watson; Deborah P M Symmons; Kimme L Hyrich
Introduction The purpose of this study was to determine whether anti-tumour necrosis factor alpha (anti-TNF-?) antibody, infliximab, can inhibit T helper 17 (Th17) differentiation in uveitis patients who have Behçet's disease (BD). Methods To measure inflammatory cytokines, ocular fluid samples from BD patients being treated with infliximab were collected. Cluster of differentiation 4 (CD4)+ T cells from BD patients with active uveitis were co-cultured with anti-cluster of differentiation 3/cluster of differentiation 28 (CD3/CD28) antibodies in the presence of infliximab. For the induction of Th17 cells, CD4+ T cells from BD patients were co-cultured with anti-CD3/CD28, anti-interferon-gamma (anti-IFN-?), anti-interleukin-4 (anti-IL-4), and recombinant proteins such as interleukin-1 beta (IL-1?), interleukin-6 (IL-6), interleukin-23 (IL-23), and TNF-?. The BD T cells were co-cultured with infliximab, and the production of interleukin-17 (IL-17) was evaluated by ELISA and flow cytometry, and the expression of retinoid-acid receptor-related orphan receptor gamma t (ROR?t) was also evaluated by flow cytometry. In addition, intraocular cells collected from mice with experimental autoimmune uveitis (EAU) were used for the assay with anti-TNF-? blocking antibody. Results Ocular fluids from active uveitis patients who have BD contained significant amounts of inflammatory cytokines such as IFN-?, IL-2, TNF-?, IL-6, and IL-17, while ocular fluids from infliximab patients did not contain any inflammatory cytokines. Activated CD4+ T cells from BD patients produced large amounts of TNF-? and IL-17, whereas T cells in the presence of infliximab failed to produce these cytokines. Polarized Th17 cell lines from BD patients produced large amounts of IL-17, and Th17 cells exposed to infliximab had significantly reduced IL-17 production. Polarized BD Th17 cells expressed large amounts of transcription factor ROR?t. In contrast, in vitro-treated infliximab Th17 cells expressed less ROR?t. Moreover, intraocular T cells from EAU mice had a high population of IL-17+ cells, and retinal antigen-specific T cells from EAU mice produced large amounts of IL-17 in the presence of retinal peptide. However, the EAU T cells produced less IL-17 if the T cells were treated with anti-TNF-? antibody. Conclusions These results indicate that anti-TNF-? therapy suppresses effector T-cell differentiation in BD patients with uveitis. Thus, suppression of effector T-cell differentiation by anti-TNF-? therapy may provide protection from severe ocular inflammation in BD.
Objectives. Anti-TNF therapy has improved outcomes for patients with highly active RA. Less is known about its effectiveness in patients with lower disease activity. The aim of this analysis is to compare the response to anti-TNF therapy between RA patients with high (DAS28 > 5.1) and moderate (DAS28 > 3.2–5.1) disease activity. Methods. A total of 4687 anti-TNF and 344 DMARD patients with high disease activity despite treatment with two standard DMARDs (including MTX) and 224 anti-TNF- and 300 DMARD-treated patients with moderate disease activity were selected from the British Society For Rheumatology Biologics Register. Mean change in HAQ over the first 12 months of enrolment was compared first between anti-TNF-treated and untreated patients in each DAS28 group, and then between anti-TNF-treated patients in the moderate and high DAS28 groups, using doubly robust estimates, adjusting for age, gender, disease duration, baseline HAQ and DAS28 score, number of previous DMARDs and steroid use. Results. Compared with anti-TNF-untreated patients within each DAS group, treated patients were younger, had higher DAS28 and HAQ and had failed a higher number of previous DMARDs. The mean adjusted change in HAQ over 12 months was similar in anti-TNF-treated patients with moderate and high disease activity at baseline: moderate ?0.26 (95% CI ?0.35, ?0.16), high ?0.28 (95% CI ?0.34, ?0.23) and mean difference ?0.03 (95% CI ?0.14, 0.08). Conclusions. Improvement in HAQ score 12 months after start of anti-TNF therapy was not dependent on baseline DAS28 scores, suggesting that substantial benefits may also be gained by treating those with moderately active disease despite standard DMARD therapy.
Deighton, Chris; Watson, Kath D.; Symmons, Deborah P. M.; Lunt, Mark
The antibody display technology (ADT) such as phage display (PD) has substantially improved the production of monoclonal antibodies (mAbs) and Ab fragments through bypassing several limitations associated with the traditional approach of hybridoma technology. In the current study, we capitalized on the PD technology to produce high affinity single chain variable fragment (scFv) against tumor necrosis factor-alpha (TNF- ?), which is a potent pro-inflammatory cytokine and plays important role in various inflammatory diseases and malignancies. To pursue production of scFv antibody fragments against human TNF- ?, we performed five rounds of biopanning using stepwise decreased amount of TNF-? (1 to 0.1 ? g), a semi-synthetic phage antibody library (Tomlinson I + J) and TG1 cells. Antibody clones were isolated and selected through enzyme-linked immunosorbent assay (ELISA) screening. The selected scFv antibody fragments were further characterized by means of ELISA, PCR, restriction fragment length polymorphism (RFLP) and Western blot analyses as well as fluorescence microscopy and flow cytometry. Based upon binding affinity to TNF-? , 15 clones were selected out of 50 positive clones enriched from PD in vitro selection. The selected scFvs displayed high specificity and binding affinity with Kd values at nm range to human TNF-? . The immunofluorescence analysis revealed significant binding of the selected scFv antibody fragments to the Raji B lymphoblasts. The effectiveness of the selected scFv fragments was further validated by flow cytometry analysis in the lipopolysaccharide (LPS) treated mouse fibroblast L929 cells. Based upon these findings, we propose the selected fully human anti-TNF-? scFv antibody fragments as potential immunotherapy agents that may be translated into preclinical/clinical applications. PMID:23432628
Abdolalizadeh, Jalal; Nouri, Mohammad; Zolbanin, Jafar Majidi; Barzegari, Abolfazl; Baradaran, Behzad; Barar, Jaleh; Coukos, George; Omidi, Yadollah
Importance Herpes zoster (HZ) reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates HZ risk, and whether monoclonal antibodies carry greater risk than etanercept. Objectives To ascertain whether initiation of anti-TNF therapy compared with non-biologic comparators is associated with increased HZ risk Design, Setting, and Patients We identified new users of anti-TNF therapy among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis-psoriatic arthritis-ankylosing spondylitis (PsO-PsA-AS) patients during 1998–2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared HZ incidence between new anti-TNF users and patients initiating non-biologic disease modifying drugs (DMARDs) within each inflammatory disease cohort (last participant follow-up Dec 31, 2007). Within these cohorts, we used Cox regression models to compare propensity-score adjusted HZ incidence between new anti-TNF and non-biologic DMARD users while controlling for baseline corticosteroid use. Main Outcome Measure Incidence of herpes zoster cases occurring after initiation of new anti- TNF or non-biologic DMARD therapy Results Among 32,208 new users of anti-TNF therapy, we identified 310 HZ cases. Crude incidence rates among anti-TNF users for RA, IBD, and PsO-PsA-AS were 12.1/1000 pt-yrs, (95% CI 10.7–13.6), 11.3/1000 (95% CI 7.7–16.7), and 4.4/1000 (95% CI 2.8–7.0) respectively. Baseline use of corticosteroids of > 10mg/day was associated with elevated risk [adjusted HR 2.13 (1.64, 2.75) compared with no baseline use. For RA patients, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators [adjusted HR 1.00 (95% CI 0.77–1.29) and comparable between all three anti-TNF therapies studied. Conclusions and Relevance Among patients with RA and other select inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk for HZ compared to patients who initiated non-biologic treatment regimens.
Winthrop, Kevin L.; Baddley, John W.; Chen, Lang; Liu, Liyan; Grijalva, Carlos G.; Delzell, Elizabeth; Beukelman, Timothy; Patkar, Nivedita M.; Xie, Fenglong; Saag, Kenneth G.; Herrinton, Lisa J.; Solomon, Daniel H.; Lewis, James D.; Curtis, Jeffrey R.
Knowledge and understanding about the immunosuppressive properties of anti-TNF therapies and the adverse effects these causes\\u000a have advanced over the last 10 years since the first of these drugs was approved. These drugs work by inhibiting tumour necrosis\\u000a factor (TNF) in the body, which plays an essential role in the immune response to invading pathogens. Anti-TNF drugs have\\u000a therapeutic value because
Current therapy of moderate-to-severe inflammatory bowel disease (IBD) often involves the use of anti-tumor necrosis factor alpha (TNF-?) agents. Although very effective, theses biologics place the patient at increased risk for developing infections and lymphomas, the latter especially when in combination with thiopurines. Appropriate patient selection, counseling, and education are all important features for the successful use of anti-TNF-? therapy. A thorough history to rule-out contraindications of this therapy and emphasis on monitoring guidelines are important steps preceding administration of anti-TNF-? agents. This therapy should only be considered if a recent evaluation has established that the patient has active IBD. In addition, it is important to exclude disease mimickers. Anti-TNF-? agents have been considered to present a globally favorable benefit/risk ratio. However, it is important that in routine practice, initiation of anti-TNF-? therapy be carefully discussed with the patient, extensively explaining the potential benefits and risks of such treatment. Prior to starting anti-TNF-? therapy, the patients need to be screened for latent tuberculosis, hepatitis B virus infection, and (usually) hepatitis C virus and HIV infection. Vaccination schedules of IBD patients should be evaluated and updated prior to the commencement of anti-TNF-? therapy. Ordinarily, immunization in adult patients with IBD should not deviate from recommended guidelines for the general population. With the exception of live vaccines, immunizations can be safely administered in patients with IBD, even those on immunosuppressants or biologics. The purpose of this review is providing an overview of appropriate steps to prepare patients with IBD for anti-TNF-? therapy. PMID:24667275
Chebli, Júlio Maria Fonseca; Gaburri, Pedro Duarte; Chebli, Liliana Andrade; da Rocha Ribeiro, Tarsila Campanha; Pinto, André Luiz Tavares; Ambrogini Júnior, Orlando; Damião, Adérson Omar Mourão Cintra
Patients with immune-mediated inflammatory diseases (IMIDs) are increasingly being treated with anti-tumor necrosis factor (TNF) agents and are at increased risk of developing tuberculosis (TB). Therefore, diagnosis and treatment of latent TB infection (LTBI) is recommended in these patients due to the initiation of anti-TNF therapy. Traditionally, LTBI has been diagnosed on the basis of clinical factors and a tuberculin skin test. Recently, interferon-gamma releasing assays (IGRAs) that can detect TB infection have become available. Considering the high-risk of developing TB in patients on anti-TNF therapy, the use of both a tuberculin skin test and an IGRA should be considered to detect and treat LTBI in patients with IMIDs. The traditional LTBI treatment regimen consisted of isoniazid monotherapy for 9 months. However, shorter regimens such as 4 months of rifampicin or 3 months of isoniazid/rifampicin are increasingly being used to improve treatment completion rates. In this review, the screening methods for diagnosing latent and active TB before anti-TNF therapy in patients with IMIDs will be briefly described, as well as the current LTBI treatment regimens, the recommendations for managing TB that develops during anti-TNF therapy, the necessity of regular monitoring to detect new TB infection, and the re-initiation of anti-TNF therapy in patients who develop TB.
Anti-TNF antibodies have acquired a prominent place in the management of IBD (including Crohn's disease and ulcerative colitis), rheumatologic conditions (such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis) and psoriasis. They have a good safety profile, especially when contraindications such as demyelinating disease, active infections and/or abscesses are ruled out, and when necessary precautions to prevent reactivation of tuberculosis are taken. However, with increasing use of these agents, paradoxical adverse events have been reported. Some of these features are shared with the underlying disease for which these drugs are given, making management of these conditions challenging. For example, anti-TNF therapy is used for the treatment of psoriasis, but psoriasiform lesions are sometimes observed in patients receiving therapy. Similarly, anti-TNF therapy is used for the treatment of rheumatologic diseases, but arthralgias and arthritis are sometimes observed in patients receiving anti-TNF agents. We review the paradoxical inflammation induced by anti-TNF agents in patients with IBD, provide hypotheses for the occurrence of this paradoxical inflammation and give practical advice on how to manage these patients. PMID:22751454
Cleynen, Isabelle; Vermeire, Séverine
A strategy of encapsulation of the antiTNF-? antibody on top of poly(lactide-co-glycolide) nanoparticles (PLGA NPs) is presented on the basis of the complexation of antiTNF-? with alginate (Alg) and subsequent assembly layer by layer with poly(L-lysine) (PLL). The assembly of the antiTNF-?/Alg complex with PLL and its stability in PBS and lysozymes are monitored on a planar support using a quartz crystal microbalance with dissipation. The assembly of the antiTNF-?/Alg complex on PLGA NPs is followed by zeta potential measurements. AntiTNF-? release from the PLGA NPs is measured in PBS at 37 and 60 °C and in the HepG2 cell line following NP uptake, using the Q-ADA kit detection kit. The release follows first-order kinetics with an initial burst. Intracellular release of antiTNF-? is confirmed by confocal Raman microscopy. PMID:23696518
Romero, Gabriela; Ochoteco, Olaia; Sanz, David J; Estrela-Lopis, Irina; Donath, Edwin; Moya, Sergio E
It is recommended to evaluate the presence of latent tuberculosis infection (LTBI) before initiating antitumor necrosis factor\\u000a ? (anti-TNF) therapy for rheumatologic diseases. We aimed to present the follow-up results of 192 patients with rheumatologic\\u000a diseases before anti-TNF therapy for LTBI. We enrolled 192 patients who were given anti-TNF therapy for their rheumatologic\\u000a diseases between April 2005 and January 2008.
Ismail Hanta; Suleyman Ozbek; Sedat Kuleci; Ali Kocabas
By employing modified Cornell model, we have evaluated the potential of adjunctive immunotherapy with DNA vaccines to shorten the tuberculosis chemotherapy period and reduce disease reactivation. We demonstrate that ?-crystallin based DNA vaccine (DNAacr) significantly reduced the chemotherapy period from 12 weeks to 8 weeks when compared with the chemotherapy alone. Immunotherapy with SodA based DNA vaccine (DNAsod) reduced the pulmonary bacilli only as much as DNAvec. Both DNAacr and DNAsod, although significantly delayed the reactivation in comparison to the chemotherapy alone, this delay was associated with the immunostimulatory sequences present in the vector backbone and was not antigen specific. Both DNA vaccines resulted in the production of significantly higher number of TEM cells than the chemotherapy alone, however, only in the case of DNAsod, this enhancement was significant over the DNAvec treatment. Overall, our findings emphasize the immunotherapeutic potential of DNAacr in shortening the duration of TB chemotherapy.
Chauhan, Priyanka; Jain, Ruchi; Dey, Bappaditya; Tyagi, Anil K.
International guidelines state that live vaccines are contraindicated in patients on anti-TNF therapy. However, we report the experience of a patient who inadvertently received live polio vaccine whilst receiving anti-TNF therapy. Patient did not suffer from any infectious sequel as a result. No clear guidelines are available for all vaccines in patients with specific rheumatic diseases. However, if we consider adult patients with rheumatic diseases to have altered immunocompetence, it is recommended that they receive the usual inactivated vaccines according to standard schedules, and live vaccines should be avoided in those who are treated with more potent forms of immune suppression. Patients should be counseled regarding the risks of live vaccines prior to treatment with anti-TNF therapy. PMID:20536606
Badsha, Humeira; Daher, Mirna; Edwards, Christopher J
Background The anti-TNF? therapy has been since its approval by the FDA, along with nonsteroidal antiinflammatory drugs (NSAIDs), one of the most important therapies for control of spondyloarthritis (SpA). The onset of Lupus Like Syndrome (LLS) has been described in patients with rheumatoid arthritis (RA) treated with anti-TNF? therapy but there is little literature on the occurrence of this entity in patients with SpA. Methods We studied 57 patients with SpA who received more than 1 year of anti-TNF? therapy (infliximab, adalimumab or etanercept). Patients were analyzed for the development of LLS, in addition to measuring ANA levels ? 1:160 and Anti-dsDNA (measured by IIF). Results In total, 7.01% of patients treated with anti-TNF? had titers of ANA ? 1:160, whereas 3.5% of patients had serum levels of dsDNA. However, only one patient (1.75%; n = 1) experienced clinical symptoms of LLS; this was a female patient with a history of psoriatic arthritis. Conclusions The presence of LLS secondary to anti-TNF? therapy in patients with SpA is observed less frequently compared with patients with RA. LLS was only detected in a patient with a history of psoriasis since youth, who developed psoriatic arthritis after 27 years of age and had received anti-TNF? therapy for > 2 years. This may be because LLS is an entity clearly associated with innate immunity, with little central role of B and T cells.
CD66b is a member of the carcinoembryonic antigen family, which mediates the adhesion between neutrophils and to endothelial cells. Allergen-specific immunotherapy is widely used to treat allergic diseases, and the molecular mechanisms underlying this therapy are poorly understood. The present work was undertaken to analyze A) the in vitro effect of allergens and immunotherapy on cell-surface CD66b expression of neutrophils from patients with allergic asthma and rhinitis and B) the in vivo effect of immunotherapy on cell-surface CD66b expression of neutrophils from nasal lavage fluid during the spring season. Myeloperoxidase expression and activity was also analyzed in nasal lavage fluid as a general marker of neutrophil activation. Results CD66b cell-surface expression is upregulated in vitro in response to allergens, and significantly reduced by immunotherapy (p<0.001). Myeloperoxidase activity in nasal lavage fluid was also significantly reduced by immunotherapy, as were the neutrophil cell-surface expression of CD66b and myeloperoxidase (p<0.001). Interestingly, CD66b expression was higher in neutrophils from nasal lavage fluid than those from peripheral blood, and immunotherapy reduced the number of CD66+MPO+ cells in nasal lavage fluid. Thus, immunotherapy positive effects might, at least in part, be mediated by the negative regulation of the CD66b and myeloperoxidase activity in human neutrophils.
Ventura, Inmaculada; Gomez, Elisa; Perez-Cano, Ramon; Blanca, Miguel; Monteseirin, Javier
Background Premature arterial stiffening and atherosclerosis are increased in patients with inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The proinflammatory protein calprotectin is associated with inflammatory arthropathies, vascular pathology, and acute coronary events. We examined the long-term effects of treatment with tumor necrosis factor (TNF)-? antagonists on aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies, and the relationships to the levels of calprotectin. Methods Fifty-five patients with RA, AS, or PsA and a clinical indication for anti-TNF-? therapy were included and followed with regular examinations for 1 year. Thirty-six patients starting with anti-TNF-? therapy were compared with a nontreatment group of 19 patients. Examinations included assessments of aortic stiffness (aortic pulse wave velocity, aPWV), CIMT, and plasma calprotectin. Results After 1 year, aPWV (mean (s.d.)) was improved in the treatment group, but not in the control group (?0.54 [0.79] m/s vs. 0.06 [0.61] m/s, respectively; P = 0.004), and CIMT progression (median (quartile cut-points, 25th and 75th percentiles)) was reduced in the treatment group compared to the control group (?0.002 [–0.038, 0.030] mm vs. 0.030 [0.011, 0.043] mm, respectively; P = 0.01). In multivariable analyses, anti-TNF-? therapy over time was associated with improved aPWV (P = 0.02) and reduced CIMT progression (P = 0.04), and calprotectin was longitudinally associated with aPWV (P = 0.02). Conclusions Long-term anti-TNF-? therapy improved aortic stiffness and CIMT progression in patients with inflammatory arthropathies. Calprotectin may be a soluble biomarker reflecting aortic stiffening in these patients.
We describe a Mycobacterium kansasii cutaneous infection that was diagnosed in a 52-year-old female patient with sarcoidosis receiving anti-TNF agents. The diagnosis was based on the positive culture of the foot ulcerative tissue. The isolation and identification of bacterium was based on phenotypic and molecular methods. Therapy and follow-up of the patient is discussed. PMID:24773076
Spiliopoulou, I; Foka, A; Bounas, A; Marangos, M N
Background Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti-tumor necrosis factor-? (anti-TNF?) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. Methods Twenty-three RA patients starting on anti-TNF? treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3?months of treatment. Results Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2?weeks (p?0.05) which was paralleled by a significant increase in microvascular endothelial-dependent function (p?0.05). However, both parameters returned towards baseline at 12?weeks. Conclusion Anti-TNF? therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function.
Objective. TRAIL is a potential biomarker of cardiovascular (CV) disease. Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with metabolic syndrome (MeS) and accelerated atherosclerosis. We assessed whether disease activity, systemic inflammation, and MeS features were associated with circulating TRAIL levels in AS patients undergoing TNF-? antagonist infliximab therapy and if infliximab infusion modified TRAIL levels. Methods. We measured TRAIL serum levels in 30 nondiabetic AS patients without CV disease undergoing anti-TNF-? therapy, immediately before and after an infliximab infusion, and in 48 matched controls. Correlations of TRAIL levels with disease activity, systemic inflammation and MeS features, adipokines, and biomarkers of endothelial activation were evaluated. Changes in TRAIL levels following anti-TNF-? infusion were analyzed. Results. TRAIL levels were higher in AS patients than controls. TRAIL levels displayed an inverse correlation with total and LDL cholesterol. We observed an inverse correlation with QUICKI and a marginal association with HOMA-IR. We also found an inverse correlation with resistin and a marginal association with apelin and OPN. Anti-TNF-? infusion did not change TRAIL levels after 120?. Conclusion. Elevated TRAIL levels in AS patients may be the result of a compensatory mechanism to reduce CV risk in these patients.
Lopez-Mejias, Raquel; Rueda-Gotor, Javier; Miranda-Filloy, Jose A.; Ubilla, Begona; Carnero-Lopez, Beatriz; Palmou-Fontana, Natalia; Gomez-Acebo, Ines; Blanco, Ricardo; Pina, Trinitario; Ochoa, Rodrigo; Gonzalez-Juanatey, Carlos; Gonzalez-Gay, Miguel A.
In this study, we investigated the safety and toxicity of isoniazid (INH) intervention therapy to the patients with latent\\u000a tuberculosis who were given tumor necrosis factor ? (TNF?) for the treatment of their rheumatologic diseases. In this prospective\\u000a clinical study, we enrolled 86 patients receiving anti-TNF? therapy for their rheumatologic diseases between April 2005 and\\u000a September 2006. Of all the
Ismail Hanta; Suleyman Ozbek; Sedat Kuleci; Murat Sert; Ali Kocabas
BACKGROUND: Substantial progress has been made in the medical management of rheumatoid arthritis (RA) over the past decade with the introduction of biologic therapies, including anti-tumour necrosis factor alpha (anti-TNF?) therapy medications. However, individuals with RA taking anti-TNF? medication continue to experience physical, psychological and functional consequences, which could potentially benefit from rehabilitation. There is evidence that therapeutic exercise should
Angela Reid; Audrey Brady; Catherine Blake; Anne-Barbara Mongey; Douglas J Veale; Oliver FitzGerald; Tara Cusack
BACKGROUND Psoriasis is a chronic immune-mediated disease, characterized by increased levels of TNF?. Anti-TNF? agents have revolutionized the treatment of severe psoriasis by targeting an important molecule involved in its pathogenesis. OBJECTIVES We report the experience of a state referral center that uses anti-TNF? agents for psoriasis. METHODS We conducted a retrospective case series. Seventy-four out of 120 patients met the inclusion criteria. Clinical and laboratory data was analyzed using the chi-squared, Wicoxon and McNemar's tests. Associations were considered statistically significant when p-value<0.05. RESULTS Forty-one subjects (55.40%) were male, with a mean age of 47.69±14.99 years. Median disease duration and pre-treatment PASI were 14.0 months (IQR 9.0-20.0), and 13.55 points (IQR 8.5-20.32). Sixty patients (81.10%) had arthropathic psoriasis. Forty-six subjects (62.20%) had comorbidities; the most frequent was dyslipidemia (25.70%). In 55.40% of patients, insufficient response to conventional therapies was the principal indication for using anti-TNF? drugs. Clinical improvement occurred in 93.20% of cases, and the post-treatment PASI median was 0.0 points (IQR 0.0-0.0). Adverse effects occurred in 6.80% of patients. Infections and elevation of transaminases occurred in 28.40% and 8.10% of cases, respectively. CONCLUSION Post-treatment reduction in PASI was satisfactory and the occurrence of adverse effects was minor, mostly mild infusion effects and local reactions at drug administration sites.
Silva, Laura Maria Andrade; Rocha, Bruno de Oliveira; Nobre, Ana Claudia Pinto; Rego, Vitoria Regina Pedreira de Almeida; Follador, Ivonise; de Oliveira, Maria de Fatima Santos Paim
Tumor necrosis factor-alpha (TNF-?) antagonists have advanced treatment of psoriasis and other chronic inflammatory diseases but are not free of adverse effects. Pyogenic granuloma is yet described in literature as a dermatological side effect of multiple drugs such as retinoids, antiretroviral, and antineoplastic drugs but, to the best of our knowledge, it has never been reported among the adverse skin reactions following anti-TNF-? therapy. We report on a 20-year-old Caucasian man with psoriatic arthritis who developed multiple eruptive periungual and subungual pyogenic granulomas following treatment with TNF-? antagonist etanercept. PMID:24552415
Patruno, Cataldo; Balato, Nicola; Cirillo, Teresa; Napolitano, Maddalena; Ayala, Fabio
We present two patients with inflammatory bowel disease who, despite negative tuberculosis screening, developed a de novo tuberculosis infection after the start of anti tumor necrosis factor alpha treatment. We discuss current screening methods and their limitations, the approach after positive screening and the timing to resume anti-TNF? treatment after TB infection. We shortly mention the immune reconstitution inflammatory syndrome (IRIS), described in a few cases after the stop of anti-TNFalpha while treating the tuberculosis infection. We conclude with some remaining questions concerning tuberculosis in IBD patients. PMID:24295645
Debeuckelaere, Celine; De Munter, Paul; Van Bleyenbergh, Pascal; De Wever, Walter; Van Assche, Gert; Rutgeerts, Paul; Vermeire, Severine
There have been increasing concerns regarding the safety of perioperative anti-tumour necrosis factor (anti-TNF) ? agents. We performed a literature review to evaluate the post-operative complications associated with perioperative anti-TNF use in patients with inflammatory bowel disease. A comprehensive review was performed with a literature search utilizing Pub Med, Cochrane, OVID and EMBASE databases according to published guidelines. To date, there are only data for infliximab. There are three published studies which have assessed post-operative complications with perioperative infliximab use in patients with Crohn’s disease (CD), four studies in ulcerative colitis (UC) patients, and one study on both CD and UC patients. Two out of the three studies in CD patients showed no increased post-operative complications associated with perioperative infliximab. Two out of four studies in UC patients also did not show an increase in post-operative complications, and the combined study with CD and UC patients did not show an increased risk as well. Study results could not be combined secondary to significant differences in study designs, patient population and definition of their endpoints. There appears to be a risk of post-operative complications associated with TNF therapy in some patients. Based on these data, careful patient selection and prospective data collection should be performed.
Ali, Tauseef; Yun, Laura; Rubin, David T
The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs. PMID:24774504
Armuzzi, A; Lionetti, P; Blandizzi, C; Caporali, R; Chimenti, S; Cimino, L; Gionchetti, P; Girolomoni, G; Lapadula, G; Marchesoni, A; Marcellusi, A; Mennini, F S; Salvarani, C; Cimaz, R
We describe the case of an 18-yr-old male under anti-TNF treatment for Crohn's disease for more than 8 months. He developed fever and biological inflammatory syndrome without absolutely no accompanying sign or symptom or paraclinical abnormality despite extensive work-up performed in the context of his immunocompromised state. Symptoms disappeared after 10 days and a diagnosis of Puumala infection was made retrospectively on a serological basis. The case illustrates that anti-TNF treatment does not worsen the course of Puumala infection and could even be associated with a milder clinical picture. PMID:21195021
Moutschen, P; Bourhaba, M; Frippiat, F; Giot, J B; Meuris, C; Léonard, P; Moutschen, M
The clinical introduction of tumour necrosis factor (TNF) inhibitors has deeply changed the treatment of inflammatory bowel diseases (IBD). It has demonstrated impressive efficacy as compared to alternative treatments, allowing for the chance to achieve near-remission and long-term improvement in function and quality of life and to alter the natural history of Crohn's disease (CD) and ulcerative colitis (UC). As a consequence of longer follow-up periods the number of side effects which may be attributed to treatment with biologics is growing significantly. Cutaneous reactions are among the most common adverse reactions. These complications include injection site reactions, cutaneous infections, immune-mediated complications such as psoriasis and lupus-like syndrome and rarely skin cancers. We review the recent literature and draw attention to dermatological side effects of anti-TNF therapy of inflammatory bowel disease. PMID:23453887
Mocci, Giammarco; Marzo, Manuela; Papa, Alfredo; Armuzzi, Alessandro; Guidi, Luisa
Tumor necrosis factor-alpha (TNF-?) inhibitors, such as etanercept, infliximab, and adalimumab, bind to TNF-? and thereby act as anti-inflammatory agents. This group of drugs has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, moderate to severe plaque psoriasis, ankylosing spodylitis, Crohn disease, and juvenile idiopathic arthritis. We describe a 56-year-old woman who developed an erythematous pruritic rash on both arms—diagnosed as granuloma annulare by skin biopsy—approximately 22 months after initiating adalimumab for treatment of rheumatoid arthritis. On stopping adalimumab there was total clearance of the skin lesions, but a similar rash developed again when her treatment was switched to another anti-TNF agent (etanercept). This clinical observation supports a link between TNF inhibition and the development of granuloma annulare.
Ratnarathorn, Mondhipa; Raychaudhuri, Siba P; Naguwa, Stanley
When the anti-TNF? drugs first came onto the market, their high price was the subject of much debate. Moreover, we must add the costs associated with their administration to the purchase price. Variations in medical practices may be the source of substantial variations in these costs.Objective. – To compare the costs involved with the use of infliximab and etanercept in
Bruno Fautrel; Marie-Christine Woronoff-Lemsi; Morgane Ethgen; Estelle Fein; Pierre Monnet; Jean Sibilia; Daniel Wendling
Objective Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-? blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-?B- and pattern recognition receptor signalling pathways. Methods Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3–6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing. Results Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response?=?0.64 (95% confidence interval: 0.44–0.95), p?=?0.025, q?=?0.95) and INFG(rs2430561) (OR?=?0.40 (0.21–0.76), p?=?0.005, q?=?0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36–0.98), p?=?0.040, q?=?0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR?=?0.24 (0.10–0.56), p?=?0.001, q?=?0.04). Conclusions In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-? gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.
Sode, Jacob; Vogel, Ulla; Bank, Steffen; Andersen, Paal Skytt; Thomsen, Marianne Kragh; Hetland, Merete Lund; Locht, Henning; Heegaard, Niels H. H.; Andersen, Vibeke
Objective To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare risks for different anti-TNF agents. Methods We designed a national prospective registry (RATIO) from 2004 to 2006, for collecting all cases of lymphoma in French patients receiving anti-TNF therapy, whatever the indication. We conducted a case-control analysis including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population used as reference.. Results We collected 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B-cell and 5 T-cell), 5 Hodgkin’s lymphoma (HL) and 2 Hodgkin’s-like lymphoma. Epstein-Barr virus (EBV) was detected in 2 of 2 Hodgkin’s-like lymphoma, 3 of 5 HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: SIR = 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4– 1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case-control study: odds ratio=4.7 (1.3– 17.7) and 4.1 (1.4–12.5), respectively. The sex and age- adjusted incidence rate of lymphoma was 42.1 per 100,000 patient-years. The standardized incidence ratio (SIR) was 2.4 (95% confidence interval [CI] 1.7–3.2). Conclusion Some lymphomas associated with immunosuppression may occur in patients receiving anti TNF therapy, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy.
Mariette, Xavier; Tubach, Florence; Bagheri, Haleh; Bardet, Michel; Berthelot, Jean-Marie; Gaudin, Philippe; Heresbach, Denis; Martin, Antoine; Schaeverbeke, Thierry; Salmon, Dominique; Lemann, Marc; Hermine, Olivier; Raphael, Martine; Ravaud, Philippe
Objective Mucosal healing (MH) is an important treatment goal in patients with inflammatory bowel disease (IBD), but factors predicting MH under medical therapy are largely unknown. In this study, we aimed to characterize predictive factors for MH in anti-TNF-alpha antibody-treated IBD patients. Methods We retrospectively analyzed 248 IBD patients (61.3% CD, 38.7% UC) treated with anti-TNF-alpha antibodies (infliximab and/or adalimumab) for MH, defined as macroscopic absence of inflammatory lesions (Mayo endoscopy score 0 or SES-CD score 0) in colonoscopies which were analyzed before and after initiation of an anti-TNF-alpha antibody treatment. Results In patients treated with only one anti-TNF-alpha antibody (“TNF1 group”, n?=?202), 56 patients (27.7%) achieved complete MH at follow-up colonoscopy (median overall follow-up time: 63 months). In a second cohort (n?=?46), which comprised patients who were consecutively treated with two anti-TNF-alpha antibodies (“TNF2 group”), 13 patients (28.3%) achieved complete MH (median overall follow-up time: 64.5 months). Compared to patients without MH, CRP values at follow-up colonoscopy were significantly lower in patients with MH (TNF1 group: p?=?8.35×10?5; TNF2 group: p?=?0.002). Multivariate analyses confirmed CRP at follow-up colonoscopy as predictor for MH in the TNF1 group (p?=?0.012). Overall need for surgery was lower in patients with MH (TNF1 group: p?=?0.01; TNF2 group: p?=?0.03). Conclusions We identified low serum CRP level at follow-up colonoscopy as predictor for MH, while MH was an excellent negative predictor for the need for surgery.
Beigel, Florian; Deml, Matthias; Schnitzler, Fabian; Breiteneicher, Simone; Goke, Burkhard
Background. Allergy to cat dander is a common form of allergic disease. Allergen immunotherapy has been demonstrated to be effective in decreasing allergic symptoms. Objectives. To examine outcomes in allergic asthmatic patients on cat immunotherapy (CIT) compared to allergic asthmatics on traditional immunotherapy (IT) without cat sensitivity. Methods. A retrospective review identified allergic asthmatics on CIT for at least three years. An equal number of allergic asthmatics on IT were identified for comparison. Outcomes investigated include measurements of risk of asthma exacerbation. Results. Thirty-five patients were identified in each group. There were no differences in the CIT group versus the comparison group regarding total number of prednisone tapers (18 tapers versus 14 tapers, resp.), number of patients requiring prednisone tapers (10 patients versus 10 patients, resp.), total number of acute visits (29 visits versus 38 visits, resp.), and number of patients requiring acute visits (15 patients versus 21 patients, resp.). When stratified by concomitant ICS use, patients on CIT were less likely to require an acute visit (46% versus 78%, resp.). Conclusions. Allergic asthmatics with cat sensitivity on CIT with close dander exposure have similar risk of asthma exacerbation compared to allergic asthmatics without cat sensitivity on immunotherapy.
Williams, Aerik A.; Cohn, John R.; Fung, Shirley M.; Padams, Patricia
Human T cell leukemia virus type 1 or HTLV-1 infection is a public health problem in endemic regions like Japan, Central America or Africa. Although the majority of HTLV-1 carriers remain asymptomatic throughout their lives, some patients could develop neurological disorder, inflammatory arthropathy also called HTLV-1-associated arthropathy or T-cell malignancy, the adult T-cell leukemia/lymphoma or ATL with a very poor prognosis. Described to be very close to rheumatoid arthritis, HTLV-1-associated arthropathy patients have few or no response to the first line therapy with corticosteroids and disease modifying antirheumatic drugs or DMARDs. The use of anti-TNF-? agents in these patients is an interesting alternative but asks the question of risk of developing an adult T-Cell leukemia/lymphoma. We reported an exceptional case of a smoldering ATL patient with an HTLV-1-associated arthropathy, refractory to corticosteroid, DMARDs and rituximab therapy, treated successfully with etanercept, without progression to aggressive ATL after 5 years. PMID:24289962
Frenzel, Laurent; Moura, Bertrand; Marcais, Ambroise; Chapdelaine, Hugo; Hermine, Olivier
Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer(®) RG505 and Resomer(®) RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5±3°C, 25±2°C/60% RH and 40±2°C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5±3°C and that the Resomer(®) RG755S, composed of 75%(w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5°C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres. PMID:24792974
Marquette, S; Peerboom, C; Yates, A; Denis, L; Langer, I; Amighi, K; Goole, J
Since the early occurrence of inflammatory bowel diseases in young people, the role of pregnancy on disease course, and the influence of different therapies on pregnancy, fetal development and the safety of breastfeeding have been one of the important questions. Biological therapy has been increasingly used and all the above mentioned questions seem to be of a great interest. The majority of research indicate that the possibility of conception in patients with IBD are the same as in a healthy population, although there is an increased risk for the child in terms of prematurity or low birth weight. Pregnancy in IBD patient should be considered as a high risk. Most medications used to achieve or maintain remission are safe in pregnancy and breastfeeding. Exceptions are thalidomide and methotrexate that are absolutely contraindicated. Anti-TNF drugs are safe but it is advised to stop the treatment after 30-32 weeks of pregnancy due to the possibility of placental transfer of medications. Infliximab is excreted into breast milk in small quantities and breastfeeding is assumed to be safe. Pregnancy in IBD patients should be planned in advance so that the medications that are contraindicated could be excluded on time and further possible complication could be prevented by constant monitoring of pregnancy. Prospective studies of monitoring throughout pregnancy and short-term and long-term forecasts of development of children whose mothers were pregnant when suffered from inflammatory bowel disease are necessary. PMID:24471298
Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through ?2-adrenoceptors (?2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor ? (TNF?) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on ?2-ARs expressed by non-neuronal satellite cells. This stimulation of ?2-ARs decreases the neuropathy-induced production of membrane-bound TNF?, resulting in relief of neuropathic allodynia. This indirect anti-TNF? action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the ?2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies. PMID:23978467
Bohren, Yohann; Tessier, Luc-Henri; Megat, Salim; Petitjean, Hugues; Hugel, Sylvain; Daniel, Dorothée; Kremer, Mélanie; Fournel, Sylvie; Hein, Lutz; Schlichter, Rémy; Freund-Mercier, Marie-José; Yalcin, Ipek; Barrot, Michel
Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) ?, interleukin- (IL-) 1?, and IL-6. However, although biological treatment with anti-TNF-? agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-? blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium.
Costa, Luisa; Caso, Paolo; Bascherini, Vittoria; Frediani, Bruno; Cimaz, Rolando; Nieves-Martin, Laura; Atteno, Mariangela; Raffaele, Carmela G. L.; Tarantino, Giusyda; Galeazzi, Mauro; Punzi, Leonardo
A 28-year-old man treated with the antitumour necrosis factor ? (TNF?) monoclonal antibody infliximab for Crohn's disease developed pulmonary tuberculosis (TB), despite testing negative for latent TB prior to treatment. On starting anti-TB treatment and withdrawal of the anti-TNF? therapy, he deteriorated both clinically and radiologically. He was diagnosed with a flare of Crohn's disease, and immune reconstitution inflammatory syndrome (IRIS) in his right upper lobe and mediastinal lymph nodes, and commenced on oral prednisolone. Anti-TNF? therapy was re-introduced, and prednisolone weaned, following 4 months of anti-TB treatment without complication. He made a full recovery from TB, although his Crohn's symptoms continue to be troublesome. There has been no reactivation of TB to date, after 2 years follow-up.
O'Dowd, Caroline; Kewin, Peter; Morris, John; Cotton, Mark
The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies. PMID:18615156
Liu, Chunyu; Batliwalla, Franak; Li, Wentian; Lee, Annette; Roubenoff, Ronenn; Beckman, Evan; Khalili, Houman; Damle, Aarti; Kern, Marlena; Furie, Richard; Dupuis, Josée; Plenge, Robert M; Coenen, Marieke J H; Behrens, Timothy W; Carulli, John P; Gregersen, Peter K
Therapeutic options for patients with more severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is accumulating evidence that anti-tumor-necrosis-factor (anti-TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis and psoriatic arthritis. The major anti-TNF-? agents currently available, infliximab (Remicade®) and etanercept (Enbrel®), are approved for the treatment of rheumatoid arthritis (RA) in many countries. In ankylosing spondylitis there is an unmet medical need, since there are almost no disease-modifying antirheumatic drugs (DMARDs) available for severely affected patients, especially those with spinal manifestations. Judging from recent data from more than 300 patients with SpA, anti-TNF therapy seems to be even more effective in SpA than in rheumatoid arthritis. However, it remains to be shown whether patients benefit from long-term treatment, whether radiological progression and ankylosis can be stopped and whether long-term biologic therapy is safe.
Braun, Juergen; Sieper, Joachim
Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (?-synuclein) in the central nervous system (CNS) is an early pathogenic event in Parkinson's disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against ?-synuclein as a promising novel treatment strategy. Since large ?-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. In support of this, (Thy-1)-h[A30P] ?-synuclein transgenic mice with motor dysfunction symptoms were found to display increased levels of ?-synuclein protofibrils in the CNS. An ?-synuclein protofibril-selective monoclonal antibody (mAb47) was evaluated in this ?-synuclein transgenic mouse model. As measured by ELISA, 14month old mice treated for 14weeks with weekly intraperitoneal injections of mAb47 displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. Besides the lower levels of pathogenic ?-synuclein demonstrated, a reduction of motor dysfunction in transgenic mice upon peripheral administration of mAb47 was indicated. Thus, immunotherapy with antibodies targeting toxic ?-synuclein species holds promise as a future disease-modifying treatment in Parkinson's disease and related disorders. PMID:24851801
Lindström, Veronica; Fagerqvist, Therese; Nordström, Eva; Eriksson, Fredrik; Lord, Anna; Tucker, Stina; Andersson, Jessica; Johannesson, Malin; Schell, Heinrich; Kahle, Philipp J; Möller, Christer; Gellerfors, Pär; Bergström, Joakim; Lannfelt, Lars; Ingelsson, Martin
Alzheimer's disease (AD) is a proteinopathy characterized by the accumulation of ?-amyloid (A?) and tau. To date, clinical trials indicate that A? immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with A? pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser(202) and Thr(205) sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting A? pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent A? pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with A? immunotherapy. PMID:24887583
Walls, Ken C; Ager, Rahasson R; Vasilevko, Vitaly; Cheng, Dave; Medeiros, Rodrigo; LaFerla, Frank M
Objectives To compare the risk of keratinoctye skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) in patients treated for rheumatoid arthritis (RA) compared with the general population, and to determine whether anti-tumour necrosis factor (TNF) therapy exacerbates this risk. Methods Patients with RA enrolled in the British Society for Rheumatology Biologics Register, a prospective national cohort established in 2001 to monitor the safety of anti-TNF, were followed until 2008. 11 881 patients treated with anti-TNF were compared with 3629 patients receiving non-biological disease-modifying antirheumatic drugs (nbDMARD). Standardised incidence ratios (SIR) were calculated for each cohort and rates between cohorts were compared using Cox proportional HR, adjusted using inverse probability of treatment weighting. Results SIR for skin cancer was increased in both cohorts compared with the English population: SIR 1.72 (95% CI 1.43 to 2.04) anti-TNF; 1.83 (95% CI 1.30 to 2.50) nbDMARD only. In patients without previous skin cancer, BCC incidence per 100 000 patient-years was 342 (95% CI 290 to 402) after anti-TNF and 407 (95% CI 288 to 558) after nbDMARD. HR after anti-TNF adjusted for treatment weighting was 0.95 (95% CI 0.53 to 1.71). SCC incidence per 100 000 patient-years: anti-TNF 53 (95% CI 33 to 79); nbDMARD 43 (95% CI 12 to 110); adjusted HR 1.16 (95% CI 0.35 to 3.84). Conclusions Skin cancers were increased among treated patients with RA. No evidence was found that anti-TNF therapy exacerbates the risk of BCC or SCC but this cannot be excluded. Patients with RA should use sun protection and be monitored for skin cancer.
Mercer, Louise K; Green, Adele C; Galloway, James B; Davies, Rebecca; Lunt, Mark; Dixon, William G; Watson, Kath D; Symmons, Deborah PM; Hyrich, Kimme L
The objective of this study is to identify single-nucleotide polymorphisms (SNPs) predictors of treatment nonresponse to the first anti-TNF-alpha agent in ankylosing spondylitis (AS). Patients were classified as "nonresponders" if they failed to achieve improvement ?50 % of the initial BASDAI. We selected candidate SNPs previously reported, associated with susceptibility or pathogenesis of AS and with other spondylarthropaties (SpAs). The predictors of nonresponse were modeled with multiple logistic regression. The predictive power of the genetic model of nonresponse to treatment was tested with AUC-ROC. One hundred and twenty-one (121) AS patients fulfilled the inclusion criteria. Of the candidate SNPs tested for association with treatment effectiveness, five independent predictors were identified: rs917997, rs755622, rs1800896, rs3740691, and rs1061622. The genetic model of nonresponse to treatment had a predictive power of 0.77 (95 % CI 0.68-0.86). Our study identified several polymorphisms which could be the useful genetic biomarkers in predicting nonresponse to anti-TNF-alpha therapy. PMID:24337767
Schiotis, Ruxandra; Sánchez, Alejandra; Escudero, Alejandro; Bartolomé, Nerea; Szczypiorska, Magdalena; Font, Pilar; Martínez, Antonio; Tejedor, Diego; Artieda, Marta; Mulero, Juan; Buzoianu, Anca; Collantes-Estévez, Eduardo
Anti-TNF treatment is effective in a majority of rheumatoid arthritis (RA), however, this treatment can unexpectedly trigger the onset or exacerbate multiple sclerosis (MS). Recent progress in cellular immunology research provides a new framework to analyze the possible mechanism underlying these puzzling contradictory effects. The delicate balance of protective CD4(+)FoxP3(+) regulatory T cells (Tregs) and pathogenic CD4(+)FoxP3(-) effector T cells (Teffs) is crucial for the outcome of anti-TNF treatment of autoimmune disease. There is convincing evidence that TNF, in addition to stimulating Teffs, is able to activate and expand Tregs through TNFR2, which is preferentially expressed by Tregs. Therefore, the contrasting effects of TNF on Tregs and Teffs are likely to determine the therapeutic effect of anti-TNF treatment. In this review, we discuss the current understanding of the general effect of TNF on the activation of T cells, and the impact of TNF on the function of Teffs and Tregs. Understanding the differential effects of TNF on Teffs and Tregs is fundamentally required for the design of more effective and safer anti-TNF or anti-TNF receptor(s) therapeutic strategy for autoimmune diseases. PMID:21513711
Chen, Xin; Oppenheim, Joost J
Anti-TNF treatment is effective in a majority of rheumatoid arthritis (RA), however, this treatment can unexpectedly trigger the onset or exacerbate multiple sclerosis (MS). Recent progress in cellular immunology research provides a new framework to analyze the possible mechanism underlying these puzzling contradictory effects. The delicate balance of protective CD4+FoxP3+ regulatory T cells (Tregs) and pathogenic CD4+FoxP3? effector T cells (Teffs) is crucial for the outcome of anti-TNF treatment of autoimmune disease. There is convincing evidence that TNF, in addition to stimulating Teffs, is able to activate and expand Tregs through TNFR2, which is preferentially expressed by Tregs. Therefore, the contrasting effects of TNF on Tregs and Teffs are likely to determine the therapeutic effect of anti-TNF treatment. In this review, we discuss the current understanding of the general effect of TNF on the activation of T cells, and the impact of TNF on the function of Teffs and Tregs. Understanding the differential effects of TNF on Teffs and Tregs is fundamentally required for the design of more effective and safer anti-TNF or anti-TNF receptor(s) therapeutic strategy for autoimmune diseases.
Chen, Xin; Oppenheim, Joost J.
Background Rheumatoid arthritis (RA) is a chronic autoinflammatory joint disease which leads to the destruction of joints and disability of the patients. Anti-tumour necrosis factor (anti-TNF) drugs can halt radiological progression better than conventional DMARDs even in clinical non-responders. Methods The efficacy of anti-TNF plus methotrexate (MTX) treatment versus MTX monotherapy on clinical and radiological outcomes were compared in early rheumatoid arthritis (RA) patients in clinical practice by retrospective analysis of an observational cohort. 49 early RA patients (group A) on first-line MTX monotherapy and 35 early RA patients (group B) on anti-TNF plus MTX treatment were selected from an observational cohort and evaluated retrospectively focusing on their first twelve months of treatment. Data on disease activity (DAS28) and functional status (HAQ-DI) were collected three monthly. One-yearly radiological progression was calculated according to the van der Heijde modified Sharp method (vdHS). Clinical non-responder patients in both groups were selectively investigated from a radiological point of view. Results Disease activity was decreased and functional status was improved significantly in both groups. One-yearly radiological progression was significantly lower in group B than in group A. The percentage of patients showing radiological non-progression or rapid radiological progression demonstrated a significant advantage for group B patients. In addition non-responder patients in group B showed similar radiological results as responders, while a similar phenomenon was not observed in patients in group A. Conclusions Clinical efficacy within our study was similar for tight-controlled MTX monotherapy as well as for combination treatment with anti-TNF and MTX. However MTX monotherapy was accompanied by more rapid radiological progression and less radiological non-progression. Anti-TNF plus MTX decreased radiological progression even in clinical non-responders supporting the advantage of anti-TNF plus MTX combination in dissociating clinical and radiological effects.
The objectives of this study are to evaluate the effect of anti-drug antibodies on the clinical efficacy and withdrawal rate of the anti-TNF? biologics in patients with rheumatic diseases. Consecutive patients with rheumatic diseases recently commenced on anti-TNF? biologics were recruited. Serum samples were collected for assay of drug level and antibody titer against the corresponding biologics. Comparison of the clinical efficacy and drug retention rate was performed between patients with and without anti-drug antibodies. Fifty-eight Chinese patients were studied (64 % women; age 47.8 ± 12.9 years; disease duration 6.7 ± 6.4 years). The proportion of patients using infliximab (IFX), adalimumab (ADA), and etanercept (ETN) was 41, 28, and 31 %, respectively. Antibodies against IFX, ADA, and ETN were demonstrated in 12(50 %), 5(31 %) and 0(0 %) patients, respectively. Patients who developed anti-drug antibodies had significantly lower levels of the corresponding drugs (IFX level: 0.004 ± 0.01 vs 3.81 ± 3.49 ?g/ml; p = 0.002; ADA level: 0.0 vs 7.6 ± 8.3 ?g/ml; p = 0.008). Anti-drug antibody-positive patients had a significantly higher cumulative drug withdrawal rate due to inefficacy (64.7 and 71.8 % vs 10.3 and 10.3 % at month 12 and month 24, respectively; p < 0.001). In rheumatoid arthritis and psoriatic arthritis, non-responders was significantly more frequent in antibody-positive patients (54 vs 13 %; p = 0.01). In spondyloarthritis, the improvement in ankylosing spondylitis disease activity score was significant in patients without antibodies (3.89 ± 0.82 to 2.22 ± 0.86; p = 0.01) but not in those with anti-drug antibodies (3.40 ± 1.67 to 3.23 ± 1.40; p = 0.73). We concluded that the presence of neutralizing antibodies is associated with lower serum levels of the anti-TNF? biologics, leading to lower efficacy and higher withdrawal rate. PMID:23887439
Mok, C C; van der Kleij, D; Wolbink, G J
The present study describes the preliminary results of the use of 99mTc-anti-TNF-? scintigraphy as a new diagnostic approach to evaluate patients presenting with Graves' ophthalmopathy (GO). Patients (n=25) presenting at different inflammatory stages of GO and 10 healthy volunteers underwent 99mTc-anti-TNF-? scintigraphy. Images were obtained 15 min after the intravenous injection of 370 MBq (10 mCi) 99mTc-anti-TNF-?. Planar images were obtained in a 256×256 matrix (each lasting 5 min) and single photon emission computed tomography (SPECT) scan lasting 13 min. Regions of interest (ROI) were drawn on the orbit and cerebral hemispheres. The uptake of 99m Tc-anti-TNF-? in these regions was compared and positive scintigraphy established when the ROI was >2.5. In addition, uptake for each positive exam was scored as either slight (2.6-5.1), moderate (5.2-7.6), or high (>7.6). In this pilot study, 69 orbits were evaluated (1 patient had only 1 eye), and 27 had a positive CAS (?3/7). Scintigraphies were positive in 38 orbits. Comparing the results of the exams with CAS, a high sensitivity and negative predictive values were determined for scintigraphy (96.3% and 96.7%, respectively). However, the specificity and the positive predictive values were 71.4% and 68.4%, respectively, with an accuracy of 81.2%. The exclusion of examinations that were slightly positive from the analysis resulted in an improvement in test accuracy (95.5%). The preliminary results suggest that 99mTc-anti-TNF-? scintigraphy is a promising procedure for the evaluation of active orbital inflammation in GO. PMID:23918686
Rebelo Pinto, E dos S; Lopes, F P P L; de Souza, S A L; da Fonseca, L M B; Vaisman, M; Gutfilen, B; dos Santos Teixeira, P de F
Summary In 1999 a vaccine approach was found to reduce amyloid deposits in transgenic mice overproducing the amyloid precursor protein. This was followed closely by demonstrations that vaccines or passive immunotherapy could rescue memory deficits in these mice. Initial human clinical trials revealed apparent autoimmune reactions in a subset of patients, but also some cases of cognitive benefit and amyloid clearance. Further work with passive immunotherapy in mouse models confirmed exceptional clearing abilities of anti-amyloid antibodies even in older mice. However, in parallel with parenchymal amyloid clearance was the appearance of microhemorrhages and increased vascular amyloid deposition. Additional clinical trials with passive immunotherapy confirmed occasional appearance of microhemorrhage and occurrence of vasogenic edema in some patients, particularly those with the apolipoprotein E4 genotype. Recent data with positron emission tomography demonstrates trial participants passively immunized with anti-A? antibodies have reduced signals with amyloid binding ligands after 18 mo of therapy. Several anti-A? immunotherapies have reached phase 3 testing and immunotherapy is likely to be the first test of the amyloid hypothesis of Alzheimer’s disease. Identifying antibody variants that retain amyloid clearance with fewer adverse reactions remains a major focus of translational research in this area.
Tumoral necrosis factor ? plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropatties, inflammatory bowel disease, and psoriasis. Nonetheless, theoretically, some other autoimmune disorders may benefit from these agents. Our aim is to review these off-label uses of anti-TNF blockers in three common conditions: Behçet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series.
Sanchez-Cano, Daniel; Callejas-Rubio, Jose Luis; Ruiz-Villaverde, Ricardo; Rios-Fernandez, Raquel; Ortego-Centeno, Norberto
Vascular inflammation plays a key role in the pathogenesis and progression of atherosclerosis, a main complication of diabetes. The present study investigated whether an aqueous extract of Portulaca oleracea (AP) prevents the TNF-?-induced vascular inflammatory process in the human umbilical vein endothelial cell (HUVEC). The stimulation of TNF-? induced overexpression of adhesion molecules affects vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and E-selectin for example. However, AP significantly suppressed TNF-?-induced over-expression of these adhesion molecules in a dose-dependent manner. In addition, pretreatment with AP dose-dependently reduced an increase of the adhesion of HL-60 cells to TNF-?-induced HUVEC. Furthermore, we observed that stimulation of TNF-? significantly increased intracellular reactive oxygen species (ROS) production. However, pretreatment with AP markedly blocked TNF-?-induced ROS production in a dose-dependent manner. The western blot and immunofluorescence analysis showed that AP inhibited the translocation of p65 NF-?B to the nucleus. In addition, AP suppressed the TNF-?-induced degradation of I?B-? and attenuated the TNF-?-induced NF-?B binding. AP also effectively reduced TNF-?-induced mRNA expressions of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 in a dose-dependent manner. Taken together, AP prevents the vascular inflammatory process through the inhibition of intracellular ROS production and NF-?B activation as well as the reduction of adhesion molecule expression in TNF-?-induced HUVEC. These results suggested that AP might have a potential therapeutic effect by inhibiting the vascular inflammation process in vascular diseases such as atherosclerosis.
Lee, An Sook; Kim, Jin Sook; Lee, Yun Jung; Kang, Dae Gill; Lee, Ho Sub
Vascular inflammation plays a key role in the pathogenesis and progression of atherosclerosis, a main complication of diabetes. The present study investigated whether an aqueous extract of Portulaca oleracea (AP) prevents the TNF-?-induced vascular inflammatory process in the human umbilical vein endothelial cell (HUVEC). The stimulation of TNF-? induced overexpression of adhesion molecules affects vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and E-selectin for example. However, AP significantly suppressed TNF-?-induced over-expression of these adhesion molecules in a dose-dependent manner. In addition, pretreatment with AP dose-dependently reduced an increase of the adhesion of HL-60 cells to TNF-?-induced HUVEC. Furthermore, we observed that stimulation of TNF-? significantly increased intracellular reactive oxygen species (ROS) production. However, pretreatment with AP markedly blocked TNF-?-induced ROS production in a dose-dependent manner. The western blot and immunofluorescence analysis showed that AP inhibited the translocation of p65 NF-?B to the nucleus. In addition, AP suppressed the TNF-?-induced degradation of I?B-? and attenuated the TNF-?-induced NF-?B binding. AP also effectively reduced TNF-?-induced mRNA expressions of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 in a dose-dependent manner. Taken together, AP prevents the vascular inflammatory process through the inhibition of intracellular ROS production and NF-?B activation as well as the reduction of adhesion molecule expression in TNF-?-induced HUVEC. These results suggested that AP might have a potential therapeutic effect by inhibiting the vascular inflammation process in vascular diseases such as atherosclerosis. PMID:22754320
Lee, An Sook; Kim, Jin Sook; Lee, Yun Jung; Kang, Dae Gill; Lee, Ho Sub
A single-dose cynomolgus monkey pharmacokinetic study was performed comparing two monoclonal anti-TNF antibodies (mAbs), GNExTNFvF and Humira®. Normal pharmacokinetic profiles were observed over the first week of the study, followed by a rapid drop in serum mAb levels after day 8. In order to determine whether an anti-therapeutic antibody (ATA) response led to the abnormal clearance of antibody in this
Kelly M. Loyet; Rong Deng; Wei-Ching Liang; Yan Wu; Henry B. Lowman; Laura E. DeForge
Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder. Systemic treatment of IBD patients with anti-tumor necrosis factor (TNF)-alpha antibodies has proven to be a highly promising approach, but several drawbacks remain, including side effects related to systemic administration and high cost of treatment. Lactococcus lactis was engineered to secrete monovalent and bivalent murine (m)TNF-neutralizing Nanobodies as therapeutic proteins. These therapeutic proteins are derived from fragments of heavy-chain camelid antibodies and are more stable than conventional antibodies. L. lactis-secreted anti-mTNF Nanobodies neutralized mTNF in vitro. Daily oral administration of Nanobody-secreting L. lactis resulted in local delivery of anti-mTNF Nanobodies at the colon and significantly reduced inflammation in mice with dextran sulfate sodium (DSS)-induced chronic colitis. In addition, this approach was also successful in improving established enterocolitis in interleukin 10 (IL10)(-/-) mice. Finally, L. lactis-secreted anti-mTNF Nanobodies did not interfere with systemic Salmonella infection in colitic IL10(-/-) mice.In conclusion, this report details a new therapeutic approach for treatment of chronic colitis, involving in situ secretion of anti-mTNF Nanobodies by orally administered L. lactis bacteria. Therapeutic application of these engineered bacteria could eventually lead to more effective and safer management of IBD in humans. PMID:19794409
Vandenbroucke, K; de Haard, H; Beirnaert, E; Dreier, T; Lauwereys, M; Huyck, L; Van Huysse, J; Demetter, P; Steidler, L; Remaut, E; Cuvelier, C; Rottiers, P
Our aim was to evaluate the effectiveness of tumour necrosis factor (TNF) inhibitors as add-on therapy for knee synovitis that did not respond to disease-modifying antirheumatic drugs (DMARDs) and other standard treatments in patients with peripheral spondyloarthritis (SpA). We retrospectively studied 27 SpA patients, in whom an anti-TNF agent was added for active peripheral arthritis with knee synovitis refractory to DMARDs and treatment with low-dose oral corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular (IA) corticosteroids. As response of knee synovitis, were considered the absence of swelling, tenderness, and decreased range of movement in the clinical examination, after 4 months of anti-TNF therapy. In twenty-four (88.9%) of the patients there was response of knee synovitis. No statistical differences in gender (P = 0.53), age (P = 0.88), disease subtype (P = 0.22), and pattern of arthritis (P = 0.20) between knee synovitis responders and nonresponders were found. Fourteen patients managed to stop DMARD therapy and six, all of whom were initially on DMARDs combination, to decrease the number of DMARDs to one, maintaining simultaneously the response of knee synovitis. Our results imply a beneficial effect of adjunctive anti-TNF therapy on knee synovitis not responding to DMARDs and other standard treatments in patients with peripheral SpA. PMID:23840963
Sakellariou, Grigorios T; Anastasilakis, Athanasios D; Bisbinas, Ilias; Gketsos, Anastasios; Berberidis, Charalampos
Introduction Immunosuppressive therapy with anti-tumour necrosis factor-? (TNF-?) agents in rheumatic patients modulates the immune system and may increase the risk of reactivating infections that are normally maintained in a latent state, such as tuberculosis. The purpose of this study was to analyse the value of QuantiFERON TB Gold In-Tube (QFT IT) and tuberculin skin test (TST) in BCG vaccinated patients with rheumatoid arthritis and ankylosing spondylitis who were qualified to receive TNF-? blockers. Material and methods Ninety patients with rheumatoid arthritis and ankylosing spondylitis were included in the study. The control group consisted of 20 healthy participants. Chest X-ray, TST and QFT IT were carried out in all persons. Results In rheumatic patients positive results of QFT IT and TST tests were identified in 15 cases (16.7%) whereas negative results of both tests were detected in 56 cases (62.2%). In the group of examined patients, 11 (12.2%) had QFT IT-/TST+ test results. In patients with QFT IT+/TST– status one active tuberculosis case was detected. In the control group QFT IT positive results were found in 4 cases (20%) and TST positive in 11 cases (55%). Treatment with TNF-? blockers was introduced in 26 rheumatology patients with the following test status: 3 with QFT IT+/TST+; 20 with QFT IT-/TST-; 3 with QFT IT-/TST+. Conclusions In the BCG vaccinated population the QFT IT assay may potentially improve the identification and selection for therapy for latent TB infection before treatment with anti-TNF agents.
Paluch-Oles, Jolanta; Koziol-Montewka, Maria; Koszarny, Arkadiusz; Majdan, Maria
Hypoallergenic mutants with reduced IgE-binding capacity but which show a similar T-cell response to the corresponding natural allergen are ideal tools for immunotherapy, for preventing a possible anaphylactic shock. An IgE conformational epitope has been identified in Cuc m 2, the major allergen and profilin from melon. Since this epitope is highly conserved in most pollen profilins, it may contribute to an explanation of cross-reactivity between pollen and food profilins. Mutants (Mut 1 and Mut 2) were generated by changing specific residues of the Cuc m 2 epitope to alanine, produced in Escherichia coli, and purified by chromatographic methods. Mut 1 showed a slight reduction in IgE binding but an allergenic activity that was similar to recombinant Cuc m 2, as measured by basophil activation test (BAT) and skin prick test (SPT). By contrast, Mut 2 displayed a substantial reduction in IgE-binding capacity (57%) and positive responses, as determined by BAT (33%) and SPT (50%), when compared to those of rCuc m 2. However, the T-cell proliferation and cytokine production induced by Mut 2 and rCuc m 2 were similar. Thus, this mutant represent potential candidate for immunotherapy of profilin allergies. PMID:22014685
Tordesillas, Leticia; Gamboa, Pedro; Sanz, Maria L; Palacín, Arantxa; Gómez-Casado, Cristina; Cuesta-Herranz, Javier; Pacios, Luis F; Salcedo, Gabriel; Díaz-Perales, Araceli
Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.
Gouw, Launce G.; Jones, Kevin B.; Sharma, Sunil; Randall, R. Lor
Biological therapies are supposed to trigger the development of autoimmune diseases. We report a case of a 27-year old woman presenting with drug induced systemic lupus erythematosus (SLE) associated with infliximab therapy. The development of paradoxical inflammation in immune-mediated inflammatory diseases patients treated with anti TNF-? suggests that an unknown inflammatory pathway may be provoked by inhibiting TNF-?. We suppose that in our case a cross reactivity between anti-infliximab antibodies and autoantibodies may lead to the development of TNF-induced immune disease. PMID:22818164
Farkas, Klaudia; Nagy, Ferenc; Kovács, László; Wittmann, Tibor; Molnár, Tamás
Alzheimer’s disease (AD) is a growing health care epidemic. It is the most common cause of dementia and its incidence is rising. Age, which influences the oxidative and inflammatory states of the brain, is the most important risk factor. Currently there is no disease modifying treatments available for this irreversible, progressive debilitating disease. Immunotherapy represents an emerging, potentially disease modifying strategy aimed at reducing the pathological lesions of AD and facilitating cognitive improvement. Many clinical trials are currently underway. This literature review highlights current knowledge regarding the physiology of aging and how it relates to the pathogenesis of AD. In addition, immunotherapy is discussed in the context of its mechanism, current studies and future goals.
Madeo, Jennifer; Frieri, Marianne
Thalidomide is an oral immunomodulatory and anti-inflammatory drug with antitumor necrosis factor-? (TNF-?) activity. Several case reports and some clinical trials have demonstrated its efficacy in the treatment of refractory Crohn's disease (CD). We report the effect and tolerability of thalidomide in 3 patients with moderate-to-severe CD who were not responsive to anti-TNF-? therapies, and review the relevant literature. The first case is of a 28-year-old female affected by Crohn's colitis complicated by a severe fistulizing perianal disease; she was treated with infliximab, adalimumab, and certolizumab pegol, which were stopped because of intolerance. The second case is of a 39-year-old female with fistulizing ileocolitis complicated by severe arthralgias and perianal disease with loss of response to infliximab and intolerance of certolizumab pegol. The third case is of a 39-year-old male with gastric and ileocolonic CD refractory to immunosuppressors and intolerant of infliximab. All the 3 cases achieved complete clinical remission and endoscopic healing of mucosal lesions at a low dose of thalidomide (50 to 150 mg/d). In our CD patients who experienced loss of response or were unable to tolerate anti-TNF-? drugs, thalidomide was an effective and well-tolerated therapy for inducing and maintaining long-term remission. PMID:24667589
Scribano, Maria Lia; Cantoro, Laura; Marrollo, Marzia; Cosintino, Rocco; Kohn, Anna
Therapeutic agents to inhibit tumour necrosis factor alpha (TNF-?) have dramatically improved the treatment options for patients with autoimmune diseases. Common side effects include an increased susceptibility towards infection. Hepatic side effects are less frequently observed. Elevated liver function tests, hyperbilirubinaemia reactivation of chronic viral hepatitis or even acute liver failure have been described. Some cases have exhibited an autoimmune phenotype with the emergence of autoantibodies and characteristic histological lesions. We report on three patients who received anti-TNF therapy for psoriasis and presented with elevated liver function tests in the further course. Histological and serum analysis revealed an autoimmune phenotype of liver injury. In light of the growing use of anti-TNF therapies, drug-induced liver injury (DILI) with an autoimmune phenotype is an important side effect. Since the pathophysiological mechanisms related to the autoimmune phenotype of liver injury during TNF-inhibition are not well understood, the cases detailed herein should help treating physicians to improve their understanding of the situation. PMID:24420801
Rösner, S; Schad, A; Kittner, J; Rahman, F; Wörns, M A; Schuchmann, M; Galle, P R; Schattenberg, J M
The aim of this study was to analyse tuberculosis (TB) risk assessment for rheumatology patients commencing anti-tumour necrosis factor-alpha (anti-TNF-alpha) therapy using the British Thoracic Society (BTS) guidelines. Data were obtained retrospectively on 856 outpatients regionally receiving anti-TNF-alpha. Prior to commencing treatment, patients had the following assessments documented: respiratory examination, 47.4%; chest X-ray, 84.5%; TB history, 92.9%; and advice about TB risk, 45.8%. Of the 856 patients, 94.3% were on immunosuppressives but 27% had a tuberculin test; 12.6% had > or =1 high-risk factors for TB. In total, 3.4% were referred to a TB specialist and of these, 24.1% had no risk factors for TB. Of patients with > or =1 risk factor, 76.9% were not referred. Only 4/28 patients at high risk for TB due to ethnicity or birthplace received chemoprophylaxis. Marked inter-unit variation was demonstrated and it was evident that patients require improved screening for TB. Greater awareness is necessary of patients with risk factors, particularly ethnicity, to facilitate more appropriate targeting of chemoprophylaxis. Multi-centre audit is a valuable clinical governance tool. PMID:19634383
John, H; Buckley, C; Koh, L; Obrenovic, K; Erb, N; Rowe, I F
Because they are difficult to treat, animal models of widespread, established metastatic cancer are rarely used to test novel\\u000a immunotherapies. Two such mouse models are used in this report to demonstrate the therapeutic efficacy and to probe the mechanisms\\u000a of a novel combination immunotherapy consisting of the cytokine interleukin-12 (IL-12) combined with a previously described\\u000a vaccine based on MHC class
Beth A. Pulaski; Virginia K. Clements; Matthew R. Pipeling; Suzanne Ostrand-Rosenberg
Tumor necrosis factor-alpha (TNF-?) is a pleiotropic inflammatory cytokine. Tumor necrosis factor-alpha was evaluated in the serum samples of patients with idiopathic retinal periphlebitis in young adults (Eales’ disease). Retinal periphlebitis was graded according to a new grading system based on severity of inflammation (grade 1–4). Quantification of the TNF-? levels was carried out using ELISA kit in the serum samples of young adults with idiopathic retinal periphlebitis (n?=?17) and healthy controls (n?=?17) of similar age. Tumor necrosis factor-? level was found to be significantly raised in cases with retinal periphlebitis as compared with controls (p?0.001). Higher levels of TNF-? were found to be associated with increased severity of retinal periphlebitis. Tumor necrosis factor-? represents a novel target for controlling inflammatory activity in idiopathic retinal periphlebitis. Higher levels of TNF-?, in association with the increased severity of retinal periphlebitis, have implications for early anti-TNF-? therapy.
Pant, Aditya B.; Khanna, Vinay K.; Singh, Kamlesh; Shukla, Rajendra K.; Meyer, Carsten H.; Singh, Vijay K.
Tumor necrosis factor-alpha (TNF-?) is a pleiotropic inflammatory cytokine. Tumor necrosis factor-alpha was evaluated in the serum samples of patients with idiopathic retinal periphlebitis in young adults (Eales' disease). Retinal periphlebitis was graded according to a new grading system based on severity of inflammation (grade 1-4). Quantification of the TNF-? levels was carried out using ELISA kit in the serum samples of young adults with idiopathic retinal periphlebitis (n?=?17) and healthy controls (n?=?17) of similar age. Tumor necrosis factor-? level was found to be significantly raised in cases with retinal periphlebitis as compared with controls (p?0.001). Higher levels of TNF-? were found to be associated with increased severity of retinal periphlebitis. Tumor necrosis factor-? represents a novel target for controlling inflammatory activity in idiopathic retinal periphlebitis. Higher levels of TNF-?, in association with the increased severity of retinal periphlebitis, have implications for early anti-TNF-? therapy. PMID:21139707
Saxena, Sandeep; Pant, Aditya B; Khanna, Vinay K; Singh, Kamlesh; Shukla, Rajendra K; Meyer, Carsten H; Singh, Vijay K
Psoriatic arthritis (PsA) is an inflammatory arthropathy associated with skin and/or nail psoriasis. TNF-?, in addition to its pro-inflammatory role, is an essential cytokine for the host's defense, and its depletion by treatment may facilitate the risk of viral infections or their reactivation. The aim of this study was to evaluate the efficacy and safety of TNF-? blockers in PsA patients with concurrent hepatitis C virus (HCV) infection. This is a multicenter study carried out in four Italian centers specialized in the diagnosis and treatment of PsA. At baseline and after 6 (T6) and 12 months (T12) of therapy, data concerning PsA activity and liver tests were registered. A total of 15 PsA patients with concomitant HCV infection were included in the study. At baseline, 13 patients had low viral load, and liver enzyme tests were within the normal range. During the observation period, these values remained stable. On the other hand, at baseline, a high viral load with slightly increased values of AST and ALT was detected in one patient. At T6 and T12, these values decreased. The remaining patient, at baseline, had low viral load, but with slightly increased AST and ALT values that normalized during the observation period. This is the greatest sample size available in the literature on this topic. The data suggests that anti-TNF-? agents are effective and safe in PsA patients with concomitant HCV. We suggest that the use of anti-TNF-? agents, accompanied by close monitoring, could be a therapeutic option. PMID:23975363
Costa, Luisa; Caso, Francesco; Atteno, Mariangela; Giannitti, Chiara; Spadaro, Antonio; Ramonda, Roberta; Vezzù, Maristella; Del Puente, Antonio; Morisco, Filomena; Fiocco, Ugo; Galeazzi, Mauro; Punzi, Leonardo; Scarpa, Raffaele
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of ?-synuclein (?-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of ?-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of ?-syn in the mThy1-?-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of ?-syn. CT ?-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated ?-syn (CT-?-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-?-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant ?-syn with 1H7 and 5C1 prevented CT cleavage of ?-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length ?-syn, but not of the CT-?-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of ?-syn suggest that antibodies might be blocking the extracellular truncation of ?-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of ?-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease. PMID:25009275
Games, Dora; Valera, Elvira; Spencer, Brian; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Patrick, Christina; Ubhi, Kiren; Nuber, Silke; Sacayon, Patricia; Zago, Wagner; Seubert, Peter; Barbour, Robin; Schenk, Dale; Masliah, Eliezer
Allergen immunotherapy has been used to treat allergic diseases, such as asthma, allergic rhinitis, and venom allergy, since first described over a century ago. The current standard of care in the United States involves subcutaneous administration of clinically relevant allergens for several months, building up to eventual monthly injections for typically 3 to 5 years. Recent advances have improved the safety and efficacy of immunotherapy. The addition of omalizumab or Toll-like receptor agonists to standard subcutaneous immunotherapy has proved beneficial. Altering the extract itself, either through chemical manipulation producing allergoids or directly producing recombinant proteins or significant peptides, has been evaluated with promising results. The use of different administration techniques, such as sublingual immunotherapy, is common in Europe and is on the immediate horizon in the United States. Other methods of administering allergen immunotherapy have been studied, including epicutaneous, intralymphatic, intranasal, and oral immunotherapy. In this review we focus on new types and routes of immunotherapy, exploring recent human clinical trial data. The promise of better immunotherapies appears closer than ever before, but much work is still needed to develop novel immunotherapies that induce immunologic tolerance and enhanced clinical efficacy and safety over that noted for subcutaneous allergen immunotherapy. PMID:24581428
Casale, Thomas B; Stokes, Jeffrey R
Background One fourth of the adult population in Europe suffer from respiratory allergy. Subcutaneous-allergen-specific-immunotherapy (SCIT) has long-term disease modifying effect on disease specific Health-Related Quality of Life (HRQoL). The purpose of this study was to assess the effect of SCIT on alternative disease outcomes in patients with grass-pollen and/or house dust mite induced allergic rhino-conjunctivitis and/or an asthma diagnosis. Focus was on expressing outcomes in terms of generic quality of life (Quality-Adjusted-Life-Years (QALY)) and reductions in sick days. Methods The study was a multi-centre study with prospective follow-up. 248 patients were initiated on SCIT. The disease specific Rhino-conjunctivitis Quality of Life Questionnaire (RQLQ) and two generic (HRQoL) instruments 15D and EQ-5D were used at baseline and at follow-up. The outcome measures included change in; disease severity, RQLQ-scores, number of days with symptoms- and number of sick days per year and finally changes in generic HRQoL and thus, QALY. Disease severity was assessed by specialist doctors; severity of rhino-conjunctivitis was classified according to the Allergic Rhinitis and its Impact on Asthma (ARIA) and asthma severity according to the Global Initiative for Asthma (GINA guideline). The remaining outcome measures were assessed by the patients in questionnaires at baseline and at follow-up. An intension to treat approach was applied. For missing items imputation of sample mean base-line values or follow-up values were used after specified criteria. The effect of SCIT on rhino-conjunctivitis and/or asthma diagnoses was analysed at follow-up using three logistic regression models. Results The disease severity showed significantly improved disease control. Mean RQLQ-score was reduced from 3.02 at baseline to 2.00 at follow-up. Average annual days with symptoms were reduced from 189 to 145 days whilst annual sick days were reduced from 3.7 to 1.2 days. The 15D-score increased from 0.83 to 0.86 and the EQ-5D-score from 0.70 to 0.77, which indicated an annual gain per patient of 0.03-0.06 QALY. Conclusions Allergic patients suffering from rhino-conjunctivitis alone or rhino-conjunctivitis and asthma experience significantly increased HRQoL and they gain 0.03-0.06 QALY, when treated with SCIT for one year. Trial registration The study was registered at ClinicalTrials.gov with the identifier: NCT01486498.
Specific allergen injection immunotherapy is highly effective in selected patients with IgE-mediated disease, including respiratory allergy and venom anaphylaxis. Research in this area provides insight into the immunologic basis of allergic disease and may assist in the development of more highly targeted treatment. Immunotherapy reduces immediate allergen-induced symptoms and concentrations of inflammatory mediators, including histamine and prostaglandin D2, in ragweed-sensitive
Stephen R. Durham; Stephen J. Till
Active immunotherapy products (widely known as “cancer vaccines”) are products intended to stimulate an immune response to mediate tumor destruction or reduce the progression of disease in patients where cancer has been diagnosed. Some quality attributes of these products are very difficult to characterize or present a high variability (especially if they are for autologous use), further complicating the interpretation of some of the clinical data. Furthermore, questions arise in the evaluation of efficacy and safety data in comparison with current chemical or biological treatments for the same indications. Some of these aspects are discussed in this paper in relationship with the regulatory requirements in the European Union and as applied to two recently assessed medicinal products, Oncophage and Provenge, both considered therapeutic “cancer vaccines” for renal cell carcinoma and prostate cancer, respectively.
Camarero, Jorge; Ruiz, Sol
Background. We wanted to verify retrospectively the proportion of patients with psoriatic arthritis who were in remission after 1 year of continuous therapy with either etanercept or adalimumab. Remission was defined as the absence of both clinical and contrast-enhanced ultrasound (CEUS) findings suggestive of joint inflammation. Patients and Methods. The data of twenty-five patients with psoriatic arthritis were available for the clinical and CEUS evaluations before and after 1 year of continuous therapy with etanercept or adalimumab. The count of swollen (ACR66), tender (ACR68), and active inflamed joints (AJC) was used to measure the severity of joint involvement. PASI was used to score the severity of psoriasis. HAQ, DLQI, VAS pain, and VAS itching were administered to each patient before starting therapy and every 3 months, up to 1 year. Results. Eight (32%) out of twenty-five patients were in remission after 1 year of therapy with etanercept or adalimumab. A significant reduction of all clinical variables analysed was seen during the course of therapy. Conclusion. Although a significant proportion of patients achieved remission of arthritis after 1 year of effective anti-TNF therapy, the majority of them continued to have either clinical or CEUS findings suggestive of persistence of joint inflammation. PMID:24653837
Bonifati, Claudio; Elia, Fulvia; Graceffa, Dario; Ceralli, Fabrizio; Maiani, Elisa; De Mutiis, Carlo; Solivetti, Francesco M
Background. We wanted to verify retrospectively the proportion of patients with psoriatic arthritis who were in remission after 1 year of continuous therapy with either etanercept or adalimumab. Remission was defined as the absence of both clinical and contrast-enhanced ultrasound (CEUS) findings suggestive of joint inflammation. Patients and Methods. The data of twenty-five patients with psoriatic arthritis were available for the clinical and CEUS evaluations before and after 1 year of continuous therapy with etanercept or adalimumab. The count of swollen (ACR66), tender (ACR68), and active inflamed joints (AJC) was used to measure the severity of joint involvement. PASI was used to score the severity of psoriasis. HAQ, DLQI, VAS pain, and VAS itching were administered to each patient before starting therapy and every 3 months, up to 1 year. Results. Eight (32%) out of twenty-five patients were in remission after 1 year of therapy with etanercept or adalimumab. A significant reduction of all clinical variables analysed was seen during the course of therapy. Conclusion. Although a significant proportion of patients achieved remission of arthritis after 1 year of effective anti-TNF therapy, the majority of them continued to have either clinical or CEUS findings suggestive of persistence of joint inflammation.
Elia, Fulvia; Ceralli, Fabrizio; Maiani, Elisa; De Mutiis, Carlo; Solivetti, Francesco M.
We review the global experience of infections in patients treated with tumour necrosis factor (TNF)-? inhibitors, which shows that the overall incidence of severe infections is at least doubled. In particular, this is true regarding tuberculosis. Screening and prophylactic measures have substantially reduced but not eliminated the risk. Recent improvements in immunologic testing for non-Bacillus Calmette-Guerin (BCG)-related antigens allow more sensitive identification of latent tuberculosis and wider use of such methods holds promise as pre-treatment screening instruments. PMID:22100287
Nacci, Francesca; Matucci-Cerinic, Marco
Aim To determine whether immunotherapy with HPV6 L1 virus like particles (VLPs) without adjuvant (VLP immunotherapy) reduces recurrence of genital warts following destructive therapy. Trial design A randomized placebo controlled blinded study of treatment of recurrent genital warts amenable to destructive therapy, conducted independently in Australia and China. Methods Patients received conventional destructive therapy of all evident warts together with intramuscular administration of 1, 5 or 25 µg of VLP immunotherapy, or of placebo immunotherapy (0.9% NaCl), as immunotherapy at week 0 and week 4. Primary outcome, assessed at week 8, was recurrence of visible warts. Results Of 33 protocol compliant Brisbane recipients of placebo immunotherapy, 11 were disease free at two months, and a further 9 demonstrated reduction of > 50% in total wart area. Wart area reduction following destructive treatment correlated with prior duration of disease. Among 102 protocol compliant Brisbane recipients of VLP immunotherapy, disease reduction was significantly greater than among the placebo immunotherapy (50% ± s.e.m. 7%) recipients for subjects receiving 5 µg or 25 µg of VLP immunotherapy/dose (71% ± s.e.m.7%) but not for those receiving 1 µg VLP immunotherapy/dose (42% ± 7%). Of 52 protocol compliant placebo immunotherapy recipients in Wenzhou, 37 were disease free at two months, and a further 8 had > 50% disease reduction. Prior disease duration was much shorter in Wenzhou subject (8.1 ± 1.1 mo) than in Brisbane subjects (53.7 ± 5.5 mo). No significant reduction in mean wart area was observed for the 168 Wenzhou protocol compliant subjects who also received VLP immunotherapy. Conclusions This study confirms the findings in a previous open label trial that administration of VLP immunotherapy may assist in clearance of recurrent genital warts in patients for whom destructive therapy is unsuccessful and that unsuccessful destructive therapy is more common with increasing prior disease duration.
Jardine, David; Lu, Jieqiang; Pang, James; Palmer, Cheryn; Tu, Quanmei; Chuah, John; Frazer, Ian H.
More research and new treatment options are needed in all stages of lung cancer. To this end immunotherapy needs a revival in view of recent improved technologies and greater understanding of the underlying biology. In this review we discuss mechanisms of tumour immunotherapy, non-specific, specific and adoptive, with particular reference to a direct therapeutic action on all subtypes of lung cancer.
Al-Moundhri, M.; O'Brien, M.; Souberbielle, B. E.
Immunotherapy for treating illicit drug abuse is a rapidly advancing field. There are currently two major approaches to developing drug-specific immunotherapies: active and passive. Active immunotherapy involves conjugating a drug-like hapten to a carrier protein and using traditional immunization approaches to generate a drug-specific immune response in the patient. In contrast, passive immunotherapy utilizes preformed monoclonal antibodies. Whether generated by active immunization or delivered passively, antibodies act as pharmacokinetic antagonists by binding the drug in the blood-stream and reducing the amount and rate of drug delivery to receptors in the brain. A newly emerging technology in anti-drug immunotherapy is the use of antibody fragments, or scFvs, rather than intact immunoglobulin G (IgG). These scFvs can retain the same binding properties as the original mAbs, and are onethird the molecular weight, providing a scaffold for creating antibody treatments with more customizable properties. Another nascent area of research utilizing the scFv scaffold is in creating drug-specific scFv-nanoparticle conjugates. These conjugates could improve upon current drug-specific antibody paradigms by increasing multivalency and allowing pharmacokinetic customization, while avoiding interactions with endogenous antibody receptor pathways. These parallel approaches to immunotherapy are moving rapidly toward the clinic and may soon provide new therapies for treating drug abuse. PMID:19592672
Peterson, Eric C; Owens, S Michael
Anti-TNF-Alpha-Adalimumab Therapy Is Associated with Persistent Improvement of Endothelial Function without Progression of Carotid Intima-Media Wall Thickness in Patients with Rheumatoid Arthritis Refractory to Conventional Therapy
To determine whether treatment with the anti-TNF-alpha blocker adalimumab yields persistent improvement of endothelial function and prevents from morphological progression of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) refractory to conventional therapy, a series of 34 consecutive RA patients, attending hospital outpatient clinics and who were switched from disease modifying antirheumatic drug therapy to anti-TNF-alpha-adalimumab treatment because of severe disease, were assessed by ultrasonography techniques before the onset of adalimumab therapy (at day 0) and then at day 14 and at month 12. Values of flow-mediated endothelium-dependent vasodilatation at day 14 and at month 12 were significantly higher (mean ± standard deviation (SD): 6.1 ± 3.9%; median: 5.7% at day 14, and mean ± SD: 7.4 ± 2.8%; median: 6.9% at month 12) than those obtained at day 0 (mean: 4.5 ± 4.0%; median: 3.6%; P = 0.03 and P < 0.001, resp.). Endothelium-independent vasodilatation results did not significantly change compared with those obtained at day 0. No significant differences were observed when carotid artery intima-media wall thickness values obtained at month 12 (mean ± SD: 0.69 ± 0.21?mm) were compared with those found at day 0 (0.65 ± 0.16?mm) (P = 0.3). In conclusion, anti-TNF-alpha-adalimumab therapy has beneficial effects on the development of the subclinical atherosclerosis disease in RA.
Gonzalez-Juanatey, Carlos; Vazquez-Rodriguez, Tomas R.; Miranda-Filloy, Jose A.; Gomez-Acebo, Ines; Testa, Ana; Garcia-Porrua, Carlos; Sanchez-Andrade, Amalia; Llorca, Javier; Gonzalez-Gay, Miguel A.
While bone marrow edema (BME) is diagnostic of spondyloarthropathy, its nature remains poorly understood. In contrast, BME in ankylosing spondylitis is caused by tumor necrosis factor (TNF)-induced vascular and cellular changes. To investigate the relationship between chronic compression and TNF signaling in compression-induced BME we utilized a tail vertebrae compression model with WT, TNF-Tg, and TNFR1&2-/- mice to evaluate: (i) healing following release of chronic compression, (ii) induction of BME in the absence of TNFR, and (iii) efficacy of anti-TNF therapy. Compression-induced normalized marrow contrast enhancement (NMCE) in WT was significantly decreased threefold (p?0.01) within 2 weeks of release, while the NMCE values in TNF-Tg vertebrae remained elevated, but had a significant decrease (p?0.05) by 6 weeks after the release of compression. TNFR1&2-/- mice were resistant to compression-induced BME. Anti-TNF therapy did not affect NMCE versus placebo. Histological examination revealed that NMCE values significantly correlated with marrow vascularity and cellularity (p?0.05), which account for 76% of the variability of NMCE. Collectively, these data demonstrate a critical role for TNF in the induction of chronic compression-induced BME, but not in its maintenance. Amelioration of BME is achieved through biomechanical stability, but is not affected by anti-TNF therapy. PMID:21445993
Papuga, M Owen; Kwok, Edmund; You, Zhigang; Rubery, Paul T; Dougherty, Paul E; Pryhuber, Gloria; Beck, Christopher A; Hilton, Matthew J; Awad, Hani A; Schwarz, Edward M
While bone marrow edema (BME) is diagnostic of spondyloarthropathy, its nature remains poorly understood. In contrast, BME in ankylosing spondylitis is caused by TNF-induced vascular and cellular changes. To investigate the relationship between chronic compression and TNF signaling in compression induced BME we utilized a tail vertebrae compression model with WT, TNF-Tg and TNFR1&2?/? mice to evaluate: 1) healing following release of chronic compression, 2) induction of BME in the absence of TNFR, and 3) efficacy of anti-TNF therapy. Compression-induced normalized marrow contrast enhancement (NMCE) in WT was significantly decreased 3-fold (p<0.01) within 2 weeks of release, while the NMCE values in TNF-Tg vertebrae remained elevated, but had a significant decrease (p<0.05) by 6 weeks after the release of compression. TNFR1&2?/? mice were resistant to compression-induced BME. Anti-TNF therapy did not affect NMCE vs. placebo. Histological examination revealed that NMCE values significantly correlated with marrow vascularity and cellularity (p<0.05), which account for 76% of the variability of NMCE. Collectively, these data demonstrate a critical role for TNF in the induction of chronic compression-induced BME, but not in its maintenance. Amelioration of BME is achieved through biomechanical stability, but is not affected by anti-TNF therapy.
Papuga, M. Owen; Kwok, Edmund; You, Zhigang; Rubery, Paul T.; Dougherty, Paul E.; Pryhuber, Gloria; Beck, Christopher A.; Hilton, Matthew J.; Awad, Hani A.; Schwarz, Edward M.
Biologics such as TNF antagonists are a new class of drugs that have greatly improved Rheumatoid Arthritis (RA) treatment. However, for unknown reasons, individual patients with RA respond to one of these drugs but not to others even those targeting the same molecule. Methods to predict response are sorely needed because these drugs are currently selected by trial and error, what is very inefficient and prejudicial for the patient and the healthcare system. Here, we have explored the discovery of protein biomarkers in serum from patients treated with infliximab, one of the major anti-TNF drugs. The study was based in a quantitative proteomics approach using 8-plex iTRAQ labeling. It combined depletion of the most abundant serum proteins, two-dimensional LC fractionation, protein identification and relative quantification with a hybrid Orbitrap mass spectrometer. This approach allowed the identification of 315 proteins of which 237 were confidently quantified with two or more peptides. The detection range covered up to 6 orders of magnitude including multiple proteins at the ng/mL level. A new set of putative biomarkers was identified comprising 14 proteins significantly more abundant in the non-responder patients. The differential proteins were enriched in apolipoproteins, components of the complement system and acute phase reactants. These results show the feasibility of this approach and provide a set of candidates for validation as biomarkers for the classification of RA patients before the beginning of treatment, so that anticipated non-responders could be treated with an alternative drug. PMID:23000593
Ortea, Ignacio; Roschitzki, Bernd; Ovalles, Juan Gabriel; Longo, Javier López; de la Torre, Inmaculada; González, Isidoro; Gómez-Reino, Juan J; González, Antonio
Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. Here, we review the major immunotherapeutic approaches currently under investigation for colorectal cancer, including cancer vaccines and adoptive cell therapy. Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval, and mainstream adoption of colorectal cancer immunotherapeutics. PMID:23725603
Xiang, Bo; Snook, Adam E; Magee, Michael S; Waldman, Scott A
Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. Here, we review the major immunotherapeutic approaches currently under investigation for colorectal cancer, including cancer vaccines and adoptive cell therapy. Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval and mainstream adoption of colorectal cancer immunotherapeutics.
Xiang, Bo; Snook, Adam E.; Magee, Michael S.; Waldman, Scott A.
Immunotherapy is a conceptually attractive approach, because it is highly specific and can deal with disseminated disease with minimal impact on normal tissues. Ability to induce antigen-specific immune responses in patients with lung cancer is now well established in early-phase clinical trials using a variety of immunotherapeutic approaches. Although no immunotherapy is likely to be a panacea, randomizedphaseIIBstudiesofferpromiseoftherapeuticactivityin both early-
Edward A. Hirschowitz; John R. Yannelli
Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4–6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor response in vivo.
Niccolai, Elena; Prisco, Domenico; D'Elios, Mario Milco; Amedei, Amedeo
Clinical trials employing immunotherapy frequently involve patients with many different types of cancer. Accordingly, this Cancergram focuses on the immunotherapy employed rather than the disease diagnosis. Adoptive, active specific, and active nonspecifi...
Clinical trials employing immunotherapy frequently involve patients with many different types of cancer. Accordingly, the Cancergram focuses on the immunotherapy employed rather than the disease diagnosis. Adoptive, active specific, and active nonspecific...
The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.
Koido, Shigeo; Ohkusa, Toshifumi; Homma, Sadamu; Namiki, Yoshihisa; Takakura, Kazuki; Saito, Keisuke; Ito, Zensho; Kobayashi, Hiroko; Kajihara, Mikio; Uchiyama, Kan; Arihiro, Seiji; Arakawa, Hiroshi; Okamoto, Masato; Gong, Jianlin; Tajiri, Hisao
Therapy for autoimmune demyelinating disorders has evolved rapidly over the past 10 years to include traditional immunosuppressants as well as novel biologicals. Antibody-mediated neuromuscular disorders are treated with therapies that acutely modulate pathogenic antibodies or chronically inhibit the humoral immune response. In other inflammatory autoimmune disorders of the peripheral and central nervous system, corticosteroids, often combined with conventional immunosuppression, and immunomodulatory treatments are used. Because autoimmune neurologic disorders are so diverse, evidence from randomized controlled trials is limited for most of the immunotherapies used in neurology. This review provides an overview of the immunotherapies currently used for neurologic disorders. PMID:22703853
Graves, Donna; Vernino, Steven
Our immune system is characterized by remarkable specificity, potency and memory – the ability of a single vaccine treatment to provide life-long protection. No pharmacologic treatment for any indication can provide the same level of safety, efficacy and long-lasting effect that a vaccine can. Thus, researchers and clinicians alike have sought to apply these characteristics to the treatment of cancer. Yet, for the last 125 years, the field has failed to realize this potential. Here, we will review some of the most promising cancer immunotherapeutic approaches in development today, as recent clinical successes signal the beginning of cancer immunotherapy’s transition from experimental to established therapy.
Snook, Adam E.; Waldman, Scott A.
Allergen specific immunotherapy, together with drugs and allergen avoidance, is a cornerstone in the management of respiratory allergy. The traditional subcutaneous route is burdened with the risk of severe adverse events; therefore, safer routes of administration (noninjection or local routes) have been investigated and developed. Controlled trials failed to demonstrate the clinical efficacy and the safety of oral and bronchial
Giorgio Walter Canonica; Giovanni Passalacqua
Conclusion The future certainly holds promise for the treatment of food allergies. Generally, future treatments can be divided into immunological\\u000a manipulation of the food-allergic subject (mucosal vaccines, new immunotherapies, cytokine level alterations) or manipulation\\u000a of the food through genetic engineering to diminish or abolish its allergenic activity.
Samuel B. Lehrer; Laurianne G. Wild; Kenneth L. Bost; Ricardo U. Sorensen
Anticancer immunotherapy holds great promises, as long-term responses to interleukin-2 have been observed in metastatic melanoma and renal cell carcinoma patients. However, improving the relative low rates of such responses has constituted a great challenge. In our experience, high-dose radiation combined with interleukin-2 provided encouraging results that are worth exploring further.
Seung, Steven K.; Curti, Brendan; Crittenden, Marka; Urba, Walter
The burden of neurological diseases in western societies has accentuated the need to develop effective therapies to stop the progression of chronic neurological diseases. Recent discoveries regarding the role of the immune system in brain damage coupled with the development of new technologies to manipulate the immune response make immunotherapies an attractive possibility to treat neurological diseases. The wide repertoire
Pablo Villoslada; Beatriz Moreno; Ignacio Melero; Jose L. Pablos; Gianvito Martino; Antonio Uccelli; Xavier Montalban; Jesus Avila; Serge Rivest; Laia Acarin; Stanley Appel; Samia J. Khoury; Patrick McGeer; Isidro Ferrer; Mario Delgado; Jose Obeso; Michal Schwartz
Significant advances have been made in the field of cancer immunology and immunotherapy over the last three decades. An important step forward was the identification of human cancer antigens eliciting spontaneous immune responses in cancer patients. The most immunogenic human cancer antigens known to date belong to the cancer-testis family of antigens, which are proteins expressed in various types of
Maries van den Broek; Lotta von Boehmer; Alexander Knuth
Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (> 30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia. PMID:23959031
Skyberg, Jerod A
Adoptive transfer of tumor-reactive T cells has emerged as a promising advance in tumor immunotherapy. Specifically, infusion of tumor-infiltrating lymphocytes has led to long-term objective clinical responses for patients with metastatic melanoma. Donor lymphocyte infusion is also an effective treatment of post-transplant lymphoproliferative disease. However, adoptive T cell therapy has restrictions in the isolation and expansion of antigen-specific lymphocytes for a large group of patients. One approach to circumvent this limitation and extend adoptive immunotherapy to other cancer types is the genetic modification of T cells with antigen-specific receptors. In this article, we review strategies to redirect T cell specificity, including T cell receptor gene transfer and antibody receptor gene transfer.
Al-Khami, Amir A; Mehrotra, Shikhar
Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (>30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia.
Skyberg, Jerod A.
Sublingual immunotherapy (SLIT) is a safe and patient-friendly variant of allergen immunotherapy. These characteristics may provide physicians with a therapy, perfectly suited to the treatment of allergic children. To give an overview of currently published studies on SLIT in children Pubmed was searched for randomised clinical trials (RCTs). In addition available systematic reviews and long-term observational studies were analysed. Until now, 13 RCTs on allergic rhinitis, 22 studies on asthma (including eight studies involving only children) and one study on atopic dermatis have been published. In addition, five systematic reviews on allergic rhinitis have been published and one is in press. One meta-analysis of adults and children with asthma has been reported. All studies report varying results. The effects and their magnitude differ between studies. Systematic reviews give inconsistent results. For allergic rhinitis three reviews appeared to be negative, two were positive and one analysis was inconsistent regarding children. In asthma a meta-analysis involving both adults and children concluded that SLIT is moderately effective. From observational studies effects of SLIT are suggested to persist after discontinuation. Randomised trials indicate that SLIT may prevent the onset of asthma and new sensitisations. As long as evidence for effectiveness is weak, SLIT cannot be firmly recommended in clinical practice. Nevertheless, the proven effectiveness of SLIT in adults supports the proof in principle of this therapy. In the near future immunotherapy trials in children may provide the required proof of effectiveness. PMID:18294100
van Wijk, Roy Gerth
The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-?2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy.
Kirkwood, John M.; Butterfield, Lisa H.; Tarhini, Ahmad A.; Zarour, Hassane; Kalinski, Pawel; Ferrone, Soldano
Allergen specific immunotherapy (ASI) is a well-documented treatment for allergic asthma, rhinitis and allergy to bee venoms. Immunotherapy with subcutaneous injections of allergens extracts has proved beneficial in reducing symptoms of allergic rhinitis and asthma. Side effects due to specific immunotherapy in short term have been largely documented. These effects were various but were usually mild. Fatal reactions are less frequent. We reported a case of a woman, with a history of allergic asthma under specific desensitization protocol who developed an acute multi-organ failure (MOF) consecutive to administration of ASI (Alustal® Stallergenes SA, France). This fatal reaction has never been described as adverse event of specific immunotherapy. We aimed to describe this dramatic reaction, expose the arguments to define the relationship between the administration of allergen extract and the occurrence of this fatal reaction.
Sana, Aissa; Salem, Chaker Ben; Ahmed, Khedher; Abdelbeki, Azouzi; Jihed, Sehli; Imene, Ben Saida; Mohamed, Boussarsar
Allergen specific immunotherapy (ASI) is a well-documented treatment for allergic asthma, rhinitis and allergy to bee venoms. Immunotherapy with subcutaneous injections of allergens extracts has proved beneficial in reducing symptoms of allergic rhinitis and asthma. Side effects due to specific immunotherapy in short term have been largely documented. These effects were various but were usually mild. Fatal reactions are less frequent. We reported a case of a woman, with a history of allergic asthma under specific desensitization protocol who developed an acute multi-organ failure (MOF) consecutive to administration of ASI (Alustal(®) Stallergenes SA, France). This fatal reaction has never been described as adverse event of specific immunotherapy. We aimed to describe this dramatic reaction, expose the arguments to define the relationship between the administration of allergen extract and the occurrence of this fatal reaction. PMID:23785560
Sana, Aissa; Ben Salem, Chaker; Ahmed, Khedher; Abdelbeki, Azouzi; Jihed, Sehli; Imene, Ben Saida; Mohamed, Boussarsar
Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe's policy-makers to coordinate actions and improve individual and public health in allergy by:Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade. PMID:23110958
Calderon, Moises A; Demoly, Pascal; Gerth van Wijk, Roy; Bousquet, Jean; Sheikh, Aziz; Frew, Anthony; Scadding, Glenis; Bachert, Claus; Malling, Hans J; Valenta, Rudolph; Bilo, Beatrice; Nieto, Antonio; Akdis, Cezmi; Just, Jocelyne; Vidal, Carmen; Varga, Eva M; Alvarez-Cuesta, Emilio; Bohle, Barbara; Bufe, Albrecht; Canonica, Walter G; Cardona, Victoria; Dahl, Ronald; Didier, Alain; Durham, Stephen R; Eng, Peter; Fernandez-Rivas, Montserrat; Jacobsen, Lars; Jutel, Marek; Kleine-Tebbe, Jörg; Klimek, Ludger; Lötvall, Jan; Moreno, Carmen; Mosges, Ralph; Muraro, Antonella; Niggemann, Bodo; Pajno, Giovanni; Passalacqua, Giovanni; Pfaar, Oliver; Rak, Sabina; Senna, Gianenrico; Senti, Gabriela; Valovirta, Erkka; van Hage, Marianne; Virchow, Johannes C; Wahn, Ulrich; Papadopoulos, Nikolaos
Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy. Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies. Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases. Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits. We call upon Europe’s policy-makers to coordinate actions and improve individual and public health in allergy by: Promoting awareness of the effectiveness of allergen specific immunotherapy Updating national healthcare policies to support allergen specific immunotherapy Prioritising funding for allergen specific immunotherapy research Monitoring the macroeconomic and health economic parameters of allergy Reinforcing allergy teaching in medical disciplines and specialties The effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.
Regulatory T cells (Tregs) suppress exuberant immune system activation and promote immunologic tolerance. Because Tregs modulate both innate and adaptive immunity, the biomedical community has developed an intense interest in using Tregs for immunotherapy. Conditions that require clinical tolerance to improve outcomes – autoimmune disease, solid organ transplantation, and hematopoietic stem cell transplantation – may benefit from Treg immunotherapy. Investigators have designed ex vivo strategies to isolate, preserve, expand, and infuse Tregs. Protocols to manipulate Treg populations in vivo have also been considered. Barriers to clinically feasible Treg immunotherapy include Treg stability, off-cell effects, and demonstration of cell preparation purity and potency. Clinical trials involving Treg adoptive transfer to treat graft versus host disease preliminarily demonstrated the safety and efficacy of Treg immunotherapy in humans. Future work will need to confirm the safety of Treg immunotherapy and establish the efficacy of specific Treg subsets for the treatment of immune-mediated disease.
Singer, Benjamin D.; King, Landon S.; D'Alessio, Franco R.
The invention relates to a method for predicting the efficacy of a cancer immunotherapy of an individual with respect to clinical benefit, which comprises the following steps: --providing a blood sample of said individual, --(a1) determining the number of lymphocytes in the blood of said individual, and/or (a2) determining the number of neutrophils in the blood of said individual, and --(b1) identifying the individual as having a predictive clinical benefit from the immunotherapy, if the number Of lymphocytes is below or equal to a lymphocyte baseline level of 1.4 to 1.8.times.10.sup.9 per liter blood, especially below or equal to 1.6.times.10.sup.9 per liter blood; or (b2) identifying the individual as having a predictive clinical benefit from the immunotherapy, if the number of neutrophils is below or equal to a neutrophil baseline level of from 4.0 to 6.0.times.10.sup.9 per liter blood, especially below or equal to 5.0.times.10.sup.9 neutrophils per liter blood; or (b3) identifying the individual as not having a predictive clinical benefit, if the number of lymphocytes is above a lymphocyte baseline level of 1.4 to 1.8.times.10.sup.9 per liter blood, especially above 1.6.times.10.sup.9 per liter blood and the number of neutrophils is above a neutrophil baseline level of from 4.0 to 6.0.times.10.sup.9 per liter blood, especially above 5.0.times.10.sup.9 neutrophils per liter blood.
Our immune system is characterized by remarkable specificity, potency, and memory -- the ability of a single vaccine treatment to provide life-long protection. No pharmacologic treatment for any indication can provide the same level of safety, efficacy, and long-lasting effect that a vaccine can. Thus, researchers and clinicians alike have sought to apply these characteristics to the treatment of cancer. Yet, for the last 125 years, the field has failed to realize this potential. Here, we will review some of the most promising cancer immunotherapeutic approaches in development today, as recent clinical successes signal the beginning of cancer immuno-therapy's transition from experimental to established therapy. PMID:23449114
Snook, Adam E; Waldman, Scott A
Most cancer patients are treated with some combination of surgery, radiation, and chemotherapy. Despite recent advances in local therapy with curative intent, chemotherapeutic treatments for metastatic disease often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore, the evaluation of novel therapeutic options is of great interest. Conventional, along with newer treatment strategies target the immune system that suppresses genitourinary (GU) malignancies. Metastatic renal cell carcinoma and non-muscle-invasive bladder caner represent the most immune-responsive types of all human cancer. This review examines the rationale and emerging evidence supporting the anticancer activity of immunotherapy, against GU malignancies.
Inamoto, Teruo; Azuma, Haruhito
Therapeutic cancer vaccination, e.g. by using tumour antigen-presenting dendritic cells (DCs) that 'educate' the immune system to recognise and attack tumour cells, represents a new concept of treatment in oncology. DCbased immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DCs emerge as a feasible and effective strategy to control residual disease in acute myeloid leukaemia (AML), in particular as a post-remission treatment to prevent full relapse. This innovative approach takes advantage of the intrinsic potential of the immune system to eradicate malignant disease. PMID:23340144
Van De Velde, A L R; Anguille, S; Berneman, Z N
Cancer, a major health problem, affects 12 million people worldwide every year. With surgery and chemo-radiation the long term survival rate for the majority of cancer patients is dismal. Thus novel treatments are urgently needed. Immunotherapy, the harnessing of the immune system to destroy cancer cells is an attractive option with potential for long term anti-tumor benefit. Cytokines are biological response modifiers that stimulate anti-tumor immune responses. In this review, we discuss the anti-tumor efficacy of the chemotactic cytokine CCL21 and its pre-clinical and clinical application in cancer. PMID:24810425
Lin, Yuan; Sharma, Sherven; John, Maie St
Cancer, a major health problem, affects 12 million people worldwide every year. With surgery and chemo-radiation the long term survival rate for the majority of cancer patients is dismal. Thus novel treatments are urgently needed. Immunotherapy, the harnessing of the immune system to destroy cancer cells is an attractive option with potential for long term anti-tumor benefit. Cytokines are biological response modifiers that stimulate anti-tumor immune responses. In this review, we discuss the anti-tumor efficacy of the chemotactic cytokine CCL21 and its pre-clinical and clinical application in cancer.
Lin, Yuan; Sharma, Sherven; John, Maie St.
Lung cancer is the leading cause of cancer-related deaths worldwide. Although treatment methods in surgery, irradiation, and chemotherapy have improved, prognosis remains unsatisfactory and developing new therapeutic strategies is still an urgent demand. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumor cells by recognition of tumor-associated antigens without damage to normal cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and phase III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumor antigens work in only a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumor cells because tumor cells escape from host immune scrutiny. Understanding of the mechanism of immune evasion regulated by tumor cells is required for the development of more effective immunotherapeutic approaches against lung cancer. This paper discusses the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer.
Ho, Ming-Yi; Tang, Shye-Jye; Sun, Kuang-Hui; Yang, Winnie
The major cause of treatment failure in human and veterinary cancer patients is tumor invasion and metastasis. The inability of local therapy (surgery, radiation, photodynamic therapy) to eradicate a metastatic cancer presents a challenge in the therapy of residual or micrometastatic disease. Because of its local therapy limitations, chromophore-enhanced selective photothermal laser treatment has been augmented with a superimposed laser-induced systemic photobiological reaction, laser immunotherapy. Laser immunotherapy is a novel cancer treatment consisting of: (1) a laser in the infrared wavelength range (i.e. 805 nm solid state laser); (2) a photosensitizer of the corresponding absorption peak [i.e. indocyanine green (ICG)]; and (3) an immunoadjuvant [i.e. glycated chitosan gel (GCG)]. The intratumor injection of the photosensitizer (ICG) and immunoadjuvant (GCG) solution is followed by noninvasive laser irradiation. The laser energy causes tumor cell destruction by photothermal interaction to reduce the tumor burden and at the same time exposes tumor antigens. The immunoadjuvant concomitantly stimulates the host to mount a systemic anti-tumor immune response against the remaining cells of the tumor and to induce a long-term, tumor-specific immunity. This study investigates the feasibility of utilizing laser immunotherapy as an adjunctive therapy for the control of feline fibrosarcoma in future.
Woods, J. P.; Bartels, Kenneth E.; Davidson, Ellen B.; Ritchey, Jerry W.; Lehenbauer, Terry W.; Nordquist, Robert E.; Chen, Wei R.
Substantial progress has been made in the treatment of leukemia in childhood. Despite this, leukemia remains a leading cause of pediatric cancer-related mortality and the prognosis is guarded for individuals with relapsed or refractory disease. Standard therapies are associated with a wide array of acute and long-term toxicities and further treatment intensification may not be tolerable or beneficial. The curative potential of allogeneic stem cell transplantation is due in part to the graft-versus-leukemia effect, which provides evidence for the therapeutic capacity of immune-based therapies. In recent years there have been significant advances in the development and application of immunotherapy in the treatment of leukemias, including the demonstration of activity in chemotherapy-resistant cases. This review summarizes immunotherapeutic approaches in the treatment of pediatric leukemia including current results and future directions.
Shah, Nirali N.; Dave, Hema; Wayne, Alan S.
Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. The growing interest over the past two decades in harnessing the immune system to eradicate cancer has been accompanied by heightened efforts to characterize cytokines and exploit their vast signaling networks to develop cancer treatments. The goal of this paper is to review the major cytokines involved in cancer immunotherapy and discuss their basic biology and clinical applications. The paper will also describe new cytokines in pre-clinical development, combinations of biological agents, novel delivery mechanisms, and potential directions for future investigation using cytokines.
Lee, Sylvia; Margolin, Kim
Underlying immunodeficiency should be suspected in every patient, irrespective of age, who has recurrent, persistent, severe, or unusual infections. Defects in immunity can be classified into primary or secondary disorders involving specific or nonspecific immune mechanisms. Several forms of primary and secondary immunodeficiency exist for which various immunotherapeutic modalities are available. Significant among these are immunoglobulins commercially available for intravenous infusion. Other therapies include transplantation of tissue such as bone marrow, fetal liver, and fetal thymus. Enzyme replacement therapy is being developed, as is the use of products unique to immunocompetent cells, such as thymus extract, thymosin, interleukins, and transfer factor. Forms of nonspecific immune modulators and stimulators are other possibilities, especially in the context of the immunotherapy of tumors. PMID:3299294
Solinger, A M
Disappointing findings from recent phase III trials on amyloid-? (A?) immunotherapy for Alzheimer's disease (AD) have shifted the focus of such treatments to the tau protein. As tau pathology correlates better with the degree of dementia than A? plaque burden, it is a more attractive target once cognitive impairments are evident, while A? therapies may be better suited for the presymptomatic phase of the disease. Over 12 years ago, we initiated a tau immunotherapy program, seeking to alleviate the functional impairments associated with tau lesions in tauopathies. We have reported that various active and passive tau immunizations diminish tau pathology and improve function, including cognition, in different mouse models. Both extra- and intracellular pathways are likely involved. The antibodies may block the spread of tau pathology via microglial phagocytosis of the antibody-tau complex and facilitate lysosomal tau clearance in neurons after endosomal uptake. We have observed such antibody internalization following intracarotid injection in mice and in various culture models. These include brain slices and primary neurons from tangle mice as well as human neuroblastoma cell lines. Antibody targeting of different intracellular protein aggregates, including ?-synuclein, A? and superoxide dismutase has been reported by others. Now, several laboratories have confirmed and extended our findings using various active and passive tau immunizations in different models, thereby clearly establishing the feasibility of this approach for clinical trials. We are also working on imaging approaches to monitor tau pathology, its consequences and the efficacy of treatments. Dire need exists for such diagnostic methods for tauopathies. Overall, therapies and diagnostic tools targeting tau pathology have a great potential for AD and other tauopathies. PMID:24029727
Sigurdsson, Einar M
This is the sixth edition of the Compendium of Tumor Immunotherapy Protocols, a publication sponsored by the International Cancer Research Data Bank, National Cancer Institute, and published on an annual basis by the International Registry of Tumor Immuno...
IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review.
Johansen, Pal; von Moos, Seraina; Mohanan, Deepa; Kundig, Thomas M.; Senti, Gabriela
Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. The traditional treatments for GBM, including surgery, radiation, and chemotherapy, only modestly improve patient survival. Therefore, immunotherapy has emerged as a novel therapeutic modality. Immunotherapeutic strategies exploit the immune system's ability to recognize and mount a specific response against tumor cells, but not normal cells. Current immunotherapeutic approaches for glioma can be divided into three categories: immune priming (active immunotherapy), immunomodulation (passive immunotherapy), and adoptive immunotherapy. Immune priming sensitizes the patient's immune cells to tumor antigens using various vaccination protocols. In the case of immunomodulation, strategies are aimed at reducing suppressive cytokines in the tumor microenvironment or using immune molecules to specifically target tumor cells. Adoptive immunotherapy involves harvesting the patient's immune cells, followed by ex vivo activation and expansion prior to re-infusion. This review will provide an overview of the interactions between the central nervous system and the immune system and discuss the challenges facing current immunotherapeutic strategies.
Rolle, Cleo E.; Sengupta, Sadhak; Lesniak, Maciej S.
Ulcerative colitis (UC) is an inflammatory bowel disease affecting large bowel with variable clinical course. The history of disease has been modified by the introduction of biologic therapy, in particular Infliximab (IFX), that has demonstrated efficacy in inducing fast symptoms remission, promoting mucosal healing and maintaining long-term remission. However, surgery is still needed for UC patients: in case of failure of medical therapy and if acute complications or a malignancy occurred. Surgical treatment is associated with a short-term post-operative mortality and morbidity respectively of 0%-4% and 30%. In this study we systematically analyzed: the role of IFX in reducing the colectomy rate, the risk of post-operative morbidity in pre-operatively IFX-treated patients and the cost-effectiveness of IFX therapy. Four of 5 analyzed randomized controlled trials demonstrated that therapy with IFX significantly reduces the colectomy rate. Moreover, pre-operative treatment with IFX doesn’t seem to increase post-operative infectious complications. By an economic point of view, the cost-effectiveness of IFX-therapy was demonstrated for UC patients suffering from moderate to severe UC in a study based on a cost estimation of the National Health Service of England and Wales. However, the argument is debated.
Rizzo, Gianluca; Pugliese, Daniela; Armuzzi, Alessandro; Coco, Claudio
Intralesional immunotherapy of melanoma has two complementary aims. One is to cause regression of the injected metastasis. The other is to incite or modulate systemic immune responses in such a way that non-injected metastases will also undergo regression. A number of phase 1 and phase II studies with cytokines, viral, or bacterial agents have been conducted but their use has remained sporadic and has not progressed to become established treatments. Two treatments have progressed to randomized phase III studies. The most promising of these is based on intralesional injection of a genetically modified herpes simplex virus (HSV) (T-Vec). Initial results have shown a significant effect on durable response rates (DRR) but effects on overall survival remain under study. The second involved injection of plasmids coding for the HLA B7 antigen (Allovectin). Despite encouraging early results the treatment did not reach its endpoints and its use has been discontinued. A phase II study involving intralesional injection of oncolytic A21 coxsackie virus (Cavatak) is also under way and is showing promise. PMID:24301265
Hersey, Peter; Gallagher, Stuart
Dendritic cells (DCs) are multifunctional cells that are pivotal in immune defense. As such they have been explored as vaccine carriers, largely in cancer immunotherapy and against some infectious diseases including HIV and viral hepatitis. However, while the use of DCs as vaccine carrier has shown some promise in cancer immunotherapy, this approach is laborious and is subject to strict quality control, which makes it expensive. Furthermore, in some individuals chronically infected with HIV, HCV and/or HBV the numbers of circulating DCs are reduced and/or their functions impaired. In vivo expansion and mobilization of DCs with Flt3L in combination with antigen and/or adjuvant targeting to critical DC receptors may be a more effective approach to control viral replication in chronically infected HIV, HBV and/or HCV patients than current DC immunotherapy approaches. PMID:24734867
Atanley, Ethel; van Drunen Littel-van den Hurk, Sylvia
LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-? and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-? production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-? release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol.Kg-1 LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol.Kg-1 only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-? production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-? production, two key therapeutic targets of neuropathic pain, 100 µmol.Kg-1 LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7-11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-? inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model of neuropathic pain without presenting hyperthermia. PMID:24941071
Lima, Cleverton K F; Silva, Rafael M; Lacerda, Renata B; Santos, Bruna L R; Silva, Rafaela V; Amaral, Luciana S; Quintas, Luís E M; Fraga, Carlos A M; Barreiro, Eliezer J; Guimaraes, Marília Z P; Miranda, Ana L P
LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-? and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-? production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-? release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol.Kg?1 LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol.Kg?1 only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-? production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-? production, two key therapeutic targets of neuropathic pain, 100 µmol.Kg?1 LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7–11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-? inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model of neuropathic pain without presenting hyperthermia.
Lima, Cleverton K. F.; Silva, Rafael M.; Lacerda, Renata B.; Santos, Bruna L. R.; Silva, Rafaela V.; Amaral, Luciana S.; Quintas, Luis E. M.; Fraga, Carlos A. M.; Barreiro, Eliezer J.; Guimaraes, Marilia Z. P.; Miranda, Ana L. P.
The added benefit of combining valacyclovir (VACV), an antiviral agent, with etanercept (ETA), an anti-tumor necrosis factor alpha (TNF-?) antibody, for the treatment of herpes simplex virus type 1 (HSV-1) encephalitis (HSE) was evaluated in a mouse model. BALB/c mice were infected intranasally with 1.85 × 104 plaque forming units of HSV-1. Groups of mice received a single intraperitoneal injection of vehicle or ETA (400 ?g/mouse) on day 3 post-infection combined or not with VACV (1 mg/ml of drinking water) from days 3 to 21 post-infection. On day 5 post-infection, groups of mice were sacrificed for determination of viral DNA load, detection of ETA in brain homogenates and for in situ hybridization. The survival rate of mice was significantly increased when VACV was administered in combination with ETA (38.5% for VACV vs 78.6% for combined treatment; P = 0.04) although VACV or ETA alone had no significant effect compared to the vehicle. The benefit of combined therapy was still present when treatment was delayed until day 4 post-infection. The viral DNA load was significantly reduced in mice treated with VACV alone (P < 0.01) or combined with ETA (P < 0.05) compared to the uninfected group whereas ETA alone had no effect. These results reinforce the notion that both virus-induced and immune-related mechanisms participate in the pathogenesis of HSE and suggest that potent antiviral agent could be combined with immune-based therapy, such as a TNF-? inhibitor, to improve prognosis of HSE. PMID:24416771
Boivin, Nicolas; Menasria, Rafik; Piret, Jocelyne; Rivest, Serge; Boivin, Guy
Alzheimer's disease has long been associated with increased inflammation in the brain. Activated microglia and increased production of the inflammatory cytokines such as TNF-?, have been proposed to contribute to the onset and progression of the disease. We investigated if systemic administration of an anti-tumor necrosis factor (TNF) biologic medication clinically validated for rheumatoid arthritis (RA), TNF receptor 2 fused to a Fc domain (TNFR2:Fc), could ameliorate the behavioral symptoms and decrease neuroinflammation in a non-transgenic mouse model mimicking some hallmarks of the disease. Seven days after a single intracebroventricular (icv) injection of aggregated amyloid beta25-35 (9nmoles), mice displayed significant cognitive deficit in spontaneous alternation (working memory) and inhibitory avoidance (long-term memory) tasks. Alternation percentage decreased from 72.4%±1.3 to chance level (52.6%±1.7); step-through retention latency decreased from 247s to 144s. Subcutaneous administration of 30mg/kg TNFR2:Fc every second day post amyloid beta25-35 icv administration counteracted the amyloid-induced decrease in alternation percentage (66.4s±1.8) and the decreased step-through retention latency (248s±9). Measurement of hippocampal TNF-? levels by ELISA after behavioral assessment showed significant elevation in animals injected with amyloid beta25-35 relative to animals injected with control peptide. In animals treated with 30mg/kg TNFR2:Fc, TNF-? levels in the hippocampus were reduced and were similar to control animals. These data suggest that peripheral administration of TNFR2:Fc counteracts amyloid-induced memory impairment and normalizes increased TNF-? levels in hippocampus of a non-transgenic mouse model of amyloid induced cognitive deficit. PMID:24726770
Detrait, E R; Danis, B; Lamberty, Y; Foerch, P
To prove clinical benefits of cancer vaccine is currently difficult, except for one phase III trial has documented improved overall survival with the vaccine, Sipuleucel-T, although induction of anti-tumor immune responses through cancer vaccine is theoretically promising and would be straightforward. In contrast, immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types. In addition, there is a promising novel cancer immunotherapy, CAR therapy—a personalized treatment that involves genetically modifying a patient’s T-cells to make them target tumor cells. We are now facing new era of cancer immunotherapy.
Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid ? (sA?) peptide is converted into oligomeric/fibrillar A?. The oligomeric forms of A? are thought to be the most toxic, while fibrillar A? becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only A? has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen. PMID:24412277
Wisniewski, Thomas; Goñi, Fernando
Background. The aim of this study was to compare the efficacy of epicutaneous immunotherapy (EPIT) to sublingual immunotherapy (SLIT) in a model of mice sensitized to Phleum pratense pollen. Methods. BALB/c mice were sensitized by sub-cutaneous route to pollen protein extract mixed treated for 8 weeks, using sham, EPIT, or SLIT. Measurements involved the serological response and cytokine profile from reactivated splenocytes, plethysmography after aerosol challenge to pollen, cell, and cytokine contents in the bronchoalveolar lavages (BALs). Results. After immunotherapy, sIgE was significantly decreased in the treated groups compared to sham (P < 0.001), whereas sIgG2a increased with EPIT and SLIT (P < 0.001 and P < 0.005 versus sham). Reactivated splenocytes secreted higher levels of Th2 cytokines with sham (P < 0.01). Penh values were higher in sham than EPIT and SLIT. Eosinophil recruitment in BAL was significantly reduced only by EPIT (P < 0.01). Conclusion. In this model of mice sensitized to pollen, EPIT was at least as efficient as SLIT.
Mondoulet, Lucie; Dioszeghy, Vincent; Ligouis, Melanie; Dhelft, Veronique; Puteaux, Emilie; Dupont, Christophe; Benhamou, Pierre-Henri
Venom immunotherapy (VIT) is the most effective form of specific immunotherapy to date. Hitherto, several relevant queries remain unanswered, namely optimal doses, duration, and means of assessment. Important progress has been lately made in terms of diagnosis by means of component-resolved diagnosis. Moreover, basophil activation test results in patients with negative serum immunoglobulin E (IgE) and skin prick test confer this technique a promising future, although these outcomes shall be considered with caution. This review aims to unravel the important advances made on diagnosis, management, and prognosis and also focuses on several undetermined aspects of VIT. PMID:24934908
Antolín-Amérigo, Darío; Moreno Aguilar, Carmen; Vega, Arantza; Alvarez-Mon, Melchor
The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Unregulated activities of these mediators can lead to the development of serious inflammatory diseases. In particular, enhanced tumour-necrosis factor-? (TNF-?) synthesis is associated with the development of rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Inhibiting TNF-? activities in these diseases
Frances Rena Bahjat; Emmanuel A. Theodorakis; Lyle L. Moldawer; Michael A. Palladino
Increased production of TNF? by alveolar macrophages and involvement of TNF? in granuloma formation suggest that this cytokine is involved in the pathophysiology of sarcoidosis. The three available TNF? blocking agents have been tested in sarcoidosis refractory to corticosteroids or immunosuppressive drugs. Data are available from isolated case reports or limited series of patients treated in open label trials with
É. Toussirot; É. Pertuiset
A new era of immunotherapy of cancer has begun, often referred to as gene therapy. The general concepts have not changed, but the available methods and reagents and the understanding of how immune responses are induced and regulated. Of importance are the following: (a) a number of gene transfer techniques, (b) the discovery of an array of cloned and functionally
Thomas Blankenstein; Sophie Cayeux; Zhihai Qin
A new era of immunotherapy of cancer has begun, often referred to as gene therapy. The general concepts have not changed, but the available methods and reagents and the understanding of how immune responses are induced and regulated. Of importance are the following: (a) a number of gene transfer techniques, (b) the discovery of an array of cloned and functionally
Thomas Blankenstein; Sophie Cayeux; Zhihai Qin
Dendritic cell immunotherapy is emerging as a promising addition to the multimodal treatment of patients with glioblastoma multiform. Initial Phase I and II trials have demonstrated favorable outcomes with minimal toxicity. In this editorial, the current status and the future challenges of this therapy are discussed. PMID:24850137
Polyzoidis, Stavros; Ashkan, Keyoumars
The results of various in vitro analyses indicate there is an active immune response against antigens associated with human malignancies. This immune response apparently can be augmented by nonspecific immunologic stimulates such as BCG. These agents are effective for destroying tumor when injected locally into intracutaneous disease but are not as effective for subcutaneous disease. Preliminary clinical trials indicated that immune stimulants are effective when administered systemically. The effect is only minimal for diseminated disease, but the therapeutic benefit is clearly augmented for patients with a minimal residual tumor burden, such as those patients with metastases to regional lymph nodes. Thus immunotherapy is a systemically active mode of therapy. Its toxicity is minimal, and it appears to be effective in a wide spectrum of the disease. However, immunotherapy is not effective for a large residual tumor burden; consequently it must be used in combination with other modes of treatment such as irradiation therapy or chemotherapy. Early experiences with BCG immunotherapy for malignant melanoma and C. parvum for oat cell carcinoma are encouraging. It is remarkable that a nonspecific immunologic stimulant does, in fact, have this effect. Immunotherapy experiments in animals suggest that in order to achieve maximal benefit. BCG must have close contact with tumor cells or must be combined with a tumor-associated antigen. If these principles are true for man, it would seem that improvements for nonspecific immunotherapy in human neoplasms would be further augmented if a tumor-related antigen could be extracted from human tumours and combined with a nonspecific immunologic stimulant. PMID:178234
Eilber, F R; Holmes, E C; Morton, D L; Ramming, K P; Sparks, F C
Evidence shows that sublingual immunotherapy (SLIT) is indicated in patients with allergic rhinitis (AR). In this article we discuss whether SLIT could offer benefit for children and adults with asthma.We reviewed individual trials on SLIT in asthmatic patients, but also asthma data reported in some SLIT trials conducted in AR patients. Findings were complemented with data from systematic reviews and metaanalysis on the subject since 2000 and some guidelines that mention immunotherapy for asthma treatment. In AR patients with concomitant persistent asthma, SLIT reduces medication needs while maintaining symptom control. This holds especially true for house dust mite SLIT. Data on pollen SLIT and lung symptom improvement with SLIT, however, are less convincing. Therefore, we suggest SLIT should be added as an optional add-on therapy for patients with asthma whenever a causative allergen has been demonstrated and AR is associated with asthma. For the future, SLIT should be studied in specifically designed asthma studies in allergic asthmatics without AR. PMID:24022465
Baena-Cagnani, Carlos E; Larenas-Linnemann, Désirée; Teijeiro, Alvaro; Canonica, Giorgio Walter; Passalacqua, Giovanni
In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines.
De Souza Reboucas, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, Maria Luisa; Irache, Juan Manuel; Gamazo, Carlos
Contents: Immunotherapy of specific types of human cancer (Immunotherapy of melanoma and other skin cancers, Immunotherapy of leukemias, lymphomas, and myeloma, Immunotherapy of childhood cancers, including leukemia, Immunotherapy of lung cancer, Immunoth...
Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called ‘nature’s adjuvants’ and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.
Palucka, Karolina; Banchereau, Jacques
We present a 42-year-old woman who experienced a systemic reaction (SR) after a subcutaneous immunotherapy (SCIT) injection. Her physician must make a decision, along with the patient, on how to proceed. We consider the medical evidence pertinent to specific risk factors for SRs to SCIT, including asthma control, concomitant medications and new medical diagnoses, the influence of pollen season, adjustments for large local reactions, initial testing results, type of buildup protocol, and administration and dosing errors. We next discuss the potential risk-mitigating actions that the patient and provider should consider and the available evidence that supports various approaches, including cessation of SCIT, decreasing allergen dose or altering the timing of injections, initiating or changing the medical pretreatment regimen, and changing to sublingual immunotherapy, and also the role for anaphylaxis preparedness. Finally, we highlight the key knowledge gaps identified in this review and provide management recommendations for this 42-year-old woman. PMID:24607038
Rank, Matthew A; Bernstein, David I
Active non-specific immunotherapy has been used to prolong remissions in acute lymphoblastic leukaemia. The series reported here used Bordetella pertussis vaccine in a controlle trial after intensive chemotherapy. Possibly immunotherapy delayed the onset of relapse in the treated patients, but no long-term remissions were obtained. Further work is needed to establish the role of immunotherapy in general, and the use of B. pertussis vaccine in particular, in the treatment of acute leukaemia.
Guyer, R. J.; Crowther, D.
HDM allergy is associated with asthma, allergic rhinitis and atopic dermatitis. In many countries childhood asthma is predominantly found in HDM-allergic children with their probability of developing disease being proportional to their IgE antibody titers and the early development of Th2 responses. While the pathogenesis is complex and increasingly linked to infection the immunologically-based allergen immunotherapy and anti-IgE antibody therapy are highly beneficial. Immunotherapy could be a short-term treatment providing lifelong relief but the current regimens depend on repeated administration of allergen over years. Immunological investigations point to a contribution of responses outside the Th2 pathway and multiple potential but unproven control mechanisms. Over half of the IgE antibodies are directed to the group 1 and 2 allergens with most of remainder to the group 4, 5, 7 and 21 allergens. This hierarchy found in high and low responders provides a platform for introducing defined allergens into immunotherapy and defined reagents for investigation.
Thomas, Wayne R.
Immunotherapy can be an effective treatment for metastatic cancer, but a significant subpopulation will not respond, likely due to the lack of antigenic mutations or the immune-evasive properties of cancer. Likewise, radiation therapy (RT) is an established cancer treatment, but local failures still occur. Clinical observations suggest that RT may expand the therapeutic reach of immunotherapy. We examine the immunobiologic and clinical rationale for combining RT and immunotherapy, two modalities yet to be used in combination in routine practice. Preclinical data indicate that RT can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of RT.
Kalbasi, Anusha; June, Carl H.; Haas, Naomi; Vapiwala, Neha
We are living in an "aluminium age" with increasing bioavailability of the metal for approximately 125 years, contributing significantly to the aluminium body burden of humans. Over the course of life, aluminium accumulates and is stored predominantly in the lungs, bones, liver, kidneys and brain. The toxicity of aluminium in humans is briefly summarised, highlighting links and possible causal relationships between a high aluminium body burden and a number of neurological disorders and disease states. Aluminium salts have been used as depot-adjuvants successfully in essential prophylactic vaccinations for almost 100 years, with a convincing positive benefit-risk assessment which remains unchanged. However, allergen-specific immunotherapy commonly consists of administering a long-course programme of subcutaneous injections using preparations of relevant allergens. Regulatory authorities currently set aluminium limits for vaccines per dose, rather than per treatment course. Unlike prophylactic vaccinations, numerous injections with higher proportions of aluminium-adjuvant per injection are applied in subcutaneous immunotherapy (SCIT) and will significantly contribute to a higher cumulative life dose of aluminium. While the human body may cope robustly with a daily aluminium overload from the environment, regulatory cumulative threshold values in immunotherapy need further addressing. Based on the current literature, predisposing an individual to an unusually high level of aluminium, such as through subcutaneous immunotherapy, has the potential to form focal accumulations in the body with the propensity to exert forms of toxicity. Particularly in relation to longer-term health effects, the safety of aluminium adjuvants in immunotherapy remains unchallenged by health authorities - evoking the need for more consideration, guidance, and transparency on what is known and not known about its safety in long-course therapy and what measures can be taken to prevent or minimise its risks. The possibility of providing an effective means of measuring aluminium accumulation in patients undergoing long-term SCIT treatment as well as reducing their aluminium body burden is discussed. PMID:24892252
Kramer, Matthias F; Heath, Matthew D
Better understanding of the underlying principles of tumor biology and immunology, enhanced by recent insights into the mechanisms of immune recognition, regulation, and tumor escape has provided new approaches for cancer immunotherapy. This article reviews the current status and future directions of cancer immunotherapy, with a focus on the recent encouraging results from immune-modulating antibodies and adoptive cell therapy. PMID:24012398
Ito, Fumito; Chang, Alfred E
For a long time, cancer immunotherapy has focused on the induction of tumor-specific T cell-mediated immune responses. Now, a mounting body of evidence indicates that efficient anticancer immune responses also rely on innate immunity. Tietze et al. have recently elucidated an antigen-nonspecific role for memory CD8+ T cells in cytokine-based cancer immunotherapy.
Sckisel, Gail D.; Murphy, William J.
Sublingual immunotherapy (SLIT) is accepted in the official documents and is currently used in many European countries. In recent years, new clinical data on efficacy and safety have been published, including meta-analyses in adults and children and surveys of safety in children younger than age 5 years. Moreover, it has been shown that, similar to the injection route, SLIT can prevent the onset of new sensitizations and the onset of asthma. Additionally, the mechanisms of action are beginning to be systematically studied. Some points need further investigation, such as the effect in asthma, the mechanisms of action, and the optimal dose to be administered. PMID:16899203
Passalacqua, Giovanni; Guerra, Laura; Compalati, Enrico; Fumagalli, Federica; Cirillo, Arianna; Canonica, Giorgio Walter
Metastatic prostate cancer remains incurable. Harnessing the body's own immune system to control or eradicate tumours has long been an attractive concept. Only recently has the field of tumour immunology provided the basic science behind the mechanisms of tumour genesis, molecular basis of the recognition of tumour associated antigens and the interactions of the antigen-presenting cells with effector cells. This research has been translated into numerous clinical immunotherapy strategies, which have reached the oncology clinic and which should provide options for our patients. PMID:12031866
Havranek, E G; Whelan, M A; Greenhalgh, R; Dalgleish, A G; Pandha, H
Purpose This review demonstrates the importance of immunobiology and immunotherapy research for understanding and treating neuroblastoma. Principal results The first suggestions of immune system-neuroblastoma interactions came from in vitro experiments showing that lymphocytes from patients were cytotoxic for their own tumor cells and from evaluations of tumors from patients that showed infiltrations of immune system cells. With the development of monoclonal antibody (mAb) technology, a number of mAbs were generated against neuroblastoma cells lines and were used to define tumor associated antigens. Disialoganglioside (GD2) is one such antigen that is highly expressed by virtually all neuroblastoma cells and so is a useful target for both identification and treatment of tumor cells with mAbs. Preclinical research using in vitro and transplantable tumor models of neuroblastoma has demonstrated that cytotoxic T lymphocytes (CTLs) can specifically recognize and kill tumor cells as a result of vaccination or of genetic engineering that endows them with chimeric antigen receptors. However, CTL based clinical trials have not progressed beyond pilot and phase I studies. In contrast, anti-GD2 mAbs have been extensively studied and modified in pre-clinical experiments and have progressed from phase I through phase III clinical trials. Thus, the one proven beneficial immunotherapy for patients with high-risk neuroblastoma uses a chimeric anti-GD2 mAb combined with IL-2 and GM-CSF to treat patients after they have received intensive cyto-reductive chemotherapy, irradiation, and surgery. Ongoing pre-clinical and clinical research emphasizes vaccine, adoptive cell therapy, and mAb strategies. Recently it was shown that the neuroblastoma microenvironment is immunosuppressive and tumor growth promoting, and strategies to overcome this are being developed to enhance anti-tumor immunotherapy. Conclusions Our understanding of the immunobiology of neuroblastoma has increased immensely over the past 40 years, and clinical translation has shown that mAb based immunotherapy can contribute to improving treatment for high-risk patients. Continued immunobiology and pre-clinical therapeutic research will be translated into even more effective immunotherapeutic strategies that will be integrated with new cytotoxic drug and irradiation therapies to improve survival and quality of life for patients with high-risk neuroblastoma.
Seeger, Robert C.
Active specific immunotherapy, or the use of tumor 'vaccines', attempts to stimulate the patient to reject his or her tumor. Nowhere has this approach been utilized more than in melanoma, often with encouraging results. The best results have occurred in the setting of minimal residual disease after resection of the primary tumor and involved lymph nodes, but responses have also been obtained in disseminated disease. Prolonged survivals of several years have been achieved in both settings, particularly the former, with little toxicity attributable to the treatment. Genetic and biochemical approaches promise considerably improved preparations of 'vaccines', with defined components and improved activity within the immediate future. PMID:7552085
Mitchell, M S
Immunotherapy is a promising approach for treating cancer. However, there are limitations inherent to current approaches which may be addressed by integrating them with biomaterial-based strategies. Material platforms have been fabricated to interact with immune cells through spatially- and temporally-controlled delivery of immune modulators and to promote immune cell crosstalk. Particle vaccines have been developed to specifically target and deliver agents to organs, cells and subcellular compartments. These strategies have been shown to generate antigen-specific CTL responses and, in some cases, tumor regression. Therefore, collaboration between immunology and materials engineering is likely to result in the creation of strong vaccines to combat cancer in the future.
Li, Weiwei Aileen; Mooney, David J.
Since the human immunodeficiency virus (HIV-1) pandemic began, few prophylactic vaccines have reached phase III trials. Only one has shown partial efficacy in preventing HIV-1 infection. The introduction of antiretroviral therapy (ART) has had considerable success in controlling infection and reducing transmission but in so doing has changed the nature of HIV-1 infection for those with access to ART. Access, compliance, and toxicity alongside the emergence of serious non-AIDS morbidity and the sometimes poor immune reconstitution in ART-treated patients have emphasized the need for additional therapies. Such therapy is intended to contribute to control of HIV-1 infection, permit structured treatment interruptions, or even establish a functional cure of permanently suppressed and controlled infection. Both immunotherapy and therapeutic vaccination have the potential to reach these goals. In this review, the latest developments in immunotherapy and therapeutic vaccination are discussed.
Tanner, Helen; Dalgleish, Angus
Basic disease-modifying treatment for relapsing forms of active multiple sclerosis (MS) is now available in many countries with high prevalence rates, for this chronic inflammatory disease of the central nervous system. Several lines of evidence support early immunomodulatory treatment with either recombinant interferon-beta or glatiramer acetate, and positive results from phase III trials encourage start of treatment even in patients with clinically isolated syndromes (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for effective escalating strategies. Patients with suboptimal treatment response to basic therapy have been treated with combination therapies, cytotoxic drugs (such as mitoxantrone and cyclophosphamide) or autologous hematopoietic stem cell transplantation. Recently, the monoclonal antibody, natalizumab, was added to this armamentarium. None of these strategies have been vigorously evaluated in large randomized, controlled phase III trials with patients who failed basic therapy. Therefore, the decision to escalate immunotherapy is still based on limited evidence. This article will review potential candidates for intensified immunosuppression and call for innovative study designs to better evaluate escalating immunotherapy in MS.
Traboulsee, Anthony; Devonshire, Virginia; Oger, Joel
Susac's syndrome is a rare but important differential diagnosis of aseptic encephalitis of young women with focal neurological deficits and white matter lesions on cerebral MRI. We report on a previously healthy 36-year-old woman who presented with encephalopathy, central weakness of her right leg and multiple white matter lesions on MRI. Shortly thereafter, inner ear deafness developed and funduscopy revealed occlusions of branch retinal arteries. A diagnosis of retino-cochlear-cerebral vasculopathy or Susac's syndrome was established and steroid-based immunotherapy with high-dose corticosteroids was initiated. Steroid reduction led to repeated clinical worsening, so that immunotherapy was sequentially escalated. Finally, high-dose cyclophosphamide every 4 weeks led to sufficient control of disease activity. Recent publications have argued for an early and aggressive immunosuppression in Susac's syndrome based on clinical and histological similarities with juvenile dermatomyositis, where such a regimen has already been established. We report on these treatment guidelines with respect to the current literature and the case presented. PMID:19888559
Klein, M; Illies, T; Georgi, S; Rosenkranz, T; Terborg, C
Sublingual immunotherapy (SLIT) was proposed for clinical practice about 20 years ago with the main aim of improving the safety and avoiding the adverse effects of traditional treatment for allergic airways disease. To date, 32 randomized controlled trials and 6 postmarketing surveys have been published that provide a robust documentation of the safety profile of the treatment.Looking at the randomized trials it emerges that the more frequent adverse event of SLIT is oral itching or swelling, followed by gastrointestinal complaints. These adverse events are invariably described as mild and easily managed by adjusting the dose. Relevant systemic adverse events (asthma, urticaria, angioedema) occur sporadically and, with the exception of oral/gastrointestinal adverse events, the incidence of adverse events seems not to differ between the placebo and active groups. The safety profile of SLIT does not differ between adults and children.The postmarketing surveys consistently show that the incidence of adverse events associated with SLIT is less than 10%, corresponding to less than 1 adverse event per 1000 doses, and is thus quite superior to the safety profile of subcutaneous immunotherapy. Of note, the most recent data show that the rate of adverse events with SLIT is not increased in children below the age of 5 years. PMID:16808542
Passalacqua, Giovanni; Guerra, Laura; Fumagalli, Federica; Canonica, Giorgio Walter
Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon ?, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed.
Schadendorf, D.; Algarra, S. M.; Bastholt, L.; Cinat, G.; Dreno, B.; Eggermont, A. M. M.; Espinosa, E.; Guo, J.; Hauschild, A.; Petrella, T.; Schachter, J.; Hersey, P.
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737
Hoos, Axel; Eggermont, Alexander M M; Janetzki, Sylvia; Hodi, F Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Old, Lloyd; Wolchok, Jedd
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd
Food allergy is a life-threatening allergic disease that is increasing in prevalence with no approved curative therapy. Standard treatment of food allergy is limited to avoidance of the allergen and supportive management of allergic symptoms and anaphylaxis. Current research, however, has been focused on developing therapy that can modify the allergic immune response in both allergen-specific and non-specific methods. This review will provide an overview of these methods including oral immunotherapy, sublingual immunotherapy, epicutaneous immunotherapy, modified food protein vaccines, anti-IgE monoclonal antibody adjuvant therapy, Chinese herbs, and helminth therapy. PMID:23021370
Virkud, Yamini V; Vickery, Brian P
Sublingual immunotherapy has been shown in some clinical studies to modulate allergen-specific antibody responses [with a decrease in the immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and activation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen-specific T-cell responses in atopic patients from a T helper (Th)2 to Th1 profile, there is currently a growing interest in eliciting regulatory T cells, capable of downregulating both Th1 and Th2 responses through the production of interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We discuss herein immune mechanisms involved during allergen-specific sublingual immunotherapy (SLIT), in comparison with subcutaneous immunotherapy. During SLIT, the allergen is captured within the oral mucosa by Langerhans-like dendritic cells expressing high-affinity IgE receptors, producing IL-10 and TGF-beta, and upregulating indoleamine dioxygenase (IDO), suggesting that such cells are prone to induce tolerance. The oral mucosa contains limited number of proinflammatory cells, such as mast cells, thereby explaining the well-established safety profile of SLIT. In this context, second-generation vaccines based on recombinant allergens in a native conformation formulated with adjuvants are designed to target Langerhans-like cells in the sublingual mucosa, with the aim to induce allergen-specific regulatory T cells. Importantly, such recombinant vaccines should facilitate the identification of biological markers of SLIT efficacy in humans. PMID:16409190
Moingeon, P; Batard, T; Fadel, R; Frati, F; Sieber, J; Van Overtvelt, L
Alopecia Areata (AA) is a common non-scarring alopecia directed against the anagenic hair follicle. Various treatment modalities have been used for the treatment of severe AA. Topical immunotherapy is the best documented treatment so far for severe and refractory AA. Dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphencyprone (DPCP) are the contact allergens used for this purpose. DNCB has been found to be mutagenic by the Ames test and is largely replaced by DPCP and SADBE. DPCP and SADBE are both known to be non-mutagenic compounds and have comparable efficacy results and relapse rates. SADBE requires special solvents and additives to maintain its potency and is more expensive than the rest. DPCP has a response rate varying from 60% in severe Alopecia Areata to 17% in patients with alopecia totalis or universalis, and shows about 88 to 100% high response rate in patients with patchy Alopecia Areata. PMID:21188022
Singh, Gurcharan; Lavanya, Ms
Alopecia Areata (AA) is a common non-scarring alopecia directed against the anagenic hair follicle. Various treatment modalities have been used for the treatment of severe AA. Topical immunotherapy is the best documented treatment so far for severe and refractory AA. Dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphencyprone (DPCP) are the contact allergens used for this purpose. DNCB has been found to be mutagenic by the Ames test and is largely replaced by DPCP and SADBE. DPCP and SADBE are both known to be non-mutagenic compounds and have comparable efficacy results and relapse rates. SADBE requires special solvents and additives to maintain its potency and is more expensive than the rest. DPCP has a response rate varying from 60% in severe Alopecia Areata to 17% in patients with alopecia totalis or universalis, and shows about 88 to 100% high response rate in patients with patchy Alopecia Areata.
Singh, Gurcharan; Lavanya, MS
Acute renal failure, now referred to as acute kidney injury, is a common and clinically important problem. Acute kidney injury frequently occurs as a result of acute tubular necrosis (ATN), which is often caused by a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation). The disease course in ATN is variable, including prolonged dialysis-dependence and chronic renal dysfunction, but there is currently no specific therapy for ATN. There is increasing evidence that the inflammatory response in ATN significantly contributes to disease severity and outcome. In this review, we summarize recent developments in the understanding of how the immune system responds to dying cells, and the relevance of these discoveries to ATN. In particular, NLRP3 inflammasome activation and IL-1?-mediated neutrophil recruitment are likely to play a key role and may provide novel therapeutic targets for immunotherapy in ATN. PMID:22401637
Berry, Miriam; Clatworthy, Menna R
... to destroy a cancer cell. They are taking advantage of the mechanism the body uses to keep ... immunotherapy, including her own work with cancer treatment vaccines, focused on stepping on the gas of the ...
Manipulation of cell renewal pathways creates T memory stem cells that can generate a sustained and targeted immune response. These findings have broad implications for vaccine development and immunotherapy.
Koehn, Brent H; Schoenberger, Stephen P
This is the seventh edition of the Compendium of Tumor Immunotherapy Protocols, a publication sponsored by the International Cancer Research Data Bank, National Cancer Institute, and published on an annual basis by the International Registry of Tumor Immu...
Allergen specific immunotherapy involves the repeated administration of allergen products in order to induce clinical and immunologic tolerance to the offending allergen. Immunotherapy is the only etiology-based treatment that has the potential for disease modification, as reflected by longterm remission following its discontinuation and possibly prevention of disease progression and onset of new allergic sensitizations. Whereas subcutaneous immunotherapy is of proven value in allergic rhinitis and asthma there is a risk of untoward side effects including rarely anaphylaxis. Recently the sublingual route has emerged as an effective and safer alternative. Whereas the efficacy of SLIT in seasonal allergy is now well-documented in adults and children, the available data for perennial allergies and asthma is less reliable and particularly lacking in children. This review evaluates the efficacy, safety and longterm benefits of SCIT and SLIT and highlights new findings regarding mechanisms, potential biomarkers and recent novel approaches for allergen immunotherapy.
Cappella, Antonio; Durham, Stephen R.
The possibility of producing local hyposensitization by administering allergens via mucosal routes was envisaged at the beginning of 1900, and local nasal immunotherapy has been extensively studied since the 1970s. Presently, there are 21 randomized controlled trials being conducted with the most common allergens, consistently showing the clinical efficacy of local nasal immunotherapy for rhinitis. Other advantages are that it has an optimal safety profile and can be self-administered at home by the patient. Moreover, there are several data from animal models and from humans that confirm the immunomodulatory effect of intranasally administered antigens. On the other hand, local nasal immunotherapy seems to be effective only on rhinitis symptoms and requires a particular technique of administration. For these reasons, its clinical use is progressively declining in favour of the sublingual route although nasal immunotherapy is validated in official documents and remains a viable alternative to injection.
Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.
Cancer immunotherapy attempts to harness the exquisite power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is clearly capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for immunotherapy is to use advances in cellular and molecular immunology to develop strategies that effectively and safely augment antitumor responses.
Blattman, Joseph N.; Greenberg, Philip D.
Background Over the last 100 years, several persistent misconceptions or ‘false beliefs’ have built up around allergen immunotherapy and its use in allergic rhinitis. This is perhaps because enthusiastic physicians administered complex allergen extracts to a diverse population of patients suffering from heterogeneous atopic conditions. Here, we review evidence that counters seven of these ‘false beliefs.’ Discussion 1. The symptoms of allergic rhinitis can be more heterogeneous, more severe and more troublesome in everyday life than many physicians believe. Large-scale epidemiological surveys show that the majority of allergic rhinitis patients have at least one symptom severe enough to interfere with sleep quality, productivity and/or well-being. 2. Allergen immunotherapy is not necessarily suitable for all allergic rhinitis patients (notably those with mild symptoms). Recent evidence from double-blind, placebo-controlled, randomized clinical trials suggests that the more severe the disease, the greater the treatment effect. 3. Allergen immunotherapy is often accused of lack of efficacy (relative to pharmacotherapy, for example). However, there are now many meta-analyses, systematic reviews and high-quality clinical trials that find overwhelmingly in favor of the efficacy of allergen immunotherapy (including sublingual formulations) in allergic rhinitis induced by pollen and, increasingly, other allergens. 4. Natural-exposure and challenge-chamber trials have shown that symptom relief may become apparent within months or even weeks of the initiation of allergen immunotherapy. 5. In pollen-induced allergic rhinitis, several years of subcutaneous or sublingual allergen immunotherapy are associated with sustained clinical efficacy after subsequent treatment cessation – confirming the disease-modifying nature of this therapy. 6. Most patients seeking treatment for allergic rhinitis are polysensitized, and allergen immunotherapy has proven efficacy in large, robust clinical trials in these groups. Polysensitization is not a contraindication to allergen immunotherapy. 7. Sublingual allergen immunotherapy is safe for home administration. A recent review calculated that 1 billion doses were administered worldwide between 2000 and 2010 and found that the 11 case reports of anaphylaxis (all non-fatal) corresponded to non-standard practice. Summary Modern, evidence-based medicine has generated more than enough robust evidence to remove misconceptions about allergen immunotherapy and allergic rhinitis.
Allergen specific CD4+ T cell clones generated from allergic individuals have been shown to produce increased levels of the cytokine interleukin 4 (IL-4), compared to allergen specific clones generated from nonallergic individuals. This difference between CD4+ T cells from allergic and nonallergic individuals with regard to cytokine production in response to allergen is thought to be responsible for the development of allergic disease with increased IgE synthesis in atopic individuals. We examined the production of IL-4 in subjects with allergic rhinitis and in allergic individuals treated with allergen immunotherapy, a treatment which involves the subcutaneous administration of increasing doses of allergen and which is highly effective and beneficial for individuals with severe allergic rhinitis. We demonstrated that the quantity of IL-4 produced by allergen specific memory CD4+ T cells from allergic individuals could be considerably reduced by in vivo treatment with allergen (allergen immunotherapy). Immunotherapy reduced IL-4 production by allergen specific CD4+ T cells to levels observed with T cells from nonallergic subjects, or to levels induced with nonallergic antigens such as tetanus toxoid. In most cases the levels of IL-4 produced were inversely related to the length of time on immunotherapy. These observations indicate that immunotherapy accomplishes its clinical effects by reducing IL-4 synthesis in allergen specific CD4+ T cells. In addition, these observations indicate that the cytokine profiles of memory CD4+ T cells can indeed be altered by in vivo therapies. Thus, the cytokine profiles of memory CD4+ T cells are mutable, and are not fixed as had been suggested by studies of murine CD4+ memory T cells. Finally, treatment of allergic diseases with allergen immunotherapy may be a model for other diseases which may require therapies that alter inappropriate cytokine profiles of memory CD4+ T cells.
Background. Immunotherapy has proven to be an useful tool in the management of allergic respiratory diseases; however, little has been studied in atopic dermatitis. Objective. To evaluate the clinical and immunological impact of immunotherapy with mites allergen extracts in atopic dermatitis. Methods. Patients with atopic dermatitis were assigned with computer-generated randomization to either of the following groups: (a) controls received only topical treatment with steroids and/or tacrolimus and (b) actively treated patients received topical treatment plus immunotherapy. Levels of serum total IgE, mites-specific IgE and IgG4 were assessed at study start and after one year of immunotherapy. Results. 31 patients in the active group and 29 in the control group completed the study. Symptoms and medication scores were significantly reduced in the active group after six months. Three patients in the control group showed new sensitizations to mites, while 3 patients in the active group showed neosensitization to shrimp with negative oral food challenge. We observed significant increase of mites-specific IgG4 levels in active group. Conclusion. Specific allergen immunotherapy induced a tolerogenic IgG4 response to mite allergens associated with favorable clinical effects in atopic dermatitis patients.
Sanchez Caraballo, Jorge Mario; Cardona Villa, Ricardo
The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.
Korman, Alan J.; Peggs, Karl S.; Allison, James P.
The four major entities that form the group of myeloproliferative neoplasms (MPN) are BCR-ABL positive chronic myeloid leukaemia (CML), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET) and polycythemia vera (PV). All four are clonal diseases of the haematopoietic stem or precursor cell, they are of a chronic nature and potentially aggravate to myelofibrosis or transform into acute leukaemia. Several strategies are pursued in the treatment of MPN. On the one hand, targeted therapies such as tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) and JAK2-inhibitors are adopted in MPN as well as rather unspecific treatment with interferon-alpha and with the newer group of immunomodulatory drugs (IMIDs). On the other hand, cellular immunotherapeutical options as allogeneic haematopoietic stem cell transplantation (HSCT) and donor lymphocyte infusion (DLI) are exerted in patients with MPN. Evidence resulting from graft-versus-leukaemia (GvL) effect was the key to develop more specific immunotherapies for patients with haematologic malignancies. In this context, CML is a model for immunotherapeutic approaches, and therefore, vaccination trials using peptides derived from leukaemia-associated antigens (LAAs) to stimulate specific T cells are currently under investigation. But also in BCR-ABL-negative MPNs, antigens have been identified and immunomodulatory treatment strategies have been performed. All of the current immunotherapeutical options in patients with MPN will be discussed throughout this review. PMID:21062247
Hofmann, Susanne; Babiak, Anna; Greiner, Jochen
Treatment of acute myeloid leukemia (AML) with current chemotherapy regimens is still disappointing, with overall survival rates of ? 40% at 5 years. It is now well established that AML cells can evade the immune system through multiple mechanisms, including the expression of the enzyme indoleamine 2,3 dioxygenase. Immunotherapeutic strategies, including both active, such as vaccination with leukemia-associated antigens, and passive, such as adoptive transfer of allogeneic natural killer cells, may overcome leukemia escape and lead to improved cure. Allogeneic hemopoeitic stem cell transplantation, the most effective treatment of AML, is the best known model of immunotherapy. Following transplant, recipient AML cells are eradicated by donor immune cells through the graft-versus-leukemia (GVL) effect. However, GVL is clinically associated with graft-versus-host disease, the major cause of mortality after transplant. GVL is mediated by donor T cells recognizing either leukemia-associated antigens or minor as well as major histocompatibility antigens. Several innovative strategies have been devised to generate leukemia reactive T cells so as to increase GVL responses with no or little graft-versus-host disease. PMID:24341888
Arpinati, Mario; Curti, Antonio
Topical immunotherapy with contact sensitizers for metastatic melanoma was first reported more than 30 years ago. Diphencyprone (DPCP) immunotherapy is frequently used to treat cutaneous warts and alopecia areata, and we have previously reported the use of DPCP as a single agent to successfully treat extensive, radiotherapy-resistant melanoma metastases on the scalp. We now report DPCP treatment of a further six patients with cutaneous metastatic melanoma. Of seven patients treated with DPCP thus far, four have demonstrated complete responses of their cutaneous lesions and three have had partial responses. The treatment was well-tolerated by all patients. Topical immunotherapy with DPCP is inexpensive and relatively non-invasive and should be considered in patients with locally advanced skin metastases that are unsuitable for other therapies. PMID:19916970
Damian, Diona L; Shannon, Kerwin F; Saw, Robyn P; Thompson, John F
Adoptive cell immunotherapy with cytokine-induced killer cell (CIK cell) represents a promising non-toxic anticancer therapy. However, the clinical efficacy of CIK cells is limited because of abnormal tumor vasculature. Metronomic chemotherapy shows promising anticancer activity by its potential antiangiogenic effect and reduced toxicity. We hypothesized that metronomic chemotherapy with paclitaxel could improve the antitumor effect of adoptive CIK cell immunotherapy. Mice health status was analyzed by measuring mice weight and observing mice behavior. Immunohistochemistry was used to investigate the recruitment of CIK cells, the expression of endothelial cell molecules, as well as the hypoxic tumor area. Metronomic paclitaxel synergized with adoptive CIK cell immunotherapy to inhibit the growth of non-small cell lung cancer (NSCLC). Metronomic paclitaxel reduced hypoxic tumor area and increased CIK cell infiltration. Hypoxia impeded the adhesion of CIK cells and reduced the expression of endothelial cell adhesion molecules. In vivo studies demonstrated that more CIK cells were found in endothelial cell adhesion molecules high expressed area. Our study provides a new rationale for combining metronomic chemotherapy with adoptive cell immunotherapy in the treatment of xenograft NSCLC tumors in immunodeficient mice. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach. PMID:24628659
Shi, Shujing; Tao, Leilei; Song, Haizhu; Chen, Longbang; Huang, Guichun
... off or destroy cancer cells. The main immunotherapy drugs used in kidney cancer are cytokines (man-made versions of natural proteins that activate the immune system). The cytokines used most often are interleukin-2 (IL-2) and interferon-alpha. Both cytokines can cause kidney cancers to shrink ...
Adoptive cell transfer after host preconditioning by lymphodepletion represents an important advance in cancer immunotherapy. Here, we describe how a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment. We also discuss how the translation of these new
Daniel J. Powell; Steven A. Rosenberg; Luca Gattinoni; Nicholas P. Restifo
An emerging problem in chronic phase CML is molecular persistence. It is mainly due to the quiescent stem cell population that are completely insensitive to Imitinib therapy. We have developed a novel immunotherapy against CML. We have screened One-Bead-O...
P. R. Kumaresan
Adoptive immunotherapy is an appealing approach to cancer treatment, with the potential for more precise targeting and reduced toxicity. While early clinical trial data using adoptive T cells against post-transplant virus-associated hematologic malignancies, lymphoma and melanoma have been promising, treating other solid tumors has proven to be more challenging. Adoptive lymphocytes have been genetically modified in many ways to improve activity and circumvent tumor evasion, including transfer of transgenic T-cell receptors and chimeric antigen receptors to redirect T cell and natural killer cell antigen specificity. Gene transfer may also allow expression of homeostatic cytokines or their receptors to overcome the lack of stimulatory signals or expression of dominant-negative receptors for inhibitory cytokines to compensate for an immunosuppressive tumor milieu. In addition, suicide genes can install a 'safety switch' on adoptively transferred cells to allow ablation if necessary. Although further refinement and validation are necessary, these genetic modification strategies offer hope for significant improvements in cancer immunotherapy. PMID:21415041
Ngo, Minhtran C; Rooney, Cliona M; Howard, Jeffrey M; Heslop, Helen E
Natural killer (NK) cells potentially play a significant role in eradicating residual disease following allogeneic haematopoietic cell transplantation, and have been explored as tools for adoptive immunotherapy for chemotherapy-refractory patients. NK cell cytotoxicity is modulated by multiple activating and inhibitory receptors that maintain a balance between self-tolerance and providing surveillance against pathogens and malignant transformation. The functional characteristics of NK cells are dictated by the strength of inhibitory receptor signalling. Major histocompatibility complex (MHC)-specific inhibitory receptor acquisition occurs sequentially during NK cell development, and is determined by the nature of immunological reconstitution after allogeneic haematopoietic cell transplantation. Polymorphisms of inhibitory receptors [killer immunoglobulin-like receptors (KIRs)] and their ligands (MHC) contribute to interindividual variability. As a result, the functional NK cell repertoire of individual donors has variable potential for graft-vs-leukaemia reactions. Models predicting NK cell alloreactivity, including KIR ligand mismatch and missing KIR ligand strategies, are discussed as algorithms for optimal NK cell donor selection. Future modifications to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signalling are being explored.
Grzywacz, Bartosz; Miller, Jeffrey S.; Verneris, Michael R.
CD4+CD25+Foxp3+ regulatory T cells (Tregs) are immunopathogenic in cancers by impeding tumor-specific immunity. B7-homologue 1 (B7-H1) (CD274) is a cosignaling molecule with pleiotropic effects, including hindering antitumor immunity. In this study, we demonstrate sex-dependent, B7-H1–dependent differences in tumor immunity and response to immunotherapy in a hormone-independent cancer, murine B16 melanoma. Antitumor immunity was better in B7-H1?/? females versus males as a result of reduced regulatory T cell function in the B7-H1?/? females, and clinical response following B7-H1 blockade as tumor immunotherapy was significantly better in wild-type females than in males, owing to greater B7-H1 blockade-mediated reduction of Treg function in females. Wild-type female Tregs expressed significantly lower B7-H1 versus males but were insensitive to estrogen in vitro. Female B7-H1?/? Tregs were exquisitely sensitive to estrogen-mediated functional reduction in vitro, suggesting that B7-H1 effects occur before terminal Treg differentiation. Immune differences were independent of known B7-H1 ligands. Sex-dependent immune differences are seldom considered in designing immune therapy or interpreting immunotherapy treatment results. Our data demonstrate that sex is an important variable in tumor immunopathogenesis and immunotherapy responses through differential Treg function and B7-H1 signaling.
Lin, Pei-Yi; Sun, Lishi; Thibodeaux, Suzanne R.; Ludwig, Sara M.; Vadlamudi, Ratna K.; Hurez, Vincent J.; Bahar, Rumana; Kious, Mark J.; Livi, Carolina B.; Wall, Shawna R.; Chen, Lieping; Zhang, Bin; Shin, Tahiro; Curiel, Tyler J.
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are immunopathogenic in cancers by impeding tumor-specific immunity. B7-homologue 1 (B7-H1) (CD274) is a cosignaling molecule with pleiotropic effects, including hindering antitumor immunity. In this study, we demonstrate sex-dependent, B7-H1-dependent differences in tumor immunity and response to immunotherapy in a hormone-independent cancer, murine B16 melanoma. Antitumor immunity was better in B7-H1(-/-) females versus males as a result of reduced regulatory T cell function in the B7-H1(-/-) females, and clinical response following B7-H1 blockade as tumor immunotherapy was significantly better in wild-type females than in males, owing to greater B7-H1 blockade-mediated reduction of Treg function in females. Wild-type female Tregs expressed significantly lower B7-H1 versus males but were insensitive to estrogen in vitro. Female B7-H1(-/-) Tregs were exquisitely sensitive to estrogen-mediated functional reduction in vitro, suggesting that B7-H1 effects occur before terminal Treg differentiation. Immune differences were independent of known B7-H1 ligands. Sex-dependent immune differences are seldom considered in designing immune therapy or interpreting immunotherapy treatment results. Our data demonstrate that sex is an important variable in tumor immunopathogenesis and immunotherapy responses through differential Treg function and B7-H1 signaling. PMID:20686128
Lin, Pei-Yi; Sun, Lishi; Thibodeaux, Suzanne R; Ludwig, Sara M; Vadlamudi, Ratna K; Hurez, Vincent J; Bahar, Rumana; Kious, Mark J; Livi, Carolina B; Wall, Shawna R; Chen, Lieping; Zhang, Bin; Shin, Tahiro; Curiel, Tyler J
Background Cryotherapy has been accepted as the mainstay in treating periunugal and palmoplantar warts. The major drawback of cryotherapy is the requirement of several unbearably painful treatment sessions. Objective This study aims to assess the efficacy of immunotherapy in viral wart treatment, as an adjunctive method to cryotherapy. Methods Retrospective chart review was performed on 124 patients visiting the hospital from January to December 2009 for the treatment of periungual and plantar warts. We analyzed the number of cryotherapy sessions necessary for treating warts and assessed the clinical benefits from the addition of other treatment modalities, by adjusting the various confounding factors. Results Of the 124 investigated patients, immunotherapy with diphenylcyclopropenone (DPCP) was performed in 14 patients (11%), together with cryotherapy. After adjusting the factors related to the therapeutic difficulties of wart, the average number of cryotherapy sessions for the immunotherapy-combined group was significantly lower (3.58±1.25) than that for the cryotherapy only group (5.10±0.44) (p=0.026). However, there were no differences in the number of treatment sessions of cryotherapy when topical 5-FU/salicylic acid agents were added to the treatment. Conclusion Immunotherapy may be a successful adjuvant to cryotherapy in reducing the number of agonizing cryotherapy sessions.
Choi, Jae Woo; Cho, Soyun
Immunotherapy is the generic name for treatment modalities aiming to reinforce the immune system against diseases in which the immune system plays a role. The design of an optimal immunotherapeutic treatment against chronic viruses and associated diseases requires a detailed understanding of the interactions between the target virus and its host, in order to define the specific strategies that may have the best chance to deliver success at each stage of disease. Recently, a first series of successes was reported for the immunotherapy of Human Papilloma Virus (HPV)-induced premalignant diseases but there is definitely room for improvement. Here I discuss a number of topics that in my opinion require more study as the answers to these questions allows us to better understand the underlying mechanisms of disease and as such to tailor treatment.
van der Burg, Sjoerd H
Introduction: Sublingual immunotherapy (SLIT) was introduced as a safer option to subcutaneous immunotherapy (SCIT) which was associated with the possible occurrence of systemic reactions including anaphylaxis and, though very rarely, fatalities. Some anaphylactic reactions to SLIT are reported, mainly in adults but also in children. It is therefore important to investigate the risk factors related to such reactions. Areas covered: Data from the literature on the safety of SLIT in children were reviewed. The data reviewed concerned the application of this treatment to patients with respiratory allergy and also possible new indications such as food allergy, atopic dermatitis and latex allergy. Reports of anaphylactic reactions were analyzed to identify the potential risk factors. Expert opinion: SLIT is a well tolerated treatment, the common side effect being local reactions in the mouth. Systemic reactions, concerning the skin and the airway, are rare and anaphylactic reactions are extremely rare. PMID:24821477
Frati, Franco; Ridolo, Erminia; Fuiano, Nicola; Barberi, Salvatore; Dell'Albani, Ilaria; Landi, Massimo; Ricciardi, Luisa; Scala, Guglielmo; Incorvaia, Cristoforo
While chemotherapy is successful at inducing remission of acute myeloid leukaemia (AML), the disease has a high probability of relapse. Strategies to prevent relapse involve consolidation chemotherapy, stem cell transplantation and immunotherapy. Evidence for immunosurveillance of AML and susceptibility of leukaemia cells to both T cell and natural killer (NK) cell attack and justifies the application of immune strategies to control residual AML persisting after remission induction. Immune therapy for AML includes allogeneic stem cell transplantation, adoptive transfer of allogeneic or autologous T cells or NK cells, vaccination with leukaemia cells, dendritic cells, cell lysates, peptides and DNA vaccines and treatment with cytokines, antibodies and immunomodulatory agents. Here we describe what is known about the immunological features of AML at presentation and in remission, the current status of immunotherapy and strategies combining treatment approaches with a view to achieving leukaemia cure.
Barrett, A J; Le Blanc, K
The clinical and immunologic efficacy of venom immunotherapy up to 50 micrograms maintenance doses (half the recommended dose) was examined in 23 patients with anaphylactic sensitivity to insect stings and is compared with that in two groups of patients treated with the full 100-micrograms recommended dose. Four of the 19 patients challenged with insect stings had mild systemic reactions not requiring treatment. This 79% clinical efficacy is significantly less than the 96% to 100% success achieved with treatment to full 100-micrograms maintenance doses. The venom-specific IgG antibody response to the 50-micrograms dose reached a level significantly lower than observed with 100 micrograms doses. We conclude that the clinical and immunologic responses to venom immunotherapy are dose dependent and are more reliably complete at the recommended maintenance dose of 100 micrograms of each venom than at a dose of 50 micrograms. PMID:7229226
Golden, D B; Kagey-Sobotka, A; Valentine, M D; Lichtenstein, L M
Diverse immunotherapy approaches have achieved success in controlling individual aspects of immune responses in animal models. Transfer of such immunotherapies to clinical trials has obtained some success in patients, with clinical responses observed or effective antigen specific immune responses achieved, but has had limited impact on patient survival. Key elements required to generate de novo cell-mediated antitumour immune responses in vivo include recruitment of antigen-presenting cells to the tumour site, loading these cells with antigen, and their migration and maturation to full antigen-presenting function. In addition, it is essential for antigen-specific T cells to locate the tumour to mediate cytotoxicity, emphasizing the need for local inflammation to target effector cell recruitment. We review those therapies that involve the tumour site as a target and source of antigen for the initiation of immune responses, and discuss strategies to generate and co-ordinate an optimal cell-mediated immune response to control tumours locally.
Crittenden, Marka R; Thanarajasingam, Uma; Vile, Richard G; Gough, Michael J
Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment
Recent mechanistic insights obtained from preclinical studies and the approval of the first immunotherapies has motivated increasing number of academic investigators and pharmaceutical/biotech companies to further elucidate the role of immunity in tumor pathogenesis and to reconsider the role of immunotherapy. Additionally, technological advances (e.g., next-generation sequencing) are providing unprecedented opportunities to draw a comprehensive picture of the tumor genomics landscape and ultimately enable individualized treatment. However, the increasing complexity of the generated data and the plethora of bioinformatics methods and tools pose considerable challenges to both tumor immunologists and clinical oncologists. In this review, we describe current concepts and future challenges for the management and analysis of data for cancer immunology and immunotherapy. We first highlight publicly available databases with specific focus on cancer immunology including databases for somatic mutations and epitope databases. We then give an overview of the bioinformatics methods for the analysis of next-generation sequencing data (whole-genome and exome sequencing), epitope prediction tools as well as methods for integrative data analysis and network modeling. Mathematical models are powerful tools that can predict and explain important patterns in the genetic and clinical progression of cancer. Therefore, a survey of mathematical models for tumor evolution and tumor-immune cell interaction is included. Finally, we discuss future challenges for individualized immunotherapy and suggest how a combined computational/experimental approaches can lead to new insights into the molecular mechanisms of cancer, improved diagnosis, and prognosis of the disease and pinpoint novel therapeutic targets. PMID:22986455
Charoentong, Pornpimol; Angelova, Mihaela; Efremova, Mirjana; Gallasch, Ralf; Hackl, Hubert; Galon, Jerome; Trajanoski, Zlatko
4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Oncology, San Francisco, CA, USA, 21-24 November 2013 Aside from temozolomide, there has been no major breakthrough for decades to improve outcome for high-grade glioma. Bevacizumab failed to show a survival advantage in two large studies - AVaglio and RTOG-0825 - and no other novel chemotherapy agents seem to be appearing on the horizon for this universally fatal disease. Consequently, the neuro-oncology fraternity is turning to immunotherapy. This became apparent in this meeting, considering a number of delegates focused their attention to presentations on immunotherapy. The ReACT study demonstrated the safety and efficacy of the combination of a promising peptide vaccine, rindopepimut, and bevacizumab with longer survival seen in patients with a higher antibody titer. Several presentations reassured that dendritic cell-based immunotherapy is safe and can generate a lasting immune response. Employing gene therapy, increased intratumor 5-fluorouracil chemotherapy concentration can be achieved using TOCA 511, and temozolomide-resistant transgenic lymphocytes could be produced through retroviral coding. Blocking immune checkpoints PDL-01, CTLA-4 and indoleamine 2,3-dioxygenase through monoclonal antibodies appears promising. PMID:24941977
The size of the lung cancer problem and the dismal results of conventional therapy justify close attention to the possibilities of immunotherapy. Lung cancer patients, like other tumor patients, are often relatively immunosuppressed although an immune response directed against autochthonous tumor cells can usually be demonstrated. All conventional forms of therapy, surgery, chemotherapy, and particularly radiation therapy, are further immunosuppressive, which, there is reason to believe, jeopardizes a successful outcome. Immunotherapy seeks to counteract this either by nonspecfic immunoenhancement or by enhancing reactivity to tumor specific antigens. The results of immunotherapy trials in lung cancer patients suggest that survival can be prolonged and survivorship increased by immunotherapy, although the benefit is inconclusuve at present. Optimal conditions for immunotherapy, as presently understood, are outlined. Practical questions about the optimal use of current immunotherapy regimens need to be answered, but a more aggressive approach to lung cancer therapy when combined with immunotherapy seems justified. Im pariicular, the criteria for operability will need to be redefined, particularly as regards oat cell cancer and large tumors which cannot be completely resected but in which "debulking" may contribute to the success of subsequent radiation and immunotherapy. Possible future immunotherapy regimens applicable to lung cancer are proposed, with the reservation that their success is likely to be directly related to their practicability. PMID:1251303
Gross, N J; DeMeester, T R
Recent reports have described a new strategy for differentiation and maturation of monocyte (Mo)-derived dendritic cells (DC) within only 48-72 h of in vitro culture (fast-DC). Mature fast-DC are as effective as mature standard-DC (generated in 7-10 days of in vitro culture) in priming and propagation of antigen-specific T-cell responses. The use of fast-DC not only reduces labor and supply cost, as well as workload and time, but also increases the DC yield from Mo, which may facilitate DC-based immunotherapy for cancer patients. Detailed protocols for generation, pulsing with different antigen sources, and transduction with adenoviral vector of Mo-derived mature fast-DC as well as using of fast-DC for priming and propagation of antigen-specific cytotoxic T-cell effectors will be described here. PMID:24619676
Researchers at the NCI's Laboratory of Molecular Biology have created an immunoconjugate using an anti-mesothelin antibody (SS1) as the targeting moiety and IL12 as the payload molecule. This allows the localized concentration of IL12 at cancer cells, reducing the toxic effects seen with systemic IL12 administration.
Amyloid-? (A?) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimer's disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of A? clearance on the development of tau pathology. Here we show that A? immunotherapy reduces not only extracellular A? plaques but also intracellular A? accumulation and
Salvatore Oddo; Lauren Billings; J. Patrick Kesslak; David H. Cribbs; Frank M. LaFerla
Summary Tumour cells can be efficiently killed by specific T cells of the immune system. Targeted immunotherapies require the identification\\u000a and characterization of appropriate antigen structures. To date, a huge number of tumour-associated antigens (TAAs) have been\\u000a identified and several attempts try to target these antigens to reduce tumour load or to prevent relapse in solid tumour like\\u000a lung cancer, prostate
J. Greiner; M. Schmitt
Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.
A major goal in cancer immunotherapy is to generate an effective anti-tumor immune response. Adoptive immunotherapy involves stimulation of tumor-specific T cells, ex vivo (outside the body), followed by transfer of expanded numbers of activated T cells b...
J. P. Schneck M. Oelke
A major goal in cancer immunotherapy is to generate an effective anti-tumor immune response. Adoptive immunotherapy involves stimulation of tumor-specific T cells, ex vivo (outside the body), followed by transfer of expanded numbers of activated T cells b...
J. P. Schneck M. Oelke
For more than a decade clinical trials have attempted to define the role of immunotherapy in the treatment of patients with acute leukemia. Based on animal studies which indicated that non-specific immune stimulation had an antitumor effect if the tumor burden was small, the use of immunotherapy during remission in patients with acute leukemia seemed appropriate following the initial report
William R. Vogler
Background Anti-tumor therapies aim at reducing to zero the number of tumor cells in a host within their end or, at least, aim at leaving the patient with a sufficiently small number of tumor cells so that the residual tumor can be eradicated by the immune system. Besides severe side-effects, a key problem of such therapies is finding a suitable scheduling of their administration to the patients. In this paper we study the effect of varying therapy-related parameters on the final outcome of the interplay between a tumor and the immune system. Results This work generalizes our previous study on hybrid models of such an interplay where interleukins are modeled as a continuous variable, and the tumor and the immune system as a discrete-state continuous-time stochastic process. The hybrid model we use is obtained by modifying the corresponding deterministic model, originally proposed by Kirschner and Panetta. We consider Adoptive Cellular Immunotherapies and Interleukin-based therapies, as well as their combination. By asymptotic and transitory analyses of the corresponding deterministic model we find conditions guaranteeing tumor eradication, and we tune the parameters of the hybrid model accordingly. We then perform stochastic simulations of the hybrid model under various therapeutic settings: constant, piece-wise constant or impulsive infusion and daily or weekly delivery schedules. Conclusions Results suggest that, in some cases, the delivery schedule may deeply impact on the therapy-induced tumor eradication time. Indeed, our model suggests that Interleukin-based therapies may not be effective for every patient, and that the piece-wise constant is the most effective delivery to stimulate the immune-response. For Adoptive Cellular Immunotherapies a metronomic delivery seems more effective, as it happens for other anti-angiogenesis therapies and chemotherapies, and the impulsive delivery seems more effective than the piece-wise constant. The expected synergistic effects have been observed when the therapies are combined.
IFN-?-adsorbed DMSA-coated magnetite nanoparticles can be used as an efficient in vivo drug delivery system for tumor immunotherapy. Magnetic nanoparticles, with adsorbed interferon-?, were targeted to the tumor site by application of an external magnetic field. A relevant therapeutic dosage of interferon in the tumor was detected and led to a notable reduction in tumor size. In general, only 10% of the total injected nanoparticles after multiple exposures were found in tissues by AC susceptibility measurements of the corresponding resected tissues. Magnetic nanoparticle biodistribution is affected by the application of an external magnetic field.
Gutiérrez, L.; Mejías, R.; Barber, D. F.; Veintemillas-Verdaguer, S.; Serna, C. J.; Lázaro, F. J.; Morales, M. P.
In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4(+) and CD8(+) T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor-associated antigens aimed at stimulating effector T-cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer. PMID:21923608
Hammerstrom, Aimee E; Cauley, Diana H; Atkinson, Bradley J; Sharma, Padmanee
Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies.
Thakur, Archana; Vaishampayan, Ulka; Lum, Lawrence G.
We have prepared this document, "Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update", according to the evidence-based criteria, revising and updating chapters of the originally published paper, "Sublingual Immunotherapy: World Allergy Organization Position Paper 2009", available at http://www.waojournal.org. Namely, these comprise: "Mechanisms of sublingual immunotherapy;" "Clinical efficacy of sublingual immunotherapy" - reporting all the data of all controlled trials published after 2009; "Safety of sublingual immunotherapy" - with the recently published Grading System for adverse reactions; "Impact of sublingual immunotherapy on the natural history of respiratory allergy" - with the relevant evidences published since 2009; "Efficacy of SLIT in children" - with detailed analysis of all the studies; "Definition of SLIT patient selection" - reporting the criteria for eligibility to sublingual immunotherapy; "The future of immunotherapy in the community care setting"; "Methodology of clinical trials according to the current scientific and regulatory standards"; and "Guideline development: from evidence-based medicine to patients' views" - including the evolution of the methods to make clinical recommendations.Additionally, we have added new chapters to cover a few emerging crucial topics: "Practical aspects of schedules and dosages and counseling for adherence" - which is crucial in clinical practice for all treatments; "Perspectives and new approaches" - including recombinant allergens, adjuvants, modified allergens, and the concept of validity of the single products. Furthermore, "Raising public awareness about sublingual immunotherapy", as a need for our patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion, are also reported in detail. PMID:24679069
Canonica, Giorgio Walter; Cox, Linda; Pawankar, Ruby; Baena-Cagnani, Carlos E; Blaiss, Michael; Bonini, Sergio; Bousquet, Jean; Calderón, Moises; Compalati, Enrico; Durham, Stephen R; van Wijk, Roy Gerth; Larenas-Linnemann, Désirée; Nelson, Harold; Passalacqua, Giovanni; Pfaar, Oliver; Rosário, Nelson; Ryan, Dermot; Rosenwasser, Lanny; Schmid-Grendelmeier, Peter; Senna, Gianenrico; Valovirta, Erkka; Van Bever, Hugo; Vichyanond, Pakit; Wahn, Ulrich; Yusuf, Osman
The Tumor Necrosis Factor is a pro-inflammatory cytokine which plays a key role in the pathogenesis of many diseases. Therefore, the anti Tumor necrosis factors have been used for treating many inflammatory pathologies such as rheumatoid arthritis or Crohn's disease with success. However, the use of these drugs has revealed during the formal years many side effects dominated by the tuberculosis. Lung cancer and asthma might be other side effects of the drugs. More recently they have been used for other pulmonary indications such as sarcoidosis. Their benefits for treating asthma is being studied. Therefore, a wise use of these drugs is mandatory to benefit from good effects and avoid hamful ones. PMID:20180383
Tritar, Fatma; Zendah, Inès; Ben M'rad, Sonia; Daghfous, Hafaoua
Nowadays, treatment of food allergy only considered the avoidance of the specific food. However, the possibility of cross-reactivity makes this practice not very effective. Immunotherapy may exhibit as a good alternative to food allergy treatment. The use of hypoallergenic molecules with reduced IgE binding capacity but with ability to stimulate the immune system is a promising tool which could be developed for immunotherapy. In this study, three mutants of Pru p 3, the principal allergen of peach, were produced based on the described mimotope and T cell epitopes, by changing the specific residues to alanine, named as Pru p 3.01, Pru p 3.02, and Pru p 3.03. Pru p 3.01 showed very similar allergenic activity as the wild type by in vitro assays. However, Pru p 3.02 and Pru p 3.03 presented reduced IgE binding with respect to the native form, by in vitro, ex vivo, and in vivo assays. In addition, Pru p 3.03 had affected the IgG4 binding capacity and presented a random circular dichroism, which was reflected in the nonrecognition by specific antibodies anti-Pru p 3. Nevertheless, both Pru p 3.02 and Pru p 3.03 maintained the binding to IgG1 and their ability to activate T lymphocytes. Thus, Pru p 3.02 and Pru p 3.03 could be good candidates for potential immunotherapy in peach-allergic patients.
Gomez-Casado, C.; Garrido-Arandia, M.; Gamboa, P.; Blanca-Lopez, N.; Canto, G.; Varela, J.; Cuesta-Herranz, J.; Pacios, L. F.; Diaz-Perales, A.; Tordesillas, L.
Amyloid-beta (A?) immunotherapy has received considerable attention as a promising approach for reducing the level of A? in the CNS of Alzheimer’s disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with A?42 developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients mat received the vaccine. Generated antibodies reduced ?-amyloid deposits in the parenchyma of patients’ brains, but no reduction in soluble A? or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of A? is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric A?, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for A? immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-A? antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD.
The clinical expression of the most common allergic diseases reflects allergic inflammation and underlines that inflammation is the main target of anti-allergic therapies. Allergen specific immunotherapy (AIT) has a recognized impact on allergic inflammation, which persists after its discontinuation, and is the only therapy able to modify the natural history of allergic march. The traditional, subcutaneous route of administration is effective in altering the phenotype of allergen-specific T cells, switching from a Th2-type response, characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy or tolerance of Th2, the latter related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual IT with high allergen doses proved to be similar compared to subcutaneous immunotherapy. Recent data obtained in biopsies clearly indicate that the pathophysiology of the oral mucosa, and in particular mucosal dendritic cells, plays a pivotal role in inducing tolerance to the administered allergen. PMID:18782023
Incorvaia, Cristoforo; Frati, Franco; Puccinelli, Paola; Marcucci, Francesco; Di Cara, Giuseppe; Sensi, Laura; Scurati, Silvia; Yacoub, Mona-Rita; Moingeon, Philippe
The promise of cell-based immunotherapies for the treatment of cancer offers the potential of therapeutic synergy with chemo- and radiotherapies that may overcome current limitations leading to durable responses and prevention of recurrence. There is a wide array of cell-based immunotherapies that are either poised to enter cancer clinical trials or are in clinical trials, and many are showing some success. Yet within this field, there are clear obstacles that need to be overcome, including limited access across tissue barriers, development of antigen tolerance, and the immunosuppressive microenvironment of tumors. Through an understanding of immune cell signaling and trafficking, immune cell populations can be selected for adoptive transfer, and delivery strategies can be developed that circumvent these obstacles to effectively direct populations of cells with robust anti-tumor efficacy to the target. Within the realm of immune cell therapies, cytokine-induced killer (CIK) cells have demonstrated promising trafficking patterns, effective delivery of synergistic therapeutics, and stand-alone efficacy. Here, we discuss the next generation of CIK therapies and their application for the effective treatment of a wide variety of cancers. PMID:24791943
Schmidt, Tobi L; Negrin, Robert S; Contag, Christopher H
Warm autoimmune hemolytic anemia (WAIHA) is one of four clinical types of autoimmune hemolytic anemia (AIHA), with the characteristics of autoantibodies maximally active at body temperature. It produces a variable anemia-sometimes mild and sometimes severe. With respect to the absence or presence of an underlying condition, WAIHA is either idiopathic (primary) or secondary, which determines the treatment strategies in practice. Conventional treatments include immune suppression with corticosteroids and, in some cases, splenectomy. In recent years, the number of clinical studies with monoclonal antibodies and immunosuppressants in the treatment of WAIHA increased as the knowledge of autoimmunity mechanisms extended. This thread of developing new tools of treating WAIHA is well exemplified with the success in using anti-CD20 monoclonal antibody, Rituximab. Following this success, other treatment methods based on the immune mechanisms of WAIHA have emerged. We reviewed these newly developed immunotherapy treatments here in order to provide the clinicians with more options in selecting the best therapy for patients with WAIHA, hoping to stimulate researchers to find more novel immunotherapy strategies. PMID:24106518
Liu, Bainan; Gu, Wangang
Purpose of the review Recent investigation has resulted in significant advances toward definitive therapeutic options for food allergy. In this review, we will explore novel immunotherapeutic interventions for the active treatment of food allergy. Recent findings Because the injection route for allergen immunotherapy to foods has been associated with an unacceptable risk of severe anaphylactic reactions, use of mucosally targeted therapeutic strategies is of significant interest for food allergy. Allergen-specific immunotherapeutic approaches such as oral, sublingual, epicutaneous, and peptide immunotherapy have demonstrated efficacy in increasing threshold dose and inducing immunologic changes associated with both desensitization and oral tolerance in animal and human trials. More global immunomodulatory strategies, such as Traditional Chinese Medicine and anti-IgE therapy have been shown to effectively target the allergic response, and clinical trials are ongoing to determine the efficacy and safety in human food allergy. Summary The advent of therapies that target the mucosal immune response to promote oral tolerance have shown great promise in the treatment of food hypersensitivity. However, there is still significant risk of adverse reactions associated with these therapeutic strategies and further study is needed to carefully advance these therapeutic modalities toward general clinical implementation.
Scurlock, Amy M.; Jones, Stacie M.
Immunotherapy is currently being intensively explored as much-needed disease-modifying treatment for neurodegenerative diseases. While Alzheimer’s disease (AD) has been the focus of numerous immunotherapeutic studies, less attention has been paid to Parkinson’s disease (PD) and other neurodegenerative disorders. The reason for this difference is that the amyloid beta (A?) protein in AD is a secreted molecule that circulates in blood and is readably recognized by antibodies. In contrast, ?-synuclein (?-syn), tau, huntingtin and other proteins involved in neurodegenerative diseases have been considered to be exclusively of intracellular nature. However, the recent discovery that toxic oligomeric versions of ?-syn and tau accumulate in the membrane and can be excreted to the extracellular environment has provided a rationale for the development of immunotherapeutic approaches for PD, dementia with Lewy bodies, frontotemporal dementia, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins. Active immunization, passive immunization, and T cell-mediated cellular immunotherapeutic approaches have been developed targeting A?, ?-syn and tau. Most advanced studies, including results from phase III clinical trials for passive immunization in AD, have been recently reported. Results suggest that immunotherapy might be a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and propagation of toxic protein aggregates. In this manuscript we provide an overview on immunotherapeutic advances for neurodegenerative disorders, with special emphasis on ?-synucleinopathies.
Valera, Elvira; Masliah, Eliezer
V?9V?2 (also termed V?2V?2) T cells, a major human peripheral blood ?? T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because ??T cells express both natural killer receptors such as NKG2D and ?? T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated ?? T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to ?? T cells. Utilizing these antimicrobial and anti-tumor properties of ?? T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of ?? T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of ?? T cell-based therapies so far performed. Based on the results of the reported trials, ?? T cells appear to be a promising tool for novel immunotherapies against certain types of diseases.
Wu, Yan-Ling; Ding, Yan-Ping; Tanaka, Yoshimasa; Shen, Li-Wen; Wei, Chuan-He; Minato, Nagahiro; Zhang, Wen
Warm autoimmune hemolytic anemia (WAIHA) is one of four clinical types of autoimmune hemolytic anemia (AIHA), with the characteristics of autoantibodies maximally active at body temperature. It produces a variable anemia—sometimes mild and sometimes severe. With respect to the absence or presence of an underlying condition, WAIHA is either idiopathic (primary) or secondary, which determines the treatment strategies in practice. Conventional treatments include immune suppression with corticosteroids and, in some cases, splenectomy. In recent years, the number of clinical studies with monoclonal antibodies and immunosuppressants in the treatment of WAIHA increased as the knowledge of autoimmunity mechanisms extended. This thread of developing new tools of treating WAIHA is well exemplified with the success in using anti-CD20 monoclonal antibody, Rituximab. Following this success, other treatment methods based on the immune mechanisms of WAIHA have emerged. We reviewed these newly developed immunotherapy treatments here in order to provide the clinicians with more options in selecting the best therapy for patients with WAIHA, hoping to stimulate researchers to find more novel immunotherapy strategies.
Modulation of a patient's immune system so that it acts against lung cancer cells has not been successful in the past decades. Advances in our understanding of the immune response to tumors resulted in the development of different kinds of novel immunotherapeutic agents. This has resulted in the development of two major approaches. First, antigen-specific immunotherapy or cancer vaccination, with the MAGE-A3 vaccine in resected early-stage non-small-cell lung cancer (NSCLC), the L-BLP25 vaccine in locally advanced NSCLC after chemoradiotherapy and belagenpumatucel-L and the TG4010 vaccine in advanced-stage NSCLC. Second, non-antigen-specific immunotherapy or cancer immunomodulation is reviewed, including how monoclonal antibodies modulate the interaction between antigen-presenting cells, T-lymphocytes and tumor cells (e.g., antibodies against CTLA-4, or against PD-1 receptor or its ligands). Recent Phase II trials with these treatments have shown promising results of efficacy and tolerability, which has led to testing in several large Phase III trials. Some of these are fully recruited, while others are still ongoing, and important results are be expected in the near future. PMID:24143916
Declerck, Sarah; Vansteenkiste, Johan
Laser immunotherapy is a special cancer treatment modality using an intratumor injection of a special formulation consisting of a novel immunoadjuvant and a laser-absorbing dye, followed by a non-invasive near-IR laser irradiation. Our early experiments using a metastatic mammary rat tumor model showed that laser immunotherapy could cause acute selective photothermal tumor destruction and induce a systemic, long-term specific anti-tumor immunity. In the current study, laser immunotherapy was used to treat metastatic prostate tumors in Copenhagen male rats. The transplantable tumors metastasize mainly to the lung and the lung cancer is usually the cause of death. Two experimental were performed in our study. The first was to study the effect of laser immunotherapy on the tumor burdens, both the primary and the metastasis in the lung. The second was to study the effect of laser immunotherapy on the long-term survival of the tumor-bearing rats. For comparison, some rat tumors were also treated by the laser-dye combination to study the photothermal effect. Tour results showed that both the photothermal effect and the laser immunotherapy could slow the growth of primary tumors and the metastatic tumors. The laser-dye-immunoadjuvant treatment resulted in more than 20 percent long-term survival rate in tumor-bearing rats. Our experimental results indicate that the laser immunotherapy has a great potential in treating metastatic tumors.
Chen, Wei R.; Ritchey, Jerry W.; Bartles, Kenneth E.; Lucroy, Michael D.; Liu, Hong; Nordquist, Robert E.
Calcitriol (1?,25-dihydroxyvitamin D3) is the active vitamin D metabolite and mediates immunological functions, which are relevant in allergy. Its therapeutic use is limited by hypercalcaemic toxicity. We have previously shown that the activation of the vitamin D receptor inhibits IgE production and that B cells can synthesize calcitriol from its precursor 25-hydroxyvitamin D3 (inactive precursor) [25(OH)D] upon antigenic stimulation. In this study, we address the impact of 25(OH)D on the development of type I sensitization and determine its role in allergen-specific immunotherapy. BALB/c mice were sensitized to OVA, under 25(OH)D-deficient or sufficient conditions. The humoral immune response over time was measured by ELISA. OVA-specific immunotherapy was established and studied in a murine model of allergic airway inflammation using lung histology, pulmonary cytokine expression analysis, and functional parameters in isolated and perfused mouse lungs. In 25(OH)D-deficient mice, OVA-specific IgE and IgG1 serum concentrations were increased compared with control mice. OVA-specific immunotherapy reduced the humoral immune reaction after OVA recall dose-dependently. Coadministration of 25(OH)D in the context of OVA-specific immunotherapy reduced the allergic airway inflammation and responsiveness upon OVA challenge. These findings were paralleled by reduced Th2 cytokine expression in the lungs. In conclusion, 25(OH)D deficiency promotes the development of type I sensitization and correction of its serum concentrations enhances the benefit of specific immunotherapy. PMID:24951815
Heine, Guido; Tabeling, Christoph; Hartmann, Bjoern; González Calera, Carla R; Kühl, Anja A; Lindner, Juliane; Radbruch, Andreas; Witzenrath, Martin; Worm, Margitta
Grazax is a lyophilisate of an extract of Timothy-grass pollen (Phleum pratense) administered by the sublingual route to induce desensitization (or hyposensitization) to grass pollen in subjects with hay fever. Since allergen avoidance measures are limited in hay fever sufferers, present treatment, at least in the United Kingdom, is almost always by symptomatic medication. The effectiveness of symptomatic treatment in hay fever is variable and depends on patient compliance and the judicious prescribing of antihistamines and anti-inflammatory preparations either alone or in combination. Desensitization (hyposensitization or specific immunotherapy) by subcutaneous injection has been shown to be very efficacious and is used for patients who do not adequately respond to drug treatment. A rare side effect of desensitizing injections is anaphylaxis, and so use is limited to specialized centers. For these reasons there has been considerable interest in specific immunotherapy by the sublingual route. Grazax has recently been approved in the United Kingdom. It is commenced at least four months prior to the expected start of the grass pollen season and in line with injection immunotherapy treatment will be recommended for a period of three years with annual reviews to assess patient outcomes. Grazax grass allergen tablets are well tolerated in patients with grass pollen allergy with most adverse events being mild local reactions. There have been no instances of anaphylaxis. In randomized double-blind placebo controlled trials Grazax reduces symptoms and medication scores in adults with hay fever. The long-term effects of Grazax are currently being investigated. PMID:18174969
Kay, A B
Allergen immunotherapy reorients inappropriate immune responses in allergic patients. Sublingual allergen immunotherapy (SLIT) has been approved, notably in the European Union, as an effective alternative to subcutaneous allergen immunotherapy (SCIT) for allergic rhinitis patients. Compared with SCIT, SLIT has a better safety profile. This is possibly because oral antigen-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical tolerance. Although 40-75% of patients receiving SLIT experience mild, transient local reactions in the oral mucosa, these primary reactions rarely necessitate dose reduction or treatment interruption. We discuss 11 published case reports of anaphylaxis (all nonfatal) diagnosed according to the World Allergy Organization criteria and relate this figure to the approximately 1 billion SLIT doses administered worldwide since 2000. Anaphylaxis risk factors associated with SCIT and/or SLIT should be characterized further. PMID:22150126
Calderón, M A; Simons, F E R; Malling, H-J; Lockey, R F; Moingeon, P; Demoly, P
Hymenoptera venom anaphylaxis after bee or wasp sting is a common problem that affects about 1.2 percent to 3.5 percent of the general population. Venom-specific immunotherapy (VIT) is an established mode of treatment for immunoglobulin (Ig) E-mediated Hymenoptera venom allergy. However, VIT may often be associated with immediate anaphylaxis which can lead to treatment withdrawal. Several cases published in recent years suggest that omalizumab, used as add-on therapy may be able to prevent anaphylaxis during VIT. We report the case of a 30-year-old woman, suffering from mild persistent asthma, who had a history of severe anaphylactic reactions after yellow jacket sting, and after eating peanuts, contact with guinea pig hair, and i.v. administration of dexamethasone natrium phosphate. Initial specific immunotherapy had to be stopped due to severe anaphylaxis (hypotension, dyspnea, and angioedema). The immunotherapy was reintroduced accompanied by the anti-immunoglobulin (Ig) E monoclonal antibody omalizumab. Subcutaneous omalizumab 150 mg was initiated 4 weeks after the anaphylaxis incident and 1 day before the resumption of VIT. Rush treatment was uneventful, and the usual cumulative dose of 111.1 microg was successfully reached. The combination of omalizumab and VIT is a valid option of therapy for these patients and could reduce asthma and food allergy symptoms. PMID:24674685
Palgan, K; Bartuzi, Z; Gotz-Zbikowska, M
Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy
Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.
Allergen immunotherapy has been used to treat allergic diseases for more than 100 years. In the U.S., the preparation of diagnostic and therapeutic extracts requires the cooperation of the extract manufacturer, who provides the individual allergen concentrates, and the practicing physician who formulates, dilutes, and administers the final patient-specific treatment extract. The guidelines, rules, and regulations for these activities have been established and continue to be developed as progress is made. The molecular characterization and standardization of allergenic extracts has allowed for improvements in defining the potency of these products. In turn, these advances have led to improved dosing regimens and formulation practices. This review will describe in detail some of these interactions and will identify issues that require more attention. PMID:23722699
Esch, Robert E; Plunkett, Greg A
Experiments in our laboratory incorporate a non-invasive approach to treat superficial tumors in animal models. Based on the concept of Laser Assisted Cancer Immunotherapy, surface irradiation provides good information to compare to invasive alternatives. The procedure involves injecting an immunoadjuvant (Glycated Chitosan) as well as a light absorbing dye (Indocyanine Green) directly into the tumor (5 to 7 mm in diameter). The temperature of the tumor is raised using an infrared diode laser operating at 804 nm, with a silica fiber tip placed a set distance away from the surface of the tumor. We monitor the surface temperature using non-invasive (infrared detector probe) as well as the internal temperature of the tumor using invasive (micro thermocouples) methods. This study aims at the success of the surface irradiation mode to treat solid tumors. * This work is supported by a grant from The National Institute of Health.
Wilson, Joshua; Chen, Hsin-Wei; Bandyopadhyay, Pradip
Sublingual immunotherapy (SLIT) is recommended in South Africa for the treatment of allergic rhinitis (with or without asthma) to house dust mites or grass pollens. Recent local studies have confirmed efficacy and safety but have also shown heterogeneity in clinical responses to the European SLIT vaccines used in the region. It has been found that regular follow-up with standardized rhinitis quality-of-life questionnaires improves compliance and encourages the patients to complete the 3-year SLIT course. Patients who discontinue usually do so in the first year because of logistic and financial reasons rather than adverse side effects. Further studies are in progress at the Allergy Diagnostic & Clinical Research Unit to identify immunologic markers of the SLIT responder phenotype. PMID:23587331
The prognosis of patients diagnosed with high-grade glioma continues to be dismal in spite of multimodal treatment. Active specific immunotherapy by means of dendritic cell vaccination is considered to be a new promising concept that aims at generating an anti-tumoral immune response. However, it is now widely accepted that the success of immunotherapeutic strategies to promote tumor regression will rely not only on enhancing the effector arm of the immune response but also on downregulation of the counteracting tolerogenic signals. In this article, we summarize evidence that galectin-1, an evolutionarily conserved glycan-binding protein that is abundantly expressed in high-grade glioma, is an important player in glioma-mediated immune escape. PMID:21469926
Verschuere, Tina; De Vleeschouwer, Steven; Lefranc, Florence; Kiss, Robert; Van Gool, Stefaan W
Radical prostatectomy for prostate cancer is followed by PSA recurrence in up to 40% of patients. One third of patients with biochemical relapse progress to uncurable metastatic disease. Therefore, alternative treatment modalities are needed both in the situation of PSA recurrence and in hormone-refractory disease. Dendritic cells (DC) are the most powerful antigen-presenting cells, able to prime naïve T-cells and to break peripheral tolerance and thus induce tumor immune responses. More than 400 prostate cancer patients have been treated with DC-based immunotherapy to date, and immune responses have been reported in two-thirds of these, resulting in clinical responses in almost half of the patients treated. Most responses, however, were modest and transient. Therefore, mechanisms of treatment failure and possibilities to improve vaccination efficacy are being discussed. PMID:17514654
Thomas-Kaskel, Anna-Katharina; Waller, Cornelius F; Schultze-Seemann, Wolfgang; Veelken, Hendrik
The description of a cell-free soluble anti-tumour factor by Carswell et al. in 1975 (Proc Natl Acad Sci USA, 72: 3666–3670) was followed by a long series of experimental and clinical investigations into the role of cell-free mediators in cancer immunotherapy. These investigations included research on the effects of macrophage–derived eicosanoids (cycloxygenase and lipoxygenase derivates of arachidonic acid) and of monokines such as tumour necrosis factor-?, interleukin-1 and granulocyte–monocyte–macrophage–colony stimulating factor) and of lymphocyte products: interleukins and interferons. The investigations yielded information on the effects of various factors on macrophage and T-cell activation in vitro, determination of direct anti-tumour properties on animal and human tumour cells in vitro and on therapeutic effectiveness in tumour-bearing individuals either alone or in combination with other therapeutic factors and their production by tumour cells. During recent years much effort has been dedicated towards the use of the tumour cells transfected with cytokine genes in the preparation of cancer vaccines. Cycloxygenase products (prostaglandins) were usually assumed to inhibit expression of anti-tumour activity by macrophages and an increase in their production in cancer patients was considered as a poor prognostic index. Lipoxygenase (leukotrienes) products were assumed to exhibit antitumour activity and to induce production of IL-1 by macrophages. Interleukins 2, 4, 6, 7, 12 and the interferons were extensively tested for their therapeutic effectiveness in experimental tumour models and in cancer clinical trials. The general conclusion on the use of cell-free mediators for cancer immunotherapy is that much still has to be done in order to assure effective and reproducible therapeutic effectiveness for routine use in the treatment of human neoplasia.
Our research is focused towards the development of an immunotherapy for prostate cancer that specifically targets the expressed prostate specific antigen (PSA) of prostate tumor cells. With over forty thousand deaths a year and the near lack of curative t...
W. M. Kast
The National Cancer Institute (NCI), Surgery Branch is seeking parties interested in collaborative research to further co-develop a methodology for the isolation of memory T cells for adoptive immunotherapy.
Here, we propose to harness the immune system by immunotherapy (IT) alongside conventional radiotherapy (RT) to improve the treatment of men with advanced or recurrent prostate cancer. The overall aim is to determine whether local irradiation of prostate ...
A critical appraisal of the literature shows that allergy skin testing is safe, economical and useful when correlated by a meticulous medical history and physical examination. Immunotherapy is beneficial in appropriately selected patients, if properly performed using licensed and preferably standardized allergenic extracts. This article reviews the labelling and standardization of those extracts, the guidelines in determining their degree of effectiveness, their current status and their different nature through inhalation, contact, injection or ingestion. It emphasizes the basic steps in dealing with potential allergic complaints, enumerating the specific indications for immunotherapy, in which conditions it gives results and the extent of these results. The cost/benefit ratio of immunotherapy and the future prospects for allergy skin testing and immunotherapy are discussed.
Local nasal immunotherapy represents an alternative route of allergen administration. It was proposed to overcome the risk of systemic reactions rarely reported during the traditional subcutaneous immunotherapy. Some studies carried out in the past generally showed good efficacy but poor tolerability. The aqueous extracts mostly used in these studies carry some drawbacks such as the volume effect, self-digestion and the difficulty of administering reproducible dosages. The recent availability of allergen extracts in powder form has led to better stability and standardization. The studies carried out with these freeze-dried allergens showed clinical efficacy and good tolerability in perennial (mite, cat) and seasonal (grass, birch, Parietaria) allergic rhinitis. According to these findings this new local nasal immunotherapy with extract in powder form represents a suitable alternative to the traditional immunotherapy in the treatment of allergic rhinitis. PMID:9188947
Andri, L; Senna, G E; Dama, A R
Immunotherapies with T-cell epitope peptides have shown a promising impact over allergic diseases as a potential therapeutic tool in in vitro and in vivo conditions. It is recognized as an effective treatment with long lasting clinical effects and subsequent reduction of the allergic inflammatory reactions. In this review, we have summarized the role of peptide based immunotherapy and emphasis has been given to the recent advancement in pollen, cat, hymenoptera venom, and food allergy. PMID:24530919
Gupta, Kriti; Kumar, Sandeep; Das, Mukul; Dwivedi, Premendra D
Bee stings are common in the United States. In part 1 of this series, we reviewed the characteristics of bumblebees, honeybees, and Africanized honeybees; the types and pathophysiology of sting reactions; and the medical management and prevention of bee stings. In this article, we review the concepts and practice of venom immunotherapy. We further discuss the diagnosis of systemic mastocytosis, initially presenting as anaphylaxis, and the efficacy of immunotherapy in patients with mastocytosis. PMID:17725061
Lewis, Felisa S; Smith, Laurie J
Pelvic gynecological malignancies account for 6% of all cancers. In the relapsed state, classical treatments are limited. There is an urgent need for new and personalized treatment. Wilms' tumor gene 1 (WT1) is the most important tumor-associated antigen. Although highly present in gynecological tumors, active immunotherapy against it is still underexplored. This review gives an insight into the importance of WT1 in pelvic gynecological malignancies and the first taken steps into the world of WT1 immunotherapy. PMID:24784346
Coosemans, A; Vergote, I; Van Gool, Sw
Background: Treatment regimens with specific immunotherapy include updosing. Due to excellent tolerance of sublingual immunotherapy (SLIT), it was hypothesized that administration of once-daily SLIT could be initiated safely without updosing. The objective was to evaluate tolerability of SLIT administered once daily without updosing. Methods: 135 patients suffering from allergic rhinitis with\\/without asthma were included in a double-blind, placebo-controlled, parallel-group study.
F. Rodriguez; M. Boquete; M. D. Ibáñez; F. de la Torre-Martínez; A. I. Tabar
Cancer remains a devastating disease as existing therapies are too often ineffective and toxicities remain unacceptably high. Immunotherapies for cancer offer the promise of the specificity and memory of the immune system against malignant cells to achieve durable cure with minimal toxicity. Beginning with the success of bone marrow transplantation for blood-borne cancers, and the more recent development of monoclonal antibody therapeutics for a variety of tumors, immunotherapies are already among the most successful class of treatments for cancer. Greater understanding of immunoregulatory mechanisms and improved techniques for immune cell manipulation and engineering have led to new immunomodulatory approaches and cell-based therapies for cancer that have generated great excitement within the biomedical community. As these technologies continue to improve, and as new approaches for harnessing the power and specificity of the immune system are developed, immunotherapies will play an increasingly important role in the treatment of cancer. Here, we review the history of immunotherapies for cancer and discuss existing and emerging immunotherapy technologies that hope to translate the promise of immunotherapy into clinical reality. PMID:24116914
Helmy, Karim Y; Patel, Shyam A; Nahas, George R; Rameshwar, Pranela
Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy.
Cha, Edward; Fong, Lawrence
Summary Background Trees belonging to the order of Fagales show a distinct geographical distribution. While alder and birch are endemic in the temperate zones of the Northern Hemisphere, hazel, hornbeam and oak prefer a warmer climate. However, specific immunotherapy of Fagales pollen-allergic patients is mainly performed using birch pollen extracts, thus limiting the success of this intervention in birch-free areas. Objectives T cells are considered key players in the modification of an allergic immune response during specific immunotherapy (SIT), therefore we thought to combine linear T cell epitope-containing stretches of the five most important Fagales allergens from birch, hazel, alder, oak and hornbeam resulting in a Fagales pollen hybrid (FPH) molecule applicable for SIT. Methods A Fagales pollen hybrid was generated by PCR-based recombination of low IgE-binding allergen epitopes. Moreover, a structural-variant FPH4 was calculated by in silico mutagenesis, rendering the protein unable to adopt the Bet v 1-like fold. Both molecules were produced in Escherichia coli, characterized physico-chemically as well as immunologically, and tested in mouse models of allergic sensitization as well as allergy prophylaxis. Results Using spectroscopic analyses, both proteins were monomeric, and the secondary structure elements of FPH resemble the ones typical for Bet v 1-like proteins, whereas FPH4 showed increased amounts of unordered structure. Both molecules displayed reduced binding capacities of Bet v 1-specific IgE antibodies. However, in a mouse model, the proteins were able to induce high IgG titres cross-reactive with all parental allergens. Moreover, prophylactic treatment with the hybrid proteins prevented pollen extract-induced allergic lung inflammation in vivo. Conclusion The hybrid molecules showed a more efficient uptake and processing by dendritic cells resulting in a modified T cell response. The proteins had a lower IgE-binding capacity compared with the parental allergens, thus the high safety profile and increased efficacy emphasize clinical application for the treatment of Fagales multi-sensitization.
Pichler, U.; Hauser, M.; Hofer, H.; Himly, M.; Hoflehner, E.; Steiner, M.; Mutschlechner, S.; Hufnagl, K.; Ebner, C.; Mari, A.; Briza, P.; Bohle, B.; Wiedermann, U.; Ferreira, F.; Wallner, M.
Purpose of review We summarize recent advances for acute myeloid leukemia (AML) in older patients, with a focus on immunotherapeutics. Although the recently updated US SEER data still show that the majority of older AML patients do not receive any therapy, this reality is slowly changing. Advances in our understanding of the biology of AML and in the field of immunology are facilitating the development of alternative therapeutic options for patients, affording more and novel opportunities for potentially curative treatment. Recent findings Data from multiple cooperative groups show that older patients benefit from the incorporation of gemtuzumab ozogamicin, an anti-CD33 mAb toxin, into induction regimens. The first prospective study for Reduced-intensity conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplantation in older AML patients was reported at ASH 2012; the approach was feasible and improved Disease-Free Survival over conventional chemotherapy. Proof-of-concept trials targeting specific antigens such as WT1 or novel unique leukemia-associated antigens are currently underway, as well as other trials using chimeric antigen receptor T cells or (Natural Killer NK/effector cells in nontransplantation settings. Summary Wider application of immunotherapies such as allogeneic hematopoietic stem cell transplantation with RIC have altered the landscape and offer potential for cure of an increasing number of older AML patients.
Vasu, Sumithira; Blum, William
Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/HBV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism(s) of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections.
Zhu, Danming; Peng, Hua; Su, Lishan; Fu, Yang-Xin; Zhang, Liguo
Successful treatment of cancer patients with a combination of monoclonal antibodies (mAb) and chemotherapeutic drugs has spawned various other forms of additional combination therapies, including vaccines or adoptive lymphocyte transfer combined with chemotherapeutics. These therapies were effective against established tumors in animal models and showed promising results in initial clinical trials in cancer patients, awaiting testing in larger randomized controlled studies. Although combination between immunotherapy and chemotherapy has long been viewed as incompatible as chemotherapy, especially in high doses meant to increase anti-tumor efficacy, has induced immunosuppression, various mechanisms may explain the reported synergistic effects of the two types of therapies. Thus direct effects of chemotherapy on tumor or host environment, such as induction of tumor cell death, elimination of regulatory T cells, and/or enhancement of tumor cell sensitivity to lysis by CTL may account for enhancement of immunotherapy by chemotherapy. Furthermore, induction of lymphopenia by chemotherapy has increased the efficacy of adoptive lymphocyte transfer in cancer patients. On the other hand, immunotherapy may directly modulate the tumor's sensitivity to chemotherapy. Thus, anti-tumor mAb can increase the sensitivity of tumor cells to chemotherapeutic drugs and patients treated first with immunotherapy followed by chemotherapy showed higher clinical response rates than patients that had received chemotherapy alone. In conclusion, combination of active specific immunotherapy or adoptive mAb or lymphocyte immunotherapy with chemotherapy has great potential for the treatment of cancer patients which needs to be confirmed in larger controlled and randomized Phase III trials.
Zhang, Tianqian; Herlyn, Dorothee
Passive immunization of amyloid precursor protein (APP) transgenic mice with anti-amyloid beta (A?) antibodies was shown to reduce A?-deposition in brain and to improve cognition. However, immunotherapy may also be accompanied by a significant increase in the frequency of intracerebral hemorrhages. Because hemorrhages are associated with amyloid-laden vessels, this raises the question whether high concentrations of anti-A? antibodies may directly
Guido J. Burbach; Andreas Vlachos; Estifanos Ghebremedhin; Domenico Del Turco; Janaky Coomaraswamy; Matthias Staufenbiel; Mathias Jucker; Thomas Deller
Delivery of tumour-associated antigens (TAA) in a way that induces effective, specific immunity is a challenge in anti-cancer vaccine design. Circumventing tumour-induced tolerogenic mechanisms in vivo is also critical for effective immunotherapy. Effective immune responses are induced by professional antigen presenting cells, in particular dendritic cells (DC). This requires presentation of the antigen to both CD4+ and CD8+ T cells in the context of strong co-stimulatory signals. Lentiviral vectors have been tested as vehicles, for both ex vivo and in vivo delivery of TAA and/or activation signals to DC, and have been demonstrated to induce potent T cell mediated immune responses that can control tumour growth. This review will focus on the use of lentiviral vectors for in vivo gene delivery to DC, introducing strategies to target DC, either targeting cell entry or gene expression to improve safety of the lentiviral vaccine or targeting dendritic cell activation pathways to enhance performance of the lentiviral vaccine. In conclusion, this review highlights the potential of lentiviral vectors as a generally applicable ‘off-the-shelf’ anti-cancer immunotherapeutic.
Arce, Frederick; Breckpot, Karine; Collins, Mary; Escors, David
Cancer immunotherapy aims at stimulating the immune system to react against cancer stealth capabilities. It consists of repeatedly injecting small doses of a tumor-associated molecule one wants the immune system to recognize, until a consistent immune response directed against the tumor cells is observed. We have applied the theory of optimal control to the problem of finding the optimal schedule of injections of an immunotherapeutic agent against cancer. The method employed works for a general ODE system and can be applied to find the optimal protocol in a variety of clinical problems where the kinetics of the drug or treatment and its influence on the normal physiologic functions have been described by a mathematical model. We show that the choice of the cost function has dramatic effects on the kind of solution the optimization algorithm is able to find. This provides evidence that a careful ODE model and optimization schema must be designed by mathematicians and clinicians using their proper different perspectives.
Piccoli, B.; Castiglione, F.
Introduction Brain tumors are a unique class of cancers since they are anatomically shielded from normal immunosurveillance by the blood brain barrier, lack a normal lymphatic drainage system and reside in a potently immunosuppressive environment. Of the primary brain cancers, glioblastoma multiforme (GBM) is the most common and aggressive in adults. Although treatment options include surgery, radiation and chemotherapy, the average lifespan of GBM patients remains at only 14.6 months post-diagnosis. Areas covered A review of key cellular and molecular immune system mediators in the context of brain tumors including TGF-?, cytotoxic T cells, Tregs, CTLA-4, PD-1, and IDO, is discussed. In addition, prognostic factors, currently utilized immunotherapeutic strategies, on-going clinical trials, and a discussion of new or potential immunotherapies for brain tumor patients are considered. Expert opinion Current drugs that improve the quality of life and overall survival in patients with brain tumors, especially for GBM, are poorly effective. This disease requires a re-analysis of currently accepted treatment strategies, as well as newly designed approaches. Here, we review the fundamental aspects of immunosuppression in brain tumors, new and promising immunotherapeutic drugs, as well as combinatorial strategies that focus on the simultaneous inhibition of immunosuppressive hubs, both in immune- and brain tumor-cells, which is critical to consider for achieving future success for the treatment of this devastating disease.
Wainwright, Derek; Nigam, Pragati; Thaci, Bart; Dey, Mahua
The microenvironments of tumors are involved in a complex and reciprocal dialog with surrounding cancer cells. Any novel treatment must consider the impact of the therapy on the microenvironment. Recently, clinical trials with laser immunotherapy (LIT) have proven to effectively treat patients with late-stage, metastatic breast cancer and melanoma. LIT is the synergistic combination of phototherapy (laser irradiation) and immunological stimulation. One prominent cell type found in the tumor stroma is the fibroblast. Fibroblast cells can secrete different growth factors and extracellular matrix modifying molecules. Furthermore, fibroblast cells found in the tumor stroma often express alpha smooth muscle actin. These particular fibroblasts are coined cancer-associated fibroblast cells (CAFs). CAFs are known to facilitate the malignant progression of tumors. A collagen lattice assay with human fibroblast cells is used to elucidate the effects LIT has on the microenvironment of tumors. Changes in the contraction of the lattice, the differentiation of the fibroblast cells, as well as the proliferation of the fibroblast cells will be determined.
Acquaviva, Joseph T.; Wood, Ethan W.; Hasanjee, Aamr; Chen, Wei R.; Vaughan, Melville B.
Alzheimer's disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease. Extracellular plaques, containing various forms of amyloid-? protein (A?), and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated tau protein, are two major pathological hallmarks of the AD brain. Aggregation, deposition, and N-terminal modification of A? protein and tau phosphorylation and aggregation are thought to precede the onset of cognitive decline, which is better correlated with tangle formation and neuron loss. Active and passive vaccines against various forms of A? have shown promise in pre-clinical animal models. However, translating these results safely and effectively into humans has been challenging. Recent clinical trials showed little or no cognitive efficacy, possibly due to the fact that the aforementioned neurodegenerative processes most likely pre-existed in the patients well before the start of immunotherapy. Efforts are now underway to treat individuals at risk for AD prior to or in the earliest stages of cognitive decline with the hope of preventing or delaying the onset of the disease. In addition, efforts to immunize against tau and other AD-related targets are underway. PMID:24148220
Lemere, Cynthia A
Individualized cancer therapy is a central goal of cancer biologists. Immunotherapy is a rational means to this end—because the immune system can recognize a virtually limitless number of antigens secondary to the biology of genetic recombination in B and T lymphocytes. The immune system is exquisitely structured to distinguish self from non-self, as demonstrated by anti-microbial immune responses. Moreover the immune system has the potential to recognize self from “altered-self”, which is the case for cancer. However, the immune system has mechanisms in place to inhibit self-reactive responses, many of which are usurped by evolving tumors. Understanding the interaction of cancer with the immune system provides insights into mechanisms that can be exploited to disinhibit anti-tumor immune responses. Here, we summarize the 2012 SITC Primer, reviewing past, present, and emerging immunotherapeutic approaches for the treatment of cancer—including targeting innate versus adaptive immune components; targeting and/or utilizing dendritic cells and T cells; the role of the tumor microenvironment; and immune checkpoint blockade.
Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. The current rationale for its use is based largely on the ability of RT to kill the cancer cells by a direct cytotoxic effect. Nevertheless, considerable evidence indicates that RT effects extend beyond the mere elimination of the more radiosensitive fraction of cancer cells present within a tumor at the time of radiation exposure. For instance, a large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This might have far-reaching consequences regarding the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective antitumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from preclinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance antitumor effects. Conversely, RT could be a useful tool to combine with immunotherapy. This article will briefly summarize what is known about the impact of RT on tumor immunity, including tumor-associated antigens, antigen-presenting cells, and effector mechanisms. In addition, the experimental evidence supporting the contention that RT can be used as a tool to induce antitumor immunity is discussed, and a new approach to radioimmunotherapy of cancer is proposed.
Demaria, Sandra [Department of Pathology, New York University School of Medicine, New York, NY (United States); Bhardwaj, Nina [Department of Medicine, New York University School of Medicine, New York, NY (United States); McBride, William H. [Department of Radiation Oncology, Experimental Division, University of California at Los Angeles School of Medicine, Los Angeles, CA (United States); Formenti, Silvia C. [Department of Radiation Oncology NYU Cancer Institute, New York University School of Medicine, New York, NY (United States)]. E-mail: firstname.lastname@example.org
Products for specific immunotherapy (SIT) are medicinal products according to the European Regulations. To obtain a marketing authorization (MA) within the European Community, the quality, safety and efficacy have to be proven. During the development phase of a medicinal product, applicants have the opportunity to apply for scientific advice by national competent authorities or the European Medicines Agency (EMA) to compile a suitable development plan for the examination of quality and performance of nonclinical and clinical trials. Moreover, a paediatric investigation plan has to be submitted to the Paediatric Committee of the EMA and has to be approved before submission of an application for MA. Several regulatory procedures exist for obtaining a MA in the European Community. The national procedure leads only to marketability in one country whereas the Mutual Recognition, the Decentralized and Centralized Procedures (CP) are intended for MA in several or all member states of the European Union. The CP is mandatory for certain medicinal products, for example for drug substances derived by biotechnological processes such as recombinant allergens. Named Patient Products for SIT are a specialty because they are manufactured on the basis of an individual prescription and marketed without a MA. PMID:21288251
Kaul, S; May, S; Lüttkopf, D; Vieths, Stefan
Allergic rhinitis (AR) may be cured by allergen immunotherapy (AIT). However, patient characteristics for prescribing AIT are not well defined. This study aimed at evaluating the patient's profile to be a candidate for AIT in a cohort of patients suffering from AR, evaluated in 20 Italian Allergy or Ear, Nose, and Throat Centers. The study has been performed on 198 patients (98 men; mean age, 26.8 years) with AR (assessed by Allergic Rhinitis and Its Impact on Asthma [ARIA] criteria). The kind and the number of prescribed allergen extracts, type of diagnosis, severity of symptoms, and patient's perception of symptoms and drug use were evaluated. Patients were subdivided in AIT-treated and without AIT (as controls) subgroups. Most of the patients (69.7%) had persistent AR with moderate–severe symptoms. The mean number of sensitization was 3.4. ARIA classification and sensitization number did not affect AIT choice, but the type of allergen was relevant. AIT-treated patients had milder symptoms than controls if assessed by doctors, but AIT patients perceived more severe symptoms and larger drug use than controls. This study shows that the choice of AIT is based on patient's perception and type of allergen, but number of sensitizations, symptom severity assessed by doctors, and ARIA classification are not relevant factors. The key message might be that it is always relevant to pay attention to the complaints referred by the patient.
Incorvaia, Cristoforo; dell'Albani, Ilaria; Masieri, Simonetta; Cavaliere, Carmine; Puccinelli, Paola; Frati, Franco
The continuous improvements of our understanding of the pathophysiological changes that occur in multiple sclerosis (MS) have translated into many novel therapeutic agents at different stages of development. These agents target more specifically the innate or the adaptive immune response. We will review agents available or under development that target the humoral pathways of the adaptive immune response. As such, humoral targeted immunotherapies that are being developed for MS are discussed herein: rituximab, ocrelizumab, and ofatumumab show promise as B-cell depleting agents. Other agents, such as atacicept were suspended during development in MS due to increased inflammatory activity versus the placebo. Although most agents were tested in relapsing-remitting forms of MS, rituximab and ocrelizumab have both been studied in progressive MS, whereas ocrelizumab only is currently moving forward in primary progressive MS trials. We provide an overview of agents available and under development that target the humoral response and include their mechanisms of action, safety profiles, and results of clinical trials. PMID:23208729
Lulu, Sabeen; Waubant, Emmanuelle
Laser immunotherapy using laser photothermal therapy and immunological stimulation could achieve tumor-specific immune responses, as indicated by our previous pre-clinical and preliminary clinical studies. To further study the effect of laser immunotherapy, we conducted an investigation combining laser immunotherapy and surgery. After laser immunotherapy, treated tumors were surgically removed at different time points. The survival rates of treated mice were compared among different groups. Furthermore, the cured mice were rechallenged to test the immunity induced by laser immunotherapy. Our results showed that the mice treated with surgical removal one week after laser immunotherapy had the highest survival rate (77%). When the tumors were removed immediately after laser immunotherapy treatment, the survival rate was 57%. Most cured mice withstood tumor rechallenges, indicating an induction of tumor immunity by laser immunotherapy. The differentiations between different surgery groups indicate that the treated tumors have contributed to the immunological responses of the hosts.
Chen, Vivian A.; Le, Henry; Li, Xiaosong; Wolf, Roman F.; Ferguson, Halie; Sarkar, Akhee; Liu, Hong; Nordquist, Robert E.; Chen, Wei R.
Purpose Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane Chondroitin Sulphate Proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)-based immunotherapy of MM. Experimental Design We assayed adhesion, motility, invasiveness, wound-healing, apoptosis and anchorage-independent growth of MM cells on cell cultures. CSPG4 expression and signaling was studied by immunoblotting. The growth of MM SCID mice xenografts induced by PPM-Mill cells, engineered to express the luciferase reporter gene, was monitored by imaging, upon treatment with CSPG4 mAb TP41.2. Animal toxicity and survival were assayed in both tumor inhibition and therapeutic experiments. Results CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of extracellular matrix components (ECM). Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of FAK and AKT, reduced expression of cyclin D1 and apoptosis. Moreover, TP41.2 significantly reduced MM cell motility, migration and invasiveness, and inhibited MM growth in soft agar. In vivo, treatment with mAb TP41.2 prevented or inhibited the growth of MM xenografts in SCID mice, with a significant increase in animal survival. Conclusion These results establish the safety of CSPG4 mAb-based immunotherapy and suggest that CSPG4 mAb-based immunotherapy may represent a novel approach for the treatment of MM.
Rivera, Zeyana; Ferrone, Soldano; Wang, Xinhui; Jube, Sandro; Yang, Haining; Pass, Harvey; Kanodia, Shreya; Gaudino, Giovanni; Carbone, Michele
Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.
Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho
In this work, possible alterations in OKT-4+ and OKT-8+ cells in relation to pollinosis in studied, 33 pollinic patients were studied. 11 of these had not received immunotherapy and the rest had been treated with specific immunotherapy. The possible effect of immunotherapy on the T helper/T suppressor ratio is evaluated. No significant differences between the two groups of patients were found neither in relation to duration of immunotherapy nor in relation to the control group. PMID:6230904
Dominguez, M A; Sanz, M L; Lobera, T; Oehling, A
Introduction Statin medications have anti-inflammatory effects. We sought to determine whether statin use in persons with inflammatory bowel disease (IBD) was associated with reduced rates of steroid use or other markers of disease activity. Methods We performed a retrospective cohort study using administrative data. Statin users with IBD were compared to statin-unexposed IBD subjects. The primary outcome was an oral steroid prescription; secondary outcomes included anti-TNF initiation, hospitalization, or abdominal surgery. Cox proportional hazard models were used to estimate hazard ratios (HR) adjusted for potential confounders. Results The study cohort included 1,986 statin-exposed and 9,871 unexposed subjects. Statin use was associated with an 18% reduction in the rate of steroid initiation [HR 0.82 (95% CI 0.71, 0.94)]. A statistically significant result was seen with atorvastatin only [HR 0.76 (95% CI 0.60, 0.96)]. Statins were associated with a reduced rate of steroids in ulcerative colitis [HRs 0.75 (95% CI 0.62, 0.91)], but not in Crohn’s disease [HR 0.91 (95% CI 0.74, 1.12)]. Statin use was associated with reduced hazard of anti-TNF use [HR 0.72 (95% CI 0.46, 1.11)], abdominal surgery [HR 0.80 (95% CI 0.63, 1.02)], and hospitalization [HR 0.88 (95% CI 0.74, 1.05)], but these results did not reach statistical significance. Conclusion In this large retrospective cohort study, statin use amongst persons with IBD was associated with reduced use of oral steroids, particularly for UC. Prospective clinical trials are needed to confirm whether adjuvant treatment of IBD with statin drugs may spare immunosuppressant therapy or ameliorate flares.
Crockett, Seth D.; Hansen, Richard A.; Sturmer, Til; Schectman, Robin; Darter, Jane; Sandler, Robert S.; Kappelman, Michael D.
Immunotherapy of cancer is being developed as an alternative or adjuvant to conventional therapies such as: surgery, chemotherapy and\\/or radiation treatment. Immunotherapy laboratories routinely process and prepare for injection large numbers of anti-tumor effector cells. The process of cryopreservation is critical to the success of immunotherapy. Standardized safe procedures are required. In the current report, we show the ability to
Angela Best; Giovi Hidalgo; Katherine Mitchell; John R. Yannelli
Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8+ T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules.
Kitamura, Hiroshi; Tsukamoto, Taiji
Pancreatic cancer is a lethal disease and remains one of the most resistant cancers to traditional therapies. Historically, chemotherapy or radiotherapy did not provide meaningful survival benefit in advanced pancreatic cancer. Gemcitabine and recently FOLFIRINOX (5-flourouracil, leucovorin, oxaliplatin and irinotecan) have provided some limited survival advantage in advanced pancreatic cancer. Targeted agents in combination with gemcitabine had not shown significant improvement in the survival. Current therapies for pancreatic cancer have their limitations; thus, we are in dire need of newer treatment options. Immunotherapy in pancreatic cancer works by recruiting and activating T cells that recognize tumor-specific antigens which is a different mechanism compared with chemotherapy and radiotherapy. Preclinical models have shown that immunotherapy and targeted therapies like vascular endothelial growth factor and epidermal growth factor inhibitors work synergistically. Hence, new immunotherapy and targeted therapies represent a viable option for pancreatic cancer. In this article, we review the vaccine therapy for pancreatic cancer. PMID:23323149
Gunturu, Krishna Soujanya; Rossi, Gabriela R; Saif, Muhammad Wasif
Immunotherapy is considered to be the only curative treatment for allergic diseases such as pollinosis, perennial rhinitis, asthma, and food allergy. The sublingual route is widely applied for immunotherapy for allergy, instead of the conventional administration by subcutaneous route. A recent meta-analysis of sublingual immunotherapy (SLIT) has shown that this approach is safe, has positive clinical effects, and provides prolonged therapeutic effects after discontinuation of treatment. However, the mechanism of SLIT and associated biomarkers are not fully understood. Biomarkers that change after or during SLIT have been reported and may be useful for response monitoring or as prognostic indicators for SLIT. In this review, we focus on the safety, therapeutic effects, including prolonged effects after treatment, and new methods of SLIT. We also discuss response monitoring and prognostic biomarkers for SLIT. Finally, we discuss immunological mechanisms of SLIT with a focus on oral dendritic cells and facilitated antigen presentation.
Fujimura, Takashi; Okamoto, Yoshitaka; Taniguchi, Masaru
Allergen-specific immunotherapy is currently the only curative treatment for allergy. Subcutaneous immunotherapy (SCIT) has been successfully used to treat patients who are allergic to insect venom, house dust mites, or tree or grass pollens. In the context of potentially severe, albeit infrequent, side effects associated with SCIT, mucosal routes of administration are being investigated to conduct allergenic desensitization. This article reviews recent developments in the field of nasal, oral, and sublingual immunotherapy as they relate to safety, clinical efficacy, and immune mechanisms of action. Implications for the design and development of improved allergy vaccines that could be used through such nonparenteral routes are discussed. Specifically, allergen presentation platforms and adjuvants facilitating the targeting of immune cells at mucosal surfaces to promote tolerance induction are reviewed. PMID:16701145
Mascarell, Laurent; Van Overtvelt, Laurence; Moingeon, Philippe
Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed. PMID:23893180
Leopardo, D; Cecere, S C; Di Napoli, M; Cavaliere, C; Pisano, C; Striano, S; Marra, L; Menna, L; Claudio, L; Perdonà, S; Setola, S; Berretta, M; Franco, R; Tambaro, R; Pignata, S; Facchini, G
There is much promise in the use of immunotherapy for the treatment of cancer. Approaches such as those using antibodies or adoptive cell transfer can mediate complete tumor regression in a proportion of patients. However, the tumor microenvironment can inhibit immune responses leading to ineffective or suboptimal responses of tumors to immunotherapy in the majority of cases. As our knowledge of the tumor microenvironment increases, many strategies are emerging for changing the immunosuppressive nature of the tumor toward a microenvironment able to support immunity. These strategies aim to enhance the ability of immunotherapies to initiate effective immune responses able to destroy tumors. In this article, we review approaches that use immunomodulators specifically to modify the tumor microenvironment, and their use in combination with other immune-based strategies for cancer therapy.
Devaud, Christel; John, Liza B; Westwood, Jennifer A; Darcy, Phillip K; Kershaw, Michael H
Hematopoietic stem cell transplantation (HSCT) is a particularly important treatment for hematologic malignancies. Unfortunately, following allogeneic HSCT, graft-versus-host disease, immunosuppression and susceptibility to opportunistic infections remain among the most substantial problems restricting the efficacy and use of this procedure, particularly for cancer. Adoptive immunotherapy and/or manipulation of the graft offer ways to attack residual cancer as well as other transplant-related complications. Recent exciting discoveries have demonstrated that HSCT could be expanded to solid tissue cancers with profound effects on the effectiveness of adoptive immunotherapy. This review will provide a background regarding HSCT, discuss the complications that make it such a complex treatment procedure following up with current immunotherapeutic strategies and discuss emerging approaches in applying immunotherapy in HSCT for cancer.
Bouchlaka, Myriam N; Redelman, Doug; Murphy, William J
Pancreatic cancer is a lethal disease and remains one of the most resistant cancers to traditional therapies. Historically, chemotherapy or radiotherapy did not provide meaningful survival benefit in advanced pancreatic cancer. Gemcitabine and recently FOLFIRINOX (5-flourouracil, leucovorin, oxaliplatin and irinotecan) have provided some limited survival advantage in advanced pancreatic cancer. Targeted agents in combination with gemcitabine had not shown significant improvement in the survival. Current therapies for pancreatic cancer have their limitations; thus, we are in dire need of newer treatment options. Immunotherapy in pancreatic cancer works by recruiting and activating T cells that recognize tumor-specific antigens which is a different mechanism compared with chemotherapy and radiotherapy. Preclinical models have shown that immunotherapy and targeted therapies like vascular endothelial growth factor and epidermal growth factor inhibitors work synergistically. Hence, new immunotherapy and targeted therapies represent a viable option for pancreatic cancer. In this article, we review the vaccine therapy for pancreatic cancer.
Gunturu, Krishna Soujanya; Rossi, Gabriela R.
Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous treatments were largely unsuccessful, glioma may be an ideal target for immune-based therapy. Recently, translational research led to several clinical trials based on tumor immunotherapy to treat patients with malignant glioma. Here we review 17 recent glioma immunotherapy clinical trials, published over the past 3 years. Various approaches were used, including passive transfer of naked and radiolabeled antibodies, tumor antigen-specific peptide immunization, and the use of patient tumor cells with or without dendritic cells as vaccines. We compare and discuss the current state of the art of clinical immunotherapy treatment, as well as its limited successes, pitfalls, and future potential.
Sampson, John H.
Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context.
Drake, Charles G.
Laser immunotherapy is a promising cancer treatment method that induces antitumor immunity and appears to be effective both locally and systemically. In this context, an important factor is the overall state of the immune system, both locally and systemically. The success of any immunotherapy treatment depends on the balance between the local immunosuppressive forces induced by the tumor and the immune response of the host organism. Factors that influence this balance include heat-shock proteins (for example HSP70), transforming growth factor ? (TGF-?), tumor necrosis factor ? (TNF-?), interleukins, and more. Laser phototherapy, which is based on non-thermal photobiological processes, has been shown to modulate the body's own immune response, both locally and systemically, with a strong influence on for example cytokine production and heat-shock protein synthesis. Laser phototherapy may therefore be an important component in the overall efficacy of laser immunotherapy, and may tip the balance between the immunosuppressive and immunostimulatory forces in favor of immunostimulation.
Hode, Tomas; Hode, Lars
Background Acute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance. Methods/design The trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been previously described. Blood samples will be taken at the onset, during, and following the cessation of CRS so as to study effector cells, cytokine/chemokine release patterns, and extracellular vesicle populations. Initially, six patients will be enrolled on study to determine safety. Provided the treatment is deemed safe, a total of 25 patients will be enrolled to determine efficacy. Discussion Cellular Immunotherapy for Refractory Hematological Malignancies provides a novel treatment for patients with relapsed/refractory acute leukemia or aggressive lymphoma. We believe this therapy offers the immunological benefit of bone marrow transplantation without the deleterious effects of myeloablative conditioning regimens and minus the risk of GVHD. Laboratory correlative studies will be performed in conjunction with the clinical trial to determine the underlying mechanism of action. This provides a true bench to bedside approach that should serve to further enrich knowledge of host tumor tolerance and mechanisms by which this may be overcome. Trial registration NCT01685606.
To foster the success of clinical trials in radio-immunotherapy (RIT), one needs to determine (i) the quantity and spatial distribution of the administered radionuclide carrier in the patient over time, (ii) the absorbed dose in the tumour sites and critical organs based on this distribution and (iii) the volume of tumour mass(es) and normal organs from computerized tomography or magnetic resonance imaging and appropriately correlated with nuclear medicine imaging techniques (such as planar, single-photon emission computerized tomography or positron-emission tomography). Treatment planning for RIT has become an important tool in predicting the relative benefit of therapy based on individualized dosimetry as derived from diagnostic, pre-therapy administration of the radiolabelled antibody. This allows the investigator to pre-select those patients who have `favourable' dosimetry characteristics (high time-averaged target: non-target ratios) so that the chances for treatment success may be more accurately quantified before placing the patient at risk for treatment-related organ toxicities. The future prospects for RIT treatment planning may yield a more accurate correlation of response and critical organ toxicity with computed absorbed dose, and the compilation of dose - volume histogram information for tumour(s) and normal organ(s) such that computing tumour control probabilities and normal tissue complication probabilities becomes possible for heterogeneous distributions of the radiolabelled antibody. Additionally, radiobiological consequences of depositing absorbed doses from exponentially decaying sources must be factored into the interpretation when trying to compute the effects of standard external beam isodose display patterns combined with those associated with RIT.
Erdi, Alev K.; Erdi, Yusuf E.; Yorke, Ellen D.; Wessels, Barry W.
Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer (NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.
Vasekar, Monali; Liu, Xin; Zheng, Hong; Belani, Chandra P
We present a theoretical study of superficial bladder cancer growth and its treatment via pulsed immunotherapy with Bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis. BCG pulsed immunotherapy is a clinically established procedure for the treatment of superficial bladder cancer. In this paper, periodic BCG instillations are modeled using impulsive differential equations, which are studied using a combination of analytical and numerical techniques. In this way, we determine critical threshold values of the BCG instillation dose and rate of pulsing for successful treatment. We also identify treatment regimes in which tumor destruction occurs, but undesirable side effects are maintained at low levels by the immune system. PMID:18716846
Bunimovich-Mendrazitsky, Svetlana; Byrne, Helen; Stone, Lewi
Food allergy has increased dramatically in prevalence over the past decade in westernized countries, and is now a major public health problem. Unfortunately for patients with food allergy, there is no effective therapy beyond food allergen avoidance, and rapid medical treatment for accidental exposures. Recently, oral immunotherapy (OIT) has been investigated as a treatment for this problem. In this review, we will discuss the progress in developing OIT for food allergy, including a novel approach utilizing Xolair (anti-IgE monoclonal antibody, omalizumab) in combination with OIT. This combination may enhance both the safety and efficacy of oral immunotherapy, and could lead to a widely available and safe therapy for food allergy.
Background To examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC) from allergic patients undergoing rush immunotherapy (RIT) that might be manifest within the first few months of treatment. Methods For this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI) expression and T-regulatory cell frequency as detected by expression of CD3+CD4+CD25bright cells at each timepoint using flow cytometry. Results In comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ?1.5-fold expression change (p less than or equal to 0.05, BH-FDR), we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR), we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1?, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints. Conclusions We observed significant changes in gene expression early in peripheral blood samples from allergic patients undergoing RIT. Moreover, serum levels for allergen specific IgG4 also increased over the course of treatment. These studies suggest that RIT induces rapid and dynamic alterations in both innate and adaptive immunity which can be observed in the periphery of allergic patients. These alterations could be directly related to the therapeutic shift in the allergen-specific class of immunoglobulin.
There is now evidence that the rules established for tumor immunology and immunotherapy in general are relevant for brain tumors. Treatment strategies explored have mainly involved vaccines using either tumor cells or components, and vaccines with defined synthetic peptides. This latter approach offers the advantage to select well-characterized antigens with selective or preferential expression on glioma. This is a prerequisite because collateral damage to the brain is not allowed. A second strategy which is reaching clinical trials is T cell therapy using the patients' own lymphocytes engineered to become tumor reactive. Tumor specificity can be conferred by forced expression of either a high-avidity T cell receptor or an antitumor antibody (the latter cells are called chimeric antigen receptors). An advantage of T cell engineering is the possibility to modify the cells to augment cellular activation, in vivo persistence and resistance to the tumor immunosuppressive milieu. A direct targeting of the hostile glioma microenvironment will additionally be required for achieving potent immunotherapy and various trials are assessing this issue. Finally, combining immunotherapy with immune checkpoint inhibitors and chemotherapy must be explored within rigorous clinical trials that favor constant interactions between the bench and bedside. Regarding immunotherapy for glioma patients, what was an unrealistic dream a decade ago is today a credible prospect. PMID:24857060
Dietrich, Pierre-Yves; Dutoit, Valérie; Walker, Paul R
Lentiviral vectors have emerged as promising tools for both gene therapy and immunotherapy purposes. They exhibit several advantages over other viral systems in that they are less immunogenic and are capable of transducing a wide range of different cell types, including dendritic cells (DC). DC transduced ex vivo with a whole range of different (tumor) antigens were capable of inducing
K Breckpot; J L Aerts; K Thielemans
Our research is focused on the development of a PSA directed immunotherapy for prostate cancer. Through repetition of the experiments with additional controls, we confirmed our conclusion of last year that PSA can serve as a tumor rejection marker in the ...
W. M. Kast
Allergen-specific immunotherapy with house dust mite (HDM) aller- gen extracts can effectively alleviate the symptoms of allergic rhinitis and as- thma. The efficacy of the immunotherapeutic treatment is highly dependent on the quality of house dust mite vaccines. This study was performed to assess the stability of house dust mite allergen vaccines prepared for sublingual immuno- therapy. Lyophilized Dermatophagoides pteronyssinus
Lidija Burazer; Katarina Milovanovic; Tanja Cirkovic-Velickovic; Marija Gavrovic-Jankulovic
Immunotherapy has been widely investigated for its potential use in cancer therapy and it becomes more and more apparent that the selection of target antigens is essential for its efficacy. Indeed, limited clinical efficacy is partly due to immune evasion mechanisms of neoplastic cells, e.g. downregulation of expression or presentation of the respective antigens. Consequently, antigens contributing to tumor cell
Valeska Hofmeister; Claudia Vetter; David Schrama; Eva-B. Bröcker; Jürgen C. Becker
Despite advances in animal studies, where the cure of the majority of mice with pre-established (albeit early-stage) tumors has become almost standard, human clinical trials have been much less successful. Here we describe some of the most recent advances in the specialist field of tumor immunology and immunotherapy, highlighting salient work to identify key problem areas and potential solutions. We
Barbara-ann Guinn; Noriyuki Kasahara; Farzin Farzaneh; Nagy A Habib; James S Norris; Albert B Deisseroth
The goal of this research is to logically integrate immunotherapy (IT) with conventional radiotherapy (RT) to improve the treatment of men with advanced or recurrent prostate cancer. The initial aim is to determine whether local RT of prostate tumors in a...
The concept of cancer immunotherapy stems from the proposed function of the immune system, called immunosurveillance, to protect against growing tumors. Due to genetic aberrations, tumor cells display an altered repertoire of MHC-associated peptides that can lead to the activation of immune cells able to eliminate the transformed cells. In some instances, under the pressure of the immune system, both
Maria Rescigno; Francesca Avogadri; Giuseppe Curigliano
It has been described two main phenotypes of helper T cells. On activation, the immune system develops the most effective Th response. Whereas Th1 cells promote cell-mediate immunity against intracellular pathogens and an over expression could favor autoimmune diseases; Th2 cells develop humoral immunity against extracellular pathogens promoting allergic response. Normally, the two profiles coexist in the same individual with different grades of expression. Recently, it has been described a new subset: Th17, which is related to tissue injury in autoimmune diseases. Then, allergic and autoimmune diseases result from an unbalanced response of the immune system. Allergen-specific immunotherapy is the only curative treatment of a specific allergy, which leads to a life-long tolerance against allergens. There are no controlled studies about the effectiveness or risks associated with allergen-specific immunotherapy in patients with autoimmune disorders. On the other hand, scleroderma is an autoimmune chronic systemic disorder of unknown etiology characterized by excess collagen deposition in the skin and viscera, along with vascular injury. We report a girl with allergic asthma and with a second degree family history of systemic sclerosis who developed localized scleroderma during allergen specific immunotherapy. Because allergy vaccination alter the balance between effector and regulatory T-cell populations, which regulate immune tolerance, a positive family history of autoimmunity in first or second degree, could be a contraindication for allergen-specific immunotherapy. PMID:19768975
Morfín Maciel, Blanca María; Castillo Morfín, Blanca María
The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this reinvigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included in order to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors.
Mitchell, Duane A.; Sampson, John H.
Severe allergic reactions during specific immunotherapy may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during specific immunotherapy in patients with allergy towards hymenoptera venom in the Iranian population. A prospective study was performed using the clinical reports of 27 patients with anaphylaxis to bee venom (Apis melifera, Geupes vespula and Geupes Polites). Ten patients treated with Cluster protocol during 2002 and 2006 After diagnosis of hymenoptera sting allergy according to history and intradermal tests, the patient were treated with Cluster protocol immunotherapy. The protocol lasted 6 weeks with an increase in the concentration of venom from 0.01 microg/ml to 100 microg/ml. None of the patient received premedication. All patients with hymenoptera venom allergy received 120 injections. Anaphylactic reactions were classified according to the Mueller-classification. The frequencies of systemic reactions during Cluster protocol were 8.33% and 5% for yellow jacket and honey bee venom respectively. No patient experienced severe systemic reaction. Cluster protocol for hymenoptera immunotherapy is a reliable method for the treatment of anaphylactic reactions to bee venom. It is safe with low cost and do not need hospitalization. PMID:18094443
Bemanian, Mohammad Hassan; Farhoudi, Abolhassan; Pourpak, Zahra; Gharagozlou, Mohammad; Movahedi, Masoud; Nabavi, Mohammad; Mozafari, Habibeh; Mohammadzadeh, Iraj; Chavoshzadeh, Zahra; Shirkhoda, Zahra
BACKGROUND For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy. METHODS In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months. RESULTS After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months. CONCLUSIONS These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.)
Burks, A. Wesley; Jones, Stacie M.; Wood, Robert A.; Fleischer, David M.; Sicherer, Scott H.; Lindblad, Robert W.; Stablein, Donald; Henning, Alice K.; Vickery, Brian P.; Liu, Andrew H.; Scurlock, Amy M.; Shreffler, Wayne G.; Plaut, Marshall; Sampson, Hugh A.
The apolipoprotein E (APOE) ?4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid ? (A?) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with A? and facilitates A? fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-A? antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1?E9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble A?40 and A?42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around A? plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in A? binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
Kim, Jungsu; Eltorai, Adam E.M.; Jiang, Hong; Liao, Fan; Verghese, Philip B.; Kim, Jaekwang; Stewart, Floy R.; Basak, Jacob M.
Combinatory strategies are becoming of increasing interest in cancer immunotherapy. Costimulation by individual members of the immunoglobulin-like (Ig)- and TNF superfamily have already shown promising antitumor potential, thus prompting the exploration of their synergistic abilities in combinatorial approaches. Here, we pursued a targeted strategy with antibody-fusion proteins composed of a tumor-directed antibody and the extracellular domain of the costimulatory ligand B7.1, 4-1BBL, OX40L, GITRL or LIGHT, respectively. Costimulatory activity was assessed in an experimental setting where initial T cell activation was induced by a bispecific antibody (tumor-related antigen × CD3). Advantage of combined targeted costimulation was shown for either B7.1 or 4-1BBL with OX40L, GITRL, LIGHT and 4-1BBL in terms of T cell proliferation and IFN-? release. Since encouraging results were obtained by the combination of B7.1 and 4-1BBL, we adapted the model system for a time-shift setting. Here, enhanced proliferation and granzyme B expression as well as reduced PD-1 expression on the T cell population demonstrated the benefit of costimulation-assisted restimulation. Finally, the antitumor potential of this combinatorial setting was confirmed in vivo in a lung metastasis mouse model. Thus, combinatorial approaches with costimulatory antibody-ligand fusion proteins seem a promising strategy to be further investigated for cancer immunotherapy. PMID:23715927
Hornig, Nora; Reinhardt, Katharina; Kermer, Vanessa; Kontermann, Roland E; Müller, Dafne
Previous studies have shown that the antitumor effects of OX40 agonists depend on the immunogenicity of the tumor and that poorly immunogenic tumors such as B16F10 melanomas do not respond to OX40 agonist treatment. In this study, we have shown that intratumoral CD4(+) T lymphodepletion sensitized poorly immunogenic B16F10 melanomas to immunotherapy with an OX40 agonist. CD4(+) T lymphodepletion dramatically altered the tumor immune microenvironment, making it more susceptible to the antitumor effects of an OX40 agonist by enhancing the accumulation of CD8(+) T cells and natural killer (NK) cells in tumor tissue. However, unexpectedly, the number of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) within tumor tissues also significantly increased as a result of CD4(+)T lymphodepletion. As a countermeasure against CD8(+) T-cell accumulation, CCR2-positive CD11b(+)Gr-1(int) (monocytic) MDSCs predominantly increased. Treatment with an OX40 agonist under CD4(+) T lymphodepletion neither reduced MDSCs nor increased CD8(+) T cells and NK cells, but further enhanced the expression of cytotoxic molecules from tumor-infiltrating effector cells. Our results suggest that combined immunotherapy using both an OX40 agonist and CD4(+) T lymphodepletion could be a promising therapeutic strategy for poorly immunogenic tumors and might be more effective if further combined with a therapeutic strategy targeting MDSCs. PMID:24468748
Fujiwara, Susumu; Nagai, Hiroshi; Shimoura, Noriko; Oniki, Shuntaro; Yoshimoto, Takayuki; Nishigori, Chikako
Background The specific active immunotherapy, employing vaccine of allergen of mite is a treatment considered as effective for the respiratory allergy and asthma. The sublingual route has minor risk of systematises reactions. The objective of this study was to determine the therapeutic effect and security of sublingual immunotherapy (ITSL) employing the standard vaccine VALERGEN-DP (BIOCEN, CUBA) in a population of asthmatic Cuban patients. Methods A phase II Clinical Trials double blind, placebo controlled in a total of 40 adult patients with mild or moderate asthma and specific sensibility preponderant to this mite. Half of patients received drops by sublingual route with growing doses up to 2000 UB. Results The treatment was effective in the reduction of clinical symptoms and medication intake as compared to conventional treatment in control group. The cutaneous sensibility to this mite was significant reduced, increasing in 1.9 log; the amount of necessary allergen to provoke a positive Prick Test. An improvement of the lung function was observed with a significant reduction (P < 0.05) of expiratory pick flow variability. The frequency of local reactions were only 0.58% of administration. Conclusions The VALERGEN-DP vaccine is an effective treatment and profitable against asthma in our population and guarantee its generalization in the Allergy Services of our health system.
Rodriguez, Jose; Castro, Raul; Labrada, Alexis; Alvarez, Mirta; Ronquillo, Mercedes; Gonzalez, Mayda; Navarro, Barbara; Mateo, Maytee; Oliva, Yunia; Garcia, Iris; Enriquez, Irene
Background Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of immunotherapeutic strategies. Methods MDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib, either as single agent or in combination with dendritic cell-based immunotherapy. Results We found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. The function of MDSC was impaired as was noticed by reduced levels of ROS and NO and reversal of T cell tolerance; resulting in refinement of immunotherapy. Conclusions We conclude that celecoxib is a powerful tool to improve dendritic cell-based immunotherapy and is associated with a reduction in the numbers and suppressive function of MDSC. These data suggest that immunotherapy approaches benefit from simultaneously blocking cyclooxygenase-2 activity.
According to scientific societies guidelines the indication for venom immunotherapy is based on the clinical history of the patient. Diagnostic tests, like skin prick test or specific IgE serum estimation are conduct to prove IgE dependent mechanism of allergy and insect identification. Recent guidelines indicates for group of patients with severe systemic reactions as a candidates for diagnostic testing and in consequence for immunotherapy. In some countries diagnostic tests are also performed in patient who have a history of large local reactions, if they are considered as a candidates for immunotherapy. Double sensitization in cases of patients unable to identify the culprit insect is a diagnostic and therapeutic problem. In our group of patients (n = 113) we confirmed the double sensitization in 30% cases. The addition of a major allergen labeling reduced the number of people actually double-sensitized to 8.84%. It was observed that in patients who are not able to identify insect double sensitization phenomenon is particularly frequent as much as 45.5% and in the determination of the major allergens in 18.2%. Such patients needed detailed diagnosis and in many cases the use of two vaccines to conduct immunotherapy. PMID:24720122
Stobiecki, Marcin; Dyga, Wojciech; Czarnobilska, Ewa
Introduction: If an immunotherapy treatment approach to treatment of acute radiation syndromes (ARS) were to be developed; consideration could be given to neutralization of radiation toxins (Specific Radiation Determinants- SRD) by specific antiradiation antibodies. To accomplish this objective, irradiated animals were injected with a preparation of antiradiation immunoglobulin G (IgG) obtained from hyperimmune donors. Radiation-indeced toxins that we call Specific Radiation Determinants (SRD) possess toxic (neurotoxic, haemotoxic and enterotoxic) characteristics as well as specific antigenic properties that combined with the direct physiochemical direct radiation damage, induce the development of many of the pathological processes associated with ARS. We tested several specific hyperimmune IgG preparations against these radiation toxins and observed that their toxic properties were neutralized by specific antiradiation IgGs. Material and Methods: Rabbits were inoculated with SRD radiation toxins to induce hyperimmune serum. The hyperimmune serum was pooled from several animals, purified, and concentrated. Enzyme-linked immunosorbent assays of the hyperimmune serum revealed high titers of IgG with specific binding to radiation toxins. The antiradiation IgG preparation was injected into laboratory animals one hour before and three hours after irradiation, and was evaluated for its ability to protect inoculated animals against the development of acute radiation syndromes. Results: Animals that were inoculated with specific antiradiation antibodies before receiving lethal irradiation at LD 100/30 exhibited 60-75% survival rate at 30 days, whereas all control animals expired by 30 days following exposure. These inoculated animals also exhibited markedly reduced clinical symptoms of ARS, even those that did not survive irradiation. Discussion: The results of our experiments demonstrate that rabbit hyperimmune serum directed against SRD toxins afford significant, albeit incomplete, protection against high doses of radiation. In comparison, the mortality rate of irradiated control animals was 100% in the same time period. The mortality rates of hyperimmune serum-treated animals varied in different groups of animals and different forms of ARS; however, significant radioprotection was observed in each group treated with IgGs activated against specific radiation toxins.
Popov, Dmitri; Maliev, Vecheslav; Casey, Rachael; Jones, Jeffrey; Kedar, Prasad
Background Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Since HCC has been shown to be immunogenic, immunotherapy is considered a promising therapeutic approach. Small interfering RNAs (siRNAs), depending on their structure and sequence, can trigger the innate immune system, which can potentially enhance the adaptive anticancer immune response in the tumor-bearing subjects. Immunostimulatory properties of nucleic acids can be applied to develop adjuvants for HCC treatment. Methods The transplantable HCC G-29 tumor in male CBA/LacSto (CBA) mice was used to study the effects of immunostimulatory RNA on tumor growth. Tumor size, metastases area in different organs of mice and mouse survival rate were analyzed. Furthermore the mouse serum IFN-? levels were measured using ELISA. Results In the present study, we found that a 19-bp RNA duplex (ImmunoStimulattory RNA or isRNA) with 3-nt overhangs at the 3?-ends of specific sequence displays immunostimulatory, antitumor, and antimetastatic activities in mice bearing HCC G-29. Our results demonstrate that isRNA strongly increases the level of interferon-? (IFN-?) by up to 25-fold relative to the level in mice injected with Lipofectamine alone (Mock), and to a lesser extent increases the level of proinflammatory cytokine interleukin-6 (IL-6) (by up to 5.5-fold relative to the Mock level), in mice blood serum. We showed that isRNA reliably (P 0.05) inhibits primary tumor growth in mice compared to the mock group. Furthermore, injections of isRNA significantly enhanced necrotic processes in the center of the primary tumor, and decreased by twofold the width of the undifferentiated peripheral zone and the number of mitotic cells in this zone. The results showed that isRNA efficiently reduces the area of metastases in the liver, kidneys, and heart of CBA/LacSto mice with HCC. Conclusions The obtained results clearly demonstrate immunostimulatory and antimetastatic properties of the isRNAs in mice with HCC. Consequently, this short double-stranded RNA can be considered as a potential adjuvant for the therapy of HCC.
The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles.
Sapoznik, Sivan; Hammer, Ohad; Ortenberg, Rona; Besser, Michal J.; Ben-Moshe, Tehila; Schachter, Jacob; Markel, Gal
Sublingual immunotherapy (SLIT) is now accepted as a viable alternative to the traditional injection route based on more than 40 clinical trials and several meta-analyses of efficacy. In addition, the safety profile is very favorable, also in younger children. Although some aspects need to be further clarified (eg, optimal doses, patient selection, and mechanisms of action), SLIT can be currently regarded as an additional therapeutic option that allergists have available. The main distinctive feature of SLIT is certainly its tolerability, safety, and convenience for the patient. Nonetheless, as happens with injection immunotherapy, it is mandatory that the prescription of SLIT is made by a trained specialist, and that a detailed diagnosis is made before prescribing it.
Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures.
Emens, Leisha A
Multiple myeloma (MM) is a good target disease in which one can apply cellular immunotherapy, which is based on the graft-versus-myeloma effect. This role of immune effector cells provides the framework for the development of immune-based therapeutic options that use antigen-presenting cells (APCs) with increased potency, such as dendritic cells (DCs), in MM. Current isolated idiotype (Id), myeloma cell lysates, myeloma dying cells, DC-myeloma hybrids, or DC transfected with tumor-derived RNA has been used for immunotherapy with DCs. Immunological inhibitory cytokines, such as TGF-?, IL-10, IL-6 and VEGF, which are produced from myeloma cells, can modulate antitumor host immune response, including the abrogation of DC function, by constitutive activation of STAT3. Therefore, even the immune responses have been observed in clinical trials, the clinical response was rarely improved following DC vaccinations in MM patients. We are going to discuss how to improve the efficacy of DC vaccination in MM.
Nguyen-Pham, Thanh-Nhan; Lee, Yoon-Kyung; Kim, Hyeoung-Joon; Lee, Je-Jung
Chemotherapy is the conventional treatment for castration-resistant prostate cancer (CRPC) which provides only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer. Several characteristics of prostate cancer make it an ideal target for immunotherapy, and FDA approved recently sipuleucel-T based on improvement in overall survival (OS) in patients with CRPC. Current trials investigate the role of various immunological approaches in the treatment of prostate cancer, as far as the clinical benefit they provide is concerned and also deal with the issue of the measurability of this benefit. Future studies will focus on the combination of immunotherapeutic agents with conventional treatments in an effort to optimize patient outcomes. PMID:24344002
Porfyris, O; Kalomoiris, P
Glioblastoma (GBM) is the most aggressive primary brain tumor. Combination therapy with surgery, radiation, and chemotherapy is not curative at present and carries a significant risk of toxicity. Advancements in the knowledge of tumor biology and tumor microenvironment have led to the development of novel targeted therapies for glioblastoma. In the past 15 years, a vast amount of pre-clinical data has been generated for glioblastoma immunotherapy. Translating these promising results into the clinic is, however, still an evolving process. Early clinical trials have demonstrated the feasibility and safety of several such approaches in patients with recurrent as well as newly diagnosed glioblastoma. Both passive as well as active immunotherapeutic modalities have also shown potential clinical benefit in at least a subset of these patients. This brief review discusses 'why' and 'how' various types of immunotherapies are being employed to treat glioblastoma. PMID:24641957
Hegde, Meenakshi; Bielamowicz, Kevin J; Ahmed, Nabil
High-dose interleukin-2 (HD IL-2) and interferon were the most commonly administered therapies before the recent introduction of targeted agents, including vascular endothelial growth factor and mammalian target of rapamycin pathway inhibitors. Although the new agents result in a progression-free survival benefit, high-dose IL-2 remains the only agent with proven efficacy in producing durable complete and partial responses in patients with metastatic renal cell carcinoma (RCC). Furthermore, although the use of single-agent interferon has decreased significantly since the introduction of targeted therapy, it remains in the frontline setting in combination with bevacizumab as a result of 2 large phase III trials. Lastly, improved understanding of immune regulation has led to the advancement of targeted immunotherapy using immune checkpoint inhibitors that have shown promising activity and are moving forward in clinical development. This article focuses on the current status of immunotherapy in the management of metastatic RCC.
George, Saby; Pili, Roberto; Carducci, Michael A.; Kim, Jenny J.
Ensuring the safety of patients who receive immunotherapy is an essential element of nursing care. Communicating changes in mental status to the medical team is important feedback for modifying or discontinuing the cycle of immunotherapy. These observations are even more crucial if neuropsychiatric toxicity (NPT) has been exhibited in a previous cycle of treatment. If nurses are aware of associative factors of NPT they can be more alert for emerging cognitive dysfunction. Early intervention will also mean the nurse will take additional measures to ensure patient safety, such as suggesting possible pharmacological alternatives and closer observation, and encouraging family members to help with orientation. The nurse can further assist by helping alleviate the patient's or family's feelings of helplessness by assuring them that the NPT will begin to subside once treatment has been terminated. PMID:8348526
Sparber, A G; Biller-Sparber, K
Activation of the host immune system represents an attractive treatment approach for cancers. In non-small-cell lung cancer (NSCLC), a variety of immunotherapies, including nonspecific immune stimulants, vaccines and checkpoint inhibitors, have been evaluated in clinical trials. Several randomized Phase III trials have failed to demonstrate clinical benefit from nonspecific immune stimulants and vaccines in the overall trial populations. Activity of vaccines in subsets of patients in these trials needs further evaluation. Unlike vaccines aimed at stimulating a cellular immune response to antigens differentially expressed in cancers, checkpoint inhibitors aim at overcoming immune inhibitory signals in the tumor microenvironment via pharmacological inhibition of immune checkpoints - a crucial tumoral immune escape mechanism. Early clinical trials of checkpoint inhibitors showed promising results with some durable responses. Better understanding of the mechanisms of immunosuppression specific to NSCLC will be crucial for successful patient selection for immunotherapy. PMID:24878420
Thomas, Anish; Jakopovic, Marko
Treatment of patients with glioblastoma multiforme (GBM) remains to be a challenge with a median survival of 14.6?months following diagnosis. Standard treatment options include surgery, radiation therapy, and systemic chemotherapy with temozolomide. Despite the fact that the brain constitutes an immunoprivileged site, recent observations after immunotherapies with lysate from autologous tumor cells pulsed on dendritic cells (DCs), peptides, protein, messenger RNA, and cytokines suggest an immunological and even clinical response from immunotherapies. Given this plethora of immunomodulatory therapies, this paper gives a structure overview of the state-of-the art in the field. Particular emphasis was also put on immunogenic antigens as potential targets for a more specific stimulation of the immune system against GBM.
Xu, Xun; Stockhammer, Florian; Schmitt, Michael
Genetic engineering of T lymphocytes to confer new antitumor specificities is a fascinating approach that may help the successful clinical translation of adoptive immunotherapy strategies. The recognition of tumor-specific antigens may be obtained inducing the membrane expression of transgene encoded antitumor T cell receptors (TCR) or chimeric antigen receptors (CAR). Few but very informative clinical trials with TCR or CAR redirected T lymphocytes have been attempted in the last years, reporting important clinical results along with disappointing failures and important warnings. In this work, we will focus on TCR and CAR redirected T lymphocytes as adoptive immunotherapy for solid tumors. We will review the main topics of these strategies from the angle of clinical applications, discussing the main issues that emerged from early clinical trials and their impact on next study designs. PMID:24365144
Leuci, Valeria; Mesiano, Giulia; Gammaitoni, Loretta; Aglietta, Massimo; Sangiolo, Dario
Immunotherapy for solid tumors has shown promise in preclinical as well as early clinical studies. However, its efficacy remains limited. The hindrance to achieving objective, long-lasting therapeutic responses in solid tumors is, in part, mediated by the dynamic nature of the tumor and its complex microenvironment. Tumor-directed therapies fail to eliminate components of the microenvironment, which can reinstate a tumorigenic milieu and contribute to recurrence. Cancer-associated fibroblasts (CAFs) form the most preponderant cell type in the solid tumor microenvironment. Given their pervasive role in facilitating tumor growth and metastatic dissemination, CAFs have emerged as attractive therapeutic targets in the tumor microenvironment. In this article, we highlight the cross-talk between CAFs and cancer cells, and discuss how targeting CAFs has the potential to improve current immunotherapy approaches for cancer.
Kakarla, Sunitha; Song, Xiao-Tong; Gottschalk, Stephen
Food allergy has increased dramatically in prevalence over the past decade in westernized countries, and is now a major public health problem. Unfortunately for patients with food allergy, there is no effective therapy beyond food allergen avoidance, and rapid medical treatment for accidental exposures. Recently, oral immunotherapy (OIT) has been investigated as a treatment for this problem. In this review, we will discuss the progress in developing OIT for food allergy, including a novel approach utilizing Xolair (anti-IgE monoclonal antibody, omalizumab) in combination with OIT. This combination may enhance both the safety and efficacy of oral immunotherapy, and could lead to a widely available and safe therapy for food allergy. PMID:23277873
Khoriaty, Evelyne; Umetsu, Dale T
Non hodgkin's lymphomas are a group of haematological malignancies in which spectacular progress has been made over the last ten years thanks to immunotherapy. Furthermore, the new WHO classification, based upon tumour immunology, the degree of tumour differentiation and cytogenetic abnormalities, has finally improved identification of each lymphoma and has enabled comparison of homogeneous populations between different clinical studies. The increase in the incidence of non hodgkin's lymphoma is related to the aging of the population and to other factors that are yet to be elucidated--a real challenge for the future. We have tried to offer an overview of the latest therapeutic advances, with a focus on (radio-) immunotherapy and haemopoietic stem cell transplantation. PMID:21688592
Firescu, R; Muylle, K; Roelandts, M; de Wind, A; Moerman, C; Lemort, M; Kentos, A; Meuleman, N; Bron, D
Background: Limited data exist regarding extended, long-term immunologic effects of immunotherapy in polysensitized individuals. To study possible long-term effects, skin tests and specific IgE levels were obtained from subjects who had previously received broad-spectrum aeroallergen immunotherapy years before. Methods: Eighty-two subjects (78% male, mean age 23 years) previously enrolled in a randomized, placebo-controlled trial of immunotherapy for treatment of childhood
Susan L. Limb; Kathryn C. Brown; Robert A. Wood; Peyton A. Eggleston; Robert G. Hamilton
Specific allergen immunotherapy (SIT) is the only disease-modifying treatment for allergic rhinitis and asthma. Subcutaneous\\u000a immunotherapy (SCIT) is the only method with a US Food and Drug Administration (FDA)-approved formulation, but safety concerns\\u000a limit administration to medical facilities. Sublingual immunotherapy (SLIT), under investigation in the United States, appears\\u000a to have a more favorable safety profile, which may expand its use
Background: Topical immunotherapy has been used in the treatment of children with alopecia areata with encouraging results.Objective: Our purpose was to determine the long-term results in 33 children with severe alopecia areata treated with topical immunotherapy.Methods: From 1983 to 1989 we treated 33 children with topical immunotherapy with squaric acid dibutylester.Results: Complete hair regrowth was observed in 10 children (30.3%).
Antonella Tosti; Maria Silvia Guidetti; Frederico Bardazzi; Cosimo Misciali
? Abstract Background: The glycoprotein CD30 is expressed and released by T lymphocytes that secrete type 2 helper cytokines of (TH2). These molecules play a role in the pathogenesis of allergic diseases. Venom immunotherapy has proven to be very effective in hymenoptera venom allergy through a shift in cytokine production from TH2-type cytokines to TH1-type cytokines. Objective: To evaluate the
FG Foschi; F Emiliani; S Savini; O Quercia; GF Stefanini
Since dendritic cells operate as professional antigen-presenting cells (APCs) and hence are capable of jumpstarting the immune system, they have been exploited to develop a variety of immunotherapeutic regimens against cancer. In the few past years, myeloid-derived suppressor cells (MDSCs) have been shown to mediate robust immunosuppressive functions, thereby inhibiting tumor-targeting immune responses. Thus, we propose that the immunomodulatory activity of MDSCs should be carefully considered for the development of efficient anticancer immunotherapies.
Escors, David; Liechtenstein, Therese; Perez-Janices, Noemi; Schwarze, Julia; Dufait, Ines; Goyvaerts, Cleo; Lanna, Alessio; Arce, Frederick; Blanco-Luquin, Idoia; Kochan, Grazyna; Guerrero-Setas, David; Breckpot, Karine
The potential role of antibodies and T lymphocytes in the eradication of cancer has been demonstrated in numerous animal models\\u000a and clinical trials. In the last decennia new strategies have been developed for the use of tumor-specific T cells and antibodies\\u000a in cancer therapy. Effective anti-tumor immunotherapy requires the identification of suitable target antigens. The expression\\u000a of tumor-specific antigens has
J. F. M. Jacobs; P. G. Coulie; C. G. Figdor; G. J. Adema; I. J. M. de Vries; P. M. Hoogerbrugge
The RFA for the Cancer Immunotherapy Trials Network was recently awarded to the Fred Hutchinson Cancer Research Center, M. A. Cheever, PI., as the Central Operations and Statistical Office. The NCI is now accepting applications for clinical Member Sites, as described in NOT-CA-10-034. Please click on the link below to obtain the specific information and documents that should be submitted to the NCI for application for Member Site status.
In spite of newly developed chemothera-peutic regiments, surgery, radiotherapy and the introduction of anti-angiogenic drugs\\u000a the prognosis in disseminated colorectal cancer is poor. Recent investigations correlating expression markers with clinical\\u000a outcome in patients with colon ancer indicate that tumor infiltrating lymphocytes are prognostically favourable, suggesting\\u000a an important role for immune cells in the defense against cancer. Hitherto undertaken adoptive immunotherapy
Per Marits; Mona Karlsson; Magnus Thörn; Ola Winqvist
BACKGROUND: Severe allergic reactions during rush-specific immunotherapy (Rush-SIT) may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during Rush-SIT in a cohort of patients with allergy towards hymenoptera venom in the mediterranean population of Albania. METHODS: A retrospective study was performed using the clinical reports of
Ervin Mingomataj; Alfred Priftanji; Etleva Qirko; Q Thai Dinh; Axel Fischer; Christian Peiser; David A Groneberg
Immunotherapy with Bacillus Calmette–Guérin (BCG)—an attenuated strain of Mycobacterium bovis (M. bovis) used for anti tuberculosis immunization—is a clinically established procedure for the treatment of superficial bladder cancer.\\u000a However, the mode of action has not yet been fully elucidated, despite much extensive biological experience. The purpose of\\u000a this paper is to develop a first mathematical model that describes tumor-immune interactions in
Svetlana Bunimovich-Mendrazitskya; Eliezer Shochat; Lewi Stone
Jack jumper ant (JJA) venom allergy is an important cause of anaphylaxis in south-eastern Australia. The efficacy and real-world effectiveness of JJA venom immunotherapy (VIT) to prevent anaphylaxis in allergic patients are now well established, with an evidence base that is at least equivalent to that supporting VIT for allergy to other insect species. The tolerability and safety of JJA VIT are comparable with those of honeybee VIT. PMID:24999895
Mullins, Raymond J; Brown, Simon G A
Neuroblastoma (NBL) is the most common extracranial pediatric solid tumor and has heterogeneous biology and behavior. Patients with high-risk disease have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. Immunotherapy is a novel therapeutic approach that harnesses the inherent activity of the immune system to control and eliminate malignant cells. One form of immunotherapy uses chimeric antigen receptors (CAR) to target tumor-associated antigens. CARs are derived from the antigen-binding domain of a monoclonal antibody (MAb) coupled with the intracellular signaling portion of the T cell receptor. CARs can combine the specificity and effectiveness of MAbs with the active bio-distribution, direct cytotoxicity, and long-term persistence of T cells. NBL provides an attractive target for CAR immunotherapy as many of its tumor-associated antigens are not expressed at significant levels on normal tissues, thus decreasing potential treatment related toxicity. Two previous clinical trials utilizing L1-cell adhesion molecule (L1-CAM) and disialoganglioside (GD2) specific CARs (GD2-CAR) have demonstrated safety and anti-tumor efficacy in heavily pretreated relapsed/refractory neuroblastoma patients. Based on these promising results and on improved techniques that can further potentiate CAR therapies, two clinical trials are currently investigating the use of GD2-CARs in children with NBL. Several approaches may further enhance anti-tumor activity and persistence of CAR modified cells, and if these can be safely translated into the clinic, CAR-based immunotherapy could become a viable adjunct or potential alternative to conventional treatment options for patients with NBL.
Heczey, Andras; Louis, Chrystal U.
Patients with head and neck squamous cell carcinoma (HNSCC) demonstrate poor survival and significant treatment morbidity with standard therapy. The immune profile in HNSCC, whether caused by carcinogen exposure or human papillomavirus (HPV), is notably immunosuppressive. Early clinical trials of immunotherapy in HNSCC were troubled by systemic toxicity or difficulties in local administration. Now, interest in immunotherapy has been revitalized by mechanistic insights into immune evasion by HNSCC, coupled to ongoing development of novel immunotherapies. This review will summarize immune escape mechanisms in HNSCC, namely downregulation of tumor antigen (TA) presentation, aberrant regulation of the signal transducer and activator of transcription (STAT) family, the immunosuppressive cytokine milieu, and dysregulation of immune effector cells. Therapeutic strategies hypothesized to specifically counter HNSCC immunosuppression will then be discussed. We will survey TA- targeted monoclonal antibodies (mAb), including the prototype cetuximab, as well as adjunctive strategies to enhance antibody-dependent cell-mediated cytotoxicity. We will review immunomodulation to restore STAT1/STAT3 activation balance. Examples of mAb therapy to block immunosuppressive cytokines, such as interleukin-6 or VEGF, will be provided. mAbs which release co-inhibitory T cell receptors such as CTLA-4 and PD-1, overexpressed in HNSCC, also hold therapeutic promise. Finally, we will describe principles for therapeutic vaccination in HPV-associated HNSCC, where non-host TAs such as viral oncoproteins represent ideal targets, and HPV-negative HNSCC, where p53 is a promising target. Insights into immunosuppression in HNSCC have elucidated mechanistic targets for immunotherapy. Rational clinical investigation may lead to effective stand alone or combinatorial treatment approaches. PMID:24126223
Gildener-Leapman, Neil; Ferris, Robert L; Bauman, Julie E
Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes.
The ideal treatment modality for tumors, particularly for those that metastasize to multiple remote sites, should eradicate the primary tumor and elicit a systemic, tumor-specific response leading to elimination of metastases and to long-term tumor immunity. Using the selective photothermal interaction as a precursor, laser immunotherapy was developed by introducing a novel immunoadjuvant administered in conjunction with the laser-absorbing dye. Specifically, an 805-nm laser and indocyanine green (ICG) was used for the selective photothermal interaction, and a novel immunoadjuvant, glycated chitosan (GC), was used as the immunological stimulant. The laser-ICG-GC combinations has been resulted in the following results in animal studies. (1) Selective destruction of deep target tumor target has been achieved; (2) Eradication of treated primary tumors and regression and disappearance of untreated distant metastases have been observed; (3) Long-term survival of tumor-bearing rats have been resulted; (4) Long-term immunity for resistance to repeated, dose-escalated subsequent tumor challenges has been induced; (5) Tumor-specific immunological responses, after laser immunotherapy treatment, have been detected at cellular and molecular levels. The procedure of laser immunotherapy and major results in animal studies will be summarized and some new results using the immunological enhancement for photodynamic therapy treatment will be presented.
Chen, Wei R.; Korbelik, Mladen; Bartels, Kenneth E.; Liu, Hong; Nordquist, Robert E.
Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug development in this area has focused primarily on antigen-specific (i.e. cancer vaccines and antibody based therapies) or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved in advanced melanoma and two phase III trials evaluating ipilimumab in men with metastatic castrate-resistant prostate cancer are underway. A phase III trial evaluating ProstVac-VF, a poxvirus-based therapeutic prostate cancer vaccine, is also underway. While there has been reason for encouragement over the past few years, many questions regarding the use of immunotherapies remain. Namely, it is unclear what stage of disease is most likely to benefit from these approaches, how best to incorporate said treatments with each other and into our current treatment regimens and which therapy is most appropriate for which disease. Herein we review some of the recent advances in immunotherapy as related to the treatment of prostate cancer and outline some of the challenges that lie ahead. PMID:24477411
Schweizer, Michael T; Drake, Charles G
Passive immunotherapy with monoclonal antibodies is an indispensable cornerstone of clinical oncology. Notably, all FDA-approved antibodies comprise the IgG class, although numerous research articles proposed monoclonal antibodies of the IgM, IgG, IgA and IgE classes directed specifically against tumor-associated antigens. In particular, for the IgE isotype class, several recent studies could demonstrate high tumoricidic efficacy. Therefore, this review specifically highlights the latest developments toward IgE-based immunotherapy of cancer. Possible mechanisms and safety aspects of IgE-mediated tumor cell death are discussed with special focus on the attracted immune cells. An outlook is given on how especially comparative oncology could contribute to further developments. Humans and dogs have a highly comparable IgE biology, suggesting that translational AllergoOncology studies in patients with canine cancer could have predictive value for the potential of IgE-based anticancer immunotherapy in human clinical oncology.
Singer, J.; Jensen-Jarolim, E.
Since the beginning of the 20th century, scientists have tried to stimulate the anti-tumour activities of the immune system to fight against cancer. However, the scientific effort devoted on the development of cancer immunotherapy has not been translated into the expected clinical success. On the contrary, classical anti-neoplastic treatments such as surgery, radiotherapy and chemotherapy are the first line of treatment. Nevertheless, there is compelling evidence on the immunogenicity of cancer cells, and the capacity of the immune system to expand cancer-specific effector cytotoxic T cells. However, the effective activation of anti-cancer T cell responses strongly depends on efficient tumour antigen presentation from professional antigen presenting cells such as dendritic cells (DCs). Several strategies have been used to boost DC antigen presenting functions, but at the end cancer immunotherapy is not as effective as would be expected according to preclinical models. In this review we comment on these discrepancies, focusing our attention on the contribution of regulatory T cells and myeloid-derived suppressor cells to the lack of therapeutic success of DC-based cancer immunotherapy.
Until recently cancer medical therapy was limited to chemotherapy that could not differentiate cancer cells from normal cells. More recently with the remarkable mushroom of immunology, newer tools became available, resulting in the novel possibility to attack cancer with the specificity of the immune system. Herein we will review some of the recent achievement of immunotherapy in such aggressive cancers as melanoma, prostatic cancer, colorectal carcinoma, and hematologic malignancies. Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs) derived from tumor infiltrating lymphocytes (TILs). The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes.
Pandolfi, F.; Cianci, R.; Pagliari, D.; Casciano, F.; Bagala, C.; Astone, A.; Landolfi, R.; Barone, C.
Although tumor antigen-specific immunotherapy, such as dendritic cell vaccine, has recently emerged as a promising clinical approach, one limitation of tumor antigen- and T-cell receptor (TcR)-specific immunotherapy is antigen-specific inhibition by antigen-specific regulatory T-cell and myeloid suppressor cells. Therefore, immunotherapy using a TcR-independent mechanism may be an alternative immunotherapeutic strategy. NKG2D (natural killer, group 2, member D) and DNAX accessory molecule-1 (DNAM-1) are both activated receptors that are strongly expressed on T-cells, ??T-cells, and NK cells. Therefore, the expression of ligands for NKG2D and DNAM-1 on tumor cells plays an important role in tumor opsonization by immune effector cell targeting. Various modulatory methods for up-regulating NKG2D and DNAM-1-ligands have been reported, and included chemotherapeutic agents and hyperthermia. Although there are many obstacles to the utilization of NKG2D and DNAM-1 for cancer therapy, combined treatments using immune cell therapy and chemotherapy that take advantage of NKG2D and DNAM-1 may be an ideal approach. PMID:22641658
Morisaki, Takashi; Onishi, Hideya; Katano, Mitsuo
Alzheimer disease (AD) is the most common form of dementia. The amyloid-? (A?) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive A? immunotherapies have been shown to lower cerebral A? levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 A? vaccine was stopped when ~6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive A? immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active A? vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, A? immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from A? immunization.
Lemere, Cynthia A.; Masliah, Eliezer
Chemotherapy has been a mainstay in cancer treatment for many years. Despite some success, the cure rate with chemotherapy remains unsatisfactory in some types of cancers, and severe side effects from these treatments are a concern. Recently, understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies, including cancer vaccines. Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity. Many developments have increased their potency in pre-clinical models, but cancer vaccines continue to have a poor clinical track record. In part, this could be due to an inability to effectively overcome tumor-induced immune suppression. It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma. Chemotherapies could be used to condition the immune system and tumor to create an environment where cancer vaccines have a better chance of success. Other types of immunotherapies could also be used to modulate the immune system. This review will discuss how immune modulation by chemotherapy or immunotherapy could be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments.
Weir, Genevieve M.; Liwski, Robert S.; Mansour, Marc
Numerous sublingual immunotherapy studies have shown efficacy using a wide variety of dosing regimens. Despite a few grade III and one anaphylactic reaction due to a patient over-dose, there have been no fatal reactions resulting from sublingual immunotherapy treatment. Although safer than SCIT, SLIT is still immunotherapy. Special consideration should be given to what will ensure the highest level of safety for the patient given his or her history, exam and allergy test results. Dosing levels for sublingual immunotherapy should be based on what is therapeutically effective for each individual patient and adjusted accordingly throughout the treatment course.
Kroker, George F.; Sabnis, Vijay K.; Morris, Mary S.; Thompson, James C.
Food allergies are increasing in prevalence and present an emerging epidemic for westernized countries. Strict dietary avoidance is the only approved management for food allergy, but accidental exposures regularly occur, leading to significant patient anxiety and decreased quality of life. Over the past decade, oral and sublingual immunotherapies have emerged as potential treatments for food allergy. While several small clinical trials have demonstrated that immunotherapy can desensitize food-allergic individuals, strategies for further enhancing safety and definitively establishing long-term efficacy are needed. This review presents an overview of recent oral and sublingual immunotherapy trials, and provides a glimpse into what the next generation of food immunotherapy may entail. PMID:23972904
Moran, Timothy P; Vickery, Brian P; Burks, A Wesley
Treatment of brain cancers, especially high grade gliomas (WHO stage III and IV) is slowly making progress, but not as fast as medical researchers and the patients would like. Immunotherapy offers the opportunity to allow the patient's own immune system a chance to help eliminate the cancer. Immunotherapy's strength is that it efficiently treats relatively small tumors in experimental animal models. For some patients, immunotherapy has worked for them while not showing long-term toxicity. In this paper, we will trace the history of immunotherapy for brain cancers. We will also highlight some of the possible directions that this field may be taking in the immediate future for improving this therapeutic option.
Ge, Lisheng; Hoa, Neil; Bota, Daniela A.; Natividad, Josephine; Howat, Andrew; Jadus, Martin R.
AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intra- and extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immunotherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryo-immunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy.
Niu, Li-Zhi; Li, Jia-Liang; Zeng, Jian-Ying; Mu, Feng; Liao, Meng-Tian; Yao, Fei; Li, Li; Liu, Chun-Yan; Chen, Ji-Bing; Zuo, Jian-Sheng; Xu, Ke-Cheng
Food allergies are increasing in prevalence and present an emerging epidemic for westernized countries. Strict dietary avoidance is the only approved management for food allergy, but accidental exposures regularly occur, leading to significant patient anxiety and decreased quality of life. Over the past decade, oral and sublingual immunotherapies have emerged as potential treatments for food allergy. While several small clinical trials have demonstrated that immunotherapy can desensitize food-allergic individuals, strategies for further enhancing safety and definitively establishing long-term efficacy are needed. This review presents an overview of recent oral and sublingual immunotherapy trials, and provides a glimpse into what the next generation of food immunotherapy may entail.
Moran, Timothy P; Vickery, Brian P; Burks, A Wesley
Peanut (Arachis hypogaea L.) is an important crop grown worldwide for food and edible oil. The surge of peanut allergy in the past 25 years has profoundly impacted both affected individuals and the peanut and related food industries. In response, several strategies to mitigate peanut allergy have emerged to reduce/eliminate the allergenicity of peanuts or to better treat peanut-allergic individuals. In this review, we give an overview of peanut allergy, with a focus on peanut proteins, including the impact of thermal processing on peanut protein structure and detection in food matrices. We discuss several strategies currently being investigated to mitigate peanut allergy, including genetic engineering, novel processing strategies, and immunotherapy in terms of mechanisms, recent research, and limitations. All strategies are discussed with considerations for both peanut-allergic individuals and the numerous industries/government agencies involved throughout peanut production and utilization. PMID:24387606
White, Brittany L; Shi, Xiaolei; Burk, Caitlin M; Kulis, Michael; Burks, A Wesley; Sanders, Timothy H; Davis, Jack P
Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical aging secondary role in many neurodegenerative diseases, including Alzheimer’s disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood brain barrier (BBB) lesions. The accumulation of amyloid beta (A?) in the cerebrovascular system is a significant risk factor for intracerebral hemorrhage (ICH), and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-A? immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits, but have been plagued by CAA-associated adverse events. While management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of beta-amyloidosis in the cerebral vasculature.
Vasilevko, Vitaly; Passos, Giselle; Quiring, Daniel; Head, Elizabeth; Fisher, Mark; Cribbs, David H.
Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome.
Rutella, Sergio; Locatelli, Franco
Background Oral allergy syndrome (OAS) triggered by fruit and vegetables often occurs in patients with pollen-induced rhinoconjunctivitis because of cross-reactive epitopes in pollen and associated foods. This open observational study examined the effect of pollen-specific sublingual immunotherapy ([SLIT] B. U. Pangramin or SLITone involving birch/alder/hazel, grasses/rye, and/or mugwort) on OAS triggered by several foods in patients treated in standard practice. Very few studies have examined SLIT use in this situation. Methods Patients (n = 102) had pollen-induced rhinoconjunctivitis and OAS and were followed for up to 12 months. Baseline OAS (triggers, symptoms, and symptom severity) was assessed by questionnaire and patient history. Change in OAS was assessed using oral challenge test with 1 or 2 dominant food triggers (and compared with the sum score calculated from the OAS questionnaire at baseline) and clinician ratings of change. Pollen-induced rhinoconjunctivitis symptoms and medication use were also measured. Results In the oral challenge test, 77.0% of patients were considered responders (decrease in sum score of ? 50%; no difference in patients receiving B. U. Pangramin or SLITone). At baseline, investigators rated OAS severity as at least moderate in 94.9% of patients compared with 36.9% after 12 months of treatment. After 12 months, OAS was rated as much or very much improved in 72.9% of patients. Sublingual immunotherapy significantly reduced rhinoconjunctivitis symptoms and medication use. Only 10% of patients experienced adverse drug reactions. Conclusion This study supplements the sparse literature on this topic and suggests that pollen-specific SLIT can reduce OAS triggered by pollen-associated foods in patients with pollen-induced rhinoconjunctivitis.
BACKGROUND: Anti-A? immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-A? antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-A? antibody treatment on radial-arm water-maze performance,
Donna M Wilcock; Amyn Rojiani; Arnon Rosenthal; Sangeetha Subbarao; Melissa J Freeman; Marcia N Gordon; Dave Morgan
Several mechanisms that impair the immune response to promote tumour progression are reported. These mechanisms aim to reduce the ability of antigen-presenting cells to present antigen and activate naïve T cells to support an active immune response or to create a suppressive environment that induce non-functional tumour-associated antigen-specific T cells. Prostate cancer (PC) alone accounts for 33% of incident cancer
Background: Specific immunotherapy (SIT) is a well-documented treatment for respiratory allergy. However, the major risk of SIT is the development of systemic anaphylactic reactions. Objectives: To evaluate the safety of SIT given by subcutaneous route for 3 years to patients with seasonal allergic rhinitis (AR) with or without asthma. Methods: A prospective open-label study of immunotherapy (Chenopodium album, Bermuda grass,
N. Arifhodzic; N. Behbehani; A. R. Duwaisan; M. Al-Mosawi; M. Khan
Background: Studies using rush immunotherapy (RIT) have shown that rapid protection can be achieved using protocols allowing a fast increment of allergen dose. We examined the early effects of RIT on basophil numbers and expression of CD203c, production of interleukin (IL)-4 and IL-13 and histamine release by basophils in the peripheral blood of patients treated with immunotherapy and controls. Methods:
Halina Plewako; Monica Arvidsson; Janne Björkander; Per Stahl Skov; Lena Håkansson; Sabina Rak
Cervical cancer is caused by high-risk, cancer-causing human papillomaviruses (HPV) and is the second highest cause of cancer deaths in women globally. The majority of cervical cancers express well-characterized HPV oncogenes, which are potential targets for immunotherapeutic vaccination. Here we develop a rabbit haemorrhagic disease virus (RHDV) virus-like particle (VLP)-based vaccine designed for immunotherapy against HPV16 positive tumours. An RHDV-VLP, modified to contain the universal helper T cell epitope PADRE and decorated with an MHC I-restricted peptide (aa 48–57) from the HPV16 E6, was tested for its immunotherapeutic efficacy against the TC-1 HPV16 E6 and E7-expressing tumour in mice. The E6-RHDV-VLP-PADRE was administered therapeutically for the treatment of a pre-existing TC-1 tumour and was delivered with antibodies either to deplete regulatory T cells (anti-CD25) or to block T cell suppression mediated through CTLA-4. As a result, the tumour burden was reduced by around 50% and the median survival time of mice to the humane endpoint was almost doubled the compared to controls. The incorporation of PADRE into the RHDV-VLP was necessary for an E6-specific enhancement of the anti-tumour response and the co-administration of the immune modifying antibodies contributed to the overall efficacy of the immunotherapy. The E6-RHDV-VLP-PADRE shows immunotherapeutic efficacy, prolonging survival for HPV tumour-bearing mice. This was enhanced by the systemic administration of immune-modifying antibodies that are commercially available for use in humans. There is potential to further modify these particles for even greater efficacy in the path to development of an immunotherapeutic treatment for HPV precancerous and cancer stages.
Jemon, Khairunadwa; Young, Vivienne; Wilson, Michelle; McKee, Sara; Ward, Vernon; Baird, Margaret; Young, Sarah; Hibma, Merilyn
It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8? DC can contribute to the priming, activation and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity are not clearly understood. We examined the importance of pDC and CD8? DC during immunotherapy of an orthotopic model of metastatic renal cell carcinoma. Immunotherapy that utilizes a recombinant adenovirus encoding tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL) in combination with an immunostimulatory CpG-containing oligodeoxynucleotide (CpG) resulted in the clearance of primary and metastatic tumors in wild-type (WT) replete BALB/c mice and prolonged survival. In comparison, mice deficient in either pDC (accomplished using a depleting mAb specific for PDCA1) or CD8? DC (through utilization of CD8? DC-deficient Batf3 (-/-) BALB/c mice) had uncontrolled tumor growth and high mortality after Ad5-TRAIL/CpG administration. The ineffectiveness of Ad5-TRAIL/CpG therapy in the anti-PDCA1-treated and Batf3 (-/-) BALB/c mice was marked by an altered activation phenotype of the DC, as well as significantly reduced expression of type I IFN-stimulated genes and IL-15/IL-15R complex production. In addition, pDC-depleted and Batf3 (-/-) BALB/c mice had significantly decreased effector CD8 T cell infiltration in the primary tumor site compared with WT mice after therapy. These data collectively suggest that pDC and CD8? DC carry out independent, but complementary, roles that are necessary to initiate an efficacious antitumor immune response after Ad5-TRAIL/CpG therapy. PMID:24711083
James, Britnie R; Brincks, Erik L; Kucaba, Tamara A; Boon, Louis; Griffith, Thomas S
Allergen immunotherapy is the only curative treatment of IgE-mediated type I respiratory allergies. Subcutaneous immunotherapy (SCIT) is used as a reference therapy and has transformed allergic treatments; it improves symptoms (asthma and rhinitis) as well as the quality of life of patients. SCIT requires repetitive administration and carries the risk of severe systemic adverse effects, including anaphylaxis. Sublingual immunotherapy is now a valid noninvasive alternative to SCIT, as a safe and efficacious treatment for respiratory allergies. In this article, we compare various routes of allergen immunotherapy, including SCIT and sublingual immunotherapy, as well as more exploratory routes currently under investigation (i.e., intralymphatic, epicutaneous, intranasal and oral). We discuss their respective advantages, as well as their foreseen modes of action. PMID:22339462
Moingeon, Philippe; Mascarell, Laurent
Carbon nanotubes (CNTs) have the potential to overcome significant challenges related to vaccine development and immunotherapy. Central to these applications is an improved understanding of CNT interactions with the immune system. Unique properties such as high aspect ratio, flexible surface chemistry, and control over structure and morphology may allow for enhanced target specificity and transport of antigens across cell membranes. Although recent work has demonstrated the potential of CNTs to amplify the immune response as adjuvants, other results have also linked their proinflammatory properties to harmful health effects. Here, we review the recent advances of CNT-based immunological research, focusing on current understandings of therapeutic efficacy and mechanisms of immunotoxicology. PMID:24630474
Fadel, Tarek R; Fahmy, Tarek M
The use of dendritic cells (DCs) for tumor immunotherapy represents a powerful approach for harnessing the patient's own immune system to eliminate tumor cells. However, suboptimal conditions for generating potent immunostimulatory DCs, as well as the induction of tolerance and suppression mediated by the tumors and its microenvironment have contributed to limited success. Combining DC vaccines with new approaches that enhance immunogenicity and overcome the regulatory mechanisms underlying peripheral tolerance may be the key to achieving effective and durable anti-tumor immune responses that translate to better clinical outcomes.
Sabado, Rachel Lubong; Bhardwaj, Nina
Glioblastoma (GBM) comprises 51% of all gliomas and is the most malignant form of brain tumors with a median survival of 18–21 months. Standard-of-care treatment includes maximal surgical resection of the tumor mass in combination with radiation and chemotherapy. However, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. Cellular immunotherapy is currently being explored as therapeutic approach to treat malignant brain tumors. In this review, we discuss advances in active, passive, and vaccine-based immunotherapeutic strategies for gliomas both at the bench and in the clinic.
Bovenberg, M Sarah S; Degeling, M Hannah; Tannous, Bakhos A
A method is needed for keeping ragweed pollen aqueous allergenic extracts at a temperature near 4 degrees C while they are in use for skin testing and immunotherapy in order to prevent deterioration in potency from warming. A polystyrene foam icebox is described which can be cooled with sacks of coolant which have been reduced to a temperature of - 17 degrees C in the freezing compartment of a standard refrigerator. Both icebox and coolant can be readily obtained from standard commercial sources and are inexpensive. When sufficient adequately cooled coolant is properly employed, this icebox will maintain the temperatures of allergenic extracts in the desirable range of 2 degrees to 4 degrees C while they are in use for skin testing and immunotherapy. PMID:850024
Van Metre, T E
Cancer is a leading cause of death among modern people largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with minimal toxicity towards normal tissue. This is best accomplished by priming the body's immune system to recognize the tumor antigens so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species leading to vascular shutdown and tumor cell death. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins. Combination regimens using PDT and immunostimulating treatments are likely to even further enhance post-PDT immunity. These immunostimulants are likely to include products derived from pathogenic microorganisms that are effectively recognized by Toll-like receptors and lead to upregulation of transcription factors for cytokines and inflammatory mediators. The following cascade of events causes activation of macrophages, dendritic and natural killer cells. Exogenous cytokine administration can be another way to increase PDT-induced immunity as well as treatment with a low dose of cyclophosphamide that selectively reduces T-regulatory cells. Although so far these combination therapies have only been used in animal models, their use in clinical trials should receive careful consideration.
Hamblin, Michael R.; Castano, Ana P.; Mroz, Pawel
Background Epicutaneous immunotherapy (EPIT) on intact skin with an epicutaneous delivery system has already been used in preclinical and clinical studies. In epicutaneous vaccination and immunotherapy, the stripping of skin before application of the allergen is suggested to facilitate the passage of allergen through immune cells. Objectives The aim of this study was to compare the immunological response induced by EPIT performed on intact and stripped skin in a mouse model of peanut allergy. Methods After oral sensitization with peanut and cholera toxin, BALB/c mice were epicutaneously treated using an epicutaneous delivery system (Viaskin® (DBV Technologies, Paris) applied either on intact skin or on stripped skin. Following EPIT, mice received an exclusive oral peanut regimen, aimed at triggering esophageal and jejunal lesions. We assessed eosinophil infiltration by histology, mRNA expression in the esophagus, antibody levels and peripheral T-cell response. Results EPIT on intact skin significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal eosinophilia (2.7?±?0.9, compared to Sham 19.9?±?1.5, p?0.01), mRNA expression of Th2 cytokines in tissue and intestinal villus sub-atrophia (2.9?±?0.2 vs Sham, 2.1?±?0.2, p?0.05). By contrast, EPIT on stripped skin reinforced Th2 systemic immunological response as well as eosinophil infiltration (26.8?±?15.1), mRNA expression of Th2 cytokines and duodenal villus/crypt-ratio (2.4?±?0.3). Conclusions Epicutaneous allergen-specific immunotherapy needs the integrity of superficial layers of the stratum corneum to warranty safety of treatment and to induce a tolerogenic profile of the immune response.
Recent advances in immunotherapy have resulted in improved survival after heart transplantation. The use of OKT3 as an induction agent has allowed the identification of a subset of patients who can be successfully withdrawn from prednisone and maintained on only cyclosporine and azathioprine. The latter regimen offers several theoretic advantages in terms of freedom from complications of long-term steroid therapy. To compare both the long-term efficacy and toxicity of steroid-free maintenance immunosuppression with triple-drug therapy, the medical records of 68 patients undergoing transplantation at the Minneapolis Heart Institute during a 3-year period (1988 through 1990) were reviewed. Thirty-six patients were treated with OKT3 induction immunotherapy, 29 were successfully tapered off prednisone by 114 +/- 44 days after transplantation, whereas 32 patients were maintained on triple-drug therapy. The incidence of treated rejection was equivalent in both groups; however, the time to first rejection was longer in patients treated with OKT3/steroid-free maintenance (205 +/- 214 vs 27 +/- 17 days) (p = 0.02). Bacterial infections during the early posttransplant period were more common in the OKT3/steroid-free maintenance group (p = 0.008); however, fungal and viral infections were equally distributed between both groups. The incidence of hypertension was slightly higher in patients maintained on prednisone (67% vs 51%; p = 0.242).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1571339
Pritzker, M R; Lake, K D; Reutzel, T J; Hoffman, F M; Jorgensen, C R; Pederson, W; Emery, R W
Purpose of Review Thyroid eye disease (TED) is a poorly understood autoimmune manifestation most commonly associated with Graves’ disease. Current nonspecific treatment paradigms offer symptomatic improvement but fail to target the underlying pathogenic mechanisms and thus, do not significantly alter the long-term disease outcome. The purpose of this review is to provide an update of the current understanding of the immunopathogenesis of TED and explore these implications for targeted immunotherapy. Recent Findings Orbital fibroblasts are integral to the pathogenesis of TED and may modulate immune responses by production of cytokines and hyaluronan in response to activation of shared autoantigens including thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-R1). Fibrocytes share many of these phenotypic and functional features, suggesting a link between systemic and site-specific disease. Use of targeted immunotherapies in TED is limited, though data from the use Rituximab (RTX), a B cell depleting agent, are encouraging. Sustained clinical response has been seen with RTX in several reports, despite return of peripheral B cell levels to pretreatment levels. Additionally, this response appears to be independent to cytokine and antibody production, suggesting possible modulation of antigen presentation as a mechanism of its effect. Summary Progressive advances in the understanding of the immunopathogenesis of TED continue to spur clinical trials utilizing targeted immune therapies. Continued understanding of the molecular mechanisms of disease will expand potential treatments for TED patients and obviate the need for reconstructive surgical therapies.
Gupta, Shivani; Douglas, Raymond
Cancer is the second most common cause of death in the world. Treatment of cancer is very challenging and immunotherapy has been developed as a potential way to fight cancer. The main obstacle with immunotherapy is that cancer cells evolve from healthy body cells in response to an accumulation of genetic mutations. As a consequence, the immune system struggles to detect the abnormal cells as they are mainly recognized as self. This implies that equipping the immune system to eliminate cancer cells is tricky, yet represents a very efficient way to constrain the growth of tumors. We became interested in developing immunotherapeutical strategies against skin cancer in the context of our observations that Langerhans cells (LC) are very potent antigen presenting cells and are able to incorporate protein antigens and present them to CD4(+) and CD8(+) T cells in the skin-draining lymph nodes. As a consequence, we developed an immunization strategy through the skin, termed epicutaneous immunization. Protein antigen applied onto barrier-disrupted skin induces long-lasting cytotoxic T-cell responses, potent enough to control and inhibit tumor growth. In this review, we suggest that immunization strategies through the skin could be a promising new approach for the treatment of skin cancer. PMID:20351746
Stoitzner, Patrizia; Sparber, Florian; Tripp, Christoph H
Cancer is the second most common cause of death in the world. Treatment of cancer is very challenging and immunotherapy has been developed as a potential way to fight cancer. The main obstacle with immunotherapy is that cancer cells evolve from healthy body cells in response to an accumulation of genetic mutations. As a consequence, the immune system struggles to detect the abnormal cells as they are mainly recognized as self. This implies that equipping the immune system to eliminate cancer cells is tricky, yet represents a very efficient way to constrain the growth of tumors. We became interested in developing immunotherapeutical strategies against skin cancer in the context of our observations that Langerhans cells (LC) are very potent antigen presenting cells and are able to incorporate protein antigens and present them to CD4+ and CD8+ T cells in the skin-draining lymph nodes. As a consequence, we developed an immunization strategy through the skin, termed epicutaneous immunization. Protein antigen applied onto barrier-disrupted skin induces long-lasting cytotoxic T-cell responses, potent enough to control and inhibit tumor growth. In this review, we suggest that immunization strategies through the skin could be a promising new approach for the treatment of skin cancer.
Stoitzner, Patrizia; Sparber, Florian; Tripp, Christoph H
Objectives: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence. Methods: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10. Results: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists. Conclusion: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers.
Scurati, Silvia; Frati, Franco; Passalacqua, Gianni; Puccinelli, Paola; Hilaire, Cecile; Incorvaia, Cristoforo
Developing effective immunotherapy for lung cancer is a daunting but hugely attractive challenge. Until recently, non-small cell lung cancer was thought of as a non-immunogenic tumor, but there is now evidence highlighting the integral role played by both inflammatory and immunological responses in lung carcinogenesis. Despite recent encouraging preclinical and phase I/II data, there is a paucity of phase III trials showing a clear clinical benefit for vaccines in lung cancer. There are many difficulties to overcome prior to the development of a successful therapy. Perhaps a measurable immune response may not translate into a clinically meaningful or radiological response. Patient selection may also be a problem for ongoing clinical studies. The majority of trials for lung cancer vaccines are focused on patients with advanced-stage disease, while the ideal candidates may be patients with a lower tumor burden stage I or II disease. Selecting the exact antigens to target is also difficult. It will likely require multiple epitopes of a diverse set of genes restricted to multiple haplotypes to generate a truly effective vaccine that is able to overcome the various immunologic escape mechanisms that tumors employ. This review discusses active immunotherapy employing protein/peptide vaccines, whole cell vaccines, and dendritic cell vaccines and examines the current data on some novel immunomodulating agents.
Kelly, Ronan J.; Gulley, James L.; Giaccone, Giuseppe
Recently, immunotherapy has emerged as a treatment strategy in the adjuvant setting of breast cancer. In this review, monoclonal antibodies in passive and peptide-based vaccines, as one of the most commonly studied in active immunotherapy approaches, are discussed. Trastuzumab, a monoclonal antibody against HER-2/neu, has demonstrated considerable efficacy. However, resistance to trastuzumab has led to development of many targeted therapies which have been examined in clinical trials. Monoclonal antibodies against immune-checkpoint molecules that are dysregulated by tumors as an immune resistance mechanism are also explained in this review. Additionally, monoclonal antibodies with the ability to target breast cancer stem cells that play a role in cancer recurrence are mentioned. Here, clinical trials of HER-2/neu B and T cells, MUC1 and hTERT cancer peptide vaccines are also presented. In addition, various strategies for enhancing vaccine efficacy including combination with monoclonal antibodies and using different delivery systems for peptide/protein-based vaccine are described. PMID:24867051
Mohit, Elham; Hashemi, Atieh; Allahyari, Mojgan
Mesothelin is a cell-surface glycoprotein present on mesothelial cells and elicits T cell responses in a variety of cancers including pancreatic, biliary and ovarian cancer. Breast cancer is not known to express mesothelin. We postulated that mesothelin may be a unique tumor-associated antigen in triple negative breast cancer (TNBC), a less common breast cancer subtype which may have been under-represented in prior studies that characterized mesothelin expression. Therefore, we screened 99 primary breast cancer samples by immunohistochemistry analysis using formalin-fixed paraffin-embedded archival tumor tissues and confirmed that mesothelin was overexpressed in the majority of TNBC (67 %) but only rarely in <5 % ER(+) or Her2-neu(+) breast cancer, respectively. To determine whether mesothelin may be exploited as a novel immunotherapy target in breast cancer, an in vitro cell killing assay was performed to compare the ability of genetically modified T cells expressing a chimeric antibody receptor (CAR) specific for mesothelin (mesoCAR T cells) or non-transduced T cells to kill mesothelin-expressing primary breast cancer cells. A significantly higher anti-tumor cytotoxicity by mesoCAR T cells was observed (31.7 vs. 8.7 %, p < 0.001). Our results suggest that mesothelin has promise as a novel immunotherapy target for TNBC for which effective targeted therapy is lacking to date. PMID:22418702
Tchou, Julia; Wang, Liang-Chuan; Selven, Ben; Zhang, Hongtao; Conejo-Garcia, Jose; Borghaei, Hossein; Kalos, Michael; Vondeheide, Robert H; Albelda, Steven M; June, Carl H; Zhang, Paul J
Visceral leishmaniasis (VL) represents the second most challenging infectious disease worldwide, leading to nearly 500,000 new cases and 60,000 deaths annually. Ninety per cent of VL cases occur in five countries namely Bangladesh, India, Nepal, Sudan and Brazil. No licensed vaccine is available till date against any form of leishmaniasis. High toxicity and increasing resistance to the current chemotherapeutic regimens have further complicated the situation in VL endemic regions of the world. To combat this situation, immunochemotherapy can provide a solution. In the present study, an attempt has been made to assess the in vivo antileishmanial efficacy of chemotherapy, immunotherapy and immunochemotherapy with the use of a first generation antigen Killed Leishmania donovani (KLD) along with a standard drug sodium stibogluconate (SSG) and a newly tested antileishmanial cisplatin. Inbred BALB/c mice were infected with 10(7) promastigotes/0.1ml of Leishmania donovani. A month after infection, these animals were given specific immunotherapy (KLD/KLD+MPL-A) or chemotherapy (SSG/cisplatin) or immunochemotherapy (SSG+KLD/SSG+KLD+MPL-A/cisplatin+KLD/cisplatin+KLD+MPL-A). Animals were sacrificed on 1, 15 and 30(th) day post treatment. The efficacy of these combinations was assessed in terms of parasite load and by immunological investigations. Infected mice and normal mice served as controls. Results showed that combination of drug and KLD significantly reduced the parasite burden, enhanced the DTH (Delayed Type Hypersensitivity) responses, showed increased levels of IgG2a and decreased levels of IgG1 as compared to mice given chemotherapy or immunotherapy alone. Further maximum protection was provided by SSG+KLD+MPL-A and it was most effective as depicted by 98.5% reduction in parasite load, a potent increase in IFN-? levels and a significant decrease in IL-10 and IL-4 levels thus skewing the immune response towards Th1 type. Hence, immunochemotherapy is more effective in control of VL in comparison to chemotherapy or immunotherapy. PMID:24747611
Joshi, Jyoti; Malla, Nancy; Kaur, Sukhbir
In the vast area of immunotherapies, the development of monoclonal antibodies as a therapeutic concept emerged as a quantum leap out of the area of traditional vaccines (Köhler and Milstein) in vitro selection and optimisation made it possible to elaborate a single biological molecule from the molecular plethora of an individual adaptive immune response and to utilize such a cloned antibody repeatedly in a generalized fashion whenever the therapeutic indication is given to humans. At present, some 25 therapeutic monoclonal antibodies are currently being marketed in oncology, exceeding sales of USD20bn in 2011. A total of about 270 antibodies are currently in Phase II and III clinical development. Working on the assumption of usually lower attrition rates for antibody candidates, we expect approximately 120 of these 270 antibodies to be finally approved. This poses some key questions. What level of differentiation is required so that the coming new antibody drugs can command premium pricing when members of the founding generation become generic and inexpensive? What will global demand for antibody drugs be in view of the rising buying power in emerging pharmaceutical ('pharmerging') markets, but which is still not comparable with that of developed ones? What would the next quantum leaps be that might potentially push antibody technology on to a next level by disruptive innovation? Presentations given at the Phacilitate Immunotherapy Leaders' Forum 2012 (9-11 May in Barcelona) reflected on these questions and provided some stimulating perspectives. PMID:22894946
Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future.
Background Allergy immunotherapy tablets (AITs) are administered by the patients in their homes and the medical compliance and persistence may therefore be poorer than for subcutaneous immunotherapy (SCIT) administered by physicians. Purpose: to compare medical compliance and persistence for AIT and SCIT treatments in Swedish patients with allergic rhinoconjunctivitis (ARC). Methods Two products for the treatment of grass pollen induced ARC were investigated: a SCIT treatment (Alutard SQ, Phleum pratense, 100,000 SQ-U/mL) and an AIT treatment (Grazax, Phleum pratense 75,000 SQ-T/2,800 BAU), ALK, Denmark). Data were drawn from the Prescribed Drug Registry 2007–2009, the National Board of Health and Welfare in Sweden. Data on patients treated and number of packages sold were used to calculate the compliance and persistence for each of the 2 products, for patients who started treatment in 2007. Compliance calculated as the duration of treatment estimated from the number of packages sold (assuming 100% compliance), divided by the actual duration of treatment (the time estimated from the first to the last observed prescription, plus the duration of the last package). Persistence: calculated as the percentage of patients who continued their treatment in 2009 with at least initiation of 1 treatment package or vial in 2009. Results Grass AIT treatment was started by 636 patients and the grass SCIT treatment by 354 patients in 2007. The persistence of treatment in 2009 was 55% for grass AIT treatment and 57% for grass SCIT treatment. The estimated average duration of treatment was 2.34 years for grass AIT and 2.47 for grass SCIT at cut-off 31 December 2009. The average number of tablets used per patient during this period was 770. For grass SCIT treatment the average number of up-dosing kits used was 1.07 and the average number of maintenance vials was 3.26 (5 injections per vial). This corresponded to a compliance of 90% for grass AIT and 82% for grass SCIT. Conclusions Compliance to treatment for grass ait and grass scit treatments were both high (>80%) and comparable. The persistence of swedish patients was comparable for grass AIT and grass SCIT treatments during the period 2007 to 2009.
Andreasen, Jakob N?rgaard; Lawton, Simon; Baech, Sussi Boberg; Svardc, Mikael
Background Basement membranes in the walls of cerebral capillaries and arteries form a major lymphatic drainage pathway for fluid and solutes from the brain. Amyloid-? (A?) draining from the brain is deposited in such perivascular pathways as cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). CAA increases in severity when A? is removed from the brain parenchyma by immunotherapy for AD. In this study we investigated the consequences of immune complexes in artery walls upon drainage of solutes similar to soluble A?. We tested the hypothesis that, following active immunization with ovalbumin, immune complexes form within the walls of cerebral arteries and impair the perivascular drainage of solutes from the brain. Mice were immunized against ovalbumin and then challenged by intracerebral microinjection of ovalbumin. Perivascular drainage of solutes was quantified following intracerebral microinjection of soluble fluorescent 3kDa dextran into the brain at different time intervals after intracerebral challenge with ovalbumin. Results Ovalbumin, IgG and complement C3 co-localized in basement membranes of artery walls 24 hrs after challenge with antigen; this was associated with significantly reduced drainage of dextran in immunized mice. Conclusions Perivascular drainage along artery walls returned to normal by 7 days. These results indicate that immune complexes form in association with basement membranes of cerebral arteries and interfere transiently with perivascular drainage of solutes from the brain. Immune complexes formed during immunotherapy for AD may similarly impair perivascular drainage of soluble A? and increase severity of CAA.
The objective was to evaluate the toxicity and feasibility of intraperitoneal (IP) infusion of tumor-specific cytotoxic T-lymphocytes (CTL) as therapy for recurrent ovarian cancer, and to determine if repetitive cycles of CTL generation and infusion measurably increases the host’s ovarian cancer immune response. In this study, seven subjects with recurrent ovarian cancer confined to the peritoneal cavity underwent up to 4 cycles, each cycle beginning with a leukapheresis for collection of precursor lymphocytes, which were stimulated in vitro with MUC1, a tumor-specific antigen found commonly in ovarian cancer cells. The resulting new CTL for each cycle were re-introduced into the host via IP infusion. Immunological parameters (killer cells, cytokine production, memory T-lymphocytes and natural killer (NK) cells) were studied. Toxicity, CA-125, and survival data were also evaluated. The tumor marker CA-125 was non statistically significantly reduced after the first month of immunotherapy. However, after that, it rose. Killer cells, cytokine production and memory T-lymphocytes increased after the first cycle of stimulation, but plateaued or reduced thereafter. The percent of NK cells inversely correlated with other immune parameters. Median survival was 11.5 months. One subject is free of disease since December, 2000. Multiple cycles, beyond one cycle, of T-cell stimulation followed by adoptive T cell infusion, may not enhance the in vivo immune response.
Wright, Stephen E.; Rewers-Felkins, Kathleen A.; Quinlin, Imelda S.; Phillips, Catherine A.; Townsend, Mary; Philip, Ramila; Dobrzanski, Mark J.; Lockwood-Cooke, Pamela R.; Robinson, William
The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours.
Korbelik, M.; Naraparaju, V. R.; Yamamoto, N.
The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours. PMID:9010027
Korbelik, M; Naraparaju, V R; Yamamoto, N
Peanut allergy is an IgE-mediated hypersensitivity. Upon peanut consumption by an allergic individual, epitopes on peanut proteins bind and cross-link peanut-specific IgE on mast cell and basophil surfaces triggering the cells to release inflammatory mediators responsible for allergic reactions. Polyphenolic phytochemicals have high affinity to bind proteins and form soluble and insoluble complexes with unique functionality. This study investigated the allergenicity of polyphenol-fortified peanut matrices prepared by complexing various polyphenol-rich plant juices and extracts with peanut flour. Polyphenol-fortified peanut matrices reduced IgE binding to one or more peanut allergens (Ara h 1, Ara h 2, Ara h 3, and Ara h 6). Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) suggested changes in secondary protein structure. Peanut protein-cranberry polyphenol fortified matrices triggered significantly less basophil degranulation than unmodified flour in an ex vivo assay using human blood and less mast cell degranulation when used to orally challenge peanut-allergic mice. Polyphenol fortification of peanut flour resulted in a hypoallergenic matrix with reduced IgE binding and degranulation capacity, likely due to changes in protein secondary structure or masking of epitopes, suggesting potential applications for oral immunotherapy. PMID:24758688
Plundrich, Nathalie J; Kulis, Mike; White, Brittany L; Grace, Mary H; Guo, Rishu; Burks, A Wesley; Davis, Jack P; Lila, Mary Ann
With the success of ipilimumab and promise of programmed death-1 pathway-targeted agents, the field of tumor immunotherapy is expanding rapidly. Newer targets for clinical development include select members of the tumor necrosis factor receptor (TNFR) family. Agonist antibodies to these co-stimulatory molecules target both T and B cells, modulating T-cell activation and enhancing immune responses. In vitro and in vivo preclinical data have provided the basis for continued development of 4-1BB, OX40, glucocorticoid-induced TNFR-related gene, herpes virus entry mediator, and CD27 as potential therapies for patients with cancer. In this review, we summarize the immune response to tumors, consider preclinical and early clinical data on select TNFR family members, discuss potential translational challenges and suggest possible combination therapies with the aim of inducing durable antitumor responses.
We use a mathematical model to describe and predict the population dynamics of tumor cells, immune cells, and other immune components in a host undergoing laser immunotherapy treatment against metastatic cancer. We incorporate key elements of the treatment into the model: a function describing the laser-induced primary tumor cell death and parameters capturing the role and strength of the primary immunoadjuvant, glycated chitosan. We focus on identifying conditions that ensure a successful treatment. In particular, we study the patient response (i.e., anti-tumor immune dynamics and treatment outcome) in two different but related mathematical models as we vary quantitative features of the immune system (supply, proliferation, death, and interaction rates). We compare immune dynamics of a `baseline' immune model against an `augmented' model (with additional cell types and antibodies) and in both, we find that using strong immunoadjuvants, like glycated chitosan, that enhance dendritic cell activity yields more promising patient outcomes.
Dawkins, Bryan A.; Laverty, Sean M.
Bacille Calmette-Guérin (BCG) is an effective treatment for patients with superficial bladder cancer and bladder carcinoma in situ (CIS). It may cause side effects usually due to local and systemic inflammatory effects. We report a case of a male patient with non-invasive urothelial carcinoma of urinary bladder (Stage T1) who developed caseating granulomas on his glans penis as a complication of intravesical BCG immunotherapy. Though there are other reported cases of BCG dissemination noted in the literature, penile granuloma is rare. The first reported case was published in 1992 and since then only eleven cases are reported. It appears that both direct infectious processes and hypersensitivity reactions contribute to the clinical manifestations of a systemic BCG infection. Our case possibly represents a local infection of M bovis involving the glans penis.
Chowdhury, Anadi Roy; Dey, Ranjan Kumar
Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field.
Matar, Pablo; Alaniz, Laura; Rozados, Viviana; Aquino, Jorge B; Malvicini, Mariana; Atorrasagasti, Catalina; Gidekel, Manuel; Silva, Marcelo; Scharovsky, O Graciela; Mazzolini, Guillermo
Substantiated in the paper is urgency of development of pathogenetically adequate immunotherapeutic approaches to the treatment of HIV-infection, that is supposed to have good prospects. Consideration is given to experimental and clinical-and-immunological findings concerning effects of different immunomoderivative drug preparations and of their synthetic analogues on the trigger mechanisms, with sequelae of their development in the cytokin-chemokin system outlined. A possibility is shown based on principle of our using with an immunotherapeutic purpose some cytokins, soluble receptors, antibodies to cytokins and receptors, those antibodies and ligands combined with toxins, chemical compounds affecting the synthesis of cytokin and other biologically active substances as well. Unspecific active immunotherapy is regarded as a good supplement to antiretroviral therapy preventing development of resistance to drugs. PMID:12587295
Nikol'ski?, I S; Iurchenko, V D
The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer. Cancer Immunol Res; 2(5); 393-8. ©2014 AACR. PMID:24795351
Anderson, Ana C
Interleukin 12 (IL-12) seemed to represent the ideal candidate for tumor immunotherapy, due to its ability to activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities. However, despite encouraging results in animal models, very modest antitumor effects of IL-12 in early clinical trials, often accompanied by unacceptable levels of adverse events, markedly dampened hopes of the successful use of this cytokine in cancer patients. Recently, several clinical studies have been initiated in which IL-12 is applied as an adjuvant in cancer vaccines, in gene therapy including locoregional injections of IL-12 plasmid and in the form of tumor-targeting immunocytokines (IL-12 fused to monoclonal antibodies). The near future will show whether this renewed interest in the use of IL-12 in oncology will result in meaningful therapeutic effects in a select group of cancer patients. PMID:24514955
Lasek, Witold; Zago?d?on, Rados?aw; Jakobisiak, Marek
The 12th annual summer symposium of The Koch Institute for Integrative Cancer Research at MIT was held in Cambridge, MA, on June 14th, 1023. The symposium entitled “Cancer Immunology and Immunotherapy” focused on recent advances in preclinical research in basic immunology and biomedical engineering, and their clinical application in cancer therapies. The day-long gathering also provided a forum for discussion and potential collaborations between engineers and clinical investigators. The major topics presented include: (i) enhancement of adoptive cell therapy by engineering to improve the ability and functionality of T-cells against tumor cells; (ii) current therapies using protein and antibody therapeutics to modulate endogenous anti-tumor immunity; and (iii) new technologies to identify molecular targets and assess therapeutic efficacy, and devices to control and target drug delivery more effectively and efficiently.
Drake, Adam; Joshi, Nikhil S.; Szeto, Gregory L; Zhu, Eric; Eisen, Herman N.; Irvine, Darrell J.
Ingenol mebutate is a diterpene ester derived from the plant Euphorbia peplus and is FDA approved for the topical treatment of actinic keratoses (AK). Shown to be efficacious with as little as a 3-day trial, this compound is being further tested for the topical treatment of other nonmelanoma skin cancers with promising preclinical data. In an effort to elucidate the molecular mechanism of this novel drug, Stahlhut et al. (2012) suggest a role for calcium and apoptosis. Further studies are needed to evaluate the intracellular mechanisms of ingenol mebutate-mediated cytotoxicity. Additionally, studies such as this not only shed light on the mechanism of ingenol mebutate and its derivatives, but also pave the way for evaluating the involvement of the immune system in eliminating drug-treated cells and tissues. This has important implications for the development of novel topical immune modulatory products and the field of topical immunotherapy. PMID:23134979
Doan, Hung Q; Gulati, Nicholas; Levis, William R
Extracorporeal photochemotherapy (ECP) is an autologous cell therapy used for the treatment of diseases involving pathogenic cells: cutaneous T-cell lymphoma, organ rejection and graft versus host disease. During an ECP procedure, patients receive a cellular product consisting of autologous mononuclear cells, containing the pathogenic cells, treated with a photosensitising agent and an UV-A radiation. The aim of the treatment is to induce a specific immune reaction modulating the activity of untreated pathogenic lymphocytes responsible for the disease and therefore an improvement of clinical manifestations. The precise mechanisms of action remain to be defined in humans. Its efficacy coupled with the absence of side effects could lead to decrease the use of immunosuppressive drugs. PCE appears as an immunotherapy using cells modified by photochemistry, which allows specific immune modulation of pathogenic lymphocytes. PMID:20153093
Hannani, D; Gabert, F; Chaperot, L; Richard, M J; Plumas, J
Oncolytic viruses (OV) selectively replicate and kill cancer cells and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer selective or can be genetically engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines and can be armed with immunomodulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy: (i) innate immune responses and the degree of inflammation induced; (ii) types of virus-induced cell death; (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture; and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers [MHC, costimulatory, and natural killer (NK) receptors], and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing granulocyte macrophage colony-stimulating factor (GM-CSF), have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between antivirus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs. Cancer Immunol Res; 2(4); 295-300. ©2014 AACR. PMID:24764576
Chiocca, E Antonio; Rabkin, Samuel D
CD43 is a sialoglycosylated membrane protein that is involved in cell proliferation and differentiation. CD43 glycoforms that are recognized by the UN1 monoclonal antibody (mAb) were expressed in lymphoblastoid T-cell lines and solid tumors, such as breast, colon, gastric, and squamous cell lung carcinomas, while unexpressed in the normal counterparts. The cancer association of UN1/CD43 epitope suggested the possibility to use the UN1 mAb for tumor diagnosis and therapy. In this study, we show that the UN1 mAb was endowed with antitumor activity in vivo because its passive transfer inhibited the growth of UN1-positive HPB-ALL lymphoblastoid T cells in mice. Furthermore, we demonstrate that tumor inhibition was due to UN1 mAb-dependent natural killer-mediated cytotoxicity. By screening a phage-displayed random peptide library, we identified the phagotope 2/165 as a mimotope of the UN1 antigen, as it harbored a peptide sequence that was specifically recognized by the UN1 mAb and inhibited the binding of the UN1 mAb to UN1-positive tumor cells. On the basis of sequence homology with the extracellular region of CD43 (amino acids 64 to 83), the 2/165 peptide sequence was likely mimicking the protein core of the UN1/CD43 epitope. When used as vaccine in mice, the 2/165 phagotope raised antibodies against the UN1/CD43 antigen, indicating that the 2/165 phagotope mimicked the UN1 antigen structure, and could represent a novel immunogen for cancer immunotherapy. These findings support the feasibility of using monoclonal antibodies to identify cancer-associated mimotopes for immunotherapy. PMID:24356816
Tuccillo, Franca Maria; Palmieri, Camillo; Fiume, Giuseppe; de Laurentiis, Annamaria; Schiavone, Marco; Falcone, Cristina; Iaccino, Enrico; Galandrini, Ricciarda; Capuano, Cristina; Santoni, Angela; D'Armiento, Francesco Paolo; Arra, Claudio; Barbieri, Antonio; Dal Piaz, Fabrizio; Venzon, David; Bonelli, Patrizia; Buonaguro, Franco Maria; Scala, Iris; Mallardo, Massimo; Quinto, Ileana; Scala, Giuseppe
Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen–loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3–4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. Conclusion. These results suggest that the efficacy of melanoma DC–based immunotherapy is enhanced when tumor antigen–loaded DCs used for vaccination express cPs. Trial registration. Clinicaltrials.gov NCT00672542. Funding. Duke Clinical Research Institute/Duke Translational Medicine Institute, Duke Melanoma Consortium, and Duke University Department of Surgery.
Dannull, Jens; Haley, N. Rebecca; Archer, Gary; Nair, Smita; Boczkowski, David; Harper, Mark; De Rosa, Nicole; Pickett, Nancy; Mosca, Paul J.; Burchette, James; Selim, Maria A.; Mitchell, Duane A.; Sampson, John; Tyler, Douglas S.; Pruitt, Scott K.
Background Double-blind, placebo-controlled (DBPC) trials are the gold standard for demonstrating clinical efficacy and tolerability. The placebo effect, although an important feature in placebo-controlled studies, has never been systematically investigated in allergen-specific immunotherapy (SIT) studies. This study was performed to examine the placebo response in SIT trials that employed a baseline observational period and two treatment years using a symptom-medication-score (SMS) as the primary endpoint. Methods The placebo effect was evaluated in six DBPC SIT studies (five studies using subcutaneous SIT (SCIT) and one sublingual (SLIT)), two grass, two birch and two house dust mite (HDM) SIT, including a total of 472 adult patients treated with a placebo. The results were reported as changes from baseline of the SMS area under the curve after two years of perennial placebo therapy during the respective evaluation periods. Pollen counts and IgG4 levels were additionally analysed. Results Subcutaneously treated placebo patients displayed a marked decrease in the SMS. The mean placebo effect in the SCIT trials with comparable allergen exposure was up to 41% in the second treatment year and, in contrast, reached only 1% in the SLIT trial. Allergen exposure had an inverse influence on the placebo effect. No changes from baseline in allergen specific IgG4 antibodies were observed in the placebo-treated patients. Conclusions SIT studies display a significant placebo effect, mainly observed in subcutaneous immunotherapy, with high variability depending on the route of application and allergen exposure. Our findings indicate the differential role of the placebo effect in SIT efficacy depending on the route of administration and pollen exposure.