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1

[The role of anti-TNF therapy in ulcerative colitis].  

PubMed

Anti-TNF-alfa molecules are currently being used to treat ulcerative colitis regarding to the fact that TNF-alpha has an important role in the pathogenesis of IBD. Although these drugs improved the therapy of patients, immunogenicity limits their potential for clinical use. Infliximab and adalimumab are effective for induction and maintenance of remission in outpatients with moderate to severe steroid-refractory ulcerative colitis. Biologics can be a drug of choice for patients with refractory proctitis and refractory pouchitis. In hospitalized patients with steroid-resistant severe ulcerative colitis who are candidates for colectomy, infliximab may be second-line option. Adequate long-term maintenance therapy with anti-TNF is required after rescue therapy for a sustained benefit. Regarding to the known risk for side-effects of anti-TNF drugs especially in patients concomitantly treated with thiopurines it is urgent future research. PMID:24471300

Cukovi?-Cavka, Silvija; Vuceli?, Boris; Urek, Marija Crncevi?; Brinar, Marko; Turk, Niksa

2013-04-01

2

Autoimmune Hepatitis Triggered by Anti-TNF-? Therapy  

PubMed Central

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. PMID:24082887

Nakayama, Satoshi

2013-01-01

3

Effects of anti-TNF-? agents on circulating endothelial-derived and platelet-derived microparticles in psoriasis.  

PubMed

Psoriasis involves TNF-? secretion leading to release of microparticles into the bloodstream. We investigated the effect of TNF blockers on microparticles levels before and after treatment in patients (twenty treated by anti-TNF-? agents and 6 by methotrexate) with severe psoriasis. Plasmatic microparticles were labelled using fluorescent monoclonal antibodies and were analysed using cytometry. Three months later, 70% of patients treated with anti-TNF-? agents achieved a reduction in PASI score of at least 75%. The clinical improvement in patients treated with anti-TNF-? agents was associated with a significant reduction of the mean number of platelet microparticles (2837/?l vs 1849/?l, P = 0.02) and of endothelial microparticles (64/?l vs 22/?l, P = 0.001). Microparticles are significantly decreased in psoriatic patients successfully treated by anti-TNF-?. Microparticles levels as circulating endothelial cells represent signs of endothelial dysfunction and are elevated in psoriasis. Then, TNF blockade may be effective to reduce cardiovascular risk through the reduction of circulating microparticles. PMID:25255926

Pelletier, Fabien; Garnache-Ottou, Francine; Biichlé, Sabeha; Vivot, Aurore; Humbert, Philippe; Saas, Philippe; Seillès, Estelle; Aubin, François

2014-12-01

4

Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis  

Microsoft Academic Search

Background: We wondered whether short-term coseasonal sublingual immunotherapy (SLIT) can reduce the development of asthma in children with hay fever in an open randomized study. Objective: We sought to determine whether SLIT is as effective as subcutaneous immunotherapy in reducing hay fever symptoms and the development of asthma in children with hay fever. Methods: One hundred thirteen children aged 5

Elio Novembre; Elena Galli; Fabiola Landi; Carlo Caffarelli; Massimo Pifferi; Emanuela De Marco; Samuele E. Burastero; Giliola Calori; Luca Benetti; Paolo Bonazza; Paola Puccinelli; Silvano Parmiani; Roberto Bernardini; Alberto Vierucci

2004-01-01

5

Anti-TNF therapeutics for the treatment of sarcoidosis.  

PubMed

Sarcoidosis is a systemic disease with an incidence of 1 to 40 per 100 000 persons per year. It predominantly affects people in the age of 20 to 40 years old. Disease course varies from mild self-limiting to chronic debilitating and life-threatening disease. Since the cause of sarcoidosis is unknown, curative therapy is not available. Immunosuppressive drugs may, however, control the symptoms of the disease. The hallmark of sarcoidosis is the formation of granulomas that are most commonly found in lungs and lymph nodes. As TNF plays an important role in both formation and maintenance of these granulomas, as well as in the immune response, anti-TNF biologicals such as infliximab and adalimumab are considered a last resort therapeutic option. Clinical effectiveness, however, varies considerably and data showing which patients would benefit most from this expensive therapy are scarce. This review summarizes current knowledge on anti-TNF therapeutics in sarcoidosis, and describes insights on prediction of response, outcome measures and antibody development. PMID:25428650

Crommelin, Heleen A; Vorselaars, Adriane D M; van Moorsel, Coline H M; Korenromp, Ingrid H E; Deneer, Vera H M; Grutters, Jan C

2014-01-01

6

[Anti-TNF therapy in treatment of luminal Crohn's disease].  

PubMed

Biologic drugs directed against main proinflammatory mediator in inflammatory bowel disease (IBD)--tumor necrosis factor alpha (TNFalpha)--represent very effective and clinically proven therapy of IBD. Meta-analysis and daily clinical practice confirm efficacy of infliximab and adalimumab in induction and maintenance of remission without steroids in patients with luminal Crohn's disease. Main therapeutic goals are reduction of complications, reduction of number of hospitalizations and surgical interventions and improvement of quality of life, work capacity and reproductive ability of patients. There are few very important issues that one must consider before starting an anti-TNF therapy in patients with luminal Crohn's disease. First, it is necessary to identify patients who failed to respond to conventional drugs and who would benefit the most from early application of biologics. It is very important to exclude presence of strictures or other complications like intraabdominal fistulas and collections before starting anti-TNF therapy. Once we decide to start biologic therapy, it is important to apply adequate dose and regime of anti-TNF therapy and to change and adjust treatment to achieve and maintain remission in patients who lose response. In general, treatment recommendations depend on disease activity and severity, extension and localization of lesions, comorbidities and possible complications of disease and/or treatment. There are few clinical instruments and laboratory surrogates that help us to assess disease activity. Most used are Crohn's Disease Activity Index (CDAI), Harvey- Bradshaw index (HBI), concentration of C-reactive protein (CRP) and fecal lactoferrin and calprotectin. In assessment of mucosal injury we rely on two complementary endoscopic indices of activity--Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (CD-SES). However, in time of diagnosis of Crohn's disease available clinical, serological or laboratory markers do not have acceptably predictive value for future disease behavior and there are still no genetic indicator that could predict disease course. There are some clinical and epidemiologic factors that could be related to unfavorable disease course. Age less than 40 years, extended disease, need for steroid therapy early after diagnosis and perianal disease are considered to predict worse prognosis in patients with luminal Crohn's disease. According to available data, it seems that early intensive therapy with anti-TNF drugs as monotherapy or in combination with immunosuppressive drugs in this group of patients increases possibility of induction of remission, mucosal healing and maintenance of steroid-free remission. Candidates for anti-TNF therapy are also patients who did not respond to conventional treatment, patients with moderate or severe disease who are intolerant to steroids, patients in whom we expect severe adverse effects from steroid treatment, patients who do not accept steroid treatment and patients with frequent relapses and need for steroids. PMID:24471301

Marko, Bani?; Prka, Lidija

2013-04-01

7

AVX-470: A Novel Oral Anti-TNF Antibody with Therapeutic Potential in Inflammatory Bowel Disease  

PubMed Central

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the GI tract that is currently treated with injected monoclonal antibodies specific for tumor necrosis factor (TNF). We developed and characterized AVX-470, a novel polyclonal antibody specific for human TNF. We evaluated the oral activity of AVX-470m, a surrogate antibody specific murine TNF, in several well-accepted mouse models of IBD. Methods AVX-470 and AVX-470m were isolated from the colostrum of dairy cows that had been immunized with TNF. The potency, specificity and affinity of both AVX-470 and AVX-470m were evaluated in vitro and compared with infliximab. AVX-470m was orally administered to mice either before or after induction of colitis and activity was measured by endoscopy, histopathology, immunohistochemistry and quantitative measurement of mRNA levels. Colitis was induced using either 2,4,6-trinitrobenzene sulfonate (TNBS) or dextran sodium sulfate (DSS). Results AVX-470 and AVX-470m were shown to be functionally comparable in vitro. Moreover, the specificity, neutralizing potency and affinity of AVX-470 were comparable to infliximab. Orally administered AVX-470m effectively reduced disease severity in several mouse models of IBD. Activity was comparable to that of oral prednisolone or parenteral etanercept. The antibody penetrated the colonic mucosa and inhibited TNF-driven mucosal inflammation with minimal systemic exposure. Conclusions AVX-470 is a novel polyclonal anti-TNF antibody with an in vitro activity profile comparable to that of infliximab. Oral administration of a surrogate antibody specific for mouse TNF is effective in treating mouse models of IBD, delivering the anti-TNF to the site of inflammation with minimal systemic exposure. PMID:23949620

Bhol, Kailash C.; Tracey, Daniel E.; Lemos, Brenda R.; Lyng, Gregory D.; Erlich, Emma C.; Keane, David M.; Quesenberry, Michael S.; Holdorf, Amy D.; Schlehuber, Lisa D.; Clark, Shawn A.; Fox, Barbara S.

2013-01-01

8

Anti-TNF therapy: past, present and future.  

PubMed

While for a century therapeutics has been dominated by small molecules, i.e. organic chemicals of ~400Da absorbable via the gut, this is no longer the case. There are now a plethora of important medicines which are proteins and injectable, which have dramatically improved the therapy of many inflammatory diseases and of cancer. Most of these are monoclonal antibodies, some are receptor Ig Fc fusion proteins, others are cytokines or enzymes. The key to this new aspect of therapeutics has been the filling of unmet needs, and the consequent commercial success, which promoted further research and development. The first 'biologic' for a common disease, rheumatoid arthritis (RA), was a monoclonal antibody, infliximab, to human tumour necrosis factor (TNF). This was based on our work, which is described in this review, summarizing how TNF was defined as a good target in RA, how it was developed is described here, as well as future indications for anti-TNF and related agents. Biologics are now the fastest growing sector of therapeutics. PMID:25411043

Monaco, Claudia; Nanchahal, Jagdeep; Taylor, Peter; Feldmann, Marc

2015-01-01

9

Biological Treatments in Behçet's Disease: Beyond Anti-TNF Therapy  

PubMed Central

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. PMID:25061259

Costa, Luisa; Caso, Paolo; Bascherini, Vittoria; Frediani, Bruno; Cimaz, Rolando; Nieves-Martín, Laura; Atteno, Mariangela; Raffaele, Carmela G. L.; Tarantino, Giusyda; Galeazzi, Mauro; Punzi, Leonardo

2014-01-01

10

Anti-TNF-Alpha Therapy Enhances the Effects of Enzyme Replacement Therapy in Rats with Mucopolysaccharidosis Type VI  

PubMed Central

Background Although enzyme replacement therapy (ERT) is available for several lysosomal storage disorders, the benefit of this treatment to the skeletal system is very limited. Our previous work has shown the importance of the Toll-like receptor 4/TNF-alpha inflammatory pathway in the skeletal pathology of the mucopolysaccharidoses (MPS), and we therefore undertook a study to examine the additive benefit of combining anti-TNF-alpha therapy with ERT in a rat model of MPS type VI. Methodology/Principal Findings MPS VI rats were treated for 8 months with Naglazyme® (recombinant human N-acetyl-galactosamine-4-sulfatase), or by a combined protocol using Naglazyme® and the rat-specific anti-TNF-alpha drug, CNTO1081. Both protocols led to markedly reduced serum levels of TNF-alpha and RANKL, although only the combined treatment reduced TNF-alpha in the articular cartilage. Analysis of cultured articular chondrocytes showed that the combination therapy also restored collagen IIA1 expression, and reduced expression of the apoptotic marker, PARP. Motor activity and mobility were improved by ERT, and these were significantly enhanced by combination treatment. Tracheal deformities in the MPS VI animals were only improved by combination therapy, and there was a modest improvement in bone length. Ceramide levels in the trachea also were markedly reduced. MicroCT analysis did not demonstrate any significant positive effects on bone microarchitecture from either treatment, nor was there histological improvement in the bone growth plates. Conclusions/Significance The results demonstrate that combining ERT with anti-TNF- alpha therapy improved the treatment outcome and led to significant clinical benefit. They also further validate the usefulness of TNF-alpha, RANKL and other inflammatory molecules as biomarkers for the MPS disorders. Further evaluation of this combination approach in other MPS animal models and patients is warranted. PMID:21887218

Eliyahu, Efrat; Wolfson, Theodore; Ge, Yi; Jepsen, Karl J.; Schuchman, Edward H.; Simonaro, Calogera M.

2011-01-01

11

Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register  

PubMed Central

Objective The 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. Methods Patients were categorised according to anti-TNF exposure as follows: (1) exposure to anti-TNF and to methotrexate (MTX) and/or leflunomide (LEF) at conception (n=21 pregnancies); (2) exposure to anti-TNF at conception (n=50); (3) exposure to anti-TNF prior to conception (n=59); (4) no exposure to anti-TNF (control group; n=10). Results Eighty-eight live births in a total of 130 pregnancies were reported in patients who received anti-TNF before or during pregnancy. The rate of spontaneous abortion was highest among patients exposed to anti-TNF at the time of conception (with MTX/LEF 33% and without MTX/LEF 24%). This compared with 17% spontaneous abortions in those with prior exposure to anti-TNF and 10% spontaneous abortions in the control group. Ten terminations were performed. Conclusion Although the results to date have been promising, no firm conclusions can be drawn about the safety of anti-TNF during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception cannot yet be changed. PMID:21362710

Verstappen, Suzanne M M; King, Yvonne; Watson, Kath D; Symmons, Deborah P M; Hyrich, Kimme L

2011-01-01

12

Association between the initiation of anti-TNF therapy and the risk of herpes zoster  

PubMed Central

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. PMID:23462785

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.

2013-01-01

13

Cutaneous Sarcoidosis Occurring during Anti-TNF-Alpha Treatment: Report of Two Cases  

Microsoft Academic Search

We report two cases of cutaneous granuloma induced by anti-TNF-? therapy: a 47-year-old man suffering from psoriatic arthritis treated with infliximab and a 56-year-old woman treated with adalimumab for polyarticular juvenile rheumatoid arthritis. The biospies confirmed the diagnosis of a ‘sarcoidosis-like’ reaction. No systemic involvement was observed. Such cases of noninfectious granulomatous diseases occurring during anti-TNF-? therapy are becoming increasingly

F. Dhaille; V. Viseux; A. Caudron; A. Dadban; C. Tribout; P. Boumier; A. Clabaut; C. Lok

2010-01-01

14

Clinical use of anti-TNF therapy and increased risk of infections  

PubMed Central

Biologics such as antitumor necrosis factor (anti-TNF) drugs have emerged as important agents in the treatment of many chronic inflammatory diseases, especially in cases refractory to conventional treatment modalities. However, opportunistic infections have become a major safety concern in patients on anti-TNF therapy, and physicians who utilize these agents must understand the increased risks of infection. A literature review of the published data on the risk of bacterial, viral, fungal, and parasitic infections associated with anti-TNF therapy was performed and the clinical presentation, diagnostic tests, management, and prevention of opportunistic infections in patients receiving anti-TNF therapy were reviewed. Awareness of the therapeutic potential and associated adverse events is necessary for maximizing therapeutic benefits while minimizing adverse effects from anti-TNF treatments. Patients should be adequately vaccinated when possible and closely monitored for early signs of infection. When serious infections occur, withdrawal of anti-TNF therapy may be necessary until the infection has been identified and properly treated. PMID:23569399

Ali, Tauseef; Kaitha, Sindhu; Mahmood, Sultan; Ftesi, Abdul; Stone, Jordan; Bronze, Michael S

2013-01-01

15

A guide to preparation of patients with inflammatory bowel diseases for anti-TNF-? therapy  

PubMed Central

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, Orlando; Damião, Adérson Omar Mourão Cintra

2014-01-01

16

Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study)  

Microsoft Academic Search

Background: Children with allergic rhinitis are likely to develop asthma. Objective: The purpose of this investigation was to determine whether specific immunotherapy can prevent the development of asthma and reduce bronchial hyperresponsiveness in children with seasonal allergic rhinoconjunctivitis. Methods: From 6 pediatric allergy centers, 205 children aged 6 to 14 years (mean age, 10.7 years) with grass and\\/or birch pollen

Christian Möller; Sten Dreborg; Hosne A. Ferdousi; Susanne Halken; Arne Høst; Lars Jacobsen; Antti Koivikko; Dieter Y. Koller; Bodo Niggemann; Lene A. Norberg; Radvan Urbanek; Erkka Valovirta; Ulrich Wahn

2002-01-01

17

New Onset of Dermatomyositis/Polymyositis during Anti-TNF-? Therapies: A Systematic Literature Review  

PubMed Central

We performed a systematic search of databases from 1990 to 2013 to identify articles concerning the new onset of dermatomyositis/polymyositis (DM/PM) in patients treated with anti-TNF-? therapy. We retrieved 13 publications describing 20 patients where the new onset of DM/PM after anti-TNF-? therapy was recorded. 17 patients were affected by rheumatoid arthritis (RA), one by Crohn's disease, one by ankylosing spondilytis, and one by seronegative arthritis. In 91% of the cases antinuclear autoantibodies were detected after the introduction of anti-TNF-? therapy. In 6 patients antisynthetase antibodies were detected and other clinical findings as interstitial lung disease (ILD) were recorded. Improvement of DM/PM after anti-TNF suspension (with the concomitant use of other immunosuppressors) was recorded in 94% of cases. The emergence of DM/PM and antisynthetase syndrome seem to be associated with the use of anti-TNF-? agents, especially in patients with chronic inflammatory diseases (mainly RA) with positive autoantibodies before therapy initiation. In particular, physicians should pay attention to patients affected by RA with positive antisynthetase antibodies and/or history of ILD. In those cases, the use of the TNF-? blocking agents may trigger the onset of PM/DM or antisynthetase syndrome or may aggravate/trigger the lung disease. PMID:24600322

Aberer, Werner; Massone, Cesare

2014-01-01

18

Patients with Ankylosing Spondylitis and Low Disease Activity because of Anti-TNF-Alpha Therapy Have Higher TRAIL Levels Than Controls: A Potential Compensatory Effect  

PubMed Central

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. PMID:24976690

López-Mejías, Raquel; Rueda-Gotor, Javier; Miranda-Filloy, José A.; Ubilla, Begoña; Carnero-López, Beatriz; Palmou-Fontana, Natalia; Gómez-Acebo, Inés; Blanco, Ricardo; Pina, Trinitario; Ochoa, Rodrigo; González-Juanatey, Carlos; González-Gay, Miguel A.

2014-01-01

19

Induction of psoriasis with anti-tnf agents in patients with inflammatory bowel disease: A report of 21 cases  

Microsoft Academic Search

AimAnti-tumor necrosis factor (TNF)-alpha agents are widely used for the treatment of both inflammatory bowel disease (IBD) and psoriasis. Psoriatic skin lesions induced by anti-TNF have been described in patients with IBD. We report a case series of psoriasis induced by anti-TNF agents in IBD patients.

Iván Guerra; Alicia Algaba; José Lázaro Pérez-Calle; María Chaparro; Ignacio Marín-Jiménez; Raquel García-Castellanos; Yago González-Lama; Antonio López-Sanromán; Noemí Manceñido; Pilar Martinez-Montiel; Elvira Quintanilla; Carlos Taxonera; Mónica Villafruela; Alberto Romero-Maté; Pilar López-Serrano; Javier P. Gisbert; Fernando Bermejo

20

Mycobacterium kansasii cutaneous infection in a patient with sarcoidosis treated with anti-TNF agents.  

PubMed

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

2014-06-01

21

Neurological adverse events in patients receiving anti-TNF therapy: a prospective imaging and electrophysiological study  

PubMed Central

Introduction The aim was to investigate the frequency of neurological adverse events in patients with rheumatoid arthritis (RA) and spondylarthropathies (SpA) treated with tumor necrosis factor (TNF) ? antagonists. Methods Seventy-seven patients eligible for anti-TNF? therapy were evaluated. There were 36 patients with RA, 41 with SpA [24 psoriatic arthritis (PsA) and 17 with ankylosing spondylitis (AS)]. All patients had a complete physical and neurological examination. Brain and cervical spine magnetic resonance imaging (MRI) and neurophysiological tests were performed in all patients before the initiation of anti-TNF? therapy and after a mean of 18 months or when clinical symptoms and signs indicated a neurological disease. Exclusion criteria included hypertension, diabetes mellitus, dyslipidemia, heart arrhythmias, atherothrombotic events, vitamin B12 and iron deficiency, head and neck trauma and neurological surgeries. Results Two patients did not receive anti-TNF? therapy because brain MRIs at baseline revealed lesions compatible with demyelinating diseases. Thus, 75 patients received anti-TNF? (38 infliximab, 19 adalimumab and 18 etanercept). Three patients developed neurological adverse events. A 35-year-old man with PsA after 8 months of infliximab therapy presented with paresis of the left facial nerve and brain MRI showed demyelinating lesions. Infliximab was discontinued and he was treated with pulses of corticosteroids recovering completely after two months. The second patient was a 45-year-old woman with RA who after 6 months of adalimumab therapy presented with optic neuritis. The third patient was a 50-year-old woman with AS, whom after 25 months of infliximab therapy, presented with tingling and numbness of the lower extremities and neurophysiological tests revealed peripheral neuropathy. In both patients anti-TNF were discontinued and they improved without treatment after 2 months. The rest of our patients showed no symptoms and MRIs showed no abnormalities. The estimated rate of neurological adverse events in patients treated with anti-TNF therapy is 4% (3/75). Conclusions Neurological adverse events after anti-TNF? therapy were observed in our patient. Brain MRI and neurophysiological tests are essential tools to discriminate neurological diseases. PMID:24938855

2014-01-01

22

Immunotherapy Reduces Allergen-Mediated CD66b Expression and Myeloperoxidase Levels on Human Neutrophils from Allergic Patients  

PubMed Central

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. PMID:24740105

Ventura, Inmaculada; Gómez, Elisa; Pérez-Cano, Ramón; Blanca, Miguel; Monteseirín, Javier

2014-01-01

23

[Anti TNF-? (infliximab) treatment for intravenous immunoglobulin (IVIG) resistance patients with acute Kawasaki disease the effects of anticytokine therapy].  

PubMed

Among the patients with acute Kawasaki disease treated with intravenous immunoglobulin (IVIG), 10-20 % demonstrate resistance or incomplete effects. Cardiac complication such as the coronary arterial aneurysm is frequent in these patients. For patients with IVIG-resistance, we have surveyed the efficacy and safety of anti-cytokine therapy with use of infliximab (Remicade), chimera type anti TNF-? agent, for children. After May, 2005, Remicade has been used in >500 pediatric patients in whom IVIG and intravenous methylprednisolone pulse therapy did not show significant effects. The efficacy and safety of Remicade on patients with IVIG-resistant Kawasaki disease has been observed but 10~20 % of patients was Remicade-resistant. Re-treatment with IVIG or steroids was also effective. The efficacy of Remicade for reducing the fever duration, CRP, WBC counts was promising, but reduction of the incidence of coronary aneurysm was not confirmed. Randomized clinical trial will be needed. PMID:25518416

Saji, Tsutomu; Takatsuki, Shinichi; Kobayashi, Toru

2014-09-01

24

[Rhumatology. The rheumatoid arthritis patient who does not respond to anti-TNF].  

PubMed

Anti-TNF treatments have given patients with rheumatoid arthritis considerable hope and relief. However, 20-30% of patients do not respond sufficiently to a given anti-TNF drug. In this situation, current strategies include switching to an alternative agent, increasing the dose of the current agent or to return to conventional DMARDs. The arrival of new biologics, which target different molecules than TNF, opens the perspective to other pathways of immunomodulation in RA. These drugs include rituximab (anti-CD20), abatacept (CTLA4Ig) and tocilizumab (anti- IL6R). Comparative studies are urgently needed to assess the efficacy of the different treatment options in order to provide the best therapeutic strategy for our patients. PMID:17354663

So, A

2007-01-10

25

[Colonic perforation due to invasive amebic colitis during anti-TNF therapy for spondyloarthritis].  

PubMed

TNF blockade has been successful in the treatment of some rheumatic diseases such as spondyloarthritis. Many infectious complications have been reported with anti-TNF therapy, mainly bacterial, mycobacterial, viral and fungal infections. Entamoeba histolytica is an extracellular protozoan parasite that mainly causes colitis and hepatic abscess; bowel perforation is an uncommon complication with high mortality. TNF is considered the principal mediator of cell immunity against amebiasis. Initially, it is chemotactic to E. histolytica, enhancing its adherence to enterocyte via galactose inhibitable lectin, and then activating macrophages to kill ameba though the release of NO, so that TNF blocking could be harmful, increasing amebic virulence. We describe the case of a 46-year-old woman with spondyloarthritis who presented a colonic perforation due to invasive amebic colitis during anti-TNF use. PMID:25458030

Restrepo, Juan Pablo; Molina, María del Pilar

2014-01-01

26

Demyelination and other neurological adverse events after anti-TNF therapy.  

PubMed

Tumor necrosis factor (TNF) ? inhibitors are an essential therapeutic option for several inflammatory diseases, like rheumatoid arthritis, spondyloarthropathies and inflammatory bowel diseases. As TNF? antagonists have become increasingly utilized, there have been a number of reports of neurological adverse events in patients receiving anti-TNF? therapy. The frequency of central nervous system adverse events after initiation of anti-TNF? therapy is unknown. However, questions have been raised about a possible causal association. Although several hypotheses have been proposed in an attempt to explain the possible relationship between TNF? antagonist and demyelination, none is considered to be adequate. Thus, in this report we deal with the implication of TNF? in multiple sclerosis and we discuss the possible relationship of TNF? antagonist and demyelinating diseases. PMID:24035809

Kaltsonoudis, Evripidis; Voulgari, Paraskevi V; Konitsiotis, Spyridon; Drosos, Alexandros A

2014-01-01

27

Successful effect of tocilizumab in anti-TNF-?-induced palmoplantar pustulosis in rheumatoid arthritis.  

PubMed

Anti-tumour necrosis factor-alpha (TNF-?) agents are effective drugs used in several chronic inflammatory diseases such as rheumatoid arthritis (RA). Psoriasiform lesions, including palmoplantar pustulosis, have been described following anti-TNF-? therapy. These lesions often resolve with topical therapy with or without discontinuation of these drugs. However, in some cases, psoriasiform lesions may persist despite anti-TNF-? withdrawal. We report on two RA patients treated with adalimumab (ADA) who developed palmoplantar pustular despite dermatological treatment and ADA discontinuation. Tocilizumab (TCZ) therapy was initiated because of persistence of skin lesions and flare of the disease. Following treatment with this drug, complete resolution of the dermatological lesions and induction of remission of RA was achieved. To the best of our knowledge, management of palmoplantar pustulosis due to TNF-? agents with TCZ leading to both improvement of the disease and resolution of the cutaneous lesions has not previously been reported. PMID:22857979

Rueda-Gotor, Javier; González-Gay, Miguel A; Blanco Alonso, Ricardo; Gonzalez-Vela, Carmen; Lopez-Obregon, Cristina; González-López, Marcos A

2012-10-01

28

Immunogenicity of Anti-TNF-? Biotherapies: I. Individualized Medicine Based on Immunopharmacological Evidence  

PubMed Central

Specific inhibition of the cytokine, tumor necrosis factor-? (TNF), has revolutionized the treatment of patients with several autoimmune diseases, and genetically engineered anti-TNF antibody constructs now constitute a heavy medicinal expenditure in many countries. Unfortunately, up to 30% of patients do not respond and about 50% of those who do loose response with time. Furthermore, safety may be compromised by immunogenicity with the induction of anti-drug-antibodies (ADA). Assessment of drug pharmacokinetics and ADA is increasingly recognized as a requirement for safe and rational use of protein drugs. The use of therapeutic strategies based on anti-TNF drug levels and ADA rather than dose-escalation has also proven to be cost-effective, as this allows individualized patient-tailored strategies rather than the current universal approach to loss of response. The objective of the present article – and the accompanying article – is to discuss the reasons for recommending assessments of circulating drug and ADA levels in patients treated with anti-TNF biopharmaceuticals and to detail some of the methodological issues that obscure cost-effective and safer therapies.

Bendtzen, Klaus

2015-01-01

29

Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis  

Microsoft Academic Search

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

C. Liu; F. Batliwalla; W. Li; A. Lee; R. Roubenoff; E. Beckman; H. Khalili; A. Damle; M. Kern; R. Furie; J. Dupuis; R. M. Plenge; M. J. H. Coenen; T. W. Behrens; J. P. Carulli; P. K. Gregersen

2008-01-01

30

Anti-TNF? therapy in the management of psoriasis: experience of a state referral center*  

PubMed Central

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. PMID:24937817

Silva, Laura Maria Andrade; Rocha, Bruno de Oliveira; Nobre, Ana Cláudia Pinto; Rêgo, Vitória Regina Pedreira de Almeida; Follador, Ivonise; de Oliveira, Maria de Fátima Santos Paim

2014-01-01

31

The epidemiology of ankylosing spondylitis and the commencement of anti?TNF therapy in daily rheumatology practice  

PubMed Central

Objectives This study aimed to describe the epidemiology of ankylosing spondylitis (AS) in rheumatology practice at the beginning of the anti?TNF (tumour necrosis factor) era, and to evaluate the initiation of anti?TNF therapy in a clinical setting where prescription is regulated by the authority's imposed reimbursement criteria. Methods Between February 2004 and February 2005, all Belgian rheumatologists in academic and non?academic outpatient settings were invited to register all AS patients who visited their practice. A random sample of these patients was further examined by an in?depth clinical profile. In a follow?up investigation, we recorded whether patients initiated anti?TNF therapy and compared this to their eligibility at baseline evaluation. Results 89 rheumatologists participated and registered 2141 patients; 1023 patients were clinically evaluated. These 847 fulfilled the New York modified criteria for definite AS and 176 for probable AS. The profile of AS in rheumatology practice is characterised by longstanding and active disease with a high frequency of extra?articular manifestations and metrological and functional impairment. At a median of 2?months after the clinical evaluation, anti?TNF therapy was initiated in 263 of 603 (44%) evaluable patients with definite AS and in 22 of 138 (16%) evaluable patients with probable AS (total 38%). More than 85% of the patients who started anti?TNF therapy had an increased Bath Ankylosing Spondylitis Disease Activity Index despite previous NSAID (non?steroidal anti?inflammatory drug) use. Conclusions Of a representative cohort of 1023 Belgian AS patients seen in daily rheumatology practice, about 40% commenced anti?TNF therapy. Decision factors to start anti?TNF therapy may include disease activity and severity. PMID:17261531

Cruyssen, Bert Vander; Ribbens, Clio; Boonen, Annelies; Mielants, Herman; de Vlam, Kurt; Lenaerts, Jan; Steinfeld, Serge; Van den Bosch, Filip; Dewulf, Lode; Vastesaeger, Nathan

2007-01-01

32

Pharmacokinetics of anti-TNF monoclonal antibodies in inflammatory bowel disease: Adding value to current practice.  

PubMed

Since anti-tumor necrosis factor (TNF) antibodies were introduced to treat patients with inflammatory bowel diseases, short- and long-term clinical and endoscopic endpoints can be achieved that were unreachable with conventional anti-inflammatory agents. Although a large proportion of patients (70-90%) initially respond to the treatment, remission rates after induction are still low (20-50%) and patients are at risk to lose response to the drug over time. This inter-individual variability in response is likely to be influenced by the observed inter-individual variability in pharmacokinetics. By extensively reviewing the literature, we evaluated the potential role of therapeutic drug monitoring to optimize dosing of anti-TNF drugs. Thereby we emphasize some of the pharmacokinetic cornerstones that can help to understand the observed concentration-effect relationship. After discussing some of the most commonly used assays to measure anti-TNF drug and anti-drug antibody concentrations, we reviewed the application of those tests and their potential clinical value in retrospective and prospective studies. PMID:25707962

Vande Casteele, Niels; Gils, Ann

2015-03-01

33

Treatment of rheumatoid arthritis with anti-TNF-alpha agents: a reappraisal.  

PubMed

It has been found that tumour necrosis factor(TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA), and the development of drugs targeting this molecule has extended the therapeutical approaches to RA patients. A number of observational studies of large patient series have also been published over the last few years, many of which have been based on national registries designed to monitor the efficacy and safety of anti-TNF agents, and allow healthcare institutions to control expenditure. Registry data can also help in identifying clinical and laboratory findings capable of predicting response. It has been suggested that the percentage of responding patients is lower in everyday clinical practice than that observed in RCTs, possibly because of patient selection, the use of a washout period before inclusion (which may artificially increase disease activity), and differences in doses, co-morbidities and adherence to therapy. A number of safety concerns have been raised since the introduction of anti-TNF agents, and they are now contraindicated in patients with advanced heart failure; however, the most widely debated current issues regard infections and neoplastic diseases. Moreover, the marketing of new and expensive biological agents has made strictly necessary to create systems capable of monitoring their safety and effectiveness in everyday practice, including the use of longitudinal observational studies. As the first published registry of anti-TNFalpha-treated patients in Italy, Lombardy Rheumatology Network (LORHEN) is already making its contribution in this direction. PMID:19017546

Caporali, Roberto; Pallavicini, Francesca Bobbio; Filippini, Matteo; Gorla, Roberto; Marchesoni, Antonio; Favalli, Ennio Giulio; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola; Montecucco, Carlomaurizio

2009-01-01

34

Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry  

Microsoft Academic Search

BackgroundAnti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs).ObjectiveTo describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors.MethodsA 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case–control study was performed with three controls treated with anti-TNF agents per

D Salmon-Ceron; F Tubach; O Lortholary; O Chosidow; S Bretagne; N Nicolas; E Cuillerier; B Fautrel; C Michelet; J Morel; X Puéchal; D Wendling; M Lemann; P Ravaud; X Mariette

2011-01-01

35

Improvement of Anti-TNF-? Antibody-Induced Palmoplantar Pustular Psoriasis Using a 308-nm Excimer Light.  

PubMed

Anti-tumor necrosis factor (TNF)-? antibody is utilized in the treatment of a variety of chronic inflammatory conditions, including psoriasis. However, it can induce paradoxical development and/or exacerbation of psoriasis in the course of anti-TNF-? antibody treatment, which is sometimes refractory to conventional treatments. Herein, we report a case of refractory palmoplantar pustular psoriasis induced by anti-TNF-? antibody treatment, which was improved by treatment with a 308-nm excimer light. The 308-nm excimer light has less long-term risks than narrow-band UVB. The 308-nm excimer light may be a good therapeutic option for refractory psoriatic skin lesions induced by anti-TNF-? antibody therapy because of localized side effects without systemic problems, short length of treatment and low cumulative dosages of UV light. PMID:23275771

Iga, Natsuko; Otsuka, Atsushi; Tanioka, Miki; Miyachi, Yoshiki; Kabashima, Kenji

2012-09-01

36

The use of anti-TNF? medications for rheumatologic disease in pregnancy  

PubMed Central

Anti-TNF? medications have led to vast improvements in the treatment of inflammatory conditions, including rheumatoid arthritis and Crohn’s disease. As these diseases often afflict women in their reproductive years, the safety of these drugs during pregnancy is an important issue. Prospectively collected data thus far appear to be reassuring; however an analysis of the FDA-reported anomalies has raised some questions. It appears that significant levels of these drugs cross the placenta as the pregnancy nears term, but little is passed through breast milk. Prior to using these medications during pregnancy, the risks and benefits of these drugs, other treatment options, and the ongoing inflammatory condition all must be carefully weighed by both doctor and patient. PMID:21072312

Clowse, Megan EB

2010-01-01

37

Large Vessel Vasculitis Occurring in Rheumatoid Arthritis Patient under Anti-TNF Therapy  

PubMed Central

Vasculitis is a heterogeneous group of disorders characterized by the presence of necrotic inflammatory phenomena and destruction of blood vessels. Vasculitis is classified as primary (idiopathic) or secondary to infections, connective tissue diseases and drugs but can also be considered as a paraneoplastic phenomenon. Evidence shows that the increasing use of biological agents results in a growing number of reports of autoimmune diseases induced by these therapies. An inflammatory articular chronic disease such as rheumatoid arthritis may be complicated by extra-articular manifestations, such as cutaneous or systemic vasculitis. Herewith, we describe the case of a great vessels arteritis in a patient affected by rheumatoid arthritis in therapy with an anti-TNF agent (etanercept). PMID:25544845

Cestelli, Valentina; Spinella, Amelia; Campomori, Federica; Esposito, Carmela; Ciaffi, Sara; Sandri, Gilda; Ferri, Clodoveo

2014-01-01

38

Risk of tuberculosis higher with monoclonal-antibody than with soluble-receptor anti-TNF therapy in the 3-year prospective French RATIO registry  

E-print Network

1 Risk of tuberculosis higher with monoclonal-antibody than with soluble- receptor anti-TNF therapy, rheumatoid arthritis, inflammatory chronic diseases Running head: Tuberculosis complicating anti-TNF therapy;60(7):1884-1894" DOI : 10.1002/art.24632 #12;2 ABSTRACT Background: Tuberculosis (TB) is associated with anti

Paris-Sud XI, Université de

39

Use of (99m)Tc-anti-TNF-? scintigraphy in a patient with non-radiographic axial spondyloarthritis.  

PubMed

The aim of this study was to describe the use of (99m)Tc-anti-TNF-? scintigraphy for detecting inflammation of the sacroiliac joints in a patient with non-radiographic axial spondyloarthritis. A 47-year-old female patient, non-smoker and non-drinker, complained of a low back pain inflammation, which began 4 years before her condition have exacerbated to morning stiffness and anterior uveitis in the last 6 months. Initially diagnosed as mechanical low back pain, she irregularly took non-steroidal anti-inflammatory drugs and corticosteroids, without significant long-lasting results. Radiographic findings were negative. There was increased uptake of (99m)Tc-anti-TNF-? in an area corresponding to the topography of ileum and sacroiliac right joint upon (99m)Tc-anti-TNF-? scintigraphy. Magnetic resonance imaging (MRI), the most used image diagnosis tool, showed minimum impregnation of gadolinium in the right sacroiliac joint and at the iliac face of the inferior third of the right sacroiliac joint. We suggest that (99m)Tc-anti-TNF-? can facilitate early diagnosis of patients with non-radiographic axial spondyloarthritis. More studies are now ongoing. PMID:25052689

de Andrade Alexandre, Dângelo José; de Souza, Sergio Augusto Lopes; Moraes do Carmo, Clarissa Canella; Schau, Bruno; da Fonseca, Lea Mirian Barbosa; Roimicher, Luis; Gutfilen, Bianca

2014-11-01

40

Efficacy and Safety of Rituximab in Biologic-Naive Patients with Rheumatoid Arthritis vs Anti-Tnf Therapy Failure  

PubMed Central

Objectives: Our aim was to compare an AntiCD20 therapy (rituximab) for rheumatoid arthritis in two patient populations (Group 1), anti-TNF? naïve patients and inadequate responders to Anti-TNF? therapy (Group 2). Methods: We analyzed the efficacy of the drug Rituximab (RTX) in RA patients who failed methotrexate (MTX) or had a relative or absolute contraindication to receive anti-TNF? therapy. Results: 25 patients were identified according to the above criteria and followed up for a mean period of 6 months. Thirteen patients were biologic naïve and twelve patients had already failed anti-TNF? therapy. Group 1 used 2> DMARDs (32% vs 20%, p<0.005), group 2 had more years of disease progression (5±1.89 v s4.10±3.92, p<0.001). The remission as measured by the DAS28 reached faster in group 1 (1.25±0.12 vs 2.15±1.64, p<0,001). Severe infections especially by herpes viruses were more frequent in group 2. Conclusions: Comparing clinical improvement in both groups the decrease of acute phase reactants and the clinical remission measured by DAS28 was reached in both groups, however it was reached more belatedly in group 2 (at 6 months), this is due to the fact that they have more years of the disease evolution and a higher HAQ. PMID:24179556

Gutierrez-Gonzalez, Luis Arturo; Gudiño, Marco Antonio Rivera; Ceija, Ibell Oropeza; Leonet, Marialina Marin; Noguera, Zair Tovar

2013-01-01

41

Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome  

PubMed Central

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. PMID:24967817

Sode, Jacob; Vogel, Ulla; Bank, Steffen; Andersen, Paal Skytt; Thomsen, Marianne Kragh; Hetland, Merete Lund; Locht, Henning; Heegaard, Niels H. H.; Andersen, Vibeke

2014-01-01

42

Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry  

PubMed Central

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. PMID:19828563

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

2010-01-01

43

Use of a third anti-TNF after failure of two previous anti-TNFs in patients with inflammatory bowel disease: is it worth it?  

PubMed

Abstract Background. Some patients with inflammatory bowel disease (IBD) never respond or lose their response to a second anti-TNF. Aim. To review the efficacy and safety of a third anti-TNF after failure of two previous anti-TNFs. Methods. Bibliographical searches in PubMed for studies evaluating infliximab, adalimumab, or certolizumab as the third anti-TNF in IBD patients whose two previous anti-TNF treatments had failed. Results. Two retrospective studies with a small sample size and limited follow up evaluated the effectiveness of a third anti-TNF patients whose two previous anti-TNFs had failed. The arguments for this switching strategy are as follows: a)favorable-albeit limited-efficacy (in the study by Allez et al., clinical response was observed in 51% of patients at week 20; and in the study by de Silva et al., over 50% of patients remained on the third anti-TNF at 1 year); b)the eventual response to the third anti-TNF is relatively quick; c) no other medical options have been approved for IBD treatment; d)the only alternative options are surgery, compassionate use with non-anti-TNFs, and clinical trials. However, there are also arguments against the prescription of a third anti-TNF: a)lack of experience, since the few available studies are limited by their small sample size; b)the relatively low response in the long term (mainly due to loss of response); c) and finally, and most importantly, the risk of severe adverse events. Conclusion. The delicate balance between pros and cons means the use of a third anti-TNF after failure of two previous agents should be considered only in patients with no other therapeutic options. Decisions should be taken on an individual basis. PMID:25636030

Gisbert, Javier P; Chaparro, María

2015-04-01

44

[Anti-TNF therapy in inflammatory bowel diseases during pregnancy and breast-feeding].  

PubMed

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

Persi?, Mladen

2013-04-01

45

Stability study of full-length antibody (anti-TNF alpha) loaded PLGA microspheres.  

PubMed

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

2014-08-15

46

Methotrexate: from its introduction to non-oncologic therapeutics to anti-TNF-?.  

PubMed

The history of the rheumatologic use of methotrexate until the 1990s will be reviewed, beginning with its pharmacology, with the focus on rheumatoid arthritis (RA). The insufficient availability of cortisone in the 1950s as well as the early recognition of its potential toxicity stimulated searches for alternative anti-inflammatory drugs. Two related derivatives of folic acid, aminopterin and amethopterin (MTX,) were found to give rapid symptomatic relief in cases of psoriasis vulgaris and psoriatic arthritis. For several years MTX was used primarily to treat psoriasis, and the dermatologic treatment protocols came to be used by rheumatologists. Giving MTX weekly rather than daily was found to diminish the risk of toxic effects. MTX became favoured over cyclophosphamide because of its lack of carcinogenicity, and although azathioprine lacked the hepatotoxicity of MTX, its anti-rheumatic effects were considered to be somewhat weaker. Although trials of MTX for the treatment of severe RA began in the 1960s, the first placebo-controlled study of MTX in RA was reported in 1985 and a comparison with Myochrysine in 1987. MTX has replaced gold compounds because it has been found to be more rapidly effective and better tolerated. The mechanisms of its anti-rheumatic effects remain incompletely explained, as are explanations of instances of its failure. Its recent use in combination with anti-TNF? agents appears to be another therapeutic advance. PMID:21044425

Benedek, T G

2010-01-01

47

Diffusion of pharmaceuticals: cross-country evidence of anti-TNF drugs.  

PubMed

This article studies the diffusion of biopharmaceuticals across European countries, focusing on anti-TNF drugs, which are used to treat autoimmune diseases (e.g., rheumatism, psoriasis). We use detailed sales information on the three brands Remicade, Enbrel and Humira for nine European countries covering the period from the first launch in 2000 until becoming blockbusters in 2009. Descriptive statistics reveal large variations across countries in per-capita consumption and price levels both overall and at the brand level. We explore potential sources for the cross-country consumption differences by estimating several multivariate regression models. Our results show that large parts of the cross-country variation are explained by time-invariant country-specific factors (e.g., disease prevalence, demographics, health care system). We also find that differences in income [gross domestic product (GDP) per capita] and health spending (share of GDP) explain the cross-country variation in consumption, while relative price differences seem to have limited impact. PMID:24146261

Brekke, Kurt Richard; Dalen, Dag Morten; Holmås, Tor Helge

2014-12-01

48

Anti-TNF-alpha agents in the treatment of psoriatic arthritis.  

PubMed

Psoriatic arthritis (PsA) is a potentially debilitating disease that may affect small and large peripheral joints, entheses and the axial skeleton. The different clinical manifestations of PsA have been accounted for by various proposals of subdividing the patients into different subgroups. According to the predominant clinical symptoms, most patients can be classified as belonging to the spectrum of spondyloarthritides (SpA) or rheumatoid arthritis (RA). The conventional therapeutic approach comprises non-steroidal anti-inflammatory drugs, systemic and intra-articular corticosteroids, and disease-modifying antirheumatic drugs such as sulfasalazine, methotrexate, ciclosporin and leflunomide. Similar to RA, recent trials in PsA have shown excellent results with the tumour necrosis factor (TNF) blockers etanercept, infliximab and adalimumab, which have positive effects not only on joints, but also on the skin when affected by psoriasis, quality of life, function and slowing of disease progress, as evidenced radiologically. Anti-TNF therapy has been generally safe in clinical trials of PsA. Taken together, there has been definite recent progress in the treatment of PsA, especially for severely affected patients. PMID:16436036

Brandt, Jan; Braun, Jürgen

2006-02-01

49

Anti-TNF levels and anti-drug antibodies, immunosuppressants and clinical outcomes in inflammatory bowel disease.  

PubMed

The anti-tumor necrosis factor-? (TNF) antibodies have revolutionized the management of ulcerative colitis and Crohn's disease. The development of assays to allow for the measurements of serum drug levels and anti-drug antibodies have provided a more objective means of therapeutic decision making, particularly among patients losing response to treatment. Additionally, more evidence is emerging that indicates the relationship between drug levels and response to therapy including clinical response, mucosal healing and sustained remission. The use of combination therapies of the anti-TNF agents and the thiopurine immunosuppressants may also decrease immunogenicity to the anti-TNF agents and potentiate response to therapy. With more evidence emerging evidence of the importance of therapeutic drug levels and anti-drug antibodies, clinicians may be able to better optimize the current arsenal of inflammatory bowel disease therapeutics to achieve greater rates of durable remission and improved quality of life. PMID:25600263

Ha, Christina; Mathur, Jagrati; Kornbluth, Asher

2015-04-01

50

Genome Wide Association (GWA) Predictors Of Anti-TNF? Therapeutic Responsiveness In Pediatric Inflammatory Bowel Disease (IBD)  

PubMed Central

Background Inter-individual variation in response to anti-TNF? therapy may be explained by genetic variability in disease pathogenesis or mechanism of action. Recent genome wide association studies (GWAS) in IBD have increased our understanding of the genetic susceptibility to IBD. Aim Test associations of known IBD susceptibility loci and novel “pharmacogenetic” GWAS identified loci with primary non-response to anti-TNF? in pediatric IBD patients and develop a predictive model of primary non-response. Methods Primary non response was defined using the HBI for CD and partial Mayo score for UC. Genotyping was performed using the Illumina Infinium platform. Chi square analysis tested associations of phenotype and genotype with primary non-response. Genetic associations were identified by testing known IBD susceptibility loci and by performing a GWAS for primary non-response. Step-wise multiple logistic regression was performed to build predictive models. Results Non-response occurred in 22 of 94 subjects. Six known susceptibility loci were associated with primary non-response (p < 0.05). Only the 21q22.2/BRWDI loci remained significant in the predictive model. The most predictive model included 3 novel “pharmacogenetic” GWAS loci, the previously identified BRWD1, pANCA and a UC diagnosis (R2 =0.82 and AUC = 0.98%). The relative risk of non-response increased 15 fold when number of risk factors increased from 0–2 to ? 3. Conclusion The combination of phenotype and genotype is most predictive of primary non response to anti-TNF? in pediatric IBD. Defining predictors of response to anti-TNF? may allow the identification of patients who will not benefit from this class of therapy. PMID:20014019

Dubinsky, Marla C; Mei, Ling; Friedman, Madison; Dhere, Tanvi; Haritunians, Talin; Hakonarson, Hakon; Kim, Cecilia; Glessner, Joseph; Targan, Stephan R; McGovern, Dermot P; Taylor, Kent D; Rotter, Jerome I

2009-01-01

51

Lymphoma in patients treated with anti-TNF. Results of the 3-year prospective French RATIO registry.  

E-print Network

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 NHLLymphoma in patients treated with anti-TNF. Results of the 3-year prospective French RATIO registry

Paris-Sud XI, Université de

52

Human papillomavirus and chlamydia trachomatis infections in rheumatoid arthritis under anti-TNF therapy: an observational study.  

PubMed

The objective of this study was to evaluate human papillomavirus (HPV) and Chlamydia trachomatis (CT) infections in RA patients pre- and post-TNF blocker. Fifty female RA patients (ACR criteria), who were eligible to anti-TNF therapy [n = 50 at baseline (BL) and n = 45 after 6 months of treatment (6 M)], and 50 age-matched healthy controls were prospectively enrolled. They were assessed for demographic data, gynecologic, sexual, cervical cytology and histological evaluations, disease parameters and current treatment. HPV DNA and CT DNA testing in cervical specimens were done using Hybrid Capture II assays. At BL, the median current age of RA patients and controls was 49 (18-74) versus 49 (18-74) years, p = 1.0. A trend of lower frequency of HPV infection was observed in AR patients pre-anti-TNF compared with controls (14 vs. 30 %, p = 0.054). Further evaluation of AR patients with and without HPV infection before anti-TNF therapy showed that the former group had higher frequency of sexual intercourses (100 vs. 48 %, p = 0.014), higher median number of sexual partners [1 (1-1) vs. 0 (0-1), p = 0.032] and higher frequency of abnormal cervical cytology (43 vs. 7 %, p = 0.029). Current age, disease duration, disease parameters and treatments were alike in both groups (p > 0.05). At 6 M after TNF blockage, HPV infection remained unchanged in five patients, whereas two became negative and one additional patient turned out to be positive (p = 1.0). CT infection was uniformly negative in RA patients pre- and post-TNF blockage and in controls. Anti-TNF does not seem to increase short-term risk of exacerbation and/or progression of HPV and CT infections in RA patients. PMID:25348220

Waisberg, Mariana G; Ribeiro, Ana C M; Candido, Wellington M; Medeiros, Poliana B; Matsuzaki, Cezar N; Beldi, Mariana C; Tacla, Maricy; Caiaffa-Filho, Helio H; Bonfa, Eloísa; Silva, Clovis A

2015-03-01

53

Previous cancer and/or lymphoma in patients with refractory IBD--con: anti-TNF or conventional immunosuppressive treatment.  

PubMed

Patients with IBD and prior cancer are at increased risk of developing recurrent or de novo cancer. Depending on the type of malignancy, risk factors include IBD itself, age, environmental factors, genetic susceptibility and exposure to immunosuppressants (IMS), namely thiopurines, methotrexate and anti-TNF? biologics. The procarcinogenic effect of IMS depends on the type of drug and length of exposure. Thiopurines increase the rates of nonmelanoma skin cancer and lymphomas. Methotrexate is less harmful, but data are scarce. Evidence favoring the 'safety' of anti-TNF monotherapy is weak because most patients have been exposed to combinations of IMS prior to the development of malignancy. Anti-TNF? biologics may promote tumor proliferation and increase the risk of melanomas. Exclusion of these patients from trials with biologics, physician concerns or fear of incident cancers and medicolegal consequences, and patient concerns have led to a paucity of data regarding IMS treatment of patients with a prior malignancy. In the absence of guidelines, IMS should be avoided especially during the first 2 years after commencing cancer therapy. Depending on disease type, location and severity, 5-ASA, antibiotics, enteric nutrition, steroids alone or in combinations, seton placement, and 'curative' or 'diverting' surgery may allow for a crucial drug-holiday period before readministration of IMS. Preventive measures include smoking cessation, UV solar protection, annual skin examination and Pap test. If unavoidable, methotrexate should be the drug of first choice followed by anti-TNF? and then thiopurines. Patients should be managed on a case-by-case basis by a multidisciplinary team of experts. PMID:25531364

Mantzaris, Gerassimos J

2014-01-01

54

Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis.  

PubMed

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

2008-01-01

55

Lack of association of variants previously associated with anti-TNF medication response in rheumatoid arthritis patients: results from a homogeneous Greek population.  

PubMed

Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece. PMID:24040234

Zervou, Maria I; Myrthianou, Efsevia; Flouri, Irene; Plant, Darren; Chlouverakis, Gregory; Castro-Giner, Francesc; Rapsomaniki, Panayiota; Barton, Anne; Boumpas, Dimitrios T; Sidiropoulos, Prodromos; Goulielmos, George N

2013-01-01

56

Lack of Association of Variants Previously Associated with Anti-TNF Medication Response in Rheumatoid Arthritis Patients: Results from a Homogeneous Greek Population  

PubMed Central

Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF–treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece. PMID:24040234

Zervou, Maria I.; Myrthianou, Efsevia; Flouri, Irene; Plant, Darren; Chlouverakis, Gregory; Castro-Giner, Francesc; Rapsomaniki, Panayiota; Barton, Anne; Boumpas, Dimitrios T.

2013-01-01

57

Drug Retention Rates and Treatment Discontinuation among Anti-TNF-? Agents in Psoriatic Arthritis and Ankylosing Spondylitis in Clinical Practice  

PubMed Central

Objective. The study aim was to determine treatment persistence rates and to identify causes of discontinuation in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients in clinical practice. Methods. Patients treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) were retrospectively included. Treatment persistence rates were analyzed by means of a stepwise logistic regression. Differences between therapy duration were assessed by means of an analysis of variance model (ANOVA), while a chi-square test was used to evaluate relationships between therapies and causes of treatment discontinuation and the administration of concomitant disease-modifying antirheumatic drugs (DMARDs) among therapies and types of disease considering completed courses of therapy versus courses that were discontinued. Results. 268 patients received a total of 353 anti-TNF treatment courses (97 ADA, 180 ETA, and 76 INF). Comparison among therapies showed significant difference regarding the treatment persistence rates due to the contrast between ETA and INF (P = 0.0062). We observed that 84.7% of patients were still responding after 6 months of follow-up. Comparison among diseases showed that there were significant differences between PsA and AS (P = 0.0073) and PsA and PsA with predominant axial involvement (P = 0.0467) in terms of duration of the therapy, while there were no significant differences with regard to the persistence rate. Conclusions. In this cohort, anti-TNF-? therapy was associated with high drug persistence rates. As in rheumatoid arthritis, switching to another anti-TNF-? agent can be an effective option when, during the treatment of AS or PsA, therapy is suspended because of inefficacy or an adverse event. Combination therapy with DMARDs was associated with a better persistence rate. PMID:25110401

Fabbroni, Marta; Costa, Luisa; Pagano, Veronica Anna; Frediani, Bruno; Manganelli, Stefania; Galeazzi, Mauro

2014-01-01

58

The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology Biologics Register  

PubMed Central

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. PMID:22241900

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

2012-01-01

59

Dose modification of anti-TNF in rheumatoid arthritis and estimated economical impact: a review of observational studies.  

PubMed

Anti-TNF drugs indicated for the treatment of moderate-to-severe active rheumatoid arthritis (RA) presents similar efficacy, safety and potential toxicity profiles, with more than 10 years' treatment experience. Several pharmacoeconomic evaluations had demonstrated their favorable cost-effectiveness profile in RA patients, based on pivotal clinical studies data from different countries and perspectives. However, in clinical practice, individual profiles of patients and drugs leads to dose modifications that may be associated with substantial cost deviations. Here, we further discuss the effect of dose titration of these biological drugs in clinical practice over their RA cost-effectiveness profiles. PMID:25555555

Borrás-Blasco, Joaquín; Navarro Ruiz, Andres

2015-02-01

60

Topical delivery of anti-TNF? siRNA and capsaicin via novel lipid-polymer hybrid nanoparticles efficiently inhibits skin inflammation in vivo  

PubMed Central

The barrier properties of the skin pose a significant but not insurmountable obstacle for development of new effective anti-inflammatory therapies. The objective of this study was to design and evaluate therapeutic efficacy of anti-nociception agent Capsaicin (Cap) and anti-TNF? siRNA (siTNF?) encapsulated cyclic cationic head Lipid-Polymer hybrid Nanocarriers (CyLiPns) against chronic skin inflammatory diseases. Physico-chemical characterizations including hydrodynamic size, surface potential and entrapment efficacies of CyLiPns were found to be 163 ± 9 nm, 35.14 ± 8.23 mV and 92% for Cap, respectively. In vitro skin distribution studies revealed that CyLiPns could effectively deliver FITC-siRNA upto 360 µm skin depth. Further, enhanced (p<0.001) Cap permeation from CyLiPns was observed compared to Capsaicin-Solution and Capzasin-HP. Therapeutic efficacies of CyLiPns were assessed using imiquamod induced psoriatic plaque like model. CyLiPns carrying both Cap and siTNF? showed significant reduced expression of TNF?, NF-?B, IL-17, IL-23 and Ki-67 genes compare to either drugs alone (p<0.05) and was in close comparison with Topgraf®;. Collectively these findings support our notion that novel cationic lipid-polymer hybrid nanoparticles can efficiently carry siTNF? and Cap into deeper dermal milieu and Cap with combination of siTNF? show synergism in treating skin inflammation. PMID:23643662

Desai, Pinaki R.; Marepally, Srujan; Patel, Apurva R.; Voshavar, Chandrashekhar; Chaudhuri, Arabinda; Singh, Mandip

2013-01-01

61

Clinical and radiological dissociation of anti-TNF plus methotrexate treatment in early rheumatoid arthritis in routine care: Results from the ABRAB study  

PubMed Central

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. PMID:25059769

2014-01-01

62

Golimumab: A novel human anti-TNF-? monoclonal antibody for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis  

PubMed Central

Introduction: The introduction of tumor necrosis factor-? (TNF-?) inhibitors represented a significant advance in the management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. Although three TNF-? inhibitors have been approved for the treatment of RA by the US Food and Drug Administration (FDA) and the European Medicinal Products Evaluation Agency (EMEA), not all patients achieve a satisfactory clinical improvement with these therapeutic agents. The mode of administration of these medications is inconvenient for some patients. Aims: Golimumab is a novel anti-TNF-? monoclonal antibody that is in clinical development for the treatment of RA, psoriatic arthritis (PsA), and ankylosing spondylitis (AS), either as a first-line biologic therapy or an alternative after other TNF-? inhibitors have been discontinued. This review summarizes the development of, and clinical evidence achieved with, golimumab. Evidence review: Golimumab has demonstrated significant efficacy in randomized, double-blind, placebo-controlled trials when administered subcutaneously once every four weeks. It has been generally well tolerated in clinical trials and demonstrates a safety profile comparable with currently available TNF-? inhibitors. Outcomes summary: Golimumab has been confirmed to be an effective treatment for patients with RA, PsA, and AS in phase III clinical trials as evaluated by traditional measures of disease activity, such as signs and symptoms, as well as measures of physical function, patient reported outcomes, and health economic measures. The efficacy and safety profile of golimumab in RA, PsA, and AS appears to be similar to other anti-TNF agents. However, golimumab has the potential advantage of once monthly subcutaneous administration and the possibility of both subcutaneous and intravenous administration. PMID:20694072

Kay, Jonathan; Rahman, Mahboob U

2010-01-01

63

[Role of anti-TNF therapy (biologics) in the treatment of chronic inflammatory bowel disease in children].  

PubMed

Inflammatory bowel disease (IBD) is diagnosed already during childhood or adolescence in every fourth patient. Compared to adult population, whereby recent studies show a tendency towards stabilization, incidence rates for children continue to rise. Though many features are shared with adult onset disease, paediatric ulcerative colitis and Crohn's Disease are, both, more aggressive and extensive already at diagnosis, with disease behaviour that changes with time. Therapeutic approaches, therefore, have to be adapted to specific needs of paediatric population. Aim of the article was to formulate guidelines on the role of biologic therapy in the treatment of paediatric onset inflammatory bowel disease, namely on the use of anti-TNF agent infliximab as it is the only biologic drug registrated for use in children with IBD. Recommendations are based on systematic review of the evidence in paediatric patients whenever it was available. However, due to lack of good randomised studies, adult practice was also taken into consideration. Finally, recommendations were dis-cussed on the consensus conference of all experts participating in the development of guidelines for adult and paediatric pa-tients.The recommendations are developed for Crohn's Disease and for Ulcerative Colitis, separately with respect to remission induction and for relapse prevention. Level of evidence is stated and following this procedure, recommendations are graded. Practice points are also provided with the aim to guide clinicians on the ward how to use biologics in the clinical practice. Com-plications of the treatment that are specific for children with inflammatory bowel disease are also addressed. These guidelines and practice points provide a structured guide for the use of anti-TNF therapy in the treatment of Crohn's Disease and Ulcerative Colitis in paediatric patients. PMID:24471292

Kolacek, Sanja

2013-04-01

64

Report of the ECCO workshop on anti-TNF therapy failures in inflammatory bowel diseases: biological roles and effects of TNF and TNF antagonists.  

PubMed

This second section of the first ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases addresses the biological roles of TNF? and the effects and mechanisms of action of TNF? antagonists. Mechanisms underlying their failure, including induction of TNF-independent inflammatory pathways and phenomena of paradoxical inflammation are discussed. PMID:21122531

Chowers, Yehuda; Sturm, Andreas; Sans, Miquel; Papadakis, Konstantinos; Gazouli, Maria; Harbord, Marcus; Jahnel, Jörg; Mantzaris, Gerassimos J; Meier, Johannes; Mottet, Christian; Peyrin-Biroulet, Laurent; Allez, Matthieu

2010-10-01

65

Significant risk and associated factors of active tuberculosis infection in Korean patients with inflammatory bowel disease using anti-TNF agents  

PubMed Central

AIM: To evaluate the incidence and risk factors of Korean tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) undergoing anti-TNF treatment. METHODS: The data of IBD patients treated with anti-TNFs in 13 tertiary referral hospitals located in the southeastern region of Korea were collected retrospectively. They failed to show response or were intolerant to conventional treatments, including steroids or immunomodulators. Screening measures for latent TB infection (LTBI) and the incidence and risk factors of active TB infection after treatment with anti-TNFs were identified. RESULTS: Overall, 376 IBD patients treated with anti-TNF agents were recruited (male 255, mean age of anti-TNF therapy 32.5 ± 13.0 years); 277 had Crohn’s disease, 99 had ulcerative colitis, 294 used infliximab, and 82 used adalimumab. Before anti-TNF treatment, screening tests for LTBI including an interferon gamma release assay or a tuberculin skin test were performed in 82.2% of patients. Thirty patients (8%) had LTBI. Sixteen cases of active TB infection including one TB-related mortality occurred during 801 person-years (PY) follow-up (1997.4 cases per 100000 PY) after anti-TNF treatment. LTBI (OR = 5.76, 95%CI: 1.57-21.20, P = 0.008) and WBC count < 5000 mm3 (OR = 4.5, 95%CI: 1.51-13.44, P = 0.007) during follow-up were identified as independently associated risk factors. CONCLUSION: Anti-TNFs significantly increase the risk of TB infection in Korean patients with IBD. The considerable burden of TB and marked immunosuppression might be attributed to this risk.

Kim, Eun Soo; Song, Geun Am; Cho, Kwang Bum; Park, Kyung Sik; Kim, Kyeong Ok; Jang, Byung Ik; Kim, Eun Young; Jeon, Seong Woo; Lee, Hyun Seok; Yang, Chang Heon; Lee, Yong Kook; Lee, Dong Wook; Kim, Sung Kook; Kim, Tae Oh; Lee, Jonghun; Kim, Hyung Wook; Jee, Sam Ryong; Park, Seun Ja; Kim, Hyun Jin

2015-01-01

66

Associations between functional polymorphisms in the NF?B signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease.  

PubMed

Antitumor necrosis factor-? (TNF-?) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NF?B-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-? signaling (TNFA (TNF-?) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NF?B (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P ? 0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NF?B through the Toll-like receptor (TLR) pathways, genes regulating TNF-? signaling and cytokines regulated by NF?B are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1?, IL-6 and IFN-? may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting. PMID:24776844

Bank, S; Andersen, P S; Burisch, J; Pedersen, N; Roug, S; Galsgaard, J; Turino, S Y; Brodersen, J B; Rashid, S; Rasmussen, B K; Avlund, S; Olesen, T B; Hoffmann, H J; Thomsen, M K; Thomsen, V Ø; Frydenberg, M; Nexø, B A; Sode, J; Vogel, U; Andersen, V

2014-12-01

67

Variation at FCGR2A and Functionally Related Genes Is Associated with the Response to Anti-TNF Therapy in Rheumatoid Arthritis  

PubMed Central

Objective Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25–30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response. Methods A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy. Results We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042). Conclusions In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA. PMID:25848939

Avila-Pedretti, Gabriela; Tornero, Jesús; Fernández-Nebro, Antonio; Blanco, Francisco; González-Alvaro, Isidoro; Cañete, Juan D.; Maymó, Joan; Alperiz, Mercedes; Fernández-Gutiérrez, Benjamín; Olivé, Alex; Corominas, Héctor; Erra, Alba; Aterido, Adrià; López Lasanta, María; Tortosa, Raül; Julià, Antonio; Marsal, Sara

2015-01-01

68

Therapeutic potential of combined anti-IL-1? IgY and anti-TNF-? IgY in guinea pigs with allergic rhinitis induced by ovalbumin.  

PubMed

We have previously demonstrated that anti-IL-1? immunoglobulin yolk(IgY) inhibits pathological responses in allergic asthma guinea pigs induced by ovalbumin(OVA). This study aims to determine whether the combined blockade of IL-1? and TNF-? can more effectively inhibit allergic inflammation in allergic rhinitis(AR) guinea pigs induced by OVA. Healthy guinea pigs treated with saline were used as the healthy control. The AR guinea pigs induced by OVA were randomly divided into (1) the AR model group containing negative control animals treated with intranasal saline; (2) the 0.1% non-specific IgY treatment group treated with non-specific IgY; (3) the 0.1% anti-TNF-? IgY treatment group treated with 0.1% anti-TNF-? IgY; (4) the 0.1% anti-IL-1? IgY treatment group treated with 0.1% anti-IL-1? IgY; (5) the 0.1% combined anti-IL-1? IgY and anti-TNF-? IgY treatment group treated with 0.1% combined anti-IL-1? IgY and anti-TNF-? IgY; and (6) the fluticasone propionate treatment group treated with fluticasone propionate. Cytokines were measured using an enzyme-linked immunosorbent assay. The results showed that IL-1?, IL-5, IL-9, IL-13, IL-18, IL-22, IL-33, TNF-?, TGF-?1 and OVA-specific IgE levels in the peripheral blood (PB) and nasal lavage fluid (NLF) significantly decreased at 2h, 4h or 8h in the 0.1% combined anti-IL-1? IgY and anti-TNF-? IgY treatment group compared to the AR model group and the 0.1% non-specific IgY treatment group (P<0.05). The data suggest that blockade of IL-1? and TNF-? by intranasal instillation of combined anti-IL-1? IgY and anti-TNF-? IgY could be a potential alternative strategy for preventing and treating allergic rhinitis. PMID:25497231

Guo-Zhu, Hu; Xi-Ling, Zhu; Zhu, Wen; Li-Hua, Wu; Dan, He; Xiao-Mu, Wu; Wen-Yun, Zhou; Wei-Xu, Hu

2015-03-01

69

Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-? therapy  

PubMed Central

Introduction The objective of this study was to investigate the effects of tumor necrosis factor (TNF)-? inhibitors on circulating T helper-type 17 (Th17) cells and Th17-related cytokines in patients with rheumatoid arthritis (RA). Methods The frequencies of circulating Th17 cells and serum levels of Th17-related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 48 RA patients both before (baseline) and six months after anti-TNF-? therapy. Therapeutic response was evaluated using European League Against Rheumatism (EULAR) response criteria. Results Significantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL-17, IL-21, IL-23 and TNF-? were observed in active RA patients than in 12 healthy controls (all P < 0.001). After anti-TNF-? therapy, 36 patients (75%) were EULAR responders (20 good responders and 16 moderate responders) and 12 (25.0%) were non-responders. The mean levels of circulating Th17 cells and IL-17 significantly decreased (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001) in parallel with clinical remission in responders. Levels of IL-6, IL-21, IL-23 and TNF-? were significantly decreased after anti-TNF-? therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased after anti-TNF-? therapy (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05) in non-responders. Logistic regression analysis identified a high baseline level of IL-17 as a significant predictor of poor therapeutic response. Conclusions The beneficial effect of anti-TNF-? therapy might involve a decrease in Th17-related cytokines in responders, whereas rising levels of circulating Th17-cells and IL-17 were observed in patients with an inadequate response to anti-TNF-? therapy. PMID:21801431

2011-01-01

70

The Anti-TNF-? Antibody Infliximab Inhibits the Expression of Fat-Transporter-Protein FAT/CD36 in a Selective Hepatic-Radiation Mouse Model.  

PubMed

Previously, we reported a radiation-induced inflammation triggering fat-accumulation through fatty-acid-translocase/cluster of differentiation protein 36 (FAT/CD36) in rat liver. Furthermore, inhibition of radiation-induced FAT/CD36-expression by anti-tumor necrosis factor-? (anti-TNF-?) (infliximab) was shown in vitro. The current study investigates fat-accumulation in a mouse-model of single-dose liver-irradiation (25-Gray) and the effect of anti-TNF-?-therapy on FAT/CD36 gene-expression. Mice livers were selectively irradiated in vivo in presence or absence of infliximab. Serum- and hepatic-triglycerides, mRNA, and protein were analyzed by colorimetric assays, RT-PCR, Immunofluorescence and Western-Blot, respectively. Sudan-staining was used demonstrating fat-accumulation in tissue. In mice livers, early (1-3 h) induction of TNF-?-expression, a pro-inflammatory cytokine, was observed. It was followed by elevated hepatic-triglyceride level (6-12 h), compared to sham-irradiated controls. In contrast, serum-triglyceride level was decreased at these time points. Similar to triglyceride level in mice livers, Sudan staining of liver cryosections showed a quick (6-12 h) increase of fat-droplets after irradiation. Furthermore, expression of fat-transporter-protein FAT/CD36 was increased at protein level caused by radiation or TNF-?. TNF-?-blockage by anti-TNF-? showed an early inhibition of radiation-induced FAT/CD36 expression in mice livers. Immunohistochemistry showed basolateral and cytoplasmic expression of FAT/CD36 in hepatocytes. Moreover, co-localization of FAT/CD36 was detected with ?-smooth muscle actin (?-SMA+) cells and F4/80+ macrophages. In summary, hepatic-radiation triggers fat-accumulation in mice livers, involving acute-phase-processes. Accordingly, anti-TNF-?-therapy prevented early radiation-induced expression of FAT/CD36 in vivo. PMID:25739082

Martius, Gesa; Cameron, Silke; Rave-Fränk, Margret; Hess, Clemens F; Wolff, Hendrik A; Malik, Ihtzaz A

2015-01-01

71

Metabolic profiling of human CD4+ cells following treatment with methotrexate and anti-TNF-? infliximab  

PubMed Central

The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. CD4+ T cells comprise a large proportion of the inflammatory cells that invade the synovial tissue and may therefore be a cell type of pathogenic importance. Both methotrexate and infliximab are effective in the treatment of inflammatory arthritis; however, the biological effects triggered by these treatments and the biochemical mechanisms underlining the cell response are still not fully understood. Thus, in this study the global metabolic changes associated with methotrexate or infliximab treatment of isolated human CD4+ T cells were examined using gas chromatography/mass spectrometry or liquid chromatography/mass spectrometry. In total 148 metabolites involved in selective pathways were found to be significantly altered. Overall, the changes observed are likely to reflect the effort of CD4+ cells to increase the production of cellular reducing power to offset the cellular stress exerted by treatment. Importantly, analysis of the global metabolic changes associated with MTX or infliximab treatment of isolated human CD4+ T cells suggested that the toxicity associated with these agents is minimal when used at clinically relevant concentrations. PMID:23974102

Chimenti, Maria Sole; Tucci, Paola; Candi, Eleonora; Perricone, Roberto; Melino, Gerry; Willis, Anne E

2013-01-01

72

Partial normalization of pubertal timing in female mice with DSS colitis treated with anti-TNF-? antibody  

PubMed Central

Background Inflammatory bowel disease (IBD) and resultant colitis occurring prior to puberty are frequently associated with delayed puberty and losses of growth and bone mineralization. Some of this delay may be due to colonic inflammation and associated systemic inflamma- tion. To date no treatments for IBD have been shown to normalize the timing of puberty. Our objective in this study was to determine whether there is a normalization of the timing of puberty during treatment of colitis using mono- clonal antibodies (abs) to tumor necrosis factor (TNF)-?. Methods We induced colitis in 23-day-old C57Bl6 female mice using 3% dextran sodium sulfate (DSS) for 7 days, followed by removal of DSS for an additional 3 days, resulting in 10 days of worsening colitis. DSS- treated mice received either TNF-? ab or Control ab on days 4 and 8 of colitis, while non-colitic Control mice received injections of TNF-? ab (Control + TNF-? ab). All groups were followed for the timing of vaginal opening until day of life 33, when they were euthanized for serum and colon collection. Results The DSS + TNF-? ab group had lower levels of systemic interleukin (IL)-6 and a partial normalization of the timing of vaginal opening compared to the DSS + Control ab group. There were no differences in weight gain, growth, or colon histological inflammatory scores between the DSS + TNFa ab and DSS + Control ab groups over the course of the experiment. Conclusions We conclude that anti-TNF-? ab treatment causes a partial normalization of pubertal timing coincident with decreased systemic inflammation in DSS colitis. These data may have implications regarding growth and bone mineralization outcomes in pediatric IBD. PMID:22322660

DeBoer, Mark Daniel; Steinman, Jeremy; Li, Yongli

2012-01-01

73

Immunological mechanisms of allergen-specific immunotherapy  

Microsoft Academic Search

Allergen-specific immunotherapy has been carried out for almost a century and remains one of the few antigen-specific treatments for inflammatory diseases. The mechanisms by which allergen-specific immunotherapy exerts its effects include the modulation of both T-cell and B-cell responses to allergen. There is a strong rationale for improving the efficacy of allergen-specific immunotherapy by reducing the incidence and severity of

Cezmi A. Akdis; Rudolf Valenta; Mark Larché

2006-01-01

74

Mite immunotherapy  

Microsoft Academic Search

Dermatophagoides pteronyssinus and D. farinae are the most common house dust mites and are among the most common sources of indoor allergens worldwide. These species are\\u000a very common in humid regions, where most allergic individuals are sensitized to house dust mites. Specific immunotherapy with\\u000a mite extracts has demonstrated clinical benefits in several doubleblind, placebo-controlled trials that are included in recent

Enrique Fernández-Caldas; Victor Iraola; Manuel Boquete; Antonio Nieto; Miguel Casanovas

2006-01-01

75

Peanut immunotherapy  

PubMed Central

Peanut allergy is common and can be a cause of severe, life-threatening reactions. It is rarely outgrown like other food allergies, such as egg and milk. Peanut allergy has a significant effect on the quality of life of sufferers and their families, due to dietary and social restrictions, but mainly stemming from fear of accidental peanut ingestion. The current management consists of strict avoidance, education and provision of emergency medication, but a disease- modifying therapy is needed for peanut allergy. Recent developments involve the use of immunotherapy, which has shown promise as an active form of treatment. Various routes of administration are being investigated, including subcutaneous, oral, sublingual and epicutaneous routes. Other forms of treatment, such as the use of vaccines and anti-IgE molecules, are also under investigation. So far, results from immunotherapy studies have shown good efficacy in achieving desensitisation to peanut with a good safety profile. However, the issue of long-term tolerance has not been fully addressed yet and larger, phase III studies are required to further investigate safety and efficacy. An assessment of cost/benefit ratio is also required prior to implementing this form of treatment. The use of immunotherapy for peanut allergy is not currently recommended for routine clinical use and should not be attempted outside specialist allergy units. PMID:25276342

2014-01-01

76

Ratio of neutrophil/lymphocyte and platelet/lymphocyte in patient with ankylosing spondylitis that are treating with anti-TNF  

PubMed Central

Ankylosing spondylitis (AS) is a type of chronic inflammatory arthritis resulting in ankylosis of the spine and inflammation in the tendons. After NSAIDs, the use of anti-TNF medications has provided a significant contribution to the treatment of patients with AS. The present study was a retrospective, controlled and multicenter study. A total of 105 patients followed in the outpatient clinics of the Department of Physical Therapy in Abant Izzet Baysal University and Harran University and 50 healthy controls were included in the study. The patients had been receiving anti-TNF therapy at least for 6 months. Hemogram results of the patient and control groups examined retrospectively. There was no significant difference between the groups in terms of N/L ratio; however, the P/L ratio was significantly different between the two groups. The present study found a significantly different P/L ratio in patients with AS when compared to the control group. However, the N/L ratio was not significantly different between the groups. The P/L ratio can be used as a marker to monitor disease progression and indicate subclinical inflammation in patients with AS. PMID:25356158

Boyraz, ?smail; Koç, Bünyamin; Boyac?, Ahmet; Tuto?lu, Ahmet; Sarman, Hakan; Özkan, Hilal

2014-01-01

77

Sublingual immunotherapy in children: facts and needs  

Microsoft Academic Search

Allergen specific immunotherapy (SIT) is the practice of administering gradually increasing doses of the specific causative allergen to reduce the clinical reactivity of allergic subjects, and is the only treatment targeting the causes of hypersensitivity and not only the symptoms, as done by drugs. The traditional, subcutaneous immunotherapy (SCIT) was burdened by the problem of systemic reactions which may be

Gian Luigi Marseglia; Cristoforo Incorvaia; Mario La Rosa; Franco Frati; Francesco Marcucci

2009-01-01

78

LC-MS Metabolomics of Psoriasis Patients Reveals Disease Severity-Dependent Increases in Circulating Amino Acids That Are Ameliorated by Anti-TNF? Treatment.  

PubMed

Psoriasis is an immune-mediated highly heterogeneous skin disease in which genetic as well as environmental factors play important roles. In spite of the local manifestations of the disease, psoriasis may progress to affect organs deeper than the skin. These effects are documented by epidemiological studies, but they are not yet mechanistically understood. In order to provide insight into the systemic effects of psoriasis, we performed a nontargeted high-resolution LC-MS metabolomics analysis to measure plasma metabolites from individuals with mild or severe psoriasis as well as healthy controls. Additionally, the effects of the anti-TNF? drug Etanercept on metabolic profiles were investigated in patients with severe psoriasis. Our analyses identified significant psoriasis-associated perturbations in three metabolic pathways: (1) arginine and proline, (2) glycine, serine and threonine, and (3) alanine, aspartate, and glutamate. Etanercept treatment reversed the majority of psoriasis-associated trends in circulating metabolites, shifting the metabolic phenotypes of severe psoriasis toward that of healthy controls. Circulating metabolite levels pre- and post-Etanercept treatment correlated with psoriasis area and severity index (PASI) clinical scoring (R(2) = 0.80; p < 0.0001). Although the responsible mechanism(s) are unclear, these results suggest that psoriasis severity-associated metabolic perturbations may stem from increased demand for collagen synthesis and keratinocyte hyperproliferation or potentially the incidence of cachexia. Data suggest that levels of circulating amino acids are useful for monitoring both the severity of disease as well as therapeutic response to anti-TNF? treatment. PMID:25361234

Kamleh, Muhammad Anas; Snowden, Stuart G; Grapov, Dmitry; Blackburn, Gavin J; Watson, David G; Xu, Ning; Ståhle, Mona; Wheelock, Craig E

2015-01-01

79

Long-term safety of anti-TNF-? in PsA patients with concomitant HCV infection: a retrospective observational multicenter study on 15 patients.  

PubMed

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

2014-02-01

80

Measurements in the Blood of BDNF for RA Patients and in Response to Anti-TNF Treatment Help Us to Clarify the Magnitude of Centrally Related Pain and to Explain the Relief of This Pain upon Treatment  

PubMed Central

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with functions related to neuronal survival/proliferation processes and inflammation. BDNF is also an important central pain mediator. The levels of BDNF have been found to be high for RA patients with severe disease and to become lowered in response to anti-TNF treatment. New information says that the levels of BDNF in the blood parallel the BDNF concentrations in the brain and that BDNF can pass the blood-brain barrier. Furthermore, most of the circulating BDNF is produced in the brain. Habitual and regular exercise, in contrast to temporary exercise, does also lead to a lowering of BDNF blood levels. Both anti-TNF treatment and habitual and regular exercise do have pain-relieving effects. It might be that the pain-relieving effect of anti-TNF treatment is related to an affection of central neuronal regions, hereby influencing BDNF production. Measurements of BDNF in the blood help us to clarify the magnitude of centrally related pain for RA patients and help us to explain the relief of this pain in response to anti-TNF treatment. PMID:21755028

Forsgren, Sture; Grimsholm, Ola; Dalén, Tore; Rantapää-Dahlqvist, Solbritt

2011-01-01

81

Immunotherapy with vaccines combining MHC class II\\/CD80 + tumor cells with interleukin-12 reduces established metastatic disease and stimulates immune effectors and monokine induced by interferon ?  

Microsoft Academic Search

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

2000-01-01

82

New directions in immunotherapy.  

PubMed

Allergen immunotherapy (AIT) is effective in reducing the clinical symptoms associated with allergic rhinitis, asthma and venom-induced anaphylaxis. Subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with unmodified allergen extracts are the most widely prescribed AIT regimens. The efficacy of these 2 routes appears comparable, but the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time. However, both require that the treatment is taken regularly over several years, e.g., monthly in a supervised medical setting with SCIT and daily at home with SLIT. Despite the difference in treatment settings, poor adherence has been reported with both routes. Emerging evidence suggests that AIT may be effective in other allergic conditions such as atopic dermatitis, venom sting-induced large local reactions, and food allergy. Research with oral immunotherapy (OIT) for food allergies suggest that many patients can be desensitized during treatment, but questions remain about whether this can produce long term tolerance. Further studies are needed to identify appropriate patients and treatment regimens with these conditions. Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified allergens and alternate routes. Intralymphatic (ILIT) has been shown to produce long-lasting clinical benefits after three injections comparable to a 3-year course of SCIT. Epicutaneous (EPIT) has demonstrated promising results for food and inhalant allergies. Vaccine modifications, such as T cell epitopes or the use of viral-like particles as an adjuvant, have been shown to provide sustained clinical benefits after a relatively short course of treatment compared to the currently available AIT treatments, SLIT and SCIT. These newer approaches may increase the utilization and adherence to AIT because the multi-year treatment requirement of currently available AIT is a likely deterrent for initiating and adhering to treatment. PMID:23315329

Cox, Linda; Compalati, Enrico; Kundig, Thomas; Larche, Mark

2013-04-01

83

Anti-TNF-? therapy does not ameliorate disease in a model of acute virus-endotoxin mediated respiratory disease in pigs  

PubMed Central

Tumour necrosis factor-? (TNF-?) has been shown to play a role in many inflammatory conditions. Currently anti-TNF-? drugs (e.g. etanercept) are used in humans for treatment of autoimmune diseases. In this study we aimed to elucidate the role of TNF-? in the development of virus-endotoxin-induced respiratory disease. Twenty-two caesarean derived colostrum deprived pigs were used. Initially, the availability in the lungs and circulation, and possible clinical and inflammatory effects of etanercept alone were assessed in 4 pigs after intratracheal and intraperitoneal administration of 0.5 mg/per route/per pig. High anti-TNF-? activity was detected in bronchoalveolar lavage (BAL) fluids, peritoneal lavage fluids and serum of all animals for at least 8 hours post inoculation (HPI). No clinical symptoms, lung lesions, lung cell infiltration or induction of IFN-?, IL-1, IL-6, IL-12 and TNF-? in BAL were detected. Subsequently, the ability of etanercept to block porcine TNF-? and its effect on the above mentioned parameters and on lung virus titres were assessed in 8 pigs. They were inoculated intratracheally with porcine respiratory coronavirus (PRCV) followed by lipopolysaccharide (LPS) 24 hours later. Etanercept was administered at the time of LPS inoculation via the same routes and dose as in the initial experiment. The parameters were compared with a control group (n=8), receiving only PRCV-LPS. Half of the animals from each group were euthanized at 4 and the rest at 8 hours after LPS inoculation. TNF-? was completely neutralized in 3 of the 4 animals euthanized at 4 HPI and significantly lower than in the PRCV-LPS group at all times. No significant differences in disease severity, lung lesions, virus replication, lung cell infiltration or levels of IFN-?, IL-1, IL-6 and IL-12/IL-23 were observed between the two groups. Blocking of TNF-? alone was not sufficient to ameliorate disease in the PRCV-LPS model of respiratory disease, possibly due to the redundancy in the proinflammatory cytokine cascade, or the involvement of other unidentified disease mediators. PMID:20466438

Atanasova, Kalina; Van Gucht, Steven; Van Reeth, Kristien

2010-01-01

84

Immunologic changes associated with allergen immunotherapy  

Microsoft Academic Search

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

1998-01-01

85

Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models  

PubMed Central

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

2014-01-01

86

Characterization of the complex formed between a potent neutralizing ovine-derived polyclonal anti-TNF? Fab fragment and human TNF?  

PubMed Central

TNF? (tumour necrosis factor ?) is an early mediator in the systemic inflammatory response to infection and is therefore a therapeutic target in sepsis. AZD9773 is an ovine-derived, polyclonal anti-TNF? Fab fragment derived from a pool of serum and currently being developed as a treatment for severe sepsis and septic shock. In the present study, we show that although AZD9773 has a modest affinity for TNF? in a binding assay, the Ki in a cell-based assay is approximately four orders of magnitude lower. We show using SEC (size exclusion chromatography) that the maximum size of the complex between AZD9773 and TNF? is consistent with approximately 12 Fabs binding to one TNF? trimer. A number of approaches were taken to map the epitopes recognized by AZD9773. These revealed that a number of different regions on TNF? are involved in binding to the polyclonal Fab. The data suggest that there are probably three epitopes per monomer that are responsible for most of the inhibition by AZD9773 and that all three can be occupied at the same time in the complex. We conclude that AZD9773 is clearly demonstrated to bind to multiple epitopes on TNF? and suggest that the polyclonal nature may account, at least in part, for the very high potency observed in cell-based assays. PMID:23863106

Abbott, W. Mark; Snow, Melanie; Eckersley, Sonia; Renshaw, Jonathan; Davies, Gareth; Norman, Richard A.; Ceuppens, Peter; Slootstra, Jerry; Benschop, Joris J.; Hamuro, Yoshitomo; Lee, Jessica E.; Newham, Peter

2013-01-01

87

Oral immunotherapy for food allergy  

Microsoft Academic Search

Current management of food allergy involves strict avoidance, education on recognizing and managing allergic reactions, and\\u000a carrying an adrenaline autoinjector. This approach is burdensome and associated with reduced quality of life. Patients with\\u000a food allergy would benefit greatly from a treatment that could achieve desensitization or long-term tolerance. Recent studies\\u000a have shown that oral immunotherapy (OIT) can induce desensitization and

Mimi L. K. Tang

2009-01-01

88

TNF is required for the induction but not the maintenance of compression-induced BME signals in murine tail vertebrae: limitations of anti-TNF therapy for degenerative disc disease  

PubMed Central

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. 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.

2011-01-01

89

Measuring patients’ satisfaction with their anti-TNF treatment in severe Crohn’s disease: scoring and psychometric validation of the Satisfaction for PAtients in Crohn’s diseasE Questionnaire (SPACE-Q©)  

PubMed Central

Background Severe Crohn’s disease management includes anti-tumor necrosis factor (anti-TNF) drugs that differ from early-stage treatments regarding efficacy, safety, and convenience. This study aimed to finalize and psychometrically validate the Satisfaction for PAtients in Crohn’s diseasE Questionnaire (SPACE-Q©), developed to measure satisfaction with anti-TNF treatment in patients with severe Crohn’s disease. Methods A total of 279 patients with severe Crohn’s disease receiving anti-TNF therapy completed the SPACE-Q 62-item pilot version at inclusion and 12 and 13 weeks after first anti-TNF injection. The final SPACE-Q scoring was defined using multitrait and regression analyses and clinical relevance considerations. Psychometric validation included clinical validity against Harvey–Bradshaw score, concurrent validity against Treatment Satisfaction Questionnaire for Medication (TSQM), internal consistency reliability, test–retest reliability, and responsiveness against the patient global impression of change (PGIC). Results Quality of completion was good (55%–67% of patients completed all items). Four items were removed from the questionnaire. Eleven scores were defined within the final 58-item SPACE-Q: disease control; symptoms, anal symptoms, and quality of life transition scales; tolerability; convenience; expectation confirmation toward efficacy, side effects, and convenience; satisfaction with treatment; and motivation. Scores met standards for concurrent validity (correlation between SPACE-Q satisfaction with treatment and TSQM satisfaction scores =0.59), internal consistency reliability (Cronbach’s ?=0.67–0.93), test–retest reliability (intraclass correlations =0.62–0.91), and responsiveness (improvement in treatment experience assessed by the SPACE-Q for patients reporting improvement on the PGIC). Significantly different mean scores were observed between groups of patients with different Harvey–Bradshaw disease severity scores. Conclusion The SPACE-Q is a valid, reliable, and responsive instrument to measure satisfaction with anti-TNF treatment in patients with severe Crohn’s disease and for use in future studies. PMID:25525343

Gilet, Hélène; Arnould, Benoit; Fofana, Fatoumata; Clerson, Pierre; Colombel, Jean-Frédéric; D’Hondt, Olivier; Faure, Patrick; Hagège, Hervé; Nachury, Maria; Nahon, Stéphane; Tucat, Gilbert; Vandromme, Luc; Cazala-Telinge, Ines; Thibout, Emmanuel

2014-01-01

90

Trends in Cancer Immunotherapy  

PubMed Central

Modulation of the immune system for therapeutic ends has a long history, stretching back to Edward Jenner’s use of cowpox to induce immunity to smallpox in 1796. Since then, immunotherapy, in the form of prophylactic and therapeutic vaccines, has enabled doctors to treat and prevent a variety of infectious diseases, including cholera, poliomyelitis, diphtheria, measles and mumps. Immunotherapy is now increasingly being applied to oncology. Cancer immunotherapy attempts to harness the power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for cancer immunotherapy is to apply advances in cellular and molecular immunology and develop strategies that effectively and safely augment antitumor responses. PMID:20703326

Murphy, Joseph F.

2010-01-01

91

Immunotherapy for malignant gliomas.  

PubMed

Cancer immunotherapy aims to harness the innate ability of the immune system to recognize and destroy malignant cells. Immunotherapy for malignant gliomas is an emerging field that promises the possibility of highly specific and less toxic treatment compared to conventional chemotherapy. In addition, immunotherapy has the added benefit of sustained efficacy once immunologic memory is induced. Although there are numerous therapeutic agents that boost general immune function and facilitate improved antitumor immunity, to date, immunotherapy for gliomas has focused primarily on active vaccination against tumor-specific antigens. The results of numerous early phase clinical trials demonstrate promising results for vaccine therapy, but no therapy has yet proven to improve survival in a randomized, controlled trial. The major barrier to immunotherapy in malignant gliomas is tumor-induced immunosuppression. The mechanisms of immunosuppression are only now being elucidated, but clearly involve a combination of factors including regulatory T cells, tumor-associated PD-L1 expression, and CTLA-4 signaling. Immunomodulatory agents have been developed to combat these immunosuppressive factors and have demonstrated efficacy in other cancers. The future of glioma immunotherapy likely lies in a combination of active vaccination and immune checkpoint inhibition. PMID:25468230

Bloch, Orin

2015-01-01

92

What Is Recent in Pancreatic Cancer Immunotherapy?  

PubMed Central

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. PMID:23509731

Niccolai, Elena; Prisco, Domenico; D'Elios, Mario Milco; Amedei, Amedeo

2013-01-01

93

Advances in Cancer Immunotherapy  

PubMed Central

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. PMID:23449114

Snook, Adam E.; Waldman, Scott A.

2014-01-01

94

Cancer immunotherapy – revisited  

Microsoft Academic Search

Our insight into antitumour immune responses has increased considerably during the past decades, yet the development of immunotherapy as a treatment modality for cancer has been hampered by several factors. These include difficulties in the selection of the optimal dose and schedule, the methods of evaluation, and financial support. Although durable clinical remissions have been observed with various immunotherapeutic strategies,

W. Joost Lesterhuis; John B. A. G. Haanen; Cornelis J. A. Punt

2011-01-01

95

Oral immunotherapy for allergic conjunctivitis.  

PubMed

Antigen-specific immunotherapy is expected to be a desirable treatment for allergic diseases. Currently, antigen-specific immunotherapy is performed by administering disease-causing antigens subcutaneously or sublingually. These approaches induce long-term remission in patients with allergic rhinitis or asthma. The oral route is an alternative to subcutaneous and sublingual routes, and can also induce long-term remission, a phenomenon known as "oral tolerance." The effectiveness of oral tolerance has been reported in the context of autoimmune diseases, food allergies, asthma, atopic dermatitis, and allergic rhinitis in both human patients and animal models. However, few studies have examined its efficacy in animal models of allergic conjunctivitis. Previously, we showed that ovalbumin feeding suppressed ovalbumin-induced experimental allergic conjunctivitis, indicating the induction of oral tolerance is effective in treating experimental allergic conjunctivitis. In recent years, transgenic rice has been developed that can induce oral tolerance and reduce the severity of anaphylaxis. The major Japanese cedar pollen antigens in transgenic rice, Cryptomeria japonica 1 and C. japonica 2, were deconstructed by molecular shuffling, fragmentation, and changes in the oligomeric structure. Thus, transgenic rice may be an effective treatment for allergic conjunctivitis. PMID:25289722

Ishida, Waka; Fukuda, Ken; Harada, Yosuke; Yagita, Hideo; Fukushima, Atsuki

2014-11-01

96

Oral and sublingual immunotherapy  

PubMed Central

Allergic diseases have continued to increase throughout the developed world. Subcutaneous immunotherapy has been a mainstay of treatment for allergic rhinitis and asthma, however, some patients are precluded from treatment. On the other hand, in the case of food allergy, treatments simply do not exist. Oral and sublingual immunotherapy, with its superior safety and ease of administration, offers an alternative for patients with allergic rhinitis and asthma and has also been promising as a potential treatment for food allergy. The review summarizes significant advances from the past year including further data on the effectiveness of existing treatments, preliminary data on novel treatments, and further understanding of the mechanisms of these new therapies. PMID:25133094

Burks, Wesley

2014-01-01

97

Neoantigens in cancer immunotherapy.  

PubMed

The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure. Recent technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens. PMID:25838375

Schumacher, Ton N; Schreiber, Robert D

2015-04-01

98

Immunotherapy of Cancer in 2012  

PubMed Central

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. PMID:22576456

Kirkwood, John M.; Butterfield, Lisa H.; Tarhini, Ahmad A.; Zarour, Hassane; Kalinski, Pawel; Ferrone, Soldano

2012-01-01

99

New treatments for allergen immunotherapy  

PubMed Central

Allergen-specific immunotherapy (SIT) represents the only curative and specific way for the treatment of allergic diseases, which have reached a pandemic dimension in industrial countries affecting up to 20-30% of the population. Although applied for 100 years to cure allergy, SIT still faces several problems related to side effects and limited efficacy. Currently, allergen-SIT is performed with vaccines based on allergen extracts that can cause severe, often life threatening, anaphylactic reactions as well as new IgE sensitization to other allergens present in the extract. Low patient adherence and high costs due to long duration (3 to 5 years) of treatment have been commonly reported. Several strategies have been developed to tackle these issues and it became possible to produce recombinant allergen-SIT vaccines with reduced allergenic activity. PMID:25258656

2014-01-01

100

Immunotherapy of melanoma  

PubMed Central

Melanoma is considered one of the immunogenic – if not the most immunogenic – malignancies. This is based on several observations.1.Spontaneous remissions occur occasionally.2.In about 5% of melanomas no primary tumour is found. The genetic aberrations of these tumours closely resemble those of cutaneous melanomas, and therefore are suggestive of spontaneous regressions of the primary tumours.3.Both primary tumours and metastases often have brisk lymphocytic infiltrates, a phenomenon that is correlated with better outcome.4.Studies of isolates of these tumour-infiltrating T lymphocytes have revealed that a proportion of these cells recognise melanoma antigens.5.Melanomas respond to immunotherapy. These observations have led to over 30 years of research on immunotherapy for melanoma; many of these efforts have failed, with only a few exceptions: interleukin-2 (IL-2) and to a lesser degree interferon-a (IFN-?). Recently, new developments in immunotherapy have revolutionised this treatment modality. Anti-CTLA4 has received approval from the Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) for the treatment of stage IV melanomas based on the improvement in overall survival in phase III trials, and more recently blockade of PD1/PDL1 interactions has shown objective clinical responses in a stage IV melanoma in early-phase clinical trials. In addition, several independent single-institution phase I/II trials using adoptive cell therapy have shown a consistently high response rate, including durable complete remissions in a substantial percentage of treated patients. Now, for the first time, immunotherapy has moved beyond the treatment of melanoma as both CTLA4 and PD1 blockade have been shown to induce objective responses in other tumour types as well. This chapter will discuss the mechanism of action, clinical efficacy and side effects of IL-2, the novel treatments consisting of the immune checkpoint blockade drugs anti-CTLA4 and anti-PD1 and adoptive cell therapy.

Haanen, John B.A.G.

2013-01-01

101

Infliximab and Etanercept Are Equally Effective in Reducing Enterocyte APOPTOSIS in Experimental Colitis  

PubMed Central

Loss of epithelial barrier integrity is considered an early step in the pathogenesis of Crohn's disease (CD), and the rate of enterocyte apoptosis is one of the determinants of the intestinal barrier function. Tumor necrosis factor-? (TNF-?), one of the major proinflammatory mediators in CD, is one of the extrinsic signals which initiate apoptosis of enterocytes. The aim of this study was to investigate the early effects of experimental colitis on enterocyte apoptosis, and the effects of two anti-TNF treatments, infliximab (IFX) and etanercept (ETC). In addition, the importance of receptor I for TNF was tested in TNFR-1-/- mice. Circulating TNF-? levels were effectively reduced by IFX and ETC (p<0.01, both) at 3 and 6 h. Apoptosis of the ileal enterocytes, assessed by TUNEL staining, staining for Fas-ligand, and bax, increased at 3 and 6h. These alterations were prevented by both anti-TNF strategies, and in TNFR-1-/- animals. The anti-apoptotic protein Bcl-2 was expressed in the ileal epithelium under control conditions, but was suppressed in DNB-colitis. Expression of Bcl-2 was maintained in both anti-TNF treatments and TNFR-1-/- mice. DNB colitis induced a very early, rapid increase of enterocyte apoptosis. Both anti-TNF strategies, IFX and ETC, were equally effective in suppressing enterocyte apoptosis, most likely by inactivation of circulating TNF-?. PMID:18645606

Fries, Walter; Muja, Carmelo; Crisafulli, Carmela; Costantino, Giuseppe; Longo, Giuseppe; Cuzzocrea, Salvatore; Mazzon, Emanuela

2008-01-01

102

[A? immunotherapy for Alzheimer's disease].  

PubMed

Alzheimer's disease (AD) is one of the neurodegenerative diseases characterized by the deposition of amyloid-?-protein (A?) as senile plaques in the brain parenchyma and phosphorylated-tau accumulation as neurofibrillary tangles in the neurons. Although details of the disease pathomechanisms remain unclear, A? likely acts as a key protein for AD initiation and progression, followed by abnormal tau phosphorylation and neuronal death (amyloid-cascade hypothesis). According to this hypothesis, A? immunization therapies are created to eliminate A? from the brain, and to prevent the neurons from damage by these pathogenic proteins. There are two methods for A? immunotherapies: active and passive immunization. Previous studies have shown A? removal and improved cognitive function in animal models of AD. Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab, have been carried out; however, all trials have failed to demonstrate apparent clinical benefits. On the contrary, side effects emerged, such as meningoencephalitis, vasogenic edema, which are currently called amyloid related imaging abnormalities (ARIA)-E and microhemorrhage (ARIA-H). In neuropathological studies of immunized cases, A? was removed from the brain parenchyma and phosphorylated-tau was reduced in the neuronal processes. Moreover, deterioration of the cerebral amyloid angiopathy (CAA) and an increase of microhemorrhages and microinfarcts were described. A? is cleared from the brain mainly via the lymphatic drainage pathway. ARIA could stem from severe CAA due to dysfunction of the drainage pathway after immunotherapy. A? immunization has a potential of cure for AD patients, although the above-described problems must be overcome before applying this therapy in clinical treatment. PMID:23568994

Sakai, Kenji; Yamada, Masahito

2013-04-01

103

The history of sublingual immunotherapy.  

PubMed

The sublingual route of administration of allergen (SLIT) has emerged as an effective treatment. Other non-injective route of administration of vaccines failed their goals; oral immunotherapy (OIT), local nasal immunotherapy (LNIT), local bronchial immunotherapy (LBIT) were reported as too expensive or unsafe or ineffective. Oral regimens were used in the first half of the 20th century but then they lost ground to injection immunotherapy. SLIT is suitable for home treatment and it has not to be regarded not only as a substitute of subcutaneous immunotherapy (SCIT), but also as a complementary or additional therapeutic tool in conventional medical practice. Currently, the balance sheet for SLIT is improving: with the steadily increasing number of patients with IgE mediated disorders, looking for a "cheap, safe and effective therapy" becomes a priority. PMID:19944001

Pajno, G B; Barberi, S

2009-01-01

104

Immunotherapy in lung cancer  

PubMed Central

Immunotherapy has emerged in recent years as a promising therapeutic approach in lung cancer. Two approaches are of particular interest: immune checkpoint inhibition, which aims to counteract the physiologic mechanisms of immune tolerance co-opted by some tumors, and vaccine therapy, which enables enhanced exposure to tumor antigen. Immune checkpoint therapies include the monoclonal antibody blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) with ipilimumab, as well as antibody blockade of the programmed cell death-1 (PD-1) receptor and the PD-1 ligand. These immune checkpoint therapies have been evaluated in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) with early evidence of activity. Vaccines include antigen specific therapies which induce specific antitumor immunity against relevant tumor-associated antigens. In lung cancer, these include the melanoma-associated antigen-A3 (MAGE-A3), membrane-associated glycoprotein (MUC-1), and the epidermal growth factor receptor (EGFR). Whole tumor vaccines have also been evaluated in lung cancer and influence the patient’s immune system to allow recognition of the tumor as foreign creating de novo immunity. This review summarizes the evidence to date for the efficacy and safety of immunotherapies in lung cancer.

Kalyan, Aparna; Zarour, Hassane; Socinski, Mark A.

2014-01-01

105

Immunotherapy in lung cancer  

PubMed Central

Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC.

Papadimitrakopoulou, Vassiliki; Welsh, James; Tang, Chad; Tsao, Anne S.

2014-01-01

106

Specific immunotherapy in grass pollen allergy  

PubMed Central

Since its description by Noon in 1911, desensitization, or allergen specific immunotherapy (SIT), has been largely used in respiratory allergic diseases treatment. It remains the only etiologic treatment for allergic diseases. The development of the sublingual route and new forms of medication, as an alternative to subcutaneous injection, has led to large scale clinical trials. Many of them had been performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing all respiratory allergic symptoms. Data on long-term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on natural history of allergic disease, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this therapeutic method in the future. The sublingual route appears to be safer with a better safety profile. This may lead to an extension of allergen specific immunotherapy indications in patients with respiratory allergic diseases. PMID:23095875

Mailhol, Claire; Didier, Alain

2012-01-01

107

Laser immunotherapy of canine and feline neoplasia  

NASA Astrophysics Data System (ADS)

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.

1998-07-01

108

Immunotherapy against APP ?-Secretase Cleavage Site Improves Cognitive Function and Reduces Neuroinflammation in Tg2576 Mice without a Significant Effect on Brain A? Levels  

Microsoft Academic Search

Background\\/Objectives: Active and passive immunization methodologies against amyloid-? (A?) are employed to clear and reduce cerebral A?towards treatment of Alzheimer’s disease (AD) patients. The therapeutic potential of these antibodies in AD patients is limited because of adverse inflammatory reactions and cerebral hemorrhage, which are associated with the treatment. We propose a novel approach to inhibit A? production via antibodies against

Idan Rakover; Michal Arbel; Beka Solomon

2007-01-01

109

Immunotherapy of Trypanosoma cruzi Infection with DNA Vaccines in Mice  

PubMed Central

The mechanisms involved in the pathology of chronic chagasic cardiomyopathy are still debated, and the controversy has interfered with the development of new treatments and vaccines. Because of the potential of DNA vaccines for immunotherapy of chronic and infectious diseases, we tested if DNA vaccines could control an ongoing Trypanosoma cruzi infection. BALB/c mice were infected with a lethal dose (5 × 104 parasites) as a model of acute infection, and then they were treated with two injections of 100 ?g of plasmid DNA 1 week apart, beginning on day 5 postinfection. Control mice had high levels of parasitemia and mortality and severe cardiac inflammation, while mice treated with plasmid DNA encoding trypomastigote surface antigen 1 or Tc24 had reduced parasitemia and mild cardiac inflammation and >70% survived the infection. The efficacy of the immunotherapy also was significant when it was delayed until days 10 and 15 after infection. Parasitological analysis of cardiac tissue of surviving mice indicated that most mice still contained detectable parasite kinetoplast DNA but fewer mice contained live parasites, suggesting that there was efficient but not complete parasite elimination. DNA vaccine immunotherapy was also evaluated in CD1 mice infected with a low dose (5 × 102 parasites) as a model of chronic infection. Immunotherapy was initiated on day 70 postinfection and resulted in improved survival and reduced cardiac tissue inflammation. These results suggest that DNA vaccines have strong potential for the immunotherapy of T. cruzi infection and may provide new alternatives for the control of Chagas' disease. PMID:14688079

Dumonteil, Eric; Escobedo-Ortegon, Javier; Reyes-Rodriguez, Norma; Arjona-Torres, Arletty; Ramirez-Sierra, Maria Jesus

2004-01-01

110

Cellular immunotherapy of cancer.  

PubMed

Standard therapies for many common cancers remain toxic and are often ineffective. Cellular immunotherapy has the potential to be a highly targeted alternative, with low toxicity to normal tissues but a high capacity to eradicate tumor. In this chapter we describe approaches that generate cellular therapies using active immunization with cells, proteins, peptides, or nucleic acids, as well as efforts that use adoptive transfer of effector cells that directly target antigens on malignant cells. Many of these approaches are proving successful in hematologic malignancy and in melanoma. In this chapter we discuss the advantages and limitations of each and how over the next decade investigators will attempt to broaden their reach, increase their efficacy, and simplify their application. PMID:20686975

Okur, Fatma V; Brenner, Malcolm K

2010-01-01

111

Cancer immunotherapy via dendritic cells  

Microsoft Academic Search

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

Jacques Banchereau; Karolina Palucka

2012-01-01

112

Cellular immunotherapy for ovarian cancer  

PubMed Central

Background Ovarian cancer is frequently diagnosed at an advanced stage, and although initially responsive to surgery and chemotherapy, has a high rate of recurrence and mortality. Cellular immunotherapy may offer the prospect of treatment to prevent or delay recurrent metastatic disease. Objective To provide an overview of current innovations in cellular immunotherapy for ovarian cancer, with an emphasis on dendritic cell vaccination and adoptive T cell immunotherapy. Methods Three key areas are explored in this review. First, an appraisal of the current state of the art of cellular immunotherapy for treatment of ovarian cancer. Second, a discussion of the immunological defenses erected by ovarian cancer to prevent immunological attack, with an emphasis on the role of tumor-associated regulatory T cells. Third, an exploration of innovative techniques that may enhance the ability of cellular immunotherapy to overcome ovarian tumor-associated immune suppression. Results/conclusion Ovarian cancer is recognized as a paradigm for tumor-associated immune suppression. Innovative approaches for antagonism of tumor-associated regulatory T cell infiltration and redirection of self antigen-driven regulatory T cell activation may provide the key to development of future strategies for cellular immunotherapy against ovarian cancer. PMID:19456205

Cannon, Martin J; O'Brien, Timothy J

2009-01-01

113

New routes for allergen immunotherapy  

PubMed Central

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. PMID:23095873

Johansen, Pål; von Moos, Seraina; Mohanan, Deepa; Kündig, Thomas M.; Senti, Gabriela

2012-01-01

114

Ovarian cancer biology and immunotherapy.  

PubMed

Ovarian cancer is the most lethal malignancy of the female reproductive system and the fifth leading cause of cancer death in women. In the year 2012 alone, United States had 22,280 new ovarian cancer cases and 15,500 deaths were reported. About 7%-10% of ovarian cancers result from an inherited tendency to develop the disease. Ovarian cancer has the ability to escape the immune system because of its pathological interactions between cancer cells and host immune cells in the tumor microenvironment create an immunosuppressive network that promotes tumor growth, protects the tumor from immune system. The levels of immune suppressive elements like regulatory T cells, plasmacytoid dendritic cells and cytokines such as IL-10, IL-6, TNF-?, and TGF-? are elevated in the tumor microenvironment. Vascular endothelial growth factor is known to have an immune suppressing role besides its angiogenic role in the tumor microenvironment. Ovarian cancer is associated with high mortality partly due to difficulties in early diagnosis and development of metastases. These problems may overcome by developing accurate mouse models that should mimic the complexity of human ovarian cancer. Such animal models are better suited to understand pathophysiology, metastases, and also for preclinical testing of targeted molecular therapeutics. Immunotherapy is an area of active investigation and off late many clinical trials is ongoing to prevent disease progression. The main aim of dendritic cells vaccination is to stimulate tumor specific effector T cells that can reduce tumor size and induce immunological memory to prevent tumor relapse. PMID:24911597

Latha, T Sree; Panati, Kalpana; Gowd, D Sravan Kumar; Reddy, Madhava C; Lomada, Dakshayani

2014-10-01

115

Multiallergen-specific immunotherapy in polysensitized patients: where are we?  

PubMed

Allergen-specific immunotherapy administered by the subcutaneous route was introduced a century ago and has been shown to be effective in the management of allergic rhinitis and asthma. More recently, the sublingual administration of allergen extracts has become popular, especially in European countries, and has also demonstrated efficacy in respiratory allergic diseases. Both modes of allergen administration during immunotherapy have been shown not only to reduce symptoms and the need for medication, but also to prevent the development of additional sensitivities in monosensitized patients, as well as asthma development in patients with allergic rhinitis, with a long-lasting effect after the completion of several years of treatment. Almost all of the well-designed and double-blinded, placebo-controlled studies evaluated treatment with single-allergen extracts. Therefore, most meta-analyses published to date evaluated immunotherapy with single allergen or extracts containing several cross-reactive allergens. As a result, in general, multiallergen immunotherapy in polysensitized patients (mixture of noncross-reactive allergens) is not recommended owing to lack of evidence. Although some guidelines have recommended against the use of multiallergen mixtures, allergists commonly use mixtures to which the patient is sensitive with the rationale that effective immunotherapy should include all major sensitivities. Literature on this subject is scarce in spite of the widespread use worldwide. Here, this issue will be extensively discussed based on currently available literature and future perspectives will also be explored. PMID:23413909

Bahceciler, Nerin Nadir; Galip, Nilufer; Cobanoglu, Nazan

2013-02-01

116

LASSBio-1135: A Dual TRPV1 Antagonist and Anti-TNF-Alpha Compound Orally Effective in Models of Inflammatory and Neuropathic Pain  

PubMed Central

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.

2014-01-01

117

The combination of valacyclovir with an anti-TNF alpha antibody increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis.  

PubMed

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

2013-12-01

118

The Combination of Valacyclovir with an Anti-TNF Alpha Antibody Increases Survival Rate Compared to Antiviral Therapy Alone in a Murine Model of Herpes Simplex Virus Encephalitis.  

PubMed

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 1.85x10(4) 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:24513309

Boivin, Nicolas; Menasria, Rafik; Piret, Jocelyne; Rivest, Serge; Boivin, Guy

2013-10-24

119

Quality of life outcomes with sublingual immunotherapy  

Microsoft Academic Search

PurposeImmunotherapy is the titrated exposure of allergens to induce immunologic tolerance and offers long-term immune modification. Traditional subcutaneous immunotherapy (SCIT) has resulted in several deaths and raised safety concerns. Sublingual immunotherapy (SLIT) is an alternative administration route for allergen-specific immunotherapy. Compared to SCIT, SLIT has a shorter escalation phase, equal or greater efficacy for rhinitis, and an improved safety profile.

Sarah K. Wise; Jamie Woody; Sarah Koepp; Rodney J. Schlosser

2009-01-01

120

Immunotherapy for malignant glioma  

PubMed Central

Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12–15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM. PMID:25722935

Suryadevara, Carter M.; Verla, Terence; Sanchez-Perez, Luis; Reap, Elizabeth A.; Choi, Bryan D.; Fecci, Peter E.; Sampson, John H.

2015-01-01

121

Immunotherapy for malignant glioma.  

PubMed

Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM. PMID:25722935

Suryadevara, Carter M; Verla, Terence; Sanchez-Perez, Luis; Reap, Elizabeth A; Choi, Bryan D; Fecci, Peter E; Sampson, John H

2015-01-01

122

Strategies of mucosal immunotherapy for allergic diseases  

Microsoft Academic Search

Incidences of allergic disease have recently increased worldwide. Allergen-specific immunotherapy (SIT) has long been a controversial treatment for allergic diseases. Although beneficial effects on clinically relevant outcomes have been demonstrated in clinical trials by subcutaneous immunotherapy (SCIT), there remains a risk of severe and sometimes fatal anaphylaxis. Mucosal immunotherapy is one advantageous choice because of its non-injection routes of administration

Yi-Ling Ye; Ya-Hui Chuang; Bor-Luen Chiang; B-L Chiang

2011-01-01

123

Epicutaneous Immunotherapy Compared with Sublingual Immunotherapy in Mice Sensitized to Pollen (Phleum pratense)  

PubMed Central

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. PMID:23724241

Mondoulet, Lucie; Dioszeghy, Vincent; Ligouis, Mélanie; Dhelft, Véronique; Puteaux, Emilie; Dupont, Christophe; Benhamou, Pierre-Henri

2012-01-01

124

Current status of cancer immunotherapy  

PubMed Central

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. PMID:25075156

Kono, K

2014-01-01

125

?? T cells for cancer immunotherapy  

PubMed Central

?? T cells contribute to the front line of lymphoid antitumor surveillance and bridge the gap between innate and adaptive immunity. They can be readily expanded to high numbers in vivo and in vitro, starting from the blood of cancer patients, and a number of Phase I trials have demonstrated that these cells can be employed in cancer immunotherapy. Sufficient patients have received ?? T cell-based immunotherapies in the context of clinical trials to evaluate their utility, and to inform the direction of new trials. A systematic approach was used to identify Phase I, Phase II, and feasibility studies testing ?? T cell-based immunotherapy in cancer patients. Studies were excluded from further analysis if they did not provide patient-specific data. Data were compiled to evaluate efficacy, with stratification by treatment approach. When possible, comparisons were made with the efficacy of second-line conventional therapeutic approaches for the same malignancy. Twelve eligible studies were identified, providing information on 157 patients who had received ?? T cell-based immunotherapy. The comparison of objective response data suggests that ?? T cell-based immunotherapy is superior to current second-line therapies for advanced renal cell carcinoma and prostate cancer, but not for non-small cell lung carcinoma. An evaluation of pooled data from 132 published in vitro experiments shows a consistent improvement in the cytotoxicity of ?? T cells in the presence of antitumor antibodies. Immunotherapy using ?? T cells alone shows promising clinical activity, but there is a strong preclinical rationale for combining this treatment modality with cancer-targeting antibodies to augment its efficacy. PMID:24734216

Fisher, Jonathan PH; Heuijerjans, Jennifer; Yan, Mengyong; Gustafsson, Kenth; Anderson, John

2014-01-01

126

Immunotherapy strategies in multiple myeloma.  

PubMed

Multiple myeloma (MM) is a B-cell malignancy characterized by the clonal proliferation of malignant plasma cells in the bone marrow and the development of osteolytic bone lesions. MM has emerged as a paradigm within the cancers for the success of drug discovery and translational medicine. This article discusses immunotherapy as an encouraging option for the goal of inducing effective and long-lasting therapeutic outcome. Divided into two distinct approaches, passive or active, immunotherapy, which targets tumor-associated antigens has shown promising results in multiple preclinical and clinical studies. PMID:25212890

Bae, Jooeun; Munshi, Nikhil C; Anderson, Kenneth C

2014-10-01

127

Immunological mechanisms in specific immunotherapy  

Microsoft Academic Search

Specific immunotherapy (SIT) represents the only curative treatment of allergy and is, therefore, of particular interest for immunological and pharmacological research. The current understanding of immunological mechanisms underlying SIT focuses on regulatory T cells (T regs), which balance Th1 and Th2 effector functions. This ensures that allergens are recognized, but tolerated by the immune system. There is clear evidence that

Carsten B. Schmidt-Weber; Kurt Blaser

2004-01-01

128

Classification of current anticancer immunotherapies.  

PubMed

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

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

2014-12-30

129

Classification of current anticancer immunotherapies  

PubMed Central

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

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

2014-01-01

130

Role of immunotherapy in the treatment of allergic asthma.  

PubMed

Allergen-specific immunotherapy (SIT) induces clinical and immunological tolerance as defined by persistence of clinical benefit and associated long-term immunological parameters after cessation of treatment. Although the efficacy of SIT has been shown in terms of reducing symptoms, medication consumption and ameliorating quality of life in both allergic rhinitis and asthma, there has long been some controversies about effectiveness of SIT in the treatment of allergic asthma. The type of allergen, the dose and protocol of immunotherapy, patient selection criteria, the severity and control of asthma, all are significant contributors to the power of efficacy in allergic asthma. The initiation of SIT in allergic asthma should be considered in case of coexisting of other allergic diseases such as allergic rhinitis, unacceptable adverse effects of medications, patient's preference to avoid long-term pharmacotherapy. Steroid sparing effect of SIT in allergic asthma is also an important benefit particularly in patients who have to use these drugs in high doses for a long-time. Symptomatic asthma is a risk factor for systemic reactions and asthma should be controlled at the time of administration of SIT. Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been found to be effective in patients with allergic asthma. Although the safety profile of SLIT seems to be better than SCIT, the results of some studies and meta-analyses suggest that the efficacy of SCIT may appear better and earlier than SLIT in children with allergic asthma. PMID:25516861

Yukselen, Ayfer; Kendirli, Seval Guneser

2014-12-16

131

Role of immunotherapy in the treatment of allergic asthma  

PubMed Central

Allergen-specific immunotherapy (SIT) induces clinical and immunological tolerance as defined by persistence of clinical benefit and associated long-term immunological parameters after cessation of treatment. Although the efficacy of SIT has been shown in terms of reducing symptoms, medication consumption and ameliorating quality of life in both allergic rhinitis and asthma, there has long been some controversies about effectiveness of SIT in the treatment of allergic asthma. The type of allergen, the dose and protocol of immunotherapy, patient selection criteria, the severity and control of asthma, all are significant contributors to the power of efficacy in allergic asthma. The initiation of SIT in allergic asthma should be considered in case of coexisting of other allergic diseases such as allergic rhinitis, unacceptable adverse effects of medications, patient’s preference to avoid long-term pharmacotherapy. Steroid sparing effect of SIT in allergic asthma is also an important benefit particularly in patients who have to use these drugs in high doses for a long-time. Symptomatic asthma is a risk factor for systemic reactions and asthma should be controlled at the time of administration of SIT. Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been found to be effective in patients with allergic asthma. Although the safety profile of SLIT seems to be better than SCIT, the results of some studies and meta-analyses suggest that the efficacy of SCIT may appear better and earlier than SLIT in children with allergic asthma. PMID:25516861

Yukselen, Ayfer; Kendirli, Seval Guneser

2014-01-01

132

Honeybee venom immunotherapy: certainties and pitfalls.  

PubMed

The honeybee is an interesting insect because of the fundamental agricultural role it plays, together with the composition of its venom, which presents new diagnostic and immunotherapeutic challenges. This article examines various aspects of honeybee venom allergy from epidemiology to diagnosis and treatment, with special emphasis on venom immunotherapy (VIT). Honeybee venom allergy represents a risk factor for severe systemic reaction in challenged allergic patients, for the diminished effectiveness of VIT, for more frequent side effects during VIT and relapse after cessation of treatment. Some strategies are available for reducing the risk of honeybee VIT-induced side effects; however, there is considerable room for further improvement in these all-important areas. At the same time, sensitized and allergic beekeepers represent unique populations for epidemiological, venom allergy immunopathogenesis and VIT mechanism studies. PMID:23194365

Bilò, M Beatrice; Antonicelli, Leonardo; Bonifazi, Floriano

2012-11-01

133

Immunotherapy for Acute Lymphocytic Leukemia  

Microsoft Academic Search

\\u000a While a majority of patients with acute lymphocytic leukemia (ALL) demonstrate response following treatment with standard\\u000a chemotherapy, subsequent progression due to the emergence of resistant disease is often encountered. The failure to eradicate\\u000a disease is most commonly observed in adult patients particularly with high-risk features such as adverse cytogenetics. In\\u000a contrast, immunotherapy may be successful in targeting chemotherapy-resistant clones. The

Jacalyn Rosenblatt; David Avigan

134

Sublingual immunotherapy and allergic rhinitis  

Microsoft Academic Search

This paper reviews the safety and efficacy of sublingual immunotherapy (SLIT) in the treatment of allergic rhinitis. The literature\\u000a from 1986 through 2007 shows approximately a 6000-fold range in doses found to be effective with SLIT. However, recent studies\\u000a in large patient populations have demonstrated a clear dose response with an effective dose range that appears to be equivalent\\u000a to

Linda Cox

2008-01-01

135

DNA Vaccines for Cancer Immunotherapy  

Microsoft Academic Search

The introduction of selected genes by direct injection of DNA represents a general strategy for short-term gene expression\\u000a in vivo. DNA vaccines may be especially useful for cancer immunotherapy because DNA allows transient expression of tumor-associated\\u000a antigens and immunostimulatory proteins by a relatively nonimmunogenic vector. This chapter focuses on how DNA vaccines stimulate\\u000a immune responses and how different immunization strategies

Heesun Kwak; Howard L. Kaufman

136

Immunotherapy of type 1 diabetes  

Microsoft Academic Search

Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing ? cells are destroyed. Diabetic patients manage\\u000a their hyperglycemia by daily insulin injections. However, insulin therapy is by no means a cure. Accordingly, a significant\\u000a effort has been ongoing to develop immunotherapies that effectively prevent and\\/or treat T1D in the clinic. This review focuses\\u000a on antigen- and antibody-based

Li Li; Zuoan Yi; Roland Tisch; Bo Wang

2008-01-01

137

Immunotherapy Targets in Pediatric Cancer  

PubMed Central

Immunotherapy for cancer has shown increasing success and there is ample evidence to expect that progress gleaned in immune targeting of adult cancers can be translated to pediatric oncology. This manuscript reviews principles that guide selection of targets for immunotherapy of cancer, emphasizing the similarities and distinctions between oncogene-inhibition targets and immune targets. It follows with a detailed review of molecules expressed by pediatric tumors that are already under study as immune targets or are good candidates for future studies of immune targeting. Distinctions are made between cell surface antigens that can be targeted in an MHC independent manner using antibodies, antibody derivatives, or chimeric antigen receptors versus intracellular antigens which must be targeted with MHC restricted T cell therapies. Among the most advanced immune targets for childhood cancer are CD19 and CD22 on hematologic malignancies, GD2 on solid tumors, and NY-ESO-1 expressed by a majority of synovial sarcomas, but several other molecules reviewed here also have properties which suggest that they too could serve as effective targets for immunotherapy of childhood cancer. PMID:22645714

Orentas, Rimas J.; Lee, Daniel W.; Mackall, Crystal

2011-01-01

138

Microenvironmental clues for glioma immunotherapy.  

PubMed

Gliomas have been viewed for decades as inaccessible for a meaningful antitumor immune response as they grow in a sanctuary site protected from infiltrating immune cells. Moreover, the glioma microenvironment constitutes a hostile environment for an efficient antitumor immune response as glioma-derived factors such as transforming growth factor ? and catabolites of the essential amino acid tryptophan paralyze T-cell function. There is growing evidence from preclinical and clinical studies that a meaningful antitumor immunity exists in glioma patients and that it can be activated by vaccination strategies. As a consequence, the concept of glioma immunotherapy appears to be experiencing a renaissance with the first phase 3 randomized immunotherapy trials entering the clinical arena. On the basis of encouraging results from other tumor entities using immunostimulatory approaches by blocking endogenous T-cell suppressive pathways mediated by cytotoxic T-lymphocyte antigen 4 or programmed cell death protein 1/programmed cell death protein 1 ligand 1 with humanized antibodies, there is now a realistic and promising option to combine active immunotherapy with agents blocking the immunosuppressive microenvironment in patients with gliomas to allow a peripheral antitumor immune response induced by vaccination to become effective. Here we review the current clinical and preclinical evidence of antimicroenvironment immunotherapeutic strategies in gliomas. PMID:24604058

Platten, Michael; Ochs, Katharina; Lemke, Dieter; Opitz, Christiane; Wick, Wolfgang

2014-04-01

139

Cellular immunotherapy for multiple myeloma.  

PubMed

Multiple myeloma is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation results in effective cytoreduction, but patients subsequently relapse from sites of chemotherapy-resistant disease. Allogeneic transplantation may result in durable responses due to anti-tumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-vs-host disease remains a challenge. A promising area of investigation is the development of immunotherapeutic approaches that target and eliminate myeloma cells more selectively. A variety of tumour-associated antigens have been identified in myeloma cells that may be targeted selectively by host immunity. Vaccination strategies targeting single antigens and whole-cell approaches, which have the advantage of presenting patient-specific and potentially unidentified antigens to immune effector cells, have shown promise in clinical studies. In addition, the use of monoclonal antibodies has been evaluated in preclinical and clinical studies. Effector cell dysfunction and the increased number of regulatory T cells in patients with malignancy may limit the efficacy of immunotherapeutic approaches. Strategies to improve upon immunotherapy for multiple myeloma involve the depletion of T regulatory cells, combining active and passive immunotherapy, the use of cytokine adjuvants, and using immunotherapy in conjunction with autologous and allogeneic transplantation. PMID:18790455

Rosenblatt, Jacalyn; Avigan, David

2008-09-01

140

House dust allergy and immunotherapy  

PubMed Central

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. PMID:22894952

Thomas, Wayne R.

2012-01-01

141

Poxviral vectors for cancer immunotherapy  

PubMed Central

Introduction Poxviral vaccines have been given to over 1 billion people in the successful global eradication of smallpox. Since then, recombinant poxviruses have been investigated extensively as a novel immunotherapy for cancer, undergoing several iterations to optimize their immunogenicity and efficacy. The current platform expressing multiple costimulatory molecules plus a tumor-associated antigen such as PSA, i.e., PSA-TRICOM (PROSTVAC-V/F), is promising and is currently in a phase III randomized, placebo-controlled clinical trial in metastatic castration-resistant prostate cancer. Areas covered This review discusses the clinical development of poxviral-based cancer vaccines, with a particular focus on the rationale for combining vaccines with other treatment modalities, including radiotherapy, chemotherapy, hormonal therapy, other immune-based therapies, and molecularly targeted therapy. We also discuss the importance of appropriate patient selection in clinical trial design. Expert Opinion Preclinical and early clinical studies with poxviral vector vaccines have shown promising results with this novel immunologic approach both as vaccine alone and combined with other therapies. The challenges of translating the science of immunotherapy to clinical practice include clinical trial design that includes appropriate patient selection, appropriate endpoints, and identification of meaningful surrogate biomarkers. PMID:22413824

Kim, Joseph W.; Gulley, James L.

2012-01-01

142

Peptide immunotherapy for childhood allergy - addressing translational challenges  

PubMed Central

Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease. Specific immunotherapy involves administering protein allergen to tolerise allergen reactive CD4+ T cells, thought key in driving allergic responses. Yet specific immunotherapy risks allergic reactions including anaphylaxis as a consequence of preformed allergen-specific IgE antibodies binding to the protein, subsequent cross-linking and mast cell degranulation. CD4+ T cells direct their responses to short "immunodominant" peptides within the allergen. Such peptides can be given therapeutically to induce T cell tolerance without facilitating IgE cross-linking. Peptide immunotherapy (PIT) offers attractive treatment potential for allergic disease. However, PIT has not yet been shown to be effective in children. This review discusses the immunological mechanisms implicated in PIT and briefly covers outcomes from adult PIT trials. This provides a context for discussion of the challenges for the application of PIT, both generally and more specifically in relation to children. PMID:22409934

2011-01-01

143

Immunotherapy for Alzheimer's disease: rational basis in ongoing clinical trials.  

PubMed

Amyloid-? (A?) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of A? in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with A?(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with A?(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel A? immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-A?/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years. PMID:21375481

Menéndez-González, Manuel; Pérez-Piñera, Pablo; Martínez-Rivera, Marta; Muñiz, Alfonso López; Vega, Jose A

2011-01-01

144

Immunotherapy of Metastases Enhances Subsequent Chemotherapy  

NASA Astrophysics Data System (ADS)

In many multimodal therapies of cancer, postsurgical chemotherapy is administered before immunotherapy for treatment of micrometastatic disease. This sequence may not be the most efficacious. Experiments in which strain 2 guinea pigs bearing syngeneic L10 hepatocarcinomas were given immunotherapy showed that infiltrating immune effector cells not only were tumoricidal but disrupted the characteristically compact structure of metastatic foci. When cytotoxic drugs were administered at the peak of this inflammatory response, the survival rate of the guinea pigs increased significantly. We conclude that postsurgical immunotherapy can enhance the effect of cytotoxic drugs administered subsequently.

Hanna, Michael G.; Key, Marc E.

1982-07-01

145

Engineering persistent interleukin-2 for cancer immunotherapy  

E-print Network

Mobilizing the immune system to recognize and destroy tumor cells is a promising strategy for treating cancer. In contrast to standard therapeutic approaches such as surgery, radiation, and chemotherapy, immunotherapy ...

Gai, Shuning

2012-01-01

146

Dendritic cell immunotherapy: clinical outcomes  

PubMed Central

The use of tumour-associated antigens for cancer immunotherapy studies is exacerbated by tolerance to these self-antigens. Tolerance may be broken by using ex vivo monocyte-derived dendritic cells (DCs) pulsed with self-antigens. Targeting tumour-associated antigens directly to DCs in vivo is an alternative and simpler strategy. The identification of cell surface receptors on DCs, and targeting antigens to DC receptors, has become a popular approach for inducing effective immune responses against cancer antigens. Many years ago, we demonstrated that targeting the mannose receptor on macrophages using the carbohydrate mannan to DCs led to appropriate immune responses and tumour protection in animal models. We conducted Phase I, I/II and II, clinical trials demonstrating the effectiveness of oxidised mannan-MUC1 in patients with adenocarcinomas. Here we summarise DC targeting approaches and their efficacy in human clinical trials. PMID:25505969

Apostolopoulos, Vasso; Pietersz, Geoffrey A; Tsibanis, Anastasios; Tsikkinis, Annivas; Stojanovska, Lily; McKenzie, Ian FC; Vassilaros, Stamatis

2014-01-01

147

Immunotherapy  

MedlinePLUS

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148

Addition of immunotherapy boosts pediatric cancer survival:  

Cancer.gov

Administering a new form of immunotherapy to children with neuroblastoma, a nervous system cancer, increased the percentage of those who were alive and free of disease progression after two years.  The percentage rose from 46 percent for children receiving a standard therapy to 66 percent for children receiving immunotherapy plus standard therapy, according to the study in the Sept. 30, 2010, New England Journal of Medicine.

149

Cancer Immunotherapy: A Treatment for the Masses  

NASA Astrophysics Data System (ADS)

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.

2004-07-01

150

Sublingual Immunotherapy in Allergic Rhinitis and Asthma  

Microsoft Academic Search

Since the recognition and approval of sublingual immunotherapy (SLIT) by the World Health Organization and the European Association\\u000a of Allergy and Clinical Immunology in 1998 [1, 2], there was been a worldwide interest in the use of this treatment for allergic\\u000a diseases.\\u000a \\u000a Sublingual immunotherapy has been shown to be effective in rhinitis and asthma; it is extremely safe and unlike

Paul Potter

151

Pollen immunotherapy: Selection, prevention, and future directions  

Microsoft Academic Search

Pollens are an important cause of allergic rhinitis and asthma. Pollen immunotherapy is effective and potentially curative.\\u000a It has been shown to prevent new sensitizations, to prevent the development of asthma in children, and to induce long-term\\u000a benefit. Standardization of allergen extracts is necessary to improve immunotherapy safety and efficacy. Knowledge of the\\u000a local plant taxonomy and allergen cross-reactivity is

Steven J. McEldowney; Robert K. Bush

2006-01-01

152

Transgenic Rice for Mucosal Vaccine and Immunotherapy  

Microsoft Academic Search

The use of recombinant allergen–based immunotherapy has improved current practical approaches to allergy treatment and has\\u000a revealed potential new clinical strategies for the control of allergic diseases. Oral immunotherapy using a rice-based oral\\u000a vaccine is one attractive strategy that was shown to be effective for the control of pollen allergies. When the peptides for\\u000a a T cell specific to Japanese

Yoshikazu Yuki; Fumio Takaiwa; Hiroshi Kiyono

153

Immunotherapy of lung cancer with Corynebacterium parvum  

Microsoft Academic Search

Thirty-one patients with inoperable carcinoma of the lung, excluding oat-cell carcinoma, were randomized to receive either chemotherapy alone, with methyl CCNU and vinblastine every 6–8 weeks (15 Pts) or such chemotherapy plus immunotherapy with IV infusions of Corynebacterium parvum (16 Pts). Prior duration of the disease was longer, and more patients had received previous therapy, in the immunotherapy group; these

Houshang Moayeri; Hiroshi Takita; J. E. Sokal

1979-01-01

154

Defining the critical hurdles in cancer immunotherapy  

PubMed Central

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

2011-01-01

155

Lung cancer: potential targets for immunotherapy.  

PubMed

Lung cancer is the most common cause of cancer-related mortality worldwide and a therapeutic challenge. Recent success with antibodies blocking immune checkpoints in non-small-cell lung cancers (NSCLC) highlights the potential of immunotherapy for lung cancer treatment, and the need for trials of combination regimens of immunotherapy plus chemotherapy that lead to immunogenic cell death. Here, we review the development of immunogenic cytotoxic compounds, vaccines, and antibodies in NSCLC, in view of their integration into personalised oncology. PMID:24461616

Tartour, Eric; Zitvogel, Laurence

2013-09-01

156

Selection of patients for sublingual immunotherapy (SLIT) versus subcutaneous immunotherapy (SCIT).  

PubMed

Allergy immunotherapy has been used to help alleviate symptoms of allergic diseases for over 100 years. In the setting of the recently approved sublingual immunotherapy, allergists are now faced with which therapeutic regimen to use in clinical practice, sublingual immunotherapy (SLIT) or subcutaneous immunotherapy (SCIT). Both SLIT and SCIT have been shown to be beneficial for the therapy of seasonal allergic rhinoconjunctivitis. Each therapeutic measure has its associated benefits. SLIT has a better safety profile with less systemic reactions and to date, no reported fatal reactions. SCIT, the primary method of allergen immunotherapy in the United States, has a slightly better efficacy profile and readily allows for treatment of polyallergic patients. This review focuses on how to incorporate SLIT into daily clinical practice and on how to choose SLIT versus SCIT. PMID:25715238

Tabatabaian, Farnaz; Casale, Thomas B

2015-03-01

157

Epstein–Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis  

PubMed Central

Defective control of Epstein–Barr virus (EBV) infection by cytotoxic CD8+ T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV-specific adoptive immunotherapy to treat MS or any other autoimmune disease. PMID:24493474

Csurhes, Peter A; Smith, Corey; Beagley, Leone; Hooper, Kaye D; Raj, Meenakshi; Coulthard, Alan; Burrows, Scott R; Khanna, Rajiv

2014-01-01

158

IgE-based Immunotherapy of Cancer -A Comparative Oncology Approach  

PubMed Central

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

Singer, Josef; Jensen-Jarolim, Erika

2014-01-01

159

Novel immunotherapies for hematologic malignancies.  

PubMed

The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise novel strategies that exploit the patient's immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematologic malignancies, including (i) conventional monoclonal therapies like rituximab; (ii) engineered monoclonal antibodies called bispecific T-cell engagers; (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4, and IDO); and (iv) adoptive cell transfer therapy with T cells engineered to express chimeric antigen receptors or T-cell receptors. We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients. PMID:25510273

Nelson, Michelle H; Paulos, Chrystal M

2015-01-01

160

Current immunotherapy for solid tumors.  

PubMed

Explorative knowledge of cellular and molecular mechanisms of immune function and regulation has provided optimism in developing cancer immunotherapy. However, three decades of experimental and clinical investigations to offer powerful immunotherapeutic strategies against solid tumors, with the possible exception of monoclonal antibody-targeted therapies, have not succeeded in significantly prolonging patient survival. Nonspecific immune approaches, including cytokine-based therapies and allogeneic hematopoietic stem cell transplantation, have so far produced consistent, although limited, results. In this review, we present the developments of cell transfer-based strategies that, in preclinical studies, have demonstrated potential efficacy, but have only established tumor regression in limited numbers of patients. The key to success demands creative combinations of tumor antigens, adjuvance, gene modification and various administration strategies in the development of cell-based therapies together with other cancer-treatment principles, often in a stepwise 'space-rocket-type' approach. Combined efforts of several scientific disciplines, such as tumor biology and immunology, as well as cell and gene research in transplantation, will open new venues. New regulation for clinical trials with advanced therapy medicine products to ensure patient safety will be highlighted. PMID:20635964

Barkholt, Lisbeth; Bregni, Marco

2009-05-01

161

Specific immunotherapy in atopic dermatitis.  

PubMed

Allergen specific immunotherapy (SIT) using house dust mite (HDM) extracts has been performed mainly with patients of asthma and allergic rhinitis. In the meanwhile, there has been a long debate on the efficacy of SIT in atopic dermatitis (AD) with only a few double-blind placebo-controlled trials. However, several randomized controlled trials of SIT in AD revealed significant improvement of clinical symptoms and also, positive result was shown by a following meta-analysis study of these trials. In order to predict and evaluate the treatment outcome, finding a biomarker that can predict treatment responses and treatment end-points is critical but it is very challenging at the same time due to the complexity of causes and mechanisms of AD. Other considerations including standardization of the easiest and safest treatment protocol and optimizing the treatment preparations should be studied as well. This review summarizes the basics of SIT in AD including the brief mechanisms, treatment methods and schedules, and also highlights the clinical efficacy of SIT in AD along with mild, controllable adverse reactions. Immunologic effects and studies of various biomarkers are also introduced and finally, future considerations with upcoming studies on SIT were discussed. PMID:25749758

Lee, Jungsoo; Park, Chang Ook; Lee, Kwang Hoon

2015-05-01

162

Immunotherapy in food allergy: towards new strategies.  

PubMed

Allergen avoidance is the standard treatment for managing food allergies. Complete avoidance is difficult, and accidental exposure often occurs. Immunotherapy is a significant focus for treating food allergies, and oral immunotherapy (OIT) appears to be particularly effective in inducing desensitization. The majority of patients who receive OIT show increased threshold doses of their food allergen. The efficacy of OIT is different among food antigen, and milk OIT is relatively difficult to achieve tolerance. OIT may induce mild to moderate symptoms during the therapy, widespread acceptance of OIT for long-term therapy is unclear. Recently, novel immunotherapies for food allergies, such as sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) and using an anti-IgE monoclonal antibody (omalizumab), have been assessed. In addition, a combination of OIT with omalizumab, which was found to increase the threshold doses of the offending foods without producing adverse reactions, may be effective and useful in the treatment of food allergies. These treatments have been used only in research settings; further studies in large numbers of patients are needed to demonstrate their long-term safety and benefits in clinical practice. PMID:25268336

Sato, Sakura; Yanagida, Noriyuki; Ogura, Kiyotake; Asaumi, Tomoyuki; Okada, Yu; Koike, Yumi; Iikura, Katsuhito; Syukuya, Akinori; Ebisawa, Motohiro

2014-09-01

163

Combining immunotherapy and radiation for prostate cancer.  

PubMed

Radiotherapy has conventionally been viewed as immunosuppressive, which has precluded its use in combination with immunotherapy for prostate and other cancers. However, the relationship between ionizing radiation and immune reactivity is now known to be more complex than was previously thought, and data on the use of radiotherapy and immunotherapy are accumulating. Herein, we review this topic in the light of recently available data in the prostate cancer setting. Recent research has shown no significant lymphopenia in patients undergoing radiotherapy for high-risk adenocarcinoma of the prostate. In addition, emerging evidence suggests that radiotherapy can have immunostimulatory effects, and that tumor cell death, coupled with related changes in antigen availability and inflammatory signals, can affect lymphocyte and dendritic cell activation. Initial studies have focused on combinations of tumor irradiation and immunotherapy, such as the autologous cellular immunotherapy sipuleucel-T and the monoclonal antibody ipilimumab, in metastatic castration-resistant prostate cancer. These combinations appear to have clinical promise, and further investigation of the potentially synergistic combination of radiotherapy and immunotherapy is continuing in clinical trials. PMID:25450032

Finkelstein, Steven E; Salenius, Sharon; Mantz, Constantine A; Shore, Neal D; Fernandez, Eduardo B; Shulman, Jesse; Myslicki, Francisco A; Agassi, Andre M; Rotterman, Yosef; DeVries, Todd; Sims, Robert

2015-02-01

164

Practical recommendations for mixing allergy immunotherapy extracts  

PubMed Central

Critical aspects of formulating allergy immunotherapy vaccines include the selection, total number, and proportions of each allergen component in therapeutic mixtures. The immunotherapy prescription, determined by a medical provider, details the dosing and schedule for treatment as well as the specific composition of the treatment vials. Allergen extracts are composed of many components such as proteins, glycoproteins, and proteases. Some components in allergen extracts are cross-reactive, meaning that treatment with an extract from one species may confer partial protection against a triggering allergen from another species. Conversely, some allergen extracts are incompatible with other extracts when combined in a mixture for treatment, resulting in lowered therapeutic potential for the patient. Therefore, knowledge of allergen extract cross-reactivities and incompatibilities guides the preparation of subcutaneous immunotherapy prescriptions. In a clinical setting, an understanding of what can and can not be mixed is one critical element in improving treatment outcomes. PMID:25860164

Daigle, Barbara J.

2015-01-01

165

New approaches to transcutaneous immunotherapy: targeting dendritic cells with novel allergen conjugates  

PubMed Central

Purpose of review This review summarizes recent preclinical and human studies evaluating allergen-specific immunotherapy via the transcutaneous route, and provides a rationale for the application of modified allergens with reduced allergenicity. Furthermore, it covers approaches to generate hypoallergenic conjugates for specific dendritic cell targeting. Recent findings Efficacy and safety of specific immunotherapy by application of allergens to the skin have been demonstrated in both animal models as well as clinical trials. However, localized adverse events have been reported, and delivery of antigens via barrier-disrupted skin has been linked to the induction of unwanted T helper 2-biased immune responses and allergic sensitization. Coupling of carbohydrates to allergens has been shown to induce formation of nanoparticles, which can specifically target dendritic cells and potentiate immune responses, and by masking B-cell epitopes, can render the molecules hypoallergenic. Summary Due to its abundance of immunocompetent cells, the skin represents an attractive target tissue for novel and enhanced immunotherapeutic approaches. However, in order to avoid adverse events and therapy-induced sensitizations, transcutaneous immunotherapy requires the use of formulations with reduced allergenic potential. Combining novel hypoallergenic conjugates with painless transcutaneous immunization techniques may provide an efficient and patient-friendly alternative to the standard specific immunotherapy practices. PMID:24169433

Weiss, Richard; Scheiblhofer, Sandra; Machado, Yoan; Thalhamer, Josef

2013-01-01

166

The Emergence of Modern Cancer Immunotherapy  

Microsoft Academic Search

The clearest example of the effectiveness of immunotherapy to mediate cancer regression comes from studies of the administration of interleukin (IL)2 to patients with metastatic melanoma and metastatic renal cancer. 1 IL-2 has no direct effect on cancer cells, and all of the antitumor effects resulting from its administration are the result of its ability to stimulate immune reactions in

Steven A. Rosenberg

2005-01-01

167

Oral immunotherapy for the treatment of food allergy.  

PubMed

Food allergies have increased significantly over recent decades and are the most common cause of admissions for anaphylaxis in childhood, particularly in children under 5 years of age. Current management of food allergy is limited to strict food allergen avoidance together with education on the recognition and emergency management of allergic reactions, and in some cases provision of self-injectable adrenaline. Although this supportive management approach is generally effective, it is burdensome for patients and families, and in turn leads to reduced quality of life. Patients with food allergy would benefit greatly from a definitive treatment that could achieve long-term tolerance. Recent studies demonstrate that oral immunotherapy (OIT) can induce desensitization and modulate allergen-specific immune responses. However, it remains uncertain whether long-term tolerance can be achieved with current OIT regimens. Increased allergen dose, duration of OIT and/or inclusion of an immune modifying adjuvant may enhance the tolerogenic potential of OLT. Allergic reactions during OIT are common, although severe reactions are infrequent. Oral immunotherapy holds promise as a novel approach to the definitive treatment of food allergy. PMID:22624447

Ismail, Intan H; Tang, Mimi L K

2012-01-01

168

Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats  

NASA Astrophysics Data System (ADS)

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

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

2011-03-01

169

Current opinion and review on peanut oral immunotherapy.  

PubMed

In the last decade, peanut oral immunotherapy research has shown promise as an alternative treatment to avoidance in peanut-allergic patients. Research has not only focused on desensitization, but also on immunologic changes and sustained-tolerance. This article reviews the current literature and the historical background of oral immunotherapy as well as immune mechanisms in oral immunotherapy and other therapies being explored in food allergic individuals. PMID:25483680

Deol, Sharon; Bird, J Andrew

2014-01-01

170

Oral and sublingual immunotherapy for food allergy.  

PubMed

IgE-mediated food allergy is a potentially life-threatening allergic disease with an increase in prevalence in developed countries over the past 15 years. Currently, there are no approved forms of therapy and the standard of care is dietary restriction and ready access to emergency medications, such as self-injectable epinephrine and antihistamines. Allergen-specific modalities of treatment currently being studied include oral immunotherapy (OIT) and sublingual immunotherapy (SLIT). Both forms demonstrate the ability to desensitize patients to a variety of specific food allergens and show great promise. However, more research is needed to evaluate the safety and efficacy of OIT and SLIT prior to routine use in clinical practice. PMID:25709745

Le, Uyenphuong H; Burks, A Wesley

2014-01-01

171

Cellular immunotherapy for plasma cell myeloma.  

PubMed

Allogeneic hematopoietic cell transplantation for plasma cell myeloma can lead to graft-vs-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies seek to induce more specific, reliable and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of DC/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs such as inhibitors of the programmed death-1 T cell regulatory pathway may synergize with cellular immunotherapies. PMID:23645169

Garfall, A L; Vogl, D T; Weiss, B M; Stadtmauer, E A

2013-11-01

172

Natural killer cell lines in tumor immunotherapy.  

PubMed

Natural killer (NK) cells are considered to be critical players in anticancer immunity. However, cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells. Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches, including activating autologous NK cells, expanding allogeneic NK cells, usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines. The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production. Additionally, genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity. In this review, NK cells in tumor immunotherapy are discussed, and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed. PMID:22460449

Cheng, Min; Zhang, Jian; Jiang, Wen; Chen, Yongyan; Tian, Zhigang

2012-03-01

173

Adoptive T Cell Immunotherapy for Cancer  

PubMed Central

Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. In recent years, there has been an increased interest in optimizing this technology in order to make it a clinically feasible treatment. One of the main treatment modalities within cancer immunotherapy has been adoptive T cell therapy (ACT). Using this approach, tumor-specific cytotoxic T cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. In the current review, we revisit some of the major successes of ACT, the major hurdles that have been overcome to optimize ACT, the remaining challenges, and future approaches to make ACT widely available. PMID:25717386

Perica, Karlo; Varela, Juan Carlos; Oelke, Mathias; Schneck, Jonathan

2015-01-01

174

Personalized dendritic cell-based tumor immunotherapy  

PubMed Central

Advances in the understanding of the immunoregulatory functions of dendritic cells (DCs) in animal models and humans have led to their exploitation as anticancer vaccines. Although DC-based immunotherapy has proven clinically safe and efficient to induce tumor-specific immune responses, only a limited number of objective clinical responses have been reported in cancer patients. These relatively disappointing results have prompted the evaluation of multiple approaches to improve the efficacy of DC vaccines. The topic of this review focuses on personalized DC-based anticancer vaccines, which in theory have the potential to present to the host immune system the entire repertoire of antigens harbored by autologous tumor cells. We also discuss the implementation of these vaccines in cancer therapeutic strategies, their limitations and the future challenges for effective immunotherapy against cancer. PMID:20161666

Janikashvili, Nona; Larmonier, Nicolas; Katsanis, Emmanuel

2010-01-01

175

Molecular biomarkers for grass pollen immunotherapy  

PubMed Central

Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines. PMID:25237628

Popescu, Florin-Dan

2014-01-01

176

Yeast-based vaccine approaches to cancer immunotherapy  

E-print Network

Saccharomyces cerevisiae stimulates dendritic cells and represents a promising candidate for cancer immunotherapy development. Effective cross-presentation of antigen delivered to dendritic cells is necessary for successful ...

Howland, Shanshan W

2008-01-01

177

Recombinant allergen immunotherapy: clinical evidence of efficacy--a review.  

PubMed

Recombinant allergens for immunotherapy aim to overcome the problems of natural extracts as they can be produced in unlimited amounts with exact physiochemical and immunological properties. These can be modified to have more favourable characteristics including reduced IgE reactivity or enhanced immunogenicity. Different types of recombinant allergens have been evaluated in clinical phase II and III trials whilst others are currently under development. In this review, we identified double-blind, placebo-controlled randomised clinical trials assessing the efficacy and safety of various recombinant allergen preparations. The majority of studies have up to now focused on cat, grass, birch, ragweed and bee venom allergens. Some studies have shown some of these preparations to be effective and well tolerated. However, there are still outstanding issues regarding optimum doses, minimising side effects and long-term effects. PMID:23740287

Makatsori, Melina; Pfaar, Oliver; Lleonart, Ramon; Calderon, Moises A

2013-08-01

178

Immunotherapy for the Treatment of Glioblastoma  

PubMed Central

Glioblastoma, the most aggressive primary brain tumor, thrives in a microenvironment of relative immunosuppression within the relatively immune-privileged central nervous system. Despite treatments with surgery, radiation therapy, and chemotherapy, prognosis remains poor. The recent success of immunotherapy in the treatment of other cancers has renewed interest in vaccine therapy for the treatment of gliomas. In this article, we outline various immunotherapeutic strategies, review recent clinical trials data, and discuss the future of vaccine therapy for glioblastoma. PMID:22290259

Thomas, Alissa A.; Ernstoff, Marc S.; Fadul, Camilo E.

2012-01-01

179

Immunotherapy of Non-Hodgkin's Lymphomas  

Microsoft Academic Search

Recent years have witnessed the development of a variety of promising immunotherapies for treating patients with non-Hodgkin's lymphomas. Foremost among these advances is the exciting success of monoclonal antibodies directed against lymphocyte surface antigens. Rituximab is a chimeric (human- mouse) anti-CD20 antibody that induces responses in approximately half of the patients with relapsed indolent lymphomas and a third of patients

John P. Leonard; Bertrand Coiffier; Ronald Levy; John Timmerman

180

Prostate cancer immunotherapy: beyond immunity to curability.  

PubMed

Metastatic prostate cancer is the second leading cause of death from cancer in the United States. It is the first prevalent cancer in which overall survival in advanced disease is modestly, but objectively, improved with outpatient delivered dendritic cell-based immunotherapy. More prostate cancer patients have enrolled through Facebook and trusted-site Internet searches in clinical trials for prostate cancer vaccine-based immunotherapy than in immunotherapy trials for lung, breast, colon, pancreas, ovarian, and bladder cancer combined in the past 7 years. Exceptional responses to anti-CTLA-4 treatment have been documented in clinics, and prostate cancer neoantigen characterization and T-cell clonotyping are in their research ascendancy. The prostate is an accessory organ; it is not required for fertility, erectile function, or urinary continence. The true evolutionary advantage of having a prostate for male mammalian physiology is a topic of speculation in seminar rooms and on bar stools, but it remains unknown. Hundreds of prostate lineage-unique proteins (PLUP) exist among the >37,000 normal human prostate lineage-unique open reading frames that can be targeted for immunologic ablation of PLUP(+) prostate cancer cells by prostate-specific autoimmunity. This bioengineered graft-versus-prostate disease is a powerful strategy that can eliminate deaths from prostate cancer. Immunologic tolerance to prostate cancer can be overcome at every clinical stage of presentation. This Cancer Immunology at the Crossroads article aims to present advances in the past two decades of basic, translational, and clinical research in prostate cancer, including bioengineering B-cell and T-cell responses, and ongoing prostate cancer immunotherapy trials. PMID:25367978

Simons, Jonathan W

2014-11-01

181

?? T Cell Immunotherapy-A Review.  

PubMed

Cancer immunotherapy utilizing V?9V?2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. V?9V?2 T cell-based immunotherapy can be classified into two categories based on the methods of activation and expansion of these cells. Although the in vivo expansion of V?9V?2 T cells by phosphoantigens or nitrogen-containing bisphosphonates (N-bis) has been translated to early-phase clinical trials, in which the safety of the treatment was confirmed, problems such as activation-induced V?9V?2 T cell anergy and a decrease in the number of peripheral blood V?9V?2 T cells after infusion of these stimulants have not yet been solved. In addition, it is difficult to ex vivo expand V?9V?2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood V?9V?2 T cells. In this article, we review the clinical studies and reports targeting V?9V?2 T cells and discuss the development and improvement of V?9V?2 T cell-based cancer immunotherapy. PMID:25686210

Kobayashi, Hirohito; Tanaka, Yoshimasa

2015-01-01

182

A? Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome  

Microsoft Academic Search

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

2004-01-01

183

New Insights into Allergen-Specific Immunotherapy in Rhinitis and Asthma  

Microsoft Academic Search

Allergen-specific immunotherapy (SIT) was introduced on an empirical basis about a century ago [1], with the erroneous rationale\\u000a of vaccinating against “airborne toxins.” Despite this wrong conception, the subcutaneous injection (SCIT) of pollen extracts\\u000a proved capable of reducing the symptoms of hay-fever, and SIT (also termed “vaccine”) became one of the cornerstones of allergy\\u000a treatment. After the discovery of IgE

Giovanni Passalacqua; Giorgio Walter Canonica

184

Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer’s disease mouse model  

PubMed Central

Cognitive decline in Alzheimer’s disease is attributed to loss of functional synapses, most likely caused by synaptotoxic, oligomeric forms of amyloid-?. Many treatment options aim at reducing amyloid-? levels in the brain, either by decreasing its production or by increasing its clearance. We quantified the effects of immunotherapy directed against oligomeric amyloid-? in Tg2576 mice, a mouse model of familial Alzheimer’s disease. Treatment of 12-month-old mice with oligomer-specific (A-887755) or conformation-unspecific (6G1) antibodies for 8 weeks did not affect fibrillar plaque density or growth. We also quantified densities of DLG4 (previously known as PSD95) expressing post-synapses and synapsin expressing presynapses immunohistochemically. We found that both pre- and post-synapses were strongly reduced in the vicinity of plaques, whereas distant from plaques, in the cortex and hippocampal CA1 field, only post-synapses were reduced. Immunotherapy alleviated this synapse loss. Synapse loss was completely abolished distant from plaques, whereas it was only attenuated in the vicinity of plaques. These results suggest that fibrillar plaques may act as reservoirs for synaptotoxic, oligomeric amyloid-? and that sequestering oligomers suffices to counteract synaptic pathology. Therefore, cognitive function may be improved by immunotherapy even when the load of fibrillar amyloid remains unchanged. PMID:25281869

Dorostkar, Mario M.; Burgold, Steffen; Filser, Severin; Barghorn, Stefan; Schmidt, Boris; Anumala, Upendra Rao; Hillen, Heinz; Klein, Corinna

2014-01-01

185

Anti-Mesothelin Cancer Immunotherapy  

Cancer.gov

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.

186

Safety of Various Dosage Regimens during Induction of Sublingual Immunotherapy  

Microsoft Academic Search

Background: Sublingual immunotherapy (SLIT) has been demonstrated to be a viable alternative to injection immunotherapy. Administration of high doses of allergens to ensure efficacy has been shown to be well tolerated. The aim of the present study was the first step to address the issue of fast-induction regimens using various induction SLIT regimens in paediatric and adult patients. Methods: Sixty-four

M. Grosclaude; P. Bouillot; R. Alt; F. Leynadier; P. Scheinmann; P. Rufin; D. Basset; R. Fadel; C. André

2002-01-01

187

OPINION Open Access Allergen immunotherapy and allergic rhinitis  

E-print Network

OPINION Open Access Allergen immunotherapy and allergic rhinitis: false beliefs Moisés A Calderón1 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

Paris-Sud XI, Université de

188

Fine-tuning anti-tumor immunotherapies via stochastic simulations  

PubMed Central

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. PMID:22536975

2012-01-01

189

Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference  

PubMed Central

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.

2014-01-01

190

Recombinant Mycobacterium bovis BCG for immunotherapy in nonmuscle invasive bladder cancer.  

PubMed

In the past three decades, intravesical instillation of Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for treating bladder cancer and it still remains at the forefront of immunotherapy for cancer patients. Although BCG-based therapy is the most effective intravesical therapy for this kind of tumor and represents the only agent known to reduce progression into muscle invasive bladder cancer, BCG is ineffective in approximately 30-40 % of cases and disease recurs in up to 50 % of patients. Since that BCG is considered an effective vehicle for delivery of antigens due to its unique characteristics, the genetic manipulation of these mycobacteria has been appealing in the search for less toxic and more potent therapeutic agents for bladder cancer immunotherapy. Herein, we discuss current advances in recombinant BCG construction, research, concerns, and future directions to promote the development of this promising immunotherapeutic approach for bladder cancer. PMID:25794874

Begnini, K R; Buss, J H; Collares, T; Seixas, F K

2015-05-01

191

The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy  

PubMed Central

The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy. PMID:25550693

Leung, Joanne

2014-01-01

192

MATHEMATICAL MODELS OF ANTI-TNF THERAPIES AND  

E-print Network

of differential reactivation risks for different drugs. We review basic epi- demiology and immunology of TB MARINO Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 1 INTRODUCTION In the last 12 years

Kirschner, Denise

193

Biological and clinical effects of anti-TNF? treatment  

Microsoft Academic Search

Tumor necrosis factor alpha (TNF?) is implicated in the pathogenesis of many chronic inflammatory diseases such as rheumatoid arthritis (RA), psoriasis and psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease, ulcerative colitis and uveitis. The availability of new pharmacological agents (infliximab, etanercept, adalimumab), able to selectively block the TNF?, has recently offered new opportunity for the treatment of these diseases.

G. Valesini; C. Iannuccelli; E. Marocchi; L. Pascoli; V. Scalzi; M. Di Franco

2007-01-01

194

Immunogenicity of Anti-TNF-? Agents in Autoimmune Diseases  

Microsoft Academic Search

Prognosis of several autoimmune diseases, especially rheumatoid arthritis (RA), ankylosing spondylitis, Crohn’s disease (CD),\\u000a and psoriasis, usually refractory to conventional treatment improved considerably with the introduction of tumor necrosis\\u000a factor alpha (TNF-?) antagonistic agents, which is now available (infliximab, etanercept, and adalimumab). However, a portion\\u000a of patients persists with active disease, infusion reactions, and relapses even during current biological therapy.

Nádia Emi Aikawa; Jozélio Freire de Carvalho; Clovis Artur Almeida Silva; Eloísa Bonfá

2010-01-01

195

Development of anti-TNF therapy for rheumatoid arthritis  

Microsoft Academic Search

The aetiology of systemic, autoimmune, chronic inflammatory diseases — such as rheumatoid arthritis — is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators — proteins that are now known as cytokines — has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-?), has an important role

Marc Feldmann

2002-01-01

196

Lymphocutaneous Sporotrichosis during Treatment with Anti-TNF-Alpha Monotherapy  

PubMed Central

Sporotrichosis is an infectious disease caused by Sporothrix schenckii, a dimorphic fungus isolated for the first time in 1896 by Benjamin Schenck from a 36-year-old male patient presenting lesions on the right hand and arm. The infection generally occurs by traumatic inoculation of soil, plants, and organic matter contaminated with the fungus. Different clinical syndromes are described as a direct consequence of S. schenckii infection, including lymphocutaneous and disseminated forms, although extracutaneous presentations are reported most frequently in AIDS patients. Here we describe the case of a 57-year-old Caucasian male diagnosed in 2004 with ankylosing spondylitis under stable treatment with adalimumab monotherapy (40?mg every other week). During a routine follow-up visit in March 2013, he presented with multiple nodular lesions arranged in a linear fashion along the left hand and forearm. After diagnostic aspiration of the lesions, lymphocutaneous sporotrichosis was diagnosed and appropriate therapy started. PMID:25755904

Ursini, Francesco; Calabria, Marilena; Bruno, Caterina; Tripolino, Cesare; Naty, Saverio; Grembiale, Rosa Daniela

2015-01-01

197

Sublingual immunotherapy: World Allergy Organization position paper 2013 update  

PubMed Central

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

2014-01-01

198

Soypeptide lunasin in cytokine immunotherapy for lymphoma.  

PubMed

Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We have previously reported that post-transplant lymphoma patients have an acquired deficiency of signal transducer and activator of transcription 4, which results in defective IFN? production during clinical immunotherapy. With the goal of further improving cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that synergistically works with cytokines on natural killer (NK) cells. Peripheral blood mononuclear cells of healthy donors and post-transplant lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Adding lunasin to IL-12- or IL-2-stimulated NK cells demonstrated synergistic effects in the induction of IFNG and GZMB involved in cytotoxicity. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFN? production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines displayed higher tumoricidal activity than those stimulated with cytokines alone using in vitro and in vivo tumor models. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation on target gene loci. Lunasin represents a different class of immune modulating agent that may augment the therapeutic responses mediated by cytokine-based immunotherapy. PMID:24363024

Chang, Hua-Chen; Lewis, David; Tung, Chun-Yu; Han, Ling; Henriquez, Sarah M P; Voiles, Larry; Lupov, Ivan P; Pelloso, David; Sinn, Anthony L; Pollok, Karen E; de Lumen, Ben O; Li, Fang; Blum, Janice S; Srivastava, Shivani; Robertson, Michael J

2014-03-01

199

Immunotherapy for Melanoma: Current Status and Perspectives  

PubMed Central

Summary Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease. PMID:20551839

Alexandrescu, Doru T.; Ichim, Thomas E.; Riordan, Neil H.; Marincola, Francesco M.; Nardo, Anna Di; Kabigting, Filamer D.; Dasanu, Constantin A.

2012-01-01

200

Immunotherapy for melanoma: current status and perspectives.  

PubMed

Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease. PMID:20551839

Alexandrescu, Doru T; Ichim, Thomas E; Riordan, Neil H; Marincola, Francesco M; Di Nardo, Anna; Kabigting, Filamer D; Dasanu, Constantin A

2010-01-01

201

Cancer Immunotherapy: Sipuleucel-T and Beyond  

PubMed Central

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

2014-01-01

202

Cellular immunotherapy for soft tissue sarcomas.  

PubMed

Soft tissue sarcomas are rare neoplasms, with approximately 9000 new cases in the USA every year. Unfortunately, during the past two decades, there has been little progress in the treatment of metastatic soft tissue sarcomas beyond the standard approaches of surgery, chemotherapy and radiation. Immunotherapy is a modality complementary to conventional therapy. It is appealing because functional antitumor activity could affect both local-regional and systemic disease, and act over a prolonged period of time. In this report, we review immunotherapeutic investigative strategies that are being developed, including several tumor vaccine, antigen vaccine and dendritic cell vaccine strategies. PMID:22401634

Finkelstein, Steven Eric; Fishman, Mayer; Conley, Anthony P; Gabrilovich, Dmitry; Antonia, Scott; Chiappori, Alberto

2012-03-01

203

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

PubMed

The interaction between the immune system and cancer was an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of sipuleucel-T and ipilimumab stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies under development are therapeutic vaccination strategies, such as sipuleucel-T and PROSTVAC-VF, or immune checkpoint blockade of CTLA-4. Improved understanding of the immune responses generated by the development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide new treatment options in prostate cancer. PMID:23757912

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

2013-05-22

204

?? T Cells and Their Potential for Immunotherapy  

PubMed Central

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. PMID:24520210

Wu, Yan-Ling; Ding, Yan-Ping; Tanaka, Yoshimasa; Shen, Li-Wen; Wei, Chuan-He; Minato, Nagahiro; Zhang, Wen

2014-01-01

205

Food allergy and the oral immunotherapy approach.  

PubMed

Food allergy represents an increasing health problem, with children being the most affected population. The symptoms can appear within minutes or hours of ingesting the offending food, producing skin manifestations, respiratory, gastrointestinal and anaphylactic reactions in the severe forms. Food allergy is established by the loss of tolerance to food proteins, and is characterized by an altered balance of regulatory T (Treg) cells and the shift to Th2 type cytokines in the intestinal lamina propria. We have described the contribution of different factors in establishing oral tolerance, such as the antigenic exposition route, the gut microenvironment, and the timing of the food introduction. Apart from avoiding the food, immunotherapy is the only intervention which produces oral desensitization to food proteins. Among the underlying immunological mechanisms of oral immunotherapy (OIT) are the changes in humoral immunity (a decrease of allergen-specific IgE and an increase of allergen-specific IgG4) and cellular changes such as the increased number of FoxP3(+) Treg cells. At present, the experiences of OIT with various foods are offering promising results. OIT appears to be safe producing low adverse reactions, and effective in inducing desensitization in most subjects with food allergy. PMID:25027549

Cabrera, Carmen M; Urra, José M

2015-02-01

206

Combining radiotherapy and immunotherapy: a revived partnership.  

PubMed Central

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 radio-sensitive 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 may have far reaching consequences on the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective anti-tumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from pre-clinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance anti-tumor effects. Conversely, RT could reveal 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 anti-tumor immunity is discussed, and a new approach to radio-immunotherapy of cancer is proposed. PMID:16199306

Demaria, Sandra; Bhardwaj, Nina; McBride, William H.; Formenti, Silvia C.

2006-01-01

207

Immunotherapy for neurodegenerative diseases: focus on ?-synucleinopathies  

PubMed Central

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. PMID:23384597

Valera, Elvira; Masliah, Eliezer

2013-01-01

208

Immunotherapy Treatments of Warm Autoimmune Hemolytic Anemia  

PubMed Central

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

Gu, Wangang

2013-01-01

209

Treatment with a combination of omalizumab and specific immunotherapy for severe anaphylaxis after a wasp sting.  

PubMed

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

2014-01-01

210

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

SciTech Connect

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

Zhang, Han [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan)] [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Sonoda, Koh-Hei, E-mail: sonodak@med.kyushu-u.ac.jp [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan)] [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan)] [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan)

2009-04-17

211

Cellular immunotherapy in multiple myeloma: lessons from preclinical models.  

PubMed

The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review, we summarize the immune cell changes that occur in multiple myeloma patients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models. PMID:25109893

Binsfeld, M; Fostier, K; Muller, J; Baron, F; Schots, R; Beguin, Y; Heusschen, R; Caers, J

2014-12-01

212

Clinical trials in cellular immunotherapy for brain/CNS tumors.  

PubMed

High-grade gliomas are the most common type of primary malignant brain/CNS tumor. There have been only modest advances in surgical techniques, radiotherapy and chemotherapy for high-grade gliomas over the past several decades. None of these have provided a major improvement in survival for patients. Recently, immunotherapy has been explored for the treatment of high-grade gliomas. Immunotherapy capitalizes on the specificity of the host immune system to selectively target tumor cells for destruction, while sparing normal brain parenchyma, thus making it a particularly attractive option. This article provides a comprehensive review of published clinical trials evaluating cellular immunotherapy in primary brain/CNS tumors. PMID:23545055

Badhiwala, Jetan; Decker, William K; Berens, Michael E; Bhardwaj, Ratan D

2013-04-01

213

Sublingual (SLIT) versus oral immunotherapy (OIT) for food allergy.  

PubMed

Food allergy is a common condition for which the only currently approved treatments are avoidance of the allergenic food and the administration of emergency medications upon accidental exposure. Over the past 10 years, significant advances have been made in the field of food immunotherapy, with efforts focusing on allergen exposure via the oral mucosa. Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are the two modalities that have been most extensively studied, and this article will review recent advances in our knowledge of the efficacy and safety of these treatments. PMID:25297805

McGowan, Emily C; Wood, Robert A

2014-12-01

214

INFORMED CONSENT FOR ALLERGY IMMUNOTHERAPY Allergy immunotherapy shots contain water extract of pollen mold or dust to which a patient has  

E-print Network

INFORMED CONSENT FOR ALLERGY IMMUNOTHERAPY Allergy immunotherapy shots contain water extract Levatol Zebeta Lopressor Metoprolol Ziac I hereby give consent to the University of Maryland Health Center for allergy immunotherapy and I further consent to the performance of such additional procedures

Milchberg, Howard

215

Troquier et al. Active tau immunotherapy Targeting phospho-Ser422 by active Tau immunotherapy in the THY-Tau22 mouse  

E-print Network

Troquier et al. Active tau immunotherapy 1 Targeting phospho-Ser422 by active Tau immunotherapy in the THY-Tau22 mouse model: a suitable therapeutic approach Running title: Active Tau immunotherapy Laëtitia Troquier1,2 , Raphaëlle Caillierez1,2 , Sylvie Burnouf1,2 , Francisco J

Paris-Sud XI, Université de

216

Rapid Isolation of Central Memory T Cells for Adoptive Immunotherapy  

Cancer.gov

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.

217

Peptide immunotherapy in models of allergic airways disease   

E-print Network

Allergen-reactive CD4+ T cells are implicated in the pathogenesis of allergic disease. Peptide immunotherapy (PIT) involves therapeutic administration of short immunodominant peptides from within the protein allergen to ...

MacKenzie, Karen Joan

2011-11-25

218

Immunotherapy for food allergies: a myth or a reality?  

PubMed

Food allergy is a worldwide issue, with an estimated prevalence of 2-10%. An effective treatment is not available for people affected and the only management is the avoidance of the allergen. Oral immunotherapy and sublingual immunotherapy have been tested by several authors, in particular for milk, egg and peanuts allergy, with significant results in term of desensitization induction. The achievement of tolerance is by the contrary doubtful, with different results obtained. In this review, we reviewed protocols of oral and sublingual immunotherapy for food allergy published in literature, mainly against milk, egg and peanut. At present, immunotherapy does not represent the gold standard in the treatment of food allergy, even if it can desensitize patients. PMID:25713990

Praticò, Andrea D; Leonardi, Salvatore

2015-02-01

219

Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy  

PubMed Central

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

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

2014-01-01

220

Clinical efficacy and safety of local nasal immunotherapy.  

PubMed

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

1997-01-01

221

Toxoplasmic encephalitis during mycophenolate mofetil immunotherapy of neuromuscular disease  

PubMed Central

Objective: To show that immunotherapy with medications such mycophenolate mofetil (MMF) can cause serious complications in patients with neuromuscular disorders. Methods: Two patients with neuromuscular disorders on immunotherapy with long-term MMF who developed toxoplasmic encephalitis (TE) were included in this case series. Results: One patient with myasthenia gravis and one patient with inflammatory myopathy on immunotherapy with long-term MMF developed severe TE. Diagnosis was based on clinical presentation, MRI brain imaging characteristics, and CSF PCR positivity for Toxoplasma gondii. Both patients were treated with pyrimethamine, sulfadiazine, and leucovorin for 2 months without clinical improvement, and both died. Conclusions: Immunotherapy with medications such as MMF can cause devastating TE in non-HIV patients with neuromuscular disorders. Early consideration and recognition of this complication is important to possibly prevent unfavorable outcomes. The utility of screening and prophylaxis against toxoplasmosis in individuals with neuroimmunologic disorders and other autoimmune disorders who receive immunosuppressive therapy requires future study. PMID:25635260

Chahin, Nizar

2015-01-01

222

Aluminium in Allergies and Allergen immunotherapy.  

PubMed

Aluminium is a hot topic in the current debate. Exposure occurs due to environmental, dietary and intentional exposure to aluminium, such as in vaccines where it was introduced in 1926. In spite of the fact that it is a typical Th2 adjuvant, aluminium redirects the immune response in systemic allergen immunotherapy (SIT) upon prolonged immunization. SIT in the US, and SLIT in general, are at present non-adjuvanted therapies, but in Europe aluminium is used as adjuvant in most SIT preparations. It enhances the safety of SIT by local deposition of the allergen. Undesired properties of aluminium adjuvants comprise acute and chronic inflammation at the injection site, its Th2 immune stimulatory capacity, its accumulation besides biodistribution in the body. The adjuvant and safety profile of aluminium adjuvants in allergy vaccines are discussed, as well as the need for putting modern delivery systems and adjuvants on the fast track. PMID:25780491

Jensen-Jarolim, Erika

2015-01-01

223

Oncolytic viruses: a novel form of immunotherapy  

PubMed Central

Oncolytic viruses are novel anticancer agents, currently under investigation in Phase I–III clinical trials. Until recently, most studies have focused on the direct antitumor properties of these viruses, although there is now an increasing body of evidence that the host immune response may be critical to the efficacy of oncolytic virotherapy. This may be mediated via innate immune effectors, adaptive antiviral immune responses eliminating infected cells or adaptive antitumor immune responses. This report summarizes preclinical and clinical evidence for the importance of immune interactions, which may be finely balanced between viral and tumor elimination. On this basis, oncolytic viruses represent a promising novel immunotherapy strategy, which may be optimally combined with existing therapeutic modalities. PMID:18925850

Prestwich, Robin J; Harrington, Kevin J; Pandha, Hardev S; Vile, Richard G; Melcher, Alan A; Errington, Fiona

2009-01-01

224

Adoptive cellular immunotherapy for childhood malignancies.  

PubMed

Clinical trials have established that T cells have the ability to prevent and treat pathogens and tumors. This is perhaps best exemplified by engraftment of allogeneic T cells in the context of hematopoietic stem-cell transplantation (HSCT), which for over the last 50 years remains one of the best and most robust examples of cell-based therapies for the treatment of hematologic malignancies. Yet, the approach to infuse T cells for treatment of cancer, in general, and pediatric tumors, in particular, generally remains on the sidelines of cancer therapy. This review outlines the current state-of-the-art and provides a rationale for undertaking adoptive immunotherapy trials with emphasis on childhood malignancies. PMID:18026145

Cooper, L J N

2008-01-01

225

The delicate balance of melanoma immunotherapy  

PubMed Central

The strategy of immune modulation for the treatment of cancer is being refined with the introduction of multiple new therapeutic agents into the clinic. Melanoma is a disease where many of these agents have demonstrated efficacy. The mechanisms of action of these agents exploit the counter-regulatory mechanisms of the immune response. However, these agents are also associated with immune-related adverse events (IRAEs), which represent tissue-specific inflammatory responses. These IRAEs highlight the delicate balance of immunologic homeostasis and, with some interventions, may occur more frequently in patients who sustain a therapeutic response. This review will discuss melanoma immunogenicity and immunotherapy. Furthermore, the spectrum and distinction between a reversible immune adverse event and autoimmunity will be highlighted. PMID:25505953

Gyorki, David E; Callahan, Margaret; Wolchok, Jedd D; Ariyan, Charlotte E

2013-01-01

226

Once Daily Sublingual Immunotherapy without Updosing – A New Treatment Schedule  

Microsoft Academic Search

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

2006-01-01

227

Laser immunotherapy: a novel treatment modality for metastatic tumors.  

PubMed

Laser immunotherapy is a novel approach for the treatment of metastatic tumors. It combines a selective photothermal laser-tissue interaction for direct tumor destruction and an immunoadjuvant-directed simulation for immune responses. In experiments using a rat metastatic tumor model, laser immunotherapy resulted in the eradication of both treated primary tumors and untreated metastases at remote sites. It also induced anti-tumor resistance. PMID:13679633

Chen, Wei R; Carubelli, Raoul; Liu, Hong; Nordquist, Robert E

2003-09-01

228

A new approach for cellular immunotherapy of nasopharyngeal carcinoma  

PubMed Central

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy that is highly prevalent in Southern China and South-East Asia. EBV-targeted immunotherapy remains a goal in the development of novel treatment strategies. A novel adenoviral polyepitope-based immunotherapy has been developed to rapidly generate high frequency EBV-specific T cells to treat patients with refractory or metastatic disease. PMID:23243622

Smith, Corey; Khanna, Rajiv

2012-01-01

229

A new approach for cellular immunotherapy of nasopharyngeal carcinoma.  

PubMed

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy that is highly prevalent in Southern China and South-East Asia. EBV-targeted immunotherapy remains a goal in the development of novel treatment strategies. A novel adenoviral polyepitope-based immunotherapy has been developed to rapidly generate high frequency EBV-specific T cells to treat patients with refractory or metastatic disease. PMID:23243622

Smith, Corey; Khanna, Rajiv

2012-11-01

230

Immunotherapy Approaches for Malignant Glioma From 2007 to 2009  

Microsoft Academic Search

Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous\\u000a treatments were largely unsuccessful, glioma may be an ideal target for immune-based therapy. Recently, translational research\\u000a led to several clinical trials based on tumor immunotherapy to treat patients with malignant glioma. Here we review 17 recent\\u000a glioma immunotherapy clinical trials,

Laura A. Johnson; John H. Sampson

2010-01-01

231

Immunotherapy of Childhood Cancer: From Biologic Understanding to Clinical Application  

PubMed Central

Purpose of review Most children with cancer can be cured with combination regimens of chemotherapy, radiation, and/or surgery. However, standard therapies are toxic to normal tissues, cancer cells commonly develop resistance to chemotherapy, and relapsed malignancy is a leading cause of mortality in pediatrics. Elucidation of the principles of the normal immune response and tumor biology, coupled with technological developments, have led to important advances in the field of cancer immunotherapy. This review summarizes the biologic basis of cancer immunotherapy and highlights recent examples of progress in the application of novel humoral and cellular immunotherapies to children and adolescents with malignancy. Recent Findings Clinical trials of immunotherapy for pediatric cancer have recently been initiated. To date, most immune-based therapies have been well tolerated and some have shown clinically significant activity against specific refractory high-risk malignancies. Summary Recent clinical trial results provide proof-of-principle that cancer immunotherapy has the capacity to overcome chemotherapy resistance without the usual toxicities associated with cytotoxic regimens. Immunotherapy holds promise in the treatment of children and adolescents with cancer and has the potential to improve both survival and quality of life. PMID:19952749

Wayne, Alan S.; Capitini, Christian M.; Mackall, Crystal L.

2010-01-01

232

The relationship between allergen immunotherapy and omalizumab for treating asthma.  

PubMed

Allergen-specific immunotherapy (AIT) is considered the only treatment capable of modifying the natural history of allergic respiratory disorders. The possible adverse events related to AIT have, until now, limited its use to mild and controlled asthma. The pre-administration or concomitant treatment of AIT and omalizumab (an anti-IgE humanized antibody), recommended for the treatment of severe allergic asthma, could be useful in reducing the adverse events due to AIT and to allow its use in patients with more severe or uncontrolled asthma. AIT/omalizumab combination has been explored in a few trials on asthma patients and also in other allergic disorders, such as rhinitis, hymenoptera systemic reaction and food allergy with significant results. We are at the beginning a new era where phenotype/endotype-based treatment will be associated with drug mass therapy and/or nonpharmacological phenotype/endotype-driven treatment to optimize disease control and/or to make the use of other treatments safer. PMID:25578528

Braido, Fulvio; Corsico, Angelo; Rogkakou, Anthi; Ronzoni, Vanessa; Baiardini, Ilaria; Canonica, Giorgio Walter

2015-04-01

233

Perspectives in vaccine adjuvants for allergen-specific immunotherapy.  

PubMed

The design of more powerful adjuvants is a tool of crucial interest to ameliorate vaccination strategies to reduce injections and/or dose of antigen, induce local immunity and obtain better protection. Effective anti-infectious vaccines should elicit protective TH1 responses, cytotoxic CD8+ cells and antibody-forming cells. However, cytokine microenvironment is a key point also in targeted therapeutic vaccinations, such as allergen-specific immunotherapy, where the interference with an already-existing but inappropriate immunity is required. In this case, safe, appropriately conditioning and potentially orally available adjuvants together with delivery to appropriate subsets of dendritic cells would be highly appreciated to properly boost innate immune cells. In fact, aluminium hydroxide, although safe, has been classically associated with the induction of a TH2 response to co-formulated antigens. Thus, detoxified lipopolysaccaride (MPL-A), CpG oligonucleotides, imidazoquinolines and adenine derivatives acting via innate sensors may represent improvements in therapeutic vaccinations for allergy as able to interfere with pathogenic TH2 cells with eventual induction of TH1 differentiation. PMID:24361819

Filì, Lucia; Cardilicchia, Elisa; Maggi, Enrico; Parronchi, Paola

2014-10-01

234

Immunotherapies to Prevent Mother-to-Child Transmission of HIV  

PubMed Central

Although pharmacological interventions have been successful in reducing prevention of maternal to child transmission (PMTCT) of HIV, there is concern that complete elimination through this mode of transmission will require other measures. Immunotherapies in infants or pregnant mothers may be able to eradicate this form of transmission. A recent vaccine trial in adults showed encouraging results, but as in most HIV safety and efficacy vaccine trials, the question of MTCT was not addressed. Concentrating transmission studies and vaccine studies in the setting of MTCT offers several advantages. MTCT has a generally reproducible known transmission rate and has been successfully used to assess pharmacological interventions on decreasing transmission. Even in resource poor settings, the infrastructure for neonatal vaccination is already in place. Although rare, both passive and active vaccination trials have been successfully completed in pediatric populations. Unfortunately, little success in affecting MTCT has been shown. Largely, a correlate of protection in any type of transmission, including MTCT, is unknown. Data supports a role for antibodies in effecting strain and transmission during MTCT. The role of antibodies in MTCT is reviewed with a focus on recent passive immunization and considerations for future studies. PMID:23432489

Hicar, Mark D.

2013-01-01

235

Streptococcal immunotherapy of a chemically induced murine fibrosarcoma: Effect of dose, route, sham surgery, and splenectomy on adjuvant action  

Microsoft Academic Search

Adjuvant immunotherapy with hemolytic streptococci abates the growth of a syngeneic methylcholanthrene (MCA)-induced fibrosarcoma propagated in C3H\\/HeJ mice. Interperitoneal (IP) administration of streptococci either prior to or after tumor inoculation reduced neoplastic outgrowth. While subcutaneous (SC) administration of streptococci prior to tumor inoculation did not influence tumor outgrowth, SC treatment afterwards was effective. Thus, therapeutic effects of streptococcal vaccine depend

Hisakazu Yamagishi; Neal R. Pellis; Barry D. Kahan

1980-01-01

236

Immunotherapy for Alzheimer's disease: hoops and hurdles.  

PubMed

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

2013-01-01

237

Temperature control in interstitial laser cancer immunotherapy  

NASA Astrophysics Data System (ADS)

Positive results of Laser-Assisted Cancer Immunotherapy (LACI) have been reported previously in the irradiation of superficial tumors. This paper reports the effect of LACI using laser interstitial therapy approach. We hypothesize that the maximum immuno response depends on laser induced tumor temperature. The measurement of tumor temperature is crucial to ensure necrosis by thermal damage and immuno response. Wister Furth female rats in this study were inoculated with 13762 MAT B III rat mammary adinocarcinoma. LACI started seven to ten days following inoculation. Contrary to surface irradation, we applied laser interstitial irradiation of tumor volume to maximize the energy deposition. A diode laser with a wavelength of 805 nm was used for tumor irradiation. The laser energy was delivered inside the tumor through a quartz fiber. Tumor temperature was measured with a micro thermocouple (interstitial), while the tumor surface temperature was controlled with an IR detector. The temperature feedback demonstrates that it is possible to maintain the average tumor temperature at the same level with reasonable accuracy in the desired range from 65°C-85°C. In some experiments we used microwave thermometry to control average temperature in deep tissue for considerable period of time, to cause maximum thermal damage to the tumor. The experimental set-up and the different temperature measurement techniques are reported in detail, including the advantages and disadvantages for each method.

Bandyopadhyay, Pradip K.; Holmes, Kyland; Burnett, Corinthius; Zharov, Vladimir P.

2003-07-01

238

Oral immunotherapy and tolerance induction in childhood.  

PubMed

Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food-allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long-term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy. PMID:23905867

Tang, M L K; Martino, D J

2013-09-01

239

[Immunotherapies for multiple sclerosis : Review and update].  

PubMed

Multiple sclerosis (MS) is an inflammatory, presumably autoimmune disease affecting the central nervous system. Early stages of the disease are characterized by conspicuous inflammation of the white and grey matter. During later stages, presumably secondary neurodegeneration leads to physical disability progression. Over the last decade increasingly effective therapeutic options have been approved. Currently 11 immunomodulatory or immunosuppressive therapies targeting relapse rate, disease progression and paraclinical disease activity are available, mostly for relapsing forms of MS. However, the ideal of "precision medicine" is still in the distant future since biomarkers for individualized treatment are lacking. For implementation of risk-management plans to minimize the risk of severe side effects, interdisciplinary collaboration between neurologists and internists is essential. In this review article we summarize practical aspects of the implemented risk-management plans, and discuss possible side effects and special caveats of the three new immunotherapies teriflunomide, dimethyl fumarate, and alemtuzumab. This article is based on, among others, the recently updated guidelines of the German Society of Neurology. Particular attention is given to the risks of new therapies, monitoring, and on special aspects needing attention when changing treatments. Teriflunomide, dimethyl fumarate, and alemtuzumab expand treatment options for relapsing-remitting MS. Treatment selection should take into consideration the safety profile of the substance, previous and concomitant diseases, and other individual factors. This requires in-depth consultation and individual assessment of current disease activity, the potential efficacy of the therapy, and the possible risks and side effects. PMID:25720530

Havla, J; Kümpfel, T; Hohlfeld, R

2015-04-01

240

The role of immunotherapy in colorectal cancer.  

PubMed

Despite landmark advances in the molecular biology and surgical adjuvant therapy of colorectal cancer in the past decade, this illness remains a significant health hazard. Conventional therapies, including surgery, radiation therapy, and chemotherapy, have had limited utility and have often resulted in unacceptable host toxicities. Therapies dependent on potentiation of the host immune response are attractive alternatives to conventional treatment because of their greater specificity and diminished toxicity. Furthermore, the efficacy of many of these therapies has been demonstrated in preclinical models, which is important given the relative refractoriness of colorectal cancer to chemotherapy. Both active specific therapies, such as tumor vaccines, and passive therapies, such as monoclonal antibodies, have been investigated. In early clinical trials, both have demonstrated modest activity. Nonspecific immune stimulation with agents such as bacillus Calmette-Guérin or methanol extraction residue appear to have little utility, but with the development of recombinant DNA technology, specific cytokines with more precisely identified targets have been synthesized in sufficient quantities for clinical trials. Finally, combinations of biologics or combinations of biologics with conventional therapies, such as fluorouracil (5-FU)/levamisole and 5-FU/interferon, have been investigated and appear to be useful in the treatment of surgically resected and advanced colorectal carcinoma, respectively. The utility of these therapies is hampered by a limited understanding of their precise mechanisms of action and optimal conditions for administration. Nevertheless, immunotherapy of colorectal carcinoma remains an important and promising area for further clinical investigation. PMID:1992528

Wadler, S

1991-02-01

241

Cellular immunotherapy for pediatric solid tumors.  

PubMed

Substantial progress has been made in the treatment of pediatric solid tumors over the past 4 decades. However, children with metastatic and or recurrent disease continue to do poorly despite the aggressive multi-modality conventional therapies. The increasing understanding of the tumor biology and the interaction between the tumor and the immune system over the recent years have led to the development of novel immune-based therapies as alternative options for some of these high-risk malignancies. The safety and anti-tumor efficacy of various tumor vaccines and tumor-antigen specific immune cells are currently being investigated for various solid tumors. In early clinical trials, most of these cellular therapies have been well tolerated and have shown promising clinical responses. Although substantial work is being done in this field, the available knowledge for pediatric tumors remains limited. We review the contemporary early phase cell-based immunotherapy efforts for pediatric solid tumors and discuss the rationale and the challenges thereof. PMID:25082406

Hegde, Meenakshi; Moll, Alexander J; Byrd, Tiara T; Louis, Chrystal U; Ahmed, Nabil

2015-01-01

242

Immunotherapy for advanced melanoma: fulfilling the promise.  

PubMed

The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:23725878

Gogas, Helen; Polyzos, Aristidis; Kirkwood, John

2013-12-01

243

Recent developments on immunotherapy for brain cancer  

PubMed Central

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. PMID:22533851

Wainwright, Derek; Nigam, Pragati; Thaci, Bart; Dey, Mahua

2012-01-01

244

Sarcoma Immunotherapy: Past Approaches and Future Directions  

PubMed Central

Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. PMID:24778572

D'Angelo, S. P.; Tap, W. D.; Schwartz, G. K.; Carvajal, R. D.

2014-01-01

245

Immunotherapy of melanoma: targeting defined antigens.  

PubMed

The clinical experience that spontaneous anti-melanoma immune reactivity can occur has stimulated the search for methods to induce this in patients diagnosed with melanoma. Non-specific approaches using a variety of immune stimulants such as BCG or cytokines have met with limited success, as have vaccines derived from tumour cells. More recently, melanoma antigens have been identified that can act as specific targets for immune recognition. Cell surface glycolipids such as the gangliosides GM2 and GD3, can be targeted by antibodies. This has provided the basis for clinical trials with ganglioside vaccines and monoclonal antibody infusions. Antigens recognized by cytotoxic lymphocytes have also been described in the last 5 years. These are peptide antigens derived from intracellular proteins which are present on the cell surface in association with HLA molecules. These antigens include MAGE 1 and 3, tyrosinase, MelanA/MART-1 and gp100. Clinical trials with these have commenced and novel treatment strategies are being developed. Since tumours can be typed for specific antigens and specific immune responses can be measured, the reasons for treatment success or failure can be analysed more effectively than in the past. For example, the emergence of antigen-negative tumour variants can be assessed. This should enable a more systematic approach for developing new immunotherapies for melanoma. PMID:10994477

Cebon, J; MacGregor, D; Scott, A; DeBoer, R

1997-06-01

246

Open questions for Alzheimer’s disease immunotherapy  

PubMed Central

Perhaps more definitively than any other class of novel Alzheimer’s disease (AD) therapy, pre-clinical studies in mouse models of amyloid ? (A?) deposition have established the disease-modifying potential of anti-A? immunotherapy. Despite disappointing results to date from anti-A? immunotherapy therapeutic trials, there is continued hope that such immunotherapies, especially if used in the preclinical stages, could prove to be the first disease-modifying therapies available for AD. The general optimism that A?-targeting and emerging tau-targeting immunotherapies may prove to be disease modifying is tempered by many unanswered questions regarding these therapeutic approaches, including but not limited to i) lack of precise understanding of mechanisms of action, ii) the factors that regulate antibody exposure in the brain, iii) the optimal target epitope, and iv) the mechanisms underlying side effects. In this review I discuss how answering these and other questions could increase the likelihood of therapeutic success. As passive immunotherapies are also likely to be extremely expensive, I also raise questions relating to cost-benefit of biologic-based therapies for AD that could limit future impact of these therapies by limiting access due to economic constraints. PMID:24393284

2014-01-01

247

Bone-marrow mesenchymal stem cells reduce rat intestinal ischemia-reperfusion injury, ZO-1 downregulation and tight junction disruption via a TNF-?-regulated mechanism  

PubMed Central

AIM: To investigate the effect of bone-marrow mesenchymal stem cells (BM MSCs) on the intestinal mucosa barrier in ischemia/reperfusion (I/R) injury. METHODS: BM MSCs were isolated from male Sprague-Dawley rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. I/R injury was induced by occlusion of the superior mesenteric artery for 30 min. Rats were treated with saline, BM MSCs (via intramucosal injection) or tumor necrosis factor (TNF)-? blocking antibodies (via the tail vein). I/R injury was assessed using transmission electron microscopy, hematoxylin and eosin (HE) staining, immunohistochemistry, western blotting and enzyme linked immunosorbent assay. RESULTS: Intestinal permeability increased, tight junctions (TJs) were disrupted, and zona occludens 1 (ZO-1) was downregulated after I/R injury. BM MSCs reduced intestinal mucosal barrier destruction, ZO-1 downregulation, and TJ disruption. The morphological abnormalities after intestinal I/R injury positively correlated with serum TNF-? levels. Administration of anti-TNF-? IgG or anti-TNF-? receptor 1 antibodies attenuated the intestinal ultrastructural changes, ZO-1 downregulation, and TJ disruption. CONCLUSION: Altered serum TNF-? levels play an important role in the ability of BM MSCs to protect against intestinal I/R injury. PMID:23801859

Shen, Zhong-Yang; Zhang, Jing; Song, Hong-Li; Zheng, Wei-Ping

2013-01-01

248

Immunotherapy of Cancer: Reprogramming Tumor-Immune Crosstalk  

PubMed Central

The advancement of cancer immunotherapy faces barriers which limit its efficacy. These include weak immunogenicity of the tumor, as well as immunosuppressive mechanisms which prevent effective antitumor immune responses. Recent studies suggest that aberrant expression of cancer testis antigens (CTAs) can generate robust antitumor immune responses, which implicates CTAs as potential targets for immunotherapy. However, the heterogeneity of tumor cells in the presence and quantity of CTA expression results in tumor escape from CTA-specific immune responses. Thus, the ability to modulate the tumor cell epigenome to homogenously induce expression of such antigens will likely render the tumor more immunogenic. Additionally, emerging studies suggest that suppression of antitumor immune responses may be overcome by reprogramming innate and adaptive immune cells. Therefore, this paper discusses recent studies which address barriers to successful cancer immunotherapy and proposes a strategy of modulation of tumor-immune cell crosstalk to improve responses in carcinoma patients. PMID:23097673

Payne, Kyle K.; Toor, Amir A.; Wang, Xiang-Yang; Manjili, Masoud H.

2012-01-01

249

Therapeutic Effects and Biomarkers in Sublingual Immunotherapy: A Review  

PubMed Central

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. PMID:22500184

Fujimura, Takashi; Okamoto, Yoshitaka; Taniguchi, Masaru

2012-01-01

250

[Current research advance on cellular immunotherapy for leukemia-review].  

PubMed

Despite the chemotherapy is successful in inducing remission of hematologic malignancy, this disease also has a high probability of relapse; besides, the toxicity of chemotherapy for these patients can not be avoided. Researchers have been attempting to eliminate tumor cells by immunotherapy. Recently, various leukemia-associated antigens (LAA) that are recognized by cytotoxic T cell (CTL) in the context of HLA class I molecules have been identified. These LAA include WT1, PR-3, RHAMM, BCR-ABL and Aur-A. On the basis of these findings, various clinical trials of immunotherapy for hematologic malignancy including tumor peptide vaccination, adoptive T cell therapy, NK cell therapy and dendritic cells-cytokine induced killer (DC-CIK) cell therapy are on going. In this review, the current status and future feasibility of cellular immunotherapy for leukemia are discussed. PMID:24156459

Tian, Hong; Chen, Guang-Hua; Xu, Yang; Qiao, Man; Liu, Hui-Wen; Wu, De-Pei

2013-10-01

251

Immunotherapy and lung cancer: current developments and novel targeted therapies.  

PubMed

Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician's therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC. PMID:25496336

Domingues, Duarte; Turner, Alice; Silva, Maria Dília; Marques, Dânia Sofia; Mellidez, Juan Carlos; Wannesson, Luciano; Mountzios, Giannis; de Mello, Ramon Andrade

2014-01-01

252

Interleukin-13 Receptor Alpha 2-Targeted Glioblastoma Immunotherapy  

PubMed Central

Glioblastoma (GBM) is the most lethal primary brain tumor, and despite several refinements in its multimodal management, generally has very poor prognosis. Targeted immunotherapy is an emerging field of research that shows great promise in the treatment of GBM. One of the most extensively studied targets is the interleukin-13 receptor alpha chain variant 2 (IL13R?2). Its selective expression on GBM, discovered almost two decades ago, has been a target for therapy ever since. Immunotherapeutic strategies have been developed targeting IL13R?2, including monoclonal antibodies as well as cell-based strategies such as IL13R?2-pulsed dendritic cells and IL13R?2-targeted chimeric antigen receptor-expressing T cells. Advanced therapeutic development has led to the completion of several clinical trials with promising outcomes. In this review, we will discuss the recent advances in the IL13R?2-targeted immunotherapy and evaluate the most promising strategy for targeted GBM immunotherapy. PMID:25247196

Crawford, Andrew C.

2014-01-01

253

Combining Immunotherapy and Targeted Therapies in Cancer Treatment  

PubMed Central

Preface During the past two decades, the paradigm for cancer treatment has evolved from relatively non-specific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain a backbone of current treatment, but are limited by a narrow therapeutic index, significant toxicities, and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are critical to tumor growth and maintenance, whereas immunotherapy endeavors to stimulate a host response that effectuates long-lived tumor destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes. PMID:22437869

Vanneman, Matthew; Dranoff, Glenn

2014-01-01

254

Carbohydrate-based particles: a new adjuvant for allergen-specific immunotherapy  

PubMed Central

The occurrence of systemic anaphylactic side-effects in the course of allergen-specific immunotherapy has been strongly reduced by the adsorption of allergens to aluminium hydroxide, the most frequently used adjuvant in humans. Using the major timothy grass pollen allergen, Phl p 5b, in its recombinant form for immunization of mice, we demonstrate that carbohydrate-based particles (CBP) exhibit several potential advantages over aluminium-hydroxide as adjuvant for immunotherapy. Similar to alum-bound rPhl p 5b, CBP-bound rPhl p 5b induced a stronger antibody and cytokine response than unbound rPhl p 5b after subcutaneous injection in mice. The antibodies induced by CBP-bound rPhl p 5b, exhibited potentially beneficial activities as they cross-reacted with group 5 allergens from five other grass species and inhibited the binding of grass pollen allergic patients IgE to Phl p 5b. Alum-bound rPhl p 5b induced a preferential allergen-specific Th2-response characterized by high immunoglobulin G1 (IgG1) antibody levels and elevated interleukin (IL)-4 and IL-5 production in cultured splenocytes. By contrast, CBP-bound rPhl p 5b, but not rPhl p 5b alone or coadministered with CBP, induced a mixed allergen-specific T helper 1 (Th1)/Th2 immune response characterized by the additional production of allergen-specific IgG2a/b antibody responses and elevated interferon-? production. Conjugation of rPhl p 5b to CBP yielded a stable vaccine formulation with preserved immunogenic features of the allergen and, in contrast to alum, induced no granulomatous tissue reactions. Based on these results, CBP is suggested as a potentially useful adjuvant for specific immunotherapy of IgE-mediated allergies. PMID:12460198

Grönlund, Hans; Vrtala, Susanne; Wiedermann, Ursula; Dekan, Gerhard; Kraft, Dietrich; Valenta, Rudolf; Van Hage-Hamsten, Marianne

2002-01-01

255

ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro.  

PubMed

CD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleavage of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)-expressing non-target cells. Because antibodies bind to sCD30, this results in unwanted antibody binding to these cells via sCD30 bridging. To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release. Shedding of CD30 can be enhanced by protein kinase C (PKC) activation, implicating the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. However, antibody-induced CD30 shedding is calcium dependent and PKC independent. This shedding involved the related metalloproteinase ADAM10 as shown by the use of the preferential ADAM10 inhibitor GI254023X and by an ADAM10-deficient cell line generated from embryonically lethal ADAM10(-/-) mouse. In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin's lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side effects of immunotherapy with monoclonal antibodies. PMID:17210715

Eichenauer, Dennis A; Simhadri, Vijaya Lakshmi; von Strandmann, Elke Pogge; Ludwig, Andreas; Matthews, Vance; Reiners, Katrin S; von Tresckow, Bastian; Saftig, Paul; Rose-John, Stefan; Engert, Andreas; Hansen, Hinrich P

2007-01-01

256

Cellular immunotherapy for refractory hematological malignancies  

PubMed Central

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. PMID:23782682

2013-01-01

257

Targeted immunotherapy for non-small cell lung cancer.  

PubMed

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. PMID:24829850

Vasekar, Monali; Liu, Xin; Zheng, Hong; Belani, Chandra P

2014-05-10

258

Porous silicon advances in drug delivery and immunotherapy  

PubMed Central

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

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

2013-01-01

259

Immunotherapy in allergy and cellular tests: state of art.  

PubMed

The basophil activation test (BAT) is an in vitro assay where the activation of basophils upon exposure to various IgE-challenging molecules is measured by flow cytometry. It is a cellular test able to investigate basophil behavior during allergy and allergy immunotherapy. A panoply of critical issues and suggestive advances have rendered this assay a promising yet puzzling tool to endeavor a full comprehension of innate immunity of allergy desensitization and manage allergen or monoclonal anti-IgE therapy. In this review a brief state of art of BAT in immunotherapy is described focusing onto the analytical issue pertaining BAT performance in allergy specific therapy. PMID:24717453

Chirumbolo, Salvatore

2014-01-01

260

Novel anti-melanoma treatment: focus on immunotherapy  

PubMed Central

Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma. PMID:25189718

Hao, Meng-Ze; Zhou, Wen-Ya; Du, Xiao-Ling; Chen, Ke-Xin; Wang, Guo-Wen; Yang, Yun; Yang, Ji-Long

2014-01-01

261

Prolonged overall survival in gastric cancer patients after adoptive immunotherapy  

PubMed Central

AIM: To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes (EAALs) in gastric cancer. METHODS: An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients, of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment (control group). EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination. Clinical data including age, gender, clinical stage, chemotherapeutic regimens, hospitalization, surgical, radiotherapy, and survival data were collected along with EAAL therapy details and side effects. Patients were followed and the relationship between treatment and overall survival (OS) data obtained for the immunotherapy and control groups were compared retrospectively. The safety of EAAL immunotherapy was also evaluated. RESULTS: After in vitro culture and proliferation, the percentages of CD3+, CD3+CD8+, CD8+CD27+, CD8+CD28+, and CD3+CD16+/CD56+ cells increased remarkably (P < 0.05), while the percentages of CD3+CD4+, CD4+CD25+, and CD3-CD16+/CD56+ (natural killer cells) were overtly decreased (P < 0.05); no significant change was observed in CD4+CD25+CD127- cells (P = 0.448). Interestingly, OS in the immunotherapy group was significantly higher than that in the control group, with 27.0 and 13.9 mo obtained for the two groups, respectively (P = 0.028, HR = 0.573, 95%CI: 0.347-0.945). These findings indicated a 42.7% decrease in the risk of death. In addition, we found that clinical stage and application of EAAL immunotherapy were independent prognostic factors for gastric cancer patients. Indeed, the OS in stage IIIc and IV patients that had received surgery was prolonged after EAAL immunotherapy (P < 0.05). Importantly, in vitro induction and proliferation of EAAL were easy and biologically safe. CONCLUSION: Overall, EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.

Zhang, Guo-Qing; Zhao, Hong; Wu, Jian-Yu; Li, Jin-Yu; Yan, Xiang; Wang, Gang; Wu, Liang-Liang; Zhang, Xiao-Gang; Shao, Yi; Wang, Yu; Jiao, Shun-Chang

2015-01-01

262

Dual B Cell Immunotherapy Is Superior to Individual Anti-CD20 Depletion or BAFF Blockade in Murine Models of Spontaneous or Accelerated Lupus  

PubMed Central

Objective To determine whether a combination of B cell depletion and BAFF blockade is more effective than monotherapy in treating models of spontaneous or accelerated systemic lupus erythematosus (SLE) in (NZB × NZW)F1 mice. Methods Clinical parameters such as disease progression–free survival, proteinuria, and renal injury were assessed in models of spontaneous, interferon-? (IFN?)–accelerated, or pristane-accelerated lupus in (NZB × NZW)F1 mice. Treatment arms included anti-CD20 (B cell depletion), B lymphocyte stimulator receptor 3 fusion protein (BR-3-Fc) (BAFF blockade), the combination of anti-CD20 and BR-3-Fc, isotype control, or cyclophosphamide. In models of spontaneous, IFN?-accelerated, or pristane-accelerated lupus, mice were treated for 24 weeks, 8 weeks, or 12 weeks, respectively. Peripheral and resident B cell subsets and various autoantibodies were examined. Results Compared to B cell depletion or BAFF blockade alone, combined therapy significantly improved disease manifestations in all 3 lupus models. In addition, marginal zone B cells, plasmablasts, and circulating and tissue plasma cells were decreased more effectively. Dual B cell immunotherapy also reduced multiple classes of pathogenic autoantibodies, consistent with its observed effectiveness in reducing immune complex–mediated renal injury. Conclusion Dual immunotherapy via B cell depletion and BAFF blockade is more efficacious than single agent immunotherapy in murine SLE models, and this combination treatment is predicted to be an effective strategy for immunotherapy in human SLE. PMID:25303150

Lin, WeiYu; Seshasayee, Dhaya; Lee, Wyne P; Caplazi, Patrick; McVay, Sami; Suto, Eric; Nguyen, Allen; Lin, Zhonghua; Sun, Yonglian; DeForge, Laura; Balazs, Mercedesz; Martin, Flavius; Zarrin, Ali A

2015-01-01

263

Safety and efficacy studies of liposomes in specific immunotherapy  

Microsoft Academic Search

Liposomes are lipid vesicles that have been extensively investigated because of their immunoadjuvant properties and their capacity to transport a variety of therapeutic agents. This article reports the results of 4 safety and efficacy studies of multilamellar liposomes used to incorporate an allergen extract in specific immunotherapy. The first study showed that cutaneous tolerance of encapsulated allergen extracts (5 grass

Sylvie Galvain; Claude André; Christine Vatrinet; Bertrand Villet

1999-01-01

264

Pollinex Quattro: an innovative four injections immunotherapy in allergic rhinitis.  

PubMed

The prevalence of seasonal allergic rhinitis in the western world is high and increasing. Besides considerably affecting physical and psychosocial aspects of patients' lives, allergic rhinitis is often associated with allergic asthma and may aggravate this condition over time. Specific immunotherapy is currently the only approved therapy that can modify the underlying disease process and induce long-term tolerance to allergens. Pollinex Quattro is a subcutaneous four injections immunotherapy consisting of tyrosine-absorbed specific allergoids and enhanced with the adjuvant monophosphoryl lipid A (MPL(®)). MPL(®) induces a significant Th 1-type immune response, characterized by an increase of allergen-specific IgG antibody levels and dampening of the IgE response during allergen exposure. Due to this dual action of stimulating the immune system, Pollinex Quattro is clinically effective after only four injections given pre-seasonally. A large clinical program has demonstrated efficacy and tolerability of Pollinex Quattro in children, adolescents and adults with grass and tree pollen allergy. A health economics study concluded that an immunotherapy with only 4 injections might be more cost-beneficial than other application forms of immunotherapy. PMID:23584250

Rosewich, Martin; Lee, Denise; Zielen, Stefan

2013-07-01

265

Adoptive immunotherapy for cancer: harnessing the T cell response  

Microsoft Academic Search

Immunotherapy based on the adoptive transfer of naturally occurring or gene-engineered T cells can mediate tumour regression in patients with metastatic cancer. Here, we discuss progress in the use of adoptively transferred T cells, focusing on how they can mediate tumour cell eradication. Recent advances include more accurate targeting of antigens expressed by tumours and the associated vasculature, and the

Mark E. Dudley; Nicholas P. Restifo; Steven A. Rosenberg

2012-01-01

266

From Bench to Bedside: Immunotherapy for Prostate Cancer  

PubMed Central

The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided. PMID:25276838

Tse, Brian Wan-Chi; Jovanovic, Lidija; Nelson, Colleen Coyne; de Souza, Paul; Power, Carl Andrew; Russell, Pamela Joan

2014-01-01

267

Can Alzheimer disease be prevented by amyloid-? immunotherapy?  

Microsoft Academic Search

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

Cynthia A. Lemere; Eliezer Masliah

2010-01-01

268

Sublingual Immunotherapy in Allergic Rhinitis: Efficacy, Safety, Adherence and Guidelines  

PubMed Central

Allergic rhinitis (AR) is a globally increasing health problem affecting the quality of life. Specific immunotherapy is an available causal treatment changing the basic allergic mechanisms of the disease. Over one hundred years, subcutaneous immunotherapy (SCIT) was developed and proved its efficacy but many adverse effects were recorded including anaphylaxis. In 1986, sublingual immunotherapy (SLIT) was introduced as an alternative solution to solve this problem. Our study aims to discuss SLIT from the points of efficacy, safety, adherence and guidelines developed. A literature search was conducted in Medline/PubMed and the Cochrane Library in January 2013 using the keywords "allergic rhinitis, sublingual immunotherapy, efficacy, safety, compliance, adherence, guidelines." All types of publications were included. We augmented our study by searching the reference lists of identified reviews. SLIT has been established in many guidelines as an evidence-based effective treatment in AR with safer profile than SCIT. The meta-analyses confirmed its efficacy and showed a significant reduction in both symptoms and medication scores. The most common recorded adverse effects were minor local effects in the mouth, gastrointestinal reactions with few cases of anaphylaxis and no fatality. Adherence is more favorable for SLIT mainly because it is safe, noninvasive and easily taken at home. We support the call to conduct large multi-centric studies to gain more statistical power and overcome the problem of heterogeneity observed in the meta-analyses. PMID:25436040

Elghanam, Karim Mohamed

2014-01-01

269

Immunotherapy: Using the Immune System to Treat Cancer  

Cancer.gov

Immunotherapies are treatments that restore or enhance the immune system’s natural ability to fight cancer. In just the past few years, the rapidly advancing field of cancer immunology has recently produced several new methods of treating cancer that increase the strength of immune responses against tumors.

270

Cancer immunotherapy: are we there yet?  

PubMed

The immune system is the built-in host defense mechanism against infectious agents as well as cancer. Protective immunity against cancer was convincingly demonstrated in the 1940s with syngeneic animal models (JNCI 18:769-778, 1976; Cancer Immun 1:6, 2001). Since then, the last century's dream has been to effectively prevent and cure cancers by immunological means. This dream has slowly but surely become a reality (Nature 480:480-489, 2011). The successful examples of immunoprophylaxis and therapy against cancers include: (i) targeted therapy using monoclonal antibodies (Nat Rev Cancer 12:278-287, 2012); (ii) allogeneic hematopoietic stem cell transplantion to elicit graft-versus-cancer effect against a variety of hematopoietic malignancies (Blood 112:4371-4383, 2008); (iii) vaccination for preventing cancers with clear viral etiology such as hepatocellular carcinoma and cervical cancer (Cancer J Clin 57:7-28, 2007; NEJM 336:1855-1859, 1997); (iv) T cell checkpoint blockade against inhibitory pathways including targeting CTLA-4 and PD-1 inhibitory molecules for the treatment of melanoma and other solid tumors (NEJM 363:711-723, 2010; NEJM 366:2443-2454, 2012; NEJM 369:122-133, 2013; NEJM 366:2455-2465, 2012); (v) antigen-pulsed autologous dendritic cell vaccination against prostate cancer (NEJM 363:411-422, 2010); and (vi) the transfer of T cells including those genetically engineered with chimeric antigen receptors allowing targeting of B cell neoplasms (NEJM 365:725-733, 2011; NEJM 368:1509-1518, 2013; Blood 118:4817-4828, 2013; Sci Transl Med 5:177ra138, 2013).This article provides an overview on the exciting and expanding immunological arsenals against cancer, and discusses critical remaining unanswered questions of cancer immunology. The inherent specificity and memory of the adaptive immune response towards cancer will undoubtedly propel cancer immunotherapy to the forefront of cancer treatment in the immediate near future. Study of the fundamental mechanisms of the immune evasion of cancer shall also advance the field of immunology towards the development of effective immunotherapeutics against a wide spectrum of human diseases. PMID:24326015

Li, Zihai; Chen, Lieping; Rubinstein, Mark P

2013-01-01

271

Immunotherapy Targeting Pathological Tau Protein in Alzheimer's Disease and Related Tauopathies  

PubMed Central

Immunotherapies that target the amyloid-? (A?) peptide in Alzheimer's disease (AD) have shown promise in animal and human studies. Although the first clinical trial was halted because of adverse reactions, this approach has been refined and additional trials are underway. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As A? and tau pathologies are likely synergistic, targeting both should be more effective and may be essential as early diagnosis prior to cognitive decline is currently not available. Also, A? immunotherapy only results in a very limited indirect clearance of tau aggregates in dystrophic neurites, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons. We are currently clarifying further the mechanism of action of this promising therapeutic approach and determining its epitope specificity. PMID:18953105

Sigurdsson, Einar M.

2009-01-01

272

Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of A? amyloidosis  

PubMed Central

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. PMID:23129750

Kim, Jungsu; Eltorai, Adam E.M.; Jiang, Hong; Liao, Fan; Verghese, Philip B.; Kim, Jaekwang; Stewart, Floy R.; Basak, Jacob M.

2012-01-01

273

Generation of hypoallergenic neoglycoconjugates for dendritic cell targeted vaccination: A novel tool for specific immunotherapy  

PubMed Central

The incidence of allergic disorders and asthma continuously increased over the past decades, consuming a considerable proportion of the health care budget. Allergen-specific subcutaneous immunotherapy represents the only intervention treating the underlying causes of type I allergies, but still suffers from unwanted side effects and low compliance. There is an urgent need for novel approaches improving safety and efficacy of this therapy. In the present study we investigated carbohydrate-mediated targeting of allergens to dermal antigen-presenting cells and its influence on immunogenicity and allergenicity. Mannan, high (40 kDa) and low (6 kDa) molecular weight dextran, and maltodextrin were covalently attached to ovalbumin and papain via mild carbohydrate oxidation resulting in neoglycocomplexes of various sizes. In particular, mannan-conjugates were efficiently taken up by dendritic cells in vivo leading to elevated humoral immune responses against the protein moiety and a shift from IgE to IgG. Beyond providing an adjuvant effect, papain glycocomplexes also proved to mask B-cell epitopes, thus rendering the allergen derivative hypoallergenic. The present data demonstrate that carbohydrate-modified allergens combine targeting of antigen presenting cells with hypoallergenicity, offering the potential for low dose allergen-specific immunotherapy while concomitantly reducing the risk of side effects. PMID:23147517

Weinberger, Esther E.; Himly, Martin; Myschik, Julia; Hauser, Michael; Altmann, Friedrich; Isakovic, Almedina; Scheiblhofer, Sandra; Thalhamer, Josef; Weiss, Richard

2013-01-01

274

Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy  

PubMed Central

Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or ?-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/?-CD40, but not IL-2 or ?-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/?-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/?-CD40 induced the IFN-?– and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/?-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/?-CD40–mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease. PMID:20921282

Weiss, Jonathan M.; Ridnour, Lisa A.; Back, Tim; Hussain, S. Perwez; He, Peijun; Maciag, Anna E.; Keefer, Larry K.; Murphy, William J.; Harris, Curtis C.; Wink, David A.

2010-01-01

275

Immunotherapy of hepatocellular carcinoma with small double-stranded RNA  

PubMed Central

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 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. PMID:24886485

2014-01-01

276

Sublingual immunotherapy in pediatric allergic rhinitis and asthma: Efficacy, safety, and practical considerations  

Microsoft Academic Search

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

Linda Cox

2007-01-01

277

Oral immunotherapy for food allergy: towards a new horizon.  

PubMed

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

2013-01-01

278

Oral Immunotherapy for Food Allergy: Towards a New Horizon  

PubMed Central

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

2013-01-01

279

Modulation of immune responses by immunotherapy in allergic diseases.  

PubMed

Allergen immunotherapy (AIT) has been used for 100 years and until now different immunoregulatory pathways have been shown to take place in its mechanisms of action. It is characterized by administration of the causative allergen and is shown to be clinically efficient even after discontinuation of therapy particularly in allergic respiratory diseases, bee venom allergy, and food allergy. Generation of antigen/allergen-specific peripheral tolerance is the key mechanism during immunotherapy. It is mediated by development of T and B regulatory cells, IgG4 isotype allergen-specific antibodies and the involvement of multiple suppressor factors, which lead to decreased tissue inflammation, early and late phase responses. Describing novel regulatory mechanisms in the process of immune tolerance induction will help to identify treatment modalities not only for allergic disorders, but also for autoimmune diseases, organ transplantation, chronic infections, and cancer. PMID:25062122

Cavkaytar, Ozlem; Akdis, Cezmi A; Akdis, Mübeccel

2014-08-01

280

Newer developments in the immunotherapy of malignant melanoma.  

PubMed

Individuals with malignant melanoma present a variety of immune abnormalities including but not limited to cellular immune dysfunction, antigen presentation deficits, and cytokine production defects. Therefore, enhancing the immune system potential represents an appealing avenue for melanoma therapy. The authors review the immune therapies currently in clinical use as well as the most promising immunotherapy candidates. Ipilimumab, a monoclonal antibody against the CTLA-4, was approved for the therapy of advanced melanoma in 2011. In addition, sizeable anti-melanoma activity has recently been shown with the use of other agents including anti-PD-1/anti-PD-1 ligand antibodies. Consequently, these experimental immunotherapy agents may soon become important items in the anti-melanoma armamentarium. PMID:23435643

Maslin, Benjamin; Alexandrescu, Doru T; Ichim, Thomas E; Dasanu, Constantin A

2014-02-01

281

Immunotherapy for Non-Small Cell Lung Cancer  

PubMed Central

Lung cancer is the leading cause of cancer-related mortality worldwide, and more than 80% of cases are of non-small cell lung cancer. Although chemotherapy and molecularly targeted therapy may provide some benefit, there is a need for newer therapies for the treatment of patients with advanced NSCLC. Immunotherapy aims to augment the recognition of cancer as foreign, to stimulate immune responsiveness, and to relieve the inhibition of the immune response that allows tolerance to tumor survival and growth. Two immunotherapeutic approaches showing promise in NSCLC are immune checkpoint inhibition and cancer vaccination. Although currently immunotherapy does not have an established role in the treatment of NSCLC, these patients should be enrolled in formal clinical trials. PMID:25309605

2014-01-01

282

Overview of cellular immunotherapy for patients with glioblastoma.  

PubMed

High grade gliomas (HGG) including glioblastomas (GBM) are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients. PMID:20953324

Vauleon, Elodie; Avril, Tony; Collet, Brigitte; Mosser, Jean; Quillien, Véronique

2010-01-01

283

Overview of Cellular Immunotherapy for Patients with Glioblastoma  

PubMed Central

High grade gliomas (HGG) including glioblastomas (GBM) are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients. PMID:20953324

Vauleon, Elodie; Avril, Tony; Collet, Brigitte; Mosser, Jean; Quillien, Véronique

2010-01-01

284

Genetic modification of natural killer cells for adoptive cellular immunotherapy.  

PubMed

Immunotherapy of cancer is a rapidly developing field; one such development is the manipulation and use of natural killer (NK) cells. These cells with 'killer instincts' are an attractive cell to utilize, as they are directly reactive toward tumor and could potentially activate the endogenous adaptive immune system. Their employment in adoptive cell transfer treatments has yielded important results and discoveries, although effective antitumor responses are limited. To address these limitations, NK cells are the target of a new generation of immunotherapy involving gene transfer. The gene modification of immune cells is a relatively recent technique and some groups have targeted NK cells for gene modification to improve their antitumor efficacy. This review will investigate studies describing the gene modification of NK cells and their encouraging antitumor effects. PMID:20635990

Pegram, Hollie J; Kershaw, Michael H; Darcy, Phillip K

2009-07-01

285

Bacterial vectors for active immunotherapy reach clinical and industrial stages  

PubMed Central

Active immunotherapy based on live attenuated bacterial vectors has matured in terms of industrial development and develops through a combination of three phenomena. First, active immunotherapy that stimulates an antigen-specific cytotoxic T-cell immune response has become a reality after several years of work. Second, there is still a need to identify vectors that can deliver antigens to the cytosol of antigen-presenting cells in vivo. Third, the recent progress in the understanding of bacterial lifestyle and in developing genetic engineering tools has enabled the design of bioengineered bugs that are capable of delivering antigens. Here, we review the mechanisms by which clinical bacterial vectors deliver antigens into the cytosol of antigen-presenting cells and summarize the development strategy of the three identified firms in this field. PMID:22894945

Le Gouëllec, Audrey; Chauchet, Xavier; Polack, Benoit; Buffat, Laurent; Toussaint, Bertrand

2012-01-01

286

Combinations of Immunotherapy and Radiation in Cancer Therapy  

PubMed Central

The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer. PMID:25506582

Vatner, Ralph E.; Cooper, Benjamin T.; Vanpouille-Box, Claire; Demaria, Sandra; Formenti, Silvia C.

2014-01-01

287

Cellular-Based Immunotherapies for Patients with Glioblastoma Multiforme  

PubMed Central

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. PMID:22474481

Xu, Xun; Stockhammer, Florian; Schmitt, Michael

2012-01-01

288

Current advances in T-cell-based cancer immunotherapy  

PubMed Central

Cancer is a leading cause of death worldwide; due to the lack of ideal cancer biomarkers for early detection or diagnosis, most patients present with late-stage disease at the time of diagnosis, thus limiting the potential for successful treatment. Traditional cancer treatments, including surgery, chemotherapy and radiation therapy, have demonstrated very limited efficacy for patients with late-stage disease. Therefore, innovative and effective cancer treatments are urgently needed for cancer patients with late-stage and refractory disease. Cancer immunotherapy, particularly adoptive cell transfer, has shown great promise in the treatment of patients with late-stage disease, including those who are refractory to standard therapies. In this review, we will highlight recent advances and discuss future directions in adoptive cell transfer based cancer immunotherapy. PMID:25524383

Wang, Mingjun; Yin, Bingnan; Wang, Helen Y; Wang, Rong-Fu

2015-01-01

289

Oral immunotherapy and anti-IgE antibody-adjunctive treatment for food allergy.  

PubMed

One of the most promising therapies for food allergy is oral immunotherapy (OIT), in which small amounts of allergen are administered in increasing amounts, with the immediate goal of desensitization and the long-term goal of tolerance. However, safety and standardization concerns prevent its widespread use, and a subgroup of patients may experience severe allergic reactions. These concerns might be addressed by another promising therapy involving anti-IgE monoclonal antibodies (mAb), which can reduce allergic reactions associated with food administration. A recent pilot study combining anti-IgE mAb with OIT suggests that anti-IgE mAb might improve the safety, rapidity, and efficacy of OIT. PMID:22244236

Nadeau, Kari C; Kohli, Arunima; Iyengar, Shuba; DeKruyff, Rosemarie H; Umetsu, Dale T

2012-02-01

290

Optimal control on bladder cancer growth model with BCG immunotherapy and chemotherapy  

NASA Astrophysics Data System (ADS)

In this paper, an optimal control model of the growth of bladder cancer with BCG (Basil Calmate Guerin) immunotherapy and chemotherapy is discussed. The purpose of this optimal control is to determine the number of BCG vaccine and drug should be given during treatment such that the growth of bladder cancer cells can be suppressed. Optimal control is obtained by applying Pontryagin principle. Furthermore, the optimal control problem is solved numerically using Forward-Backward Sweep method. Numerical simulations show the effectiveness of the vaccine and drug in controlling the growth of cancer cells. Hence, it can reduce the number of cancer cells that is not infected with BCG as well as minimize the cost of the treatment.

Dewi, C.; Trisilowati

2015-03-01

291

Targeting Multiple-Myeloma-Induced Immune Dysfunction to Improve Immunotherapy Outcomes  

PubMed Central

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. PMID:22567028

Rutella, Sergio; Locatelli, Franco

2012-01-01

292

Strategies to mitigate peanut allergy: production, processing, utilization, and immunotherapy considerations.  

PubMed

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

2014-01-01

293

Specific immunotherapy of experimental myasthenia gravis in vitro and in vivo: the Guided Missile strategy.  

PubMed

Current immunotherapy of myasthenia gravis (MG) is often effective, but entails risks of infection and neoplasia. The "Guided Missile" strategy described here is designed to target and eliminate the individual's unique AChR-specific T cell repertoire, without otherwise interfering with the immune system. We genetically engineered dendritic cells to present AChR epitopes and simultaneously express Fas ligand in an ongoing EAMG model. In both in vitro and in vivo experiments, these engineered cells specifically killed AChR-responsive T cells without otherwise damaging the immune system. AChR antibodies were markedly reduced in the treated mice. Translation of this method to treat human MG is possible. PMID:22769060

Sun, W; Adams, R N; Miagkov, A; Lu, Y; Juon, H-S; Drachman, D B

2012-10-15

294

The biochemical aftermath of anti-amyloid immunotherapy  

Microsoft Academic Search

BACKGROUND: Active and passive immunotherapy in both amyloid-beta precursor protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the A? peptide 1-42 (AN-1792) and subjected to detailed postmortem

Chera L Maarouf; Ian D Daugs; Tyler A Kokjohn; Walter M Kalback; R Lyle Patton; Dean C Luehrs; Eliezer Masliah; James AR Nicoll; Marwan N Sabbagh; Thomas G Beach; Eduardo M Castaño; Alex E Roher

2010-01-01

295

The potential of peptide immunotherapy in allergy and asthma  

Microsoft Academic Search

Allergic conditions contribute significantly to the burden of chronic disease in the industrialized world. Current treatments\\u000a offer varying degrees of palliation. The sole proven disease-modifying strategy, specific or whole-allergen immunotherapy,\\u000a is limited because of the associated risk of systemic adverse effects, such as anaphylaxis. Short, linear allergen-derived\\u000a peptides, corresponding to T cell epitopes, offer the possibility of a safer approach

F. Runa Ali; A. Barry Kay; Mark Larché

2002-01-01

296

The future of antigen-specific immunotherapy of allergy  

Microsoft Academic Search

More than 25% of the population in industrialized countries suffers from immunoglobulin-E-mediated allergies. The antigen-specific immunotherapy that is in use at present involves the administration of allergen extracts to patients with the aim to cure allergic symptoms. However, the risk of therapy-induced side effects limits its broad application. Recent work indicates that the epitope complexity of natural allergen extracts can

Rudolf Valenta

2002-01-01

297

Monitoring antioxidant enzymes in red cells during allergen immunotherapy  

Microsoft Academic Search

The aim of this report was to answer the question how specific immunotherapy influences the antioxidant enzyme system in patients\\u000a with respiratory allergy and in longer perspective to find markers suitable to assess the efficacy of treatment. In open prospective\\u000a randomised study 28 patients (18 females and 10 males, age 14–48 years) with seasonal respiratory allergy were treated with\\u000a allergen

N. Lukan; O. Racz; I. Mocnejova; I. Tkac

2008-01-01

298

Identification of T-cell epitopes for cancer immunotherapy  

Microsoft Academic Search

The effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and

J H Kessler; C J M Melief

2007-01-01

299

Mucosal immunotherapy for protection from pneumonic infection with Francisella tularensis.  

PubMed

Previous studies have demonstrated that systemically administered immunotherapy can protect mice from systemic challenge with the bacterial pathogen Francisella tularensis. However, for protection from inhalational challenge with this bacterium, we wondered if mucosally administered immunotherapy might be more effective. Therefore, we administered cationic liposome-DNA complexes (CLDC), which are potent activators of innate immunity, intranasally (i.n.) and assessed the effectiveness of protection from lethal inhalational challenge with F. tularensis. We found that pretreatment by i.n. administration of CLDC 24h prior to bacterial challenge elicited nearly complete protection of BALB/c mice from lethal challenge with F. tularensis LVS strain. We also observed that mucosal CLDC immunotherapy provided a statistically significant increase in survival time in mice challenged with the highly virulent F. tularensis Schu4 strain. Protection was associated with a significant reduction in bacterial burden in the lungs, liver, and spleen. Mucosal administration of CLDC elicited significantly increased expression of IL-12, IFN-gamma, TNF-alpha, IFN-beta and IFN-alpha genes in the lung as detected by real-time quantitative PCR. In vitro treatment of F. tularensis infected macrophages with CLDC-elicited cytokines also significantly suppressed intracellular replication of F. tularensis in infected macrophages. In vivo, depletion of NK cells prior to administration of CLDC completely abolished the protective effects of CLDC immunotherapy. CLDC-elicited protection was also dependent on induction of IFN-gamma production in vivo. We conclude therefore that activation of local pulmonary innate immune responses is capable of eliciting significant protection from inhalational exposure to a virulent bacterial pathogen. PMID:19490961

Troyer, Ryan M; Propst, Katie L; Fairman, Jeff; Bosio, Catherine M; Dow, Steven W

2009-07-16

300

Novel approaches to immunotherapy for B-cell malignancies  

Microsoft Academic Search

Immunotherapy for cancer refers to a wide array of novel therapeutic interventions that harness the immune system to target\\u000a and eradicate malignant cells in the host. Advances in the understanding of how tumor cells evade host immune detection, coupled\\u000a with improved gene transduction technologies, have enabled investigators to propose and test novel immune-based therapies\\u000a for B-cell malignancies. As a result,

Renier J. Brentjens

2004-01-01

301

Genetically Engineered Antigen Specificity in T Cells for Adoptive Immunotherapy  

Microsoft Academic Search

\\u000a Antigen specificity has been genetically conferred to human T cells for therapy through the transfer of sequences encoding\\u000a antigen-specific T-cell receptors (TCRs) or through the antigen-specific antibody-based chimeric antigen receptors (CARs).\\u000a By either method, the advantage of the adoptive transfer of modified T cells over immunotherapies developed to date such as\\u000a vaccines or cytokines alone is that T cells have

Bruce L. Levine

302

Advances in Chimeric Antigen Receptor Immunotherapy for Neuroblastoma  

PubMed Central

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. PMID:24333408

Heczey, Andras; Louis, Chrystal U.

2014-01-01

303

The path to reactivation of antitumor immunity and checkpoint immunotherapy.  

PubMed

Cancer immunology has recently made major therapeutic inroads that represent clinical application of basic insights into mechanisms that govern immunity against tumors. Research into fundamental elements of T-cell and natural killer-cell biology, including the basis of antigen recognition, activation, proliferation, and survival, has informed the design of new therapeutic approaches to augment the body's natural anticancer immune response. Here, we describe some of the key steps that have provided the foundation for current strategies of immunotherapy. PMID:25281320

Kim, Hye-Jung; Cantor, Harvey

2014-10-01

304

Mechanistic basis of immunotherapies for type 1 diabetes mellitus.  

PubMed

Type 1 diabetes (T1D) is an autoimmune disease for which there is no cure. The pancreatic beta cells are the source of insulin that keeps blood glucose normal. When susceptible individuals develop T1D, their beta cells are destroyed by autoimmune T lymphocytes and no longer produce insulin. T1D patients therefore depend on daily insulin injections for survival. Gene therapy in T1D aims at the induction of new islets to replace those that have been destroyed by autoimmunity. A major goal of T1D research is to restore functional beta cell mass while eliminating diabetogenic T cells in the hope of achieving insulin independence. Multiple therapeutic strategies for the generation of new beta cells have been under intense investigations. However, newly formed beta cells would be immediately destroyed by diabetogenic T cells. Therefore, successful islet induction therapy must be supported by potent immunotherapy that will protect the newly formed beta cells. Herein, we will summarize the current information on immunotherapies that aim at modifying T cell response to beta cells. We will first outline the immune mechanisms that underlie T1D development and progression and review the scientific background and rationale for specific modes of immunotherapy. Numerous clinical trials using antigen-specific strategies and immune-modifying drugs have been published, though most have proved too toxic or have failed to provide long-term beta cell protection. To develop an effective immunotherapy, there must be a continued effort on defining the molecular basis that underlies T cell response to pancreatic islet antigens in T1D. PMID:23348026

Chen, Wenhao; Xie, Aini; Chan, Lawrence

2013-04-01

305

Immunotherapy: Disrupting the Cancer Treatment World  

MedlinePLUS

... lot of difficult side effects, such as reduced libido and impotence. Sharma, in a clinical trial, treated ... use it often. NCI needs to start paying attention – these drugs are important.” Lichentfeld agrees that better ...

306

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift  

PubMed Central

The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed. PMID:23291374

2013-01-01

307

IgE-based immunotherapy of cancer: challenges and chances  

PubMed Central

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. PMID:24117861

Singer, J; Jensen-Jarolim, E

2014-01-01

308

Laser immunotherapy: a novel approach for metastatic tumors  

NASA Astrophysics Data System (ADS)

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.

2004-08-01

309

A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12  

PubMed Central

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales. PMID:20843320

2010-01-01

310

Tumour immunogenicity, antigen presentation and immunological barriers in cancer immunotherapy  

PubMed Central

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. PMID:24634791

Escors, David

2014-01-01

311

Clinical evaluation of cellular immunotherapy in acute myeloid leukaemia.  

PubMed

Immunotherapy is currently under active investigation as an adjuvant therapy to improve the overall survival of patients with acute myeloid leukaemia (AML) by eliminating residual leukaemic cells following standard therapy. The graft-versus-leukaemia effect observed following allogeneic haematopoietic stem cell transplantation has already demonstrated the significant role of immune cells in controlling AML, paving the way to further exploitation of this effect in optimized immunotherapy protocols. In this review, we discuss the current state of cellular immunotherapy as adjuvant therapy for AML, with a particular focus on new strategies and recently published results of preclinical and clinical studies. Therapeutic vaccines that are being tested in AML include whole tumour cells as an autologous source of multiple leukaemia-associated antigens (LAA) and autologous dendritic cells loaded with LAA as effective antigen-presenting cells. Furthermore, adoptive transfer of cytotoxic T cells or natural killer cells is under active investigation. Results from phase I and II trials are promising and support further investigation into the potential of cellular immunotherapeutic strategies to prevent or fight relapse in AML patients. PMID:21519825

Smits, Evelien L J; Lee, Cindy; Hardwick, Nicola; Brooks, Suzanne; Van Tendeloo, Viggo F I; Orchard, Kim; Guinn, Barbara-Ann

2011-06-01

312

Targeting AKT signaling sensitizes cancer to cellular immunotherapy.  

PubMed

The promise of cancer immunotherapy is long-term disease control with high specificity and low toxicity. However, many cancers fail immune interventions, and secretion of immunosuppressive factors, defective antigen presentation, and expression of death ligands or serpins are regarded as main escape mechanisms. Here, we study whether deregulation of growth and survival factor signaling, which is encountered in most human cancers, provides another level of protection against immunologic tumor eradication. We show in two models that activated cell autonomous protein kinase B (PKB)/AKT signaling mediates resistance against tumor suppression by antigen-specific CTLs in vitro and adoptively transferred cellular immune effectors in vivo. PKB/AKT-dependent immunoresistance of established tumors is reversed by genetic suppression of endogenous Mcl-1, an antiapoptotic member of the Bcl-2 family. Mechanistically, deregulated PKB/AKT stabilizes Mcl-1 expression in a mammalian target of rapamycin (mTOR)-dependent pathway. Treatment with the mTOR inhibitor rapamycin effectively sensitizes established cancers to adoptive immunotherapy in vivo. In conclusion, cancer cell-intrinsic PKB/AKT signaling regulates the susceptibility to immune-mediated cytotoxicity. Combined targeting of signal transduction pathways may be critical for improvement of cancer immunotherapies. PMID:18483275

Hähnel, Patricia S; Thaler, Sonja; Antunes, Edite; Huber, Christoph; Theobald, Matthias; Schuler, Martin

2008-05-15

313

Mechanisms and ?pplications of ?nterleukins in Cancer Immunotherapy  

PubMed Central

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

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

2015-01-01

314

Greater risk of incident asthma cases in adults with Allergic Rhinitis and Effect of Allergen Immunotherapy: A Retrospective Cohort Study  

Microsoft Academic Search

Asthma and rhinitis are often co-morbid conditions. As rhinitis often precedes asthma it is possible that effective treatment\\u000a of allergic rhinitis may reduce asthma progression.\\u000a \\u000a \\u000a The aim of our study is to investigate history of allergic rhinitis as a risk factor for asthma and the potential effect of\\u000a allergen immunotherapy in attenuating the incidence of asthma.\\u000a \\u000a \\u000a \\u000a Hospital-referred non-asthmatic adults, aged

Riccardo Polosa; Wael K Al-Delaimy; Cristina Russo; Giovita Piccillo; Maria Sarvà

2005-01-01

315

Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3(+) regulatory T cells.  

PubMed

Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg ) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8(+) T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-?RII) mice to recombination-activating gene (Rag)1(-/-) recipients. We then used this robust established adoptive transfer system and co-transferred CD8(+) T cells from dnTGF-?RII mice with either C57BL/6 or dnTGF-?RII forkhead box protein 3 (FoxP3(+) ) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-?RII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Treg versus?dnTGF-?RII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-?RII mice. Our data reflect the therapeutic potential of wild-type CD4(+) FoxP3(+) Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC. PMID:25041369

Tanaka, H; Zhang, W; Yang, G-X; Ando, Y; Tomiyama, T; Tsuneyama, K; Leung, P; Coppel, R L; Ansari, A A; Lian, Z X; Ridgway, W M; Joh, T; Gershwin, M E

2014-11-01

316

Passive immunotherapy against A? in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage  

Microsoft Academic Search

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

2004-01-01

317

The role of immunotherapy in solid tumors: report from the Campania Society of Oncology Immunotherapy (SCITO) meeting, Naples 2014.  

PubMed

The therapeutic approach to advanced or metastatic solid tumors, either with chemotherapy or targeted therapies, is mainly palliative. Resistance to chemotherapy occurs very frequently and is one of the most important reasons for disease progression. Immunotherapy has the potential to mount an ongoing, dynamic immune response that can kill tumor cells for an extended time after the conventional therapy has been administered. Such a long-lasting response is potentially able to completely eradicate tumor cells, rather than producing only a temporary killing of cells. The most promising immune-based treatments are monoclonal antibodies that act as checkpoint inhibitors (e.g. ipilimumab and nivolumab), adoptive cell therapy (e.g. T-cells expressing chimeric antigen receptors) and vaccines (e.g. sipuleucel-T). Ipilimumab is currently approved for the treatment of metastatic melanoma and sipuleucel-T is approved for advanced prostate cancer. There is great interest in immunotherapy in other solid tumors, potentially used alone or in a multimodal fashion with chemotherapy and/or biological drugs. In this paper, we review recent advances in immuno-oncology in solid malignancies (except melanoma) as were discussed at the inaugural meeting of the Campania Society of Oncology Immunotherapy (SCITO). PMID:25331657

Ascierto, Paolo A; Addeo, Raffaele; Cartenì, Giacomo; Daniele, Bruno; De Laurentis, Michele; Ianniello, Giovanni; Morabito, Alessandro; Palmieri, Giovannella; Pepe, Stefano; Perrone, Francesco; Pignata, Sandro; Montesarchio, Vincenzo

2014-10-21

318

Safety and Immunogenicity of a Cluster Specific Immunotherapy in Children with Bronchial Asthma and Mite Allergy  

Microsoft Academic Search

Background: Cluster specific immunotherapy (SIT) is a modern form of allergen immunotherapy allowing safe administration of high allergen doses in a short time interval compared to classic SIT. In the current study, we investigated the safety profile and immunological effect of cluster SIT in children with allergic asthma due to house dust mite allergy. Methods: A total of 34 children

R. Schubert; O. Eickmeier; H. Garn; P. C. Baer; T. Mueller; J. Schulze; M. A. Rose; M. Rosewich; H. Renz; S. Zielen

2009-01-01

319

Does Immunotherapy Protect Equines from Reinfection by the Oomycete Pythium insidiosum??  

PubMed Central

A cutaneous Pythium insidiosum reinfection was diagnosed in an equine in Brazil. Lesions with focal presentation appeared 2 years apart. The first infection and even immunotherapy were not likely to develop enough immune response to prevent reinfection. The use of adjuvants should be considered in the immunotherapy of pythiosis. PMID:21715582

Santos, Carlos E. P.; Marques, Luiz C.; Zanette, Régis A.; Jesus, Francielli P. K.; Santurio, Janio M.

2011-01-01

320

Does immunotherapy protect equines from reinfection by the oomycete Pythium insidiosum?  

PubMed

A cutaneous Pythium insidiosum reinfection was diagnosed in an equine in Brazil. Lesions with focal presentation appeared 2 years apart. The first infection and even immunotherapy were not likely to develop enough immune response to prevent reinfection. The use of adjuvants should be considered in the immunotherapy of pythiosis. PMID:21715582

Santos, Carlos E P; Marques, Luiz C; Zanette, Régis A; Jesus, Francielli P K; Santurio, Janio M

2011-08-01

321

Allergen immunotherapy: Therapeutic vaccines for allergic diseases A WHO position paper  

Microsoft Academic Search

The World Health Organization and various allergy, asthma, and immunology societies throughout the world met on January 27 through 29, 1997, in Geneva, Switzerland to write guidelines for allergen immunotherapy. Over the ensuing year, the editors and panel members reached a consensus about the information to include in the WHO position paper “Allergen immunotherapy: Therapeutic vaccines for allergic diseases.”The historical

Jean Bousquet; Richard Lockey; Hans-Jorgen Malling

1998-01-01

322

The cryopreservation of high concentrated PBMC for dendritic cell (DC)-based cancer immunotherapy  

Microsoft Academic Search

Peripheral blood mononuclear cells (PBMC) have been accepted as a unique material for cancer immunotherapy using dendritic cells (DC) or activated lymphocytes that are being developed as an alternative or adjuvant to conventional therapies such as surgery, chemotherapy and radiation treatment. Although successful cryopreservation of large numbers of PBMC is critical for the immunotherapy, subsequent functional study of the effects

Yoon Jeong Heo; Cheol Hun Son; Joo-Seop Chung; You-Soo Park; Jeong Hwa Son

2009-01-01

323

Immunoinformatics and Modeling Perspective of T Cell Epitope-Based Cancer Immunotherapy: A Holistic Picture  

Microsoft Academic Search

Cancer immunotherapy is fast gaining global attention with its unique position as a potential therapy showing promise in cancer prevention and cure. It utilizes the natural system of immunity as opposed to chemotherapy and radiotherapy that utilize chemical drugs and radiation, respectively. Cancer immunotherapy essentially involves treatment and\\/or prevention with vaccines in the form of peptide vaccines (T and B

Seema Mishra; Subrata Sinha

2009-01-01

324

Monitoring of NK-Cell Immunotherapy using non-invasive Imaging Modalities  

PubMed Central

Cancer immunotherapies can be guided by cellular imaging techniques, which can identify the presence or absence of immune-cell accumulation in the tumor tissue in-vivo and in real time. This review summarizes various new and evolving imaging techniques employed for tracking and monitoring of adoptive NK-cell immunotherapies. PMID:20631071

Jha, Priyanka; Golovko, Daniel; Bains, Sukhmine; Hostetter, Daniel; Meier, Reinhard; Wendland, Michael F; Daldrup-Link, Heike E

2010-01-01

325

Immunology and immunotherapy approaches for prostate cancer  

Microsoft Academic Search

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

E Elkord

2007-01-01

326

Oral and sublingual peanut immunotherapy is not ready for general use.  

PubMed

Food oral immunotherapy (OIT) is an investigational peanut allergy treatment aimed to achieve specific oral tolerance induction. Allergic children are given titrated oral (or sublingual) doses of their allergen on a daily basis, unlike in subcutaneous immunotherapy (SCIT). OIT is theorized to cause a shift from a Th2 to a Th1 regulatory environment, reflected by increases in food-specific IgG4/IgE, and the production of FoxP3. Peanut OIT holds special promise because peanut allergy has an unfavorable natural history and is rarely outgrown. A high percentage of the participants experience symptoms during peanut OIT, including anaphylaxis, warranting epinephrine and/or discontinuation of therapy. This is a concerning fact given that the studies have mostly targeted only older children, with less historical reactivity for enrollment. The handful of peanut OIT studies have shown that some participants can be desensitized to peanut, but none have shown that long-term tolerance can be reestablished. Factors predictive of which patients are most likely to succeed and become desensitized through OIT are unknown. Some private practices have begun offering peanut OIT as a therapy. Such practice is potentially dangerous given the safety and efficacy of OIT in randomized controlled clinical trials is still not well established. Therefore, until further investigation emerges that conclusively demonstrates OIT is safe, intermediate and long-term outcomes are better established, the number of participants that experience symptoms is reduced, and proof of concept established in patients of all ages, (irrespective of past reaction severity), OIT is not ready for use in the general allergy practice. PMID:23676568

Greenhawt, Matthew J

2013-01-01

327

Failure of anti tumor-derived endothelial cell immunotherapy depends on augmentation of tumor hypoxia  

PubMed Central

We have previously demonstrated that Tenascin-C (TNC)+ human neuroblastoma (NB) cells transdifferentiate into tumor-derived endothelial cells (TDEC), which have been detected both in primary tumors and in tumors formed by human NB cell lines in immunodeficient mice. TDEC are genetically unstable and may favor tumor progression, suggesting that their elimination could reduce tumor growth and dissemination. So far, TDEC have never been targeted by antibody-mediated immunotherapy in any of the tumor models investigated. To address this issue, immunodeficient mice carrying orthotopic NB formed by the HTLA-230 human cell line were treated with TDEC-targeting cytotoxic human (h)CD31, that spares host-derived endothelial cells, or isotype-matched mAbs. hCD31 mAb treatment did not affect survival of NB-bearing mice, but increased significantly hypoxia in tumor microenvironment, where apoptotic and proliferating TDEC coexisted, indicating the occurrence of vascular remodeling. Tumor cells from hCD31 mAb treated mice showed i) up-regulation of epithelial-mesenchymal transition (EMT)-related and vascular mimicry (VM)-related gene expression, ii) expression of endothelial (i.e. CD31 and VE-cadherin) and EMT-associated (i.e. Twist-1, N-cadherin and TNC) immunophenotypic markers, and iii) up-regulation of high mobility group box-1 (HMGB-1) expression. In vitro experiments with two NB cell lines showed that hypoxia was the common driver of all the above phenomena and that human recombinant HMGB-1 amplified EMT and TDEC trans-differentiation. In conclusion, TDEC targeting with hCD31 mAb increases tumor hypoxia, setting the stage for the occurrence of EMT and of new waves of TDEC trans-differentiation. These adaptive responses to the changes induced by immunotherapy in the tumor microenvironment allow tumor cells to escape from the effects of hCD31 mAb. PMID:25362644

Pezzolo, Annalisa; Marimpietri, Danilo; Raffaghello, Lizzia; Cocco, Claudia; Pistorio, Angela; Gambini, Claudio; Cilli, Michele; Horenstein, Alberto; Malavasi, Fabio; Pistoia, Vito

2014-01-01

328

Failure of anti tumor-derived endothelial cell immunotherapy depends on augmentation of tumor hypoxia.  

PubMed

We have previously demonstrated that Tenascin-C (TNC)(+) human neuroblastoma (NB) cells transdifferentiate into tumor-derived endothelial cells (TDEC), which have been detected both in primary tumors and in tumors formed by human NB cell lines in immunodeficient mice. TDEC are genetically unstable and may favor tumor progression, suggesting that their elimination could reduce tumor growth and dissemination. So far, TDEC have never been targeted by antibody-mediated immunotherapy in any of the tumor models investigated. To address this issue, immunodeficient mice carrying orthotopic NB formed by the HTLA-230 human cell line were treated with TDEC-targeting cytotoxic human (h)CD31, that spares host-derived endothelial cells, or isotype-matched mAbs. hCD31 mAb treatment did not affect survival of NB-bearing mice, but increased significantly hypoxia in tumor microenvironment, where apoptotic and proliferating TDEC coexisted, indicating the occurrence of vascular remodeling. Tumor cells from hCD31 mAb treated mice showed i) up-regulation of epithelial-mesenchymal transition (EMT)-related and vascular mimicry (VM)-related gene expression, ii) expression of endothelial (i.e. CD31 and VE-cadherin) and EMT-associated (i.e. Twist-1, N-cadherin and TNC) immunophenotypic markers, and iii) up-regulation of high mobility group box-1 (HMGB-1) expression. In vitro experiments with two NB cell lines showed that hypoxia was the common driver of all the above phenomena and that human recombinant HMGB-1 amplified EMT and TDEC trans-differentiation. In conclusion, TDEC targeting with hCD31 mAb increases tumor hypoxia, setting the stage for the occurrence of EMT and of new waves of TDEC trans-differentiation. These adaptive responses to the changes induced by immunotherapy in the tumor microenvironment allow tumor cells to escape from the effects of hCD31 mAb. PMID:25362644

Pezzolo, Annalisa; Marimpietri, Danilo; Raffaghello, Lizzia; Cocco, Claudia; Pistorio, Angela; Gambini, Claudio; Cilli, Michele; Horenstein, Alberto; Malavasi, Fabio; Pistoia, Vito

2014-11-15

329

Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models.  

PubMed

A major barrier for cancer immunotherapy is the presence of suppressive cell populations in patients with cancer, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206(+)). CD11b(+) myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were coinjected with tumor cells. Tumor-specific CD8(+) T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFN? production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies. PMID:25370534

Shen, Li; Sundstedt, Anette; Ciesielski, Michael; Miles, Kiersten Marie; Celander, Mona; Adelaiye, Remi; Orillion, Ashley; Ciamporcero, Eric; Ramakrishnan, Swathi; Ellis, Leigh; Fenstermaker, Robert; Abrams, Scott I; Eriksson, Helena; Leanderson, Tomas; Olsson, Anders; Pili, Roberto

2015-02-01

330

A recombinant hypoallergenic parvalbumin mutant for immunotherapy of IgE-mediated fish allergy.  

PubMed

IgE-mediated allergy to fish is a frequent cause of severe anaphylactic reactions. Parvalbumin, a small calcium-binding protein, is the major fish allergen. We have recently isolated a cDNA coding for carp parvalbumin, Cyp c 1, and expressed in Escherichia coli a recombinant Cyp c 1 molecule, which contained most IgE epitopes of saltwater and freshwater fish. In this study, we introduced mutations into the calcium-binding domains of carp parvalbumin by site-directed mutagenesis and produced in E. coli three parvalbumin mutants containing amino acid exchanges either in one (single mutants; Mut-CD and Mut-EF) or in both of the calcium-binding sites (double mutant; Mut-CD/EF). Circular dichroism analyses of the purified derivatives and the wild-type allergen showed that Mut-CD/EF exhibited the greatest reduction of overall protein fold. Dot blot assays and immunoblot inhibition experiments performed with sera from 21 fish-allergic patients showed that Mut-CD/EF had a 95% reduced IgE reactivity and represented the derivative with the least allergenic activity. The latter was confirmed by in vitro basophil histamine release assays and in vivo skin prick testing. The potential applicability for immunotherapy of Mut-CD/EF was demonstrated by the fact that mouse IgG Abs could be raised by immunization with the mutated molecule, which cross-reacted with parvalbumins from various fish species and inhibited the binding of fish-allergic patients' IgE to the wild-type allergen. Using the hypoallergenic carp parvalbumin mutant Mut-CD/EF, it may be possible to treat fish allergy by immunotherapy. PMID:17475857

Swoboda, Ines; Bugajska-Schretter, Agnes; Linhart, Birgit; Verdino, Petra; Keller, Walter; Schulmeister, Ulrike; Sperr, Wolfgang R; Valent, Peter; Peltre, Gabriel; Quirce, Santiago; Douladiris, Nikolaos; Papadopoulos, Nikolaos G; Valenta, Rudolf; Spitzauer, Susanne

2007-05-15

331

Regulation of cytotoxic T-Lymphocyte trafficking to tumors by chemoattractants: implications for immunotherapy.  

PubMed

Cancer immunotherapy has recently emerged as an important treatment modality. FDA approval of provenge, ipilimumab and pembrolizumab has started to deliver on the long awaited promise of cancer immunotherapy. Many new modalities of immunotherapies targeting cytotoxic T lymphocytes (CTLs) responses, such as adoptive cell therapies and vaccines, are in advanced clinical trials. In all these immunotherapies, migration of CTLs to the tumor site is a critical step for achieving therapeutic efficacy. However, inefficient infiltration of activated CTLs into established tumors is increasingly being recognized as one of the major hurdles limiting efficacy. Mechanisms that control migration of CTLs to tumors are poorly defined. In this review, the authors discuss the chemoattractants and their receptors that have been implicated in endogenous- or immunotherapy-induced CTL recruitment to tumors and the potential for targeting these pathways for therapeutic efficacy. PMID:25482400

Sharma, Rajesh K; Chheda, Zinal S; Jala, Venkatakrishna R; Haribabu, Bodduluri

2015-04-01

332

Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: study design and recruitment  

Microsoft Academic Search

BACKGROUND: For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the efficacy of sublingual immunotherapy with house dust mite allergen compared to

Cindy MA de Bot; Heleen Moed; Marjolein Y Berger; Esther Röder; Hans de Groot; Johan C de Jongste; Roy Gerth van Wijk; Johannes C van der Wouden

2008-01-01

333

Dendritic Cell-Based Immunotherapy for Myeloid Leukemias  

PubMed Central

Acute and chronic myeloid leukemia (AML, CML) are hematologic malignancies arising from oncogene-transformed hematopoietic stem/progenitor cells known as leukemia stem cells (LSCs). LSCs are selectively resistant to various forms of therapy including irradiation or cytotoxic drugs. The introduction of tyrosine kinase inhibitors has dramatically improved disease outcome in patients with CML. For AML, however, prognosis is still quite dismal. Standard treatments have been established more than 20?years ago with only limited advances ever since. Durable remission is achieved in less than 30% of patients. Minimal residual disease (MRD), reflected by the persistence of LSCs below the detection limit by conventional methods, causes a high rate of disease relapses. Therefore, the ultimate goal in the treatment of myeloid leukemia must be the eradication of LSCs. Active immunotherapy, aiming at the generation of leukemia-specific cytotoxic T cells (CTLs), may represent a powerful approach to target LSCs in the MRD situation. To fully activate CTLs, leukemia antigens have to be successfully captured, processed, and presented by mature dendritic cells (DCs). Myeloid progenitors are a prominent source of DCs under homeostatic conditions, and it is now well established that LSCs and leukemic blasts can give rise to “malignant” DCs. These leukemia-derived DCs can express leukemia antigens and may either induce anti-leukemic T cell responses or favor tolerance to the leukemia, depending on co-stimulatory or -inhibitory molecules and cytokines. This review will concentrate on the role of DCs in myeloid leukemia immunotherapy with a special focus on their generation, application, and function and how they could be improved in order to generate highly effective and specific anti-leukemic CTL responses. In addition, we discuss how DC-based immunotherapy may be successfully integrated into current treatment strategies to promote remission and potentially cure myeloid leukemias. PMID:24427158

Schürch, Christian M.; Riether, Carsten; Ochsenbein, Adrian F.

2013-01-01

334

Dendritic cell-based immunotherapy for myeloid leukemias.  

PubMed

Acute and chronic myeloid leukemia (AML, CML) are hematologic malignancies arising from oncogene-transformed hematopoietic stem/progenitor cells known as leukemia stem cells (LSCs). LSCs are selectively resistant to various forms of therapy including irradiation or cytotoxic drugs. The introduction of tyrosine kinase inhibitors has dramatically improved disease outcome in patients with CML. For AML, however, prognosis is still quite dismal. Standard treatments have been established more than 20?years ago with only limited advances ever since. Durable remission is achieved in less than 30% of patients. Minimal residual disease (MRD), reflected by the persistence of LSCs below the detection limit by conventional methods, causes a high rate of disease relapses. Therefore, the ultimate goal in the treatment of myeloid leukemia must be the eradication of LSCs. Active immunotherapy, aiming at the generation of leukemia-specific cytotoxic T cells (CTLs), may represent a powerful approach to target LSCs in the MRD situation. To fully activate CTLs, leukemia antigens have to be successfully captured, processed, and presented by mature dendritic cells (DCs). Myeloid progenitors are a prominent source of DCs under homeostatic conditions, and it is now well established that LSCs and leukemic blasts can give rise to "malignant" DCs. These leukemia-derived DCs can express leukemia antigens and may either induce anti-leukemic T cell responses or favor tolerance to the leukemia, depending on co-stimulatory or -inhibitory molecules and cytokines. This review will concentrate on the role of DCs in myeloid leukemia immunotherapy with a special focus on their generation, application, and function and how they could be improved in order to generate highly effective and specific anti-leukemic CTL responses. In addition, we discuss how DC-based immunotherapy may be successfully integrated into current treatment strategies to promote remission and potentially cure myeloid leukemias. PMID:24427158

Schürch, Christian M; Riether, Carsten; Ochsenbein, Adrian F

2013-01-01

335

Systemic chemo-immunotherapy for advanced-stage hepatocellular carcinoma  

PubMed Central

AIM: To evaluate the therapeutic efficacy of systemic chemo-immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: Twenty-six patients with advanced HCC were treated by using systemic chemo-immunotherapy (PIAF regimen), which consisted of cisplatin (20 mg/m2) intravenously daily for 4 consecutive day, doxorubicin (40 mg/m2) intravenously on day 1, 5-fluorouracil (400 mg/m2) intravenously daily for 4 consecutive day, and human recombinant ?-interferon-2a (5 Mu/m2) subcutaneous injection daily for 4 consecutive day. The treatment was repeated every 3 wk, with a maximum of six cycles. RESULTS: A total of 90 cycles of PIAF treatment were administered, with a mean number of 3.9 cycles per patient. Eight patients received six cycles of treatment (group A), and the remaining 18 were subjected to two to five cycles (group B). There were 0 complete response, 4 partial responses, 9 static diseases and 13 progressive diseases, with a disease control rate of 50% (13/26). The 1-year survival rate was 24.3%, with a median survival time of 6.0 mo. Group A had a remarkably better survival as compared with group B, the 1- and 2-year survival rates were 62.5% vs 6.1% and 32.3% vs 0%, and a median survival time was 12.5 mo vs 5.0 mo (P = 0.001). CONCLUSION: Systemic chemo-immunotherapy using PIAF regimen represented an effective treatment and could improve the survival rate and prolong the survival time in selected patients with advanced HCC. PMID:15832431

Yin, Xiao-Yu; Lü, Ming-De; Liang, Li-Jian; Lai, Jia-Ming; Li, Dong-Ming; Kuang, Ming

2005-01-01

336

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking  

PubMed Central

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

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

2014-01-01

337

NK cell-based immunotherapy for malignant diseases.  

PubMed

Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced. PMID:23604045

Cheng, Min; Chen, Yongyan; Xiao, Weihua; Sun, Rui; Tian, Zhigang

2013-05-01

338

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking  

NASA Astrophysics Data System (ADS)

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

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

2014-11-01

339

Intact skin and not stripped skin is crucial for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT) in mice  

PubMed Central

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?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. PMID:23140259

2012-01-01

340

Directing dendritic cell immunotherapy towards successful cancer treatment  

PubMed Central

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. PMID:20473346

Sabado, Rachel Lubong; Bhardwaj, Nina

2010-01-01

341

Cytokines as targets of immunotherapy in bacterial pneumonia.  

PubMed

The generation of a vigorous inflammatory response is essential for the rapid clearance of microbes from the alveolar space. The magnitude of the inflammatory response is tightly controlled by host-derived cytokines, which mediate lung inflammation by serving as leukocyte chemoattractants, leukocyte activating factors, or afferent signals in the induction or regulation of other effector molecules. In this article the role of specific cytokines in lung innate immunity will be reviewed. Future directions regarding the use of specific forms of immunotherapy, including compartmentalized cytokine delivery with gene therapy as adjuvant therapy in the treatment of pneumonia, will be explored. PMID:10695657

Standiford, T J; Tsai, W C; Mehrad, B; Moore, T A

2000-02-01

342

Developing T cell cancer immunotherapy in the dog with lymphoma.  

PubMed

Immunotherapy is not a new concept for veterinary medicine; however, adoptive T cell therapy is a new area of research in humans and canines alike. In humans, T cell therapy has been used against many different tumor histologies, including lymphoma, melanoma, and colon cancer. Although in dogs this approach has currently only been applied to lymphoma, other tumor types are under investigation. There are many different strategies used to take advantage of cell-mediated antitumor properties of T cells. This review will discuss many of the current strategies used in both humans and canines in regards to adoptive T cell therapy. PMID:24936037

O'Connor, Colleen M; Wilson-Robles, Heather

2014-01-01

343

Alleviating oxidative stress in cancer immunotherapy: a role for histamine?  

Microsoft Academic Search

Interleukin-2 is a remarkable activator of lymphocytes with anti-neoplastic properties such as T-cells or natural killer cells,\\u000a but tumor regression only rarely occurs in interleukin-2-treated cancer patients. In this review, we focus on interactions\\u000a between monocytes\\/macrophages and T-cells\\/natural killer-cells, and in particular the role of such interactions for the outcome\\u000a of cancer immunotherapy with interleukin-2. We propose that interleukin-2 therapy

K Hellstrand; M Brune; C Dahlgren; M Hansson; S Hermodsson; P Lindnér; U-H Mellqvist; P Naredi

2000-01-01

344

Efficacy and safety of emerging immunotherapies in psoriasis.  

PubMed

Psoriasis is a common chronic inflammatory disease of the skin. Current biologic therapies are highly effective in the treatment of psoriasis, transforming the lives of patients with this significantly disabling disease. Advances in the understanding of the immunological pathogenesis of psoriasis have led to the development of new biologic therapies, targeting specific inflammatory cytokines upregulated in psoriasis. These include the IL-17 antagonists, secukinumab, brodalumab and ixekizumab; the IL-23 antagonists, guselkumab and tildrakizumab; and the oral small molecule therapies, tofacitinib and apremilast. Here, we review evidence for the efficacy and safety of these novel psoriasis therapies, providing clinicians with an overview of the next era in immunotherapy for psoriasis. PMID:25713988

Yiu, Zenas Zn; Warren, Richard B

2015-02-01

345

Vaccine against autoimmune disease: antigen-specific immunotherapy?  

PubMed Central

Recent interest in testing whether the success of antigen-specific immunotherapy (ASIT) for autoimmune diseases in mice can be translated to humans has highlighted the need for better tools to study and understand human autoimmunity. Clinical development of ASIT for allergy has been instructive, but limited understanding of CD4 T cell epitope/determinant hierarchies hampers the rational design and monitoring of ASIT. Definitive identification of pathogenic T cell epitopes as is now known in celiac disease and recent initiatives to optimize immune monitoring will facilitate rational design, monitoring and mechanistic understanding of ASIT for human autoimmune diseases. PMID:23478068

Anderson, Robert P; Jabri, Bana

2013-01-01

346

T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity  

PubMed Central

Background Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. Methods and Findings In this study we address the mechanism of action of peptide immunotherapy (PIT) in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs) after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs. Conclusion This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen. PMID:15783262

2005-01-01

347

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

PubMed

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

2014-08-01

348

Cancer CARtography: Charting out a new approach to cancer immunotherapy  

PubMed Central

Recently, chimeric antigen receptor (CAR) T-cell immunotherapy has entered clinical trials in patients with relapsed or refractory B-ALL. 19–28z CAR T-cells express a fusion protein comprised of an anti-CD19 mAb fused with CD28 costimulatory and CD3-zeta chain signaling domains. The current paper demonstrates that administration of 19–28z CAR T-cells in patients with relapsed or refractory B-ALL in a Phase I clinical trial has led to 88% of patients undergoing complete remission. Despite the benefits, CAR T-cell therapy is associated with cytokine release syndrome (CRS) toxicities. The authors demonstrated criteria to diagnose severe CRS (sCRS) and treated sCRS with either high dose steroids or with tocilizumab, an IL-6 receptor-specific mAb. Although both alleviated sCRS, steroid treatment negated the beneficial effects of CAR T-cell therapy, whereas tocilizumab did not. Taken together, CAR T-cell immunotherapy can be used as a safe and effective approach against tumors with known tumor-associated antigens. PMID:25186600

Patel, Jaina M.; Dale, Gordon A.; Vartabedian, Vincent F.; Dey, Paulami; Selvaraj, Periasamy

2014-01-01

349

Cancer CARtography: charting out a new approach to cancer immunotherapy.  

PubMed

Evaluation of: Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6(224), 224ra25 (2014). Recently, chimeric antigen receptor (CAR) T-cell immunotherapy has entered clinical trials in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. 19-28z CAR T cells express a fusion protein comprised of an anti-CD19 mAb fused with CD28 costimulatory and CD3-zeta-chain signaling domains. The current paper demonstrates that administration of 19-28z CAR T cells in patients with relapsed or refractory B-ALL in a Phase I clinical trial has led to 88% of patients undergoing complete remission. Despite the benefits, CAR T-cell therapy is associated with cytokine release syndrome toxicities. The authors demonstrated criteria to diagnose severe cytokine release syndrome (sCRS) and treated sCRS with either high-dose steroids or with tocilizumab, an IL-6 receptor-specific mAb. Although both alleviated sCRS, steroid treatment negated the beneficial effects of CAR T-cell therapy, whereas tocilizumab did not. Taken together, CAR T-cell immunotherapy can be used as a safe and effective approach against tumors with known tumor-associated antigens. PMID:25186600

Patel, Jaina M; Dale, Gordon A; Vartabedian, Vincent F; Dey, Paulami; Selvaraj, Periasamy

2014-01-01

350

Clinical Development of Listeria monocytogenes–Based Immunotherapies  

PubMed Central

Active immunotherapy targeting dendritic cells (DCs) has shown great promise in preclinical models and in human clinical trials for the treatment of malignant disease. Sipuleucel-T (Provenge, Dendreon, Seattle, WA), which consists of antigen-loaded dendritic cells (DCs), recently became the first targeted therapeutic cancer vaccine to be approved by the US Food and Drug Administration (FDA). However, ex vivo therapies such as Provenge have practical limitations and elicit an immune response with limited scope. By contrast, live-attenuated Listeria monocytogenes (Lm) naturally targets DCs in vivo and stimulates both innate and adaptive cellular immunity. Lm-based vaccines engineered to express cancer antigens have demonstrated striking efficacy in several animal models and have resulted in encouraging anecdotal survival benefit in early human clinical trials. Two different Lm-based vaccine platforms have advanced into phase II clinical trials in cervical and pancreatic cancer. Future Lm-based clinical vaccine candidates are expected to feature polyvalent antigen expression and to be used in combination with other immunotherapies or conventional therapies such as radiotherapy and chemotherapy to augment efficacy. PMID:22595054

Le, Dung T.; Dubensky, Thomas W.; Brockstedt, Dirk G.

2013-01-01

351

Lm-LLO-Based Immunotherapies and HPV-Associated Disease  

PubMed Central

HPV infection is a direct cause of neoplasia and malignancy. Cellular immunologic activity against cells expressing HPV E6 and E7 is sufficient to eliminate the presence of dysplastic or neoplastic tissue driven by HPV infection. Live attenuated Listeria monocytogenes- (Lm-) based immunotherapy (ADXS11-001) has been developed for the treatment of HPV-associated diseases. ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7. In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome. ADXS11-001 is currently being evaluated in Phase 2 clinical trials for cervical intraepithelial neoplasia, cervical cancer, and HPV-positive head and neck cancer. The use of a live attenuated bacterium is a more complex and complete method of cancer immunotherapy, as over millennia Lm has evolved to infect humans and humans have evolved to prevent and reject this infection over millennia. This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology. PMID:22481930

Wallecha, Anu; French, Chris; Petit, Robert; Singh, Reshma; Amin, Ashok; Rothman, John

2012-01-01

352

HDAC inhibitors and immunotherapy; a double edged sword?  

PubMed

Epigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. Histone deacetylase (HDAC) inhibitors are well known to affect cancer cell viability and biology and are already in use for the treatment of cancer patients. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer. PMID:25115382

Kroesen, Michiel; Gielen, Paul; Brok, Ingrid C; Armandari, Inna; Hoogerbrugge, Peter M; Adema, Gosse J

2014-08-30

353

Immunotherapy for Lung Cancer: Has it Finally Arrived?  

PubMed Central

The possible link between infection/inflammation/immune activation and a cancer patient’s outcome from both a causative and outcome point of view has long been postulated. Substantial progress in the understanding of tumor-associated antigens/epitopes, immune cellular subpopulations, cytokine pathways/expression, the tumor microenvironment, and the balance between tumor-immune suppression and stimulation have been made over the past decade. This knowledge has heralded a new era of tumor immunotherapy utilizing vaccines, immune checkpoint inhibition, and oncolytic viruses. Despite significant progress in the molecular era now with targeted therapeutics such as EGFR tyrosine kinase inhibitors and ALK fusion protein inhibitors that have significantly improved the outcome of these specific lung cancer subpopulations, the overall 5?year survival for all non-small cell lung cancer (NSCLC) is still <20%. Unlike malignancies such as malignant melanoma, renal cell carcinoma, and neuroblastoma given their documented spontaneous remission rates lung cancer historically has been felt to be resistant to immune approaches likely related to an immunosuppressive tumor microenvironment and/or lack of immune recognition. Defining responding populations, understanding the mechanism(s) underlying durable immune responses, and the role of chemotherapy, radiation, oncolytic viruses, and other tumor disrupting agents in augmenting immune responses have led to improved optimization of immune therapeutic strategies. The purpose of this review is to focus on the recent advances in lung immunotherapy with an emphasis on recent clinical trials in the last 5?years in NSCLC. PMID:25374843

Mostafa, Ahmed A.; Morris, Don G.

2014-01-01

354

Langerhans cells as targets for immunotherapy against skin cancer  

PubMed Central

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

2010-01-01

355

Adherence issues related to sublingual immunotherapy as perceived by allergists  

PubMed Central

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. PMID:20622914

Scurati, Silvia; Frati, Franco; Passalacqua, Gianni; Puccinelli, Paola; Hilaire, Cecile; Incorvaia, Cristoforo

2010-01-01

356

Molecular Recognition of Gangliosides and Their Potential for Cancer Immunotherapies  

PubMed Central

Gangliosides are sialic-acid-containing glycosphingolipids expressed on all vertebrate cells. They are primarily positioned in the plasma membrane with the ceramide part anchored in the membrane and the glycan part exposed on the surface of the cell. These lipids have highly diverse structures, not the least with respect to their carbohydrate chains, with N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) being the two most common sialic-acid residues in mammalian cells. Generally, human healthy tissue is deficient in NeuGc, but this molecule is expressed in tumors and in human fetal tissues, and was hence classified as an onco-fetal antigen. Gangliosides perform important functions through carbohydrate-specific interactions with proteins, for example, as receptors in cell–cell recognition, which can be exploited by viruses and other pathogens, and also by regulating signaling proteins, such as the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), through lateral interaction in the membrane. Through both mechanisms, tumor-associated gangliosides may affect malignant progression, which makes them attractive targets for cancer immunotherapies. In this review, we describe how proteins recognize gangliosides, focusing on the molecular recognition of gangliosides associated with cancer immunotherapy, and discuss the importance of these molecules in cancer research. PMID:25101077

Krengel, Ute; Bousquet, Paula A.

2014-01-01

357

Experimental and clinical studies with active specific immunotherapy.  

PubMed

The factors involved in constructing vaccines for clinical testing are shown in Figure 3. The definition of melanoma antigens which are likely to be immunogenic is greatly facilitated by identification of reactive antibodies in sera or human hybridoma supernatants. It is also possible that antigens defined by murine monoclonal antibodies or extraction of melanoma specimens will be proven immunogenic with appropriately constructed vaccines, but this is unlikely unless immunohistologic testing and extraction of normal tissues show lack of expression on normal cells. With the use of purified antigens it has been possible to immunize with more antigen and to present the antigen in a more immunogenic fashion. On the other hand, the use of whole tumor cells or cell fractions provides the possibility of obtaining immune responses against antigens not previously known to be immunogenic, especially if linked with the production of human monoclonal antibodies. Experimental models for vaccine construction play a critical role in the selection of optimal adjuvants or vehicles for antigen presentation and for comparing different approaches to anti suppressor cell treatment. (Formula: see text). The ability to consistently induce high titer antibody responses against a single antigen, the ganglioside GM2, represents a foot in the door of active specific immunotherapy against malignant melanoma in man. When we are able to immunize as well against 2 or 3 additional melanoma antigens, the door will be open for testing the hypothesis that active specific immunotherapy can play a role in preventing recurrence or treating measurable cancer in man. PMID:2654953

Livingston, P O

1989-01-01

358

Production of human natural killer cells for adoptive immunotherapy using a computer-controlled stirred-tank bioreactor.  

PubMed

Large-scale ex vivo expansion of human natural killer (NK) cells for adoptive immunotherapy requires assurance of good manufacturing practices. However, maximal expansion of NK is also desired to facilitate clinical trials with large numbers of IL-2-activated NK (ANK). A closed-system stirred-tank bioreactor is amenable to computer control of culture variables, thereby reducing the risk of contamination. We demonstrate that NK cultured in 250-ml spinner flasks expand 2.5-fold more than NK cultured in stationary tissue culture wells. We further show that during 33 days of culture, it is feasible to control the pH between 7.0 and 7.2 and the dissolved oxygen concentration at 40% of air saturation via direct on-line computer control in a 750-ml stirred-tank bioreactor. On-line measurement of optical density by a laser turbidity sensor, as a measure of cell concentration, correlated well with actual cell count data. NK expansion in the 750-ml bioreactor was 7-fold greater than in stationary tissue culture controls and 3-fold greater than in spinner flask controls. Consumption rates of glucose and oxygen and the production rate of lactate were measured and will be used to develop a nutrient feeding strategy to convert the batch reactor experiment into closed-system fed-batch or continuous flow modes. Computer-controlled stirred-tank bioreactors may facilitate clinical trials with high-purity ANK populations for adoptive immunotherapy. PMID:8938519

Pierson, B A; Europa, A F; Hu, W S; Miller, J S

1996-10-01

359

Atypical severe immune-related adverse effects resulting from sequenced immunotherapy in melanoma.  

PubMed

We report unusual severe toxicity in three patients treated at our institution with sequenced immunotherapy for metastatic melanoma. These three patients illustrate the unusual potential toxicity of sequential administration of anti-programmed cell death 1 followed by ipilimumab, and the need for careful monitoring of these toxicities associated with sequential immunotherapies. Data from forthcoming trials and national databases such as MELBASE, recently implemented in France, will be helpful in providing further insights into the risks and benefits of sequential immunotherapy schedules. PMID:25464388

Danlos, François-Xavier; Pagès, Cécile; Roux, Jennifer; Jebali, Majdi; Gornet, Jean-Marc; Bagot, Martine; Lebbé, Céleste

2015-04-01

360

CYTOTOXIC T-LYMPHOCYTE IMMUNOTHERAPY FOR OVARIAN CANCER: A PILOT STUDY  

PubMed Central

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. PMID:22306908

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

2012-01-01

361

MSK team makes key discovery in understanding immunotherapy's successes -- and its failures  

Cancer.gov

A collaborative team of leaders in the field of cancer immunology from Memorial Sloan Kettering Cancer Center has made a key discovery that advances the understanding of why some patients respond to ipilimumab, an immunotherapy drug, while others do not.

362

Financial viability and technical evaluation of dendritic cell-carrying "vaccination nodes" for immunotherapy  

E-print Network

Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumor cells. Despite the amount of ongoing intensive research to prevent cancer, tumor cells continue to evade immune responses. Currently, ...

Song, Andrew, M. Eng. Massachusetts Institute of Technology

2008-01-01

363

Inverse opal hydrogel scaffolds as lymphoid microenvironments for the study of immune cell migration and immunotherapy  

E-print Network

Immunotherapies harness the inherent potential of the body to destroy foreign or infected cells, by stimulating new or enhancing existing immune responses. One way to boost insufficient native immunity might be to engineer ...

Stachowiak, Agnieszka (Agnieszka N.)

2007-01-01

364

Oral immunotherapy for the treatment of food allergy.  

PubMed

Oral immunotherapy (OIT) is an emerging new therapy for food allergy. With multiple small exploratory trials and some large randomized-controlled phase 2 trials recently published and under way, there is a clear progress and interest toward making this a treatment option for patients suffering from food allergies. However, there are still many questions to be answered and parameters to fine-tune before OIT becomes an accepted option outside of the research setting. This review covers the main milestones in the development of OIT for food allergy and further discusses important specific issues that will have direct impact on its clinical application. More specifically, previous publications showing evidence for the induction of tolerance are specifically reviewed and varying safety, tolerability and efficacy parameters from previous reports are also discussed. PMID:25424935

Begin, Philippe; Chinthrajah, R Sharon; Nadeau, Kari C

2014-01-01

365

Peanut oral immunotherapy: is it ready for clinical practice?  

PubMed

The prevalence of peanut allergy in the United States and other Westernized countries has tripled in the past 15 years, now affecting more than 1% of the population. Strict peanut avoidance is the current standard of care. In the past decade, a number of small, largely uncontrolled clinical trials have suggested that oral immunotherapy (OIT) can effectively desensitize most children with peanut allergy. Some in the allergy community now feel that OIT is ready for clinical practice. In this review, the evidence base in the medical literature is examined. Although peanut OIT shows promise, the evidence currently available on its effectiveness, risk benefit, and potential long-term consequences is insufficient to support its use in clinical practice. Appropriately designed, prospective clinical trials are urgently needed to determine whether OIT is a safe, effective form of therapy for food allergy. PMID:24229817

Sampson, Hugh A

2013-01-01

366

Can immunotherapy specifically target acute myeloid leukemic stem cells?  

PubMed Central

Accumulating evidence supports the role of leukemic stem cells (LSCs) in the high relapse rate of acute myeloid leukemia (AML) patients. The clinical relevance of LSCs, which were originally characterized in xenograft models, has recently been confirmed by the finding that stem cell-like gene expression signatures can predict the clinical outcome of AML patients. The targeted elimination of LSCs might hence constitute an efficient therapeutic approach to AML. Here, we review immunotherapeutic strategies that target LSC-associated antigens, including T cell-mediated and monoclonal antibody-based regimens. Attention is given to the issue of antigen specificity because this is relevant to the therapeutic window and determines the superiority of LSC-targeting immunotherapy. PMID:23526057

Snauwaert, Sylvia; Vandekerckhove, Bart; Kerre, Tessa

2013-01-01

367

Sublingual allergen immunotherapy for respiratory allergies: what is new?  

PubMed

Sublingual immunotherapy (SLIT) is a disease-modifying treatment for respiratory allergies that has been used for many years in Europe and has also recently been approved for use in North America. Its use is thus likely to increase. There is more evidence available regarding SLIT efficacy and its good safety profile, making it an appealing treatment option. The majority of studies have mostly focused on grass pollens; however, there are now data available regarding efficacy for other allergens. This review will summarize recent findings from SLIT clinical trials for respiratory allergies, including efficacy, safety, post-discontinuation effects and use in different age groups. Grass pollen, tree pollen, house dust mite and ragweed SLIT studies will be evaluated. PMID:25407099

Makatsori, Melina; Calderon, Moises A

2014-12-01

368

Tumour cell damage and leucocyte infiltration after laser immunotherapy treatment.  

PubMed

Immune response after laser-photosensitiser application could be crucial in treatment of cancers, because without it there could be no systemic, long-term tumour control. Laser immunotherapy, a novel method for treatment of metastatic tumours, uses a near-infrared laser, a laser-absorbing dye indocyanine green, and an immunoadjuvant glycated chitosan. This modality has shown an induced antitumour immune response in treatment of rat mammary metastatic tumours. The influence of this new method on the cellular structure of the tumours and on the infiltrating immune cells was studied using optical and electron microscopes. The tumour samples were examined before and immediately after the treatment for acute effects, which appeared mainly photothermal. Two weeks after treatment, significant infiltrating lymphocytes and plasma cells were found around the surviving tumour cells. These morphological findings suggest that both cell-mediated and humoral immune responses could be responsible for the observed tumour eradication and induced long-term tumour resistance. PMID:24590198

Chen, W R; Liu, H; Nordquist, J A; Nordquist, R E

2000-01-01

369

Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy  

PubMed Central

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. PMID:24855562

2014-01-01

370

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy  

PubMed Central

Sepsis — severe life-threatening infection with organ dysfunction — initiates a complex interplay of host pro- and anti-inflammatory processes. In a real sense, sepsis can be considered a race to the death between the pathogens and the host immune system. It is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly-touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses is leading to a novel approach to treat this highly lethal condition. Biomarker-guided immunotherapy administered to patients at the proper immune phase of sepsis represents a potential major advance in the treatment of sepsis and more broadly in the field of infectious disease. PMID:24232462

Hotchkiss, Richard S.; Monneret, Guillaume; Payen, Didier

2014-01-01

371

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy.  

PubMed

Sepsis - which is a severe life-threatening infection with organ dysfunction - initiates a complex interplay of host pro-inflammatory and anti-inflammatory processes. Sepsis can be considered a race to the death between the pathogens and the host immune system, and it is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses provides a novel approach for treating this highly lethal condition. Biomarker-guided immunotherapy that is administered to patients at the proper immune phase of sepsis is potentially a major advance in the treatment of sepsis and in the field of infectious disease. PMID:24232462

Hotchkiss, Richard S; Monneret, Guillaume; Payen, Didier

2013-12-01

372

Drug-mediated and cellular immunotherapy in multiple myeloma.  

PubMed

Multiple myeloma is an immunologically relevant disease, which subverts and suppresses immunity, but that may also be amenable to immunological control. Novel drug and cell-based therapies provide an opportunity for the design of antimyeloma immunotherapy. Reversing the immunosuppression associated myeloma remains a substantial challenge. The minimal residual disease setting achieved by autologous stem cell transplant or highly efficacious induction therapy may reverse this immunoparesis and provide a setting for induction of antimyeloma T-cell responses. Adoptive cytotoxic T-lymphocyte/NK therapy and comprehensive treatment with immunomodulatory drug therapy represent means by which antimyeloma immune responses may be promoted. In addition, apoptosis-inducing therapies may prime endogenous antigen presentation via immunogenic cell death, which again may be enhanced by the addition of immunomodulatory drug therapy. PMID:20635931

Ritchie, David S; Quach, Hang; Fielding, Kate; Neeson, Paul

2010-03-01

373

Checkpoint immunotherapy for cancer - superior survival, unaccustomed toxicities.  

PubMed

Novel cancer immunotherapy antibodies are moving from clinical trials into routine practice, delivering sustained benefits and prolonged survival to patients with melanoma, lung, kidney and other cancers. These immunostimulatory antibodies non-specifically activate the patient's own immune system by inhibiting immune system checkpoint proteins. This mechanism of action is entirely different to traditional cancer treatments such as chemotherapy. Whilst there are virtually no immediate toxicities, serious life-threatening autoimmune side effects such as colitis, dermatitis, hypophysitis, pneumonitis and hepatitis can occur, sometimes starting long after the treatment has been given. Recognition, referral and prompt treatment with immunosuppressive drugs like corticosteroids can control these immune-related side effects without compromising efficacy. This exciting new class of drugs is defining a new paradigm in cancer therapy. PMID:25444021

Gedye, Craig; van der Westhuizen, Andre; John, Tom

2014-12-01

374

Epidermal growth factor receptor and variant III targeted immunotherapy.  

PubMed

Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review, we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these approaches. PMID:25342601

Congdon, Kendra L; Gedeon, Patrick C; Suryadevara, Carter M; Caruso, Hillary G; Cooper, Laurence J N; Heimberger, Amy B; Sampson, John H

2014-10-01

375

Cytomegalovirus as a Novel Target for Immunotherapy of Glioblastoma Multiforme  

PubMed Central

Progress in the treatment of glioblastoma multiforme (GBM) over the last few decades has remained marginal and GBM is still universally fatal with short survival times after initial diagnosis. Much research is focused on finding new therapeutics for GBM and immune-based approaches have shown great promise. The detection of cytomegalovirus (CMV) antigens in malignant cells has suggested that treatment strategies based on immunological intervention, such as adoptive transfer of antiviral T cells or vaccination with viral epitopes, could be exploited as cancer therapy. Here, we review the rationale for using CMV as a therapeutic target and discuss the first clinical evidence for safety and efficacy of CMV-specific cellular immunotherapy for GBM. PMID:25340042

Schuessler, Andrea; Walker, David G.; Khanna, Rajiv

2014-01-01

376

Ingenol Mebutate: Potential for Further Development of Cancer Immunotherapy  

PubMed Central

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 elim1nating 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.

2014-01-01

377

Immunotherapy prospects in the treatment of lung cancer and mesothelioma  

PubMed Central

A very recent finding is the role of immune activation in cancer. The assumption that stimulating the patient’s immune system to attack tumors is a valuable treatment option in malignant diseases has gained more acceptance. However the high immunosuppressive effects caused by the tumor limits this beneficial effect. There is a delicate balance between immunoactivation and immunosuppression in a patient. Especially in non small cell lung cancer (NSCLC), the role of immunosuppressive cells hampering immune activation is high. But also in small cell lung cancer (SCLC) and mesothelioma immunosuppressive activity is high. This is suggested to be related to the type of tumor, advanced stage of the disease, and the tumor load. In this review, we provide an overview of the progress and challenges in the immunotherapeutic approaches in lung cancer. We conclude with the concept that immunotherapy in thoracic malignancies must be tailored made to the balance of the immune system. PMID:25806279

Lievense, Lysanne A.; Hoogsteden, Henk C.; Hegmans, Joost P.

2014-01-01

378

Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy.  

PubMed

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. PMID:24855562

Schaer, David A; Hirschhorn-Cymerman, Daniel; Wolchok, Jedd D

2014-01-01

379

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome  

PubMed Central

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. PMID:23934126

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.

2013-01-01

380

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.  

PubMed

The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments. PMID:25428507

Gubin, Matthew M; Zhang, Xiuli; Schuster, Heiko; Caron, Etienne; Ward, Jeffrey P; Noguchi, Takuro; Ivanova, Yulia; Hundal, Jasreet; Arthur, Cora D; Krebber, Willem-Jan; Mulder, Gwenn E; Toebes, Mireille; Vesely, Matthew D; Lam, Samuel S K; Korman, Alan J; Allison, James P; Freeman, Gordon J; Sharpe, Arlene H; Pearce, Erika L; Schumacher, Ton N; Aebersold, Ruedi; Rammensee, Hans-Georg; Melief, Cornelis J M; Mardis, Elaine R; Gillanders, William E; Artyomov, Maxim N; Schreiber, Robert D

2014-11-27

381

Oncolytic Viruses and Their Application to Cancer Immunotherapy  

PubMed Central

Oncolytic viruses (OVs) selectively replicate in 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 immune modulatory 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; they include: (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, co-stimulatory, NK receptors), and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing GM-CSF, have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between anti-virus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs. PMID:24764576

Chiocca, EA; Rabkin, SD

2015-01-01

382

Chordoma and chondrosarcoma gene profile: implications for immunotherapy  

PubMed Central

Chordoma and chondrosarcoma are malignant bone tumors characterized by the abundant production of extracellular matrix. The resistance of these tumors to conventional therapeutic modalities has prompted us to delineate the gene expression profile of these two tumor types, with the expectation to identify potential molecular therapeutic targets. Furthermore the transcriptional profile of chordomas and chrondrosarcomas was compared to a wide variety of sarcomas as well as to that of normal tissues of similar lineage, to determine whether they express unique gene signatures among other tumors of mesenchymal origin, and to identify changes associated with malignant transformation. A HG-U133A Affymetrix Chip platform was used to determine the gene expression signature in 6 chordoma and 14 chondrosarcoma lesions. Validation of selected genes was performed by qPCR and immunohistochemistry (IHC) on an extended subset of tumors. By unsupervised clustering, chordoma and chondrosarcoma tumors grouped together in a genomic cluster distinct from that of other sarcoma types. They shared overexpression of many extracellular matrix genes including aggrecan, type II & X collagen, fibronectin, matrillin 3, high molecular weight-melanoma associated antigen (HMW-MAA), matrix metalloproteinase MMP-9, and MMP-19. In contrast, T Brachyury and CD24 were selectively expressed in chordomas, as were Keratin 8,13,15,18 and 19. Chondrosarcomas are distinguished by high expression of type IX and XI collagen. Because of its potential usefulness as a target for immunotherapy, the expression of HMW-MAA was analyzed by IHC and was detected in 62% of chordomas and 48% of chondrosarcomas, respectively. Furthermore, western blotting analysis showed that HMW-MAA synthesized by chordoma cell lines has a structure similar to that of the antigen synthesized by melanoma cells. In conclusion, chordomas and chondrosarcomas share a similar gene expression profile of up-regulated extracellular matrix genes. HMW-MAA represents a potential useful target to apply immunotherapy to these tumors. PMID:18641983

Schwab, Joseph H.; Boland, Patrick J.; Agaram, Narasimhan P.; Socci, Nicholas D.; Guo, Tianhua; O’Toole, Gary C.; Wang, Xinhui; Ostroumov, Elena; Hunter, Christopher J.; Block, Joel A.; Doty, Stephen; Ferrone, Soldano; Healey, John H.

2012-01-01

383

Subcutaneous and sublingual immunotherapy in children: Complete update on controversies, dosing, and efficacy  

Microsoft Academic Search

For this review, articles on immunotherapy dosing in pediatric respiratory allergy were identified via PubMed, through congressional\\u000a abstracts for 2008, in reference lists of recent review articles, and via personal communication with experts. In pediatric\\u000a subcutaneous immunotherapy (SCIT), doses shown to be effective, mostly in aluminium-adsorbed preparations administered every\\u000a 6 weeks, contain 20 ?g of group 5 major allergen, 12

Désirée Larenas-Linnemann

2008-01-01

384

A view on dendritic cell immunotherapy in ovarian cancer: how far have we come?  

PubMed Central

Ovarian cancer is the second most important pelvic gynaecologic malignancy and nowadays still kills 80% of patients. New treatment options are mandatory. Although it has been shown that ovarian cancer is an immunogenic tumor, the possibility of developing immunotherapy has been neglected for a long time. This article focuses on the importance of the immune system in the development and progression of cancer and the possibilities and problems of dendritic cell-based immunotherapy to influence the immune system.

Coosemans, A.; Baert, T.; Vergote, I.

2015-01-01

385

Decreased production of interleukin-2 receptors after immunotherapy to house dust  

Microsoft Academic Search

The magnitude of the T-cell immune response depends on both the amount and the duration of interaction between interleukin 2 (IL-2) and interleukin-2 receptors (IL-2R). In a previous study, we found that IL-2 production was decreased after immunotherapy. In order to delineate further the mechanisms for the decreased lymphoproliferative response after immunotherapy,in vitro production of soluble IL-2R (SIL-2R) was studied

Kue-Hsiung Hsieh

1988-01-01

386

A Pilot Study of Consolidative Immunotherapy in Patients with High-Risk Pediatric Sarcomas  

PubMed Central

Purpose Patients with metastatic or recurrent Ewing’s sarcoma (ESFT) and alveolar rhabdomyosarcoma (AR) have <25% 5-yr. survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients. Experimental Design 52 patients with translocation positive, recurrent or metastatic ESFT or AR underwent pre-chemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations and dendritic cells (DCs) pulsed with peptides derived from tumor specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate dose rhIL-2, cohort 2 received low dose rhIL-2 and cohort 3 did not receive rhIL-2. Results All immunotherapy recipients generated influenza specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2+ patients developed E7 specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year OS for all patients apheresed (median potential follow-up 7.3 yrs) with a 43% 5-year OS for patients initiating immunotherapy. Conclusions Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that post-chemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent DCs. PMID:18676758

Mackall, Crystal L.; Rhee, Eunice H.; Read, Elizabeth J.; Khuu, Hanh M.; Leitman, Susan F.; Bernstein, Donna; Tesso, Merertu; Long, Lauren M.; Grindler, David; Merino, Margret; Kopp, William; Tsokos, Maria; Berzofsky, Jay A.; Helman, Lee J.

2008-01-01

387

Immunotherapy for pythiosis: Effect on NTPDase activity in lymphocytes of an experimental model.  

PubMed

NTPDase (EC 3.6.1.5) occurs in lymphocytes and plays an important role in immune function, in that hydrolyzes extracellular nucleoside tri- and/or diphosphates to form AMP. Pythium insidiosum causes the disease pythiosis, a pyogranulomatous disease of horses, dogs, cattle, cats and humans. Most antifungal drugs are ineffective against this pathogen, and immunotherapy, a treatment approach that relies on the injection of P. insidiosum antigen, has been successfully used in humans and horses to manage this disease. In this study, we investigated NTPDase activity in lymphocytes from rabbits inoculated with zoospores of P. insidiosum. After immunotherapy, we investigated the relationship between enzymatic activity and the pattern of the immune response. One milliliter of zoospores was inoculated subcutaneously into the coastal region of each rabbit. An average of 17,500 viable mobile zoospores/mL of induction medium was administered. Inoculated rabbits were checked weekly, and the subcutaneous nodular area (cm²) was measured 28 days after inoculation. Rabbits that developed lesions received four doses of immunotherapy at intervals of 14 days. Blood samples were collected by heart puncture twice a month for the determination of NTPDase activity. The results demonstrated that NTPDase activity in lymphocytes was increased in relation to ATP hydrolysis (by about 100%) in pythiosis and returned to normal values after immunotherapy. The data demonstrating NTPDase activity before and after immunotherapy reinforce the previously elaborated hypothesis that the change from a Th2 to a Th1 immune response is responsible for the curative properties of immunotherapy. PMID:20970953

Bach, Barbara Charlotte; Leal, Daniela Bitencourt Rosa; Ruchel, Jader Betsch; Souza, Viviane do Carmo Gonçalves; Maboni, Grazieli; Dal Pozzo, Marcelo; Schlemmer, Karine Bizzi; Alves, Sydney Hartz; Santurio, Janio Morais

2010-12-01

388

Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?  

PubMed Central

Alzheimer’s disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (A?) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics. Within the past decade convincing data has arisen positioning the soluble prefibrillar A?-aggregates as the prime toxic agents in AD. However, different A? aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against A? is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of A?-aggregates than to focus on a single aggregate species for immunization. PMID:23663286

2013-01-01

389

Modulation of dendritic cell innate and adaptive immune functions by oral and sublingual immunotherapy.  

PubMed

Sublingual (SLIT) and oral immunotherapy (OIT) are promising treatments for food allergy, but underlying mechanisms are poorly understood. Dendritic cells (DCs) induce and maintain Th2-type allergen-specific T cells, and also regulate innate immunity through their expression of Toll-like receptors (TLRs). We examined how SLIT and OIT influenced DC innate and adaptive immune responses in children with IgE-mediated cow's milk (CM) allergy. SLIT, but not OIT, decreased TLR-induced IL-6 secretion by myeloid DCs (mDCs). SLIT and OIT altered mDC IL-10 secretion, a potent inhibitor of Fc?RI-dependent pro-inflammatory responses. OIT uniquely augmented IFN-? and decreased IL-6 secretion by plasmacytoid DCs (pDCs), which was associated with reduced TLR-induced IL-13 release in pDC-T cell co-cultures. Both SLIT and OIT decreased Th2 cytokine secretion to CM in pDC-T, but not mDC-T, co-cultures. Therefore, SLIT and OIT exert unique effects on DC-driven innate and adaptive immune responses, which may inhibit allergic inflammation and promote tolerance. PMID:25173802

Frischmeyer-Guerrerio, Pamela A; Keet, Corinne A; Guerrerio, Anthony L; Chichester, Kristin L; Bieneman, Anja P; Hamilton, Robert G; Wood, Robert A; Schroeder, John T

2014-11-01

390

Repeated antigen painting and sublingual immunotherapy in mice convert sublingual dendritic cell subsets.  

PubMed

The sublingual mucosa (SLM) is utilized as the site for sublingual immunotherapy (SLIT) to induce tolerance against allergens. The contribution of SLM-dendritic cells (SLM-DCs) has not been clarified. The aim of this study was to examine the dynamics and phenotype of SLM-DCs after topical antigen painting and SLIT. SLM-DCs were histologically evaluated after FITC painting. A novel murine Japanese cedar pollinosis (JCP) model was generated and change in SLM-DCs after SLIT was examined. The density of SLM-DCs was clearly lower compared with the buccal mucosa and dorsal surface of the tongue. Topical FITC painting on the SLM induced maximal recruitment of submucosal DCs (smDCs) at 6h, but most smDCs had vanished at 24h. Repeated painting on the SLM induced exhaustion and conversion of the smDC phenotype. CD206(high)CD11c(low) round-type cells with fewer dendrites and less lymph node migration capacity became dominant. In the murine model of JCP, SLIT efficiently inhibited clinical symptoms and allergen-mediated immunological responses. SLIT markedly reduced the number of SLM-DCs, converted to the round-type dominant phenotype and inhibited the activation of regional lymph node DCs. Topical antigen painting on the SLM induced rapid exhaustion and conversion of smDCs. The unique dynamics of SLM-DCs may contribute to tolerance induction in SLIT. PMID:25168308

Zhang, Chenyang; Ohno, Tatsukuni; Kang, Siwen; Takai, Toshiro; Azuma, Miyuki

2014-09-29

391

Phosphoantigens overcome human TCRVgamma9+ gammadelta Cell immunosuppression by TGF-beta: relevance for cancer immunotherapy.  

PubMed

Human gammadelta cells expressing TCRVgamma9 are HLA-unrestricted CTLs with high relevance for cancer immunotherapy. Many tumor cell types produce TGF-beta, however, a cytokine strongly immunosuppressive for conventional T CD4, CD8, and NK cells. Whether TGF-beta also inhibits TCRVgamma9+ lymphocytes was unknown. Because phosphoantigens (PAgs), such as bromohydrin pyrophosphate, selectively activate the antitumor functions of TCRVgamma9+ T cells, in this study, we investigated whether TGF-beta modulates these functions. We report that TGF-beta does not block activation of TCRVgamma9+ T cells but inhibits their PAg/IL-2-induced proliferation and maturation into effector cells and finally reduces the cytotoxic activity of these gammadelta T cells when exposed to lymphoma target cells. TGF-beta did not bias their differentiation pattern toward gammadelta Th17 or gammadelta regulatory T cells. Nevertheless, increasing doses of PAg stimulus countered TGF-beta inhibition. So, although TGF-beta impairs TCRVgamma9+ gammadelta cells like other cytolytic lymphocytes, PAg alone or combined to therapeutic mAb has the ability to bypass its immunosuppressive activity. PMID:20483742

Capietto, Aude-Hélène; Martinet, Ludovic; Cendron, Delphine; Fruchon, Séverine; Pont, Frédéric; Fournié, Jean-Jacques

2010-06-15

392

Feasibility analysis of p62 (SQSTM1)-encoding DNA vaccine as a novel cancer immunotherapy.  

PubMed

Cancer immunotherapy is a thriving field, but its clinical achievements are modest so far. One of its major hurdles seems to be finding a feasible cancer antigen as a target for immune response. After many years of research, three major criteria for choice of tumor antigens emerged. An antigen should be: (i) immunogenic; (ii) essential for cancers cells (to avoid its loss through immunoediting), but dispensable for normal tissues to reduce the risk of toxicity, and (iii) overexpressed in tumors as compared to the normal tissues. Here we argue that p62 (SQSTM1), a protein involved in autophagy and signal transduction, fits all the above criteria and can be chosen as a novel cancer antigen. Accordingly, we carried out an extensive study and found antitumor and antimetastatic activity of p62-encoding DNA vaccine in five types of commonly used transplantable tumor models of mice and rats, and spontaneous tumors in several dogs. Given that toxicity of p62 vaccine was minimal, if any, we believe that p62-encoding vaccine merits further clinical development. PMID:25277339

Gabai, Vladimir L; Shifrin, Victor I

2014-10-01

393

Immunotherapy of radioresistant mammary tumors with early metastasis using molecular chaperone vaccines combined with ionizing radiation  

PubMed Central

In the present study, exposure of mammary tumor cells derived from mice transgenic for the polyomavirus middle T (PyMT) oncogene to ionizing radiation resulted in the generation of a tumor cell population that preferentially expressed cancer stem cell markers. In addition, these cells were more resistant to further radiation treatments and appeared to acquire enhanced capacity for dissemination to the lungs of mice. We therefore tested an immunotherapy approach to treatment of local and disseminated mammary tumor cells in a murine model, employing a recently developed molecular chaperone-based vaccine that specifically targets the radioresistant subpopulation of tumor cells. Heat shock protein 70-peptide complexes (Hsp70.PC-F) were extracted from fusions of dendritic cells (DC) and radiation enriched tumor cells and the resulting chaperone vaccines used to treat mice with pre-existing lung metastases. Immunization of mice with the Hsp70.PC-F vaccine resulted in a T-cell-mediated immune response including a significant increase in CD4 and CD8 T cell proliferations and the induction of effector T cells capable of targeting radioresistant tumor cells. Importantly, the growth of primary tumors was inhibited and the number of tumor cells metastasizing to lung significantly reduced by combining chaperone vaccine with radiotherapy. These results indicate that Hsp70.PC-F vaccine can induce specific immunity to radioresistant populations of mammary tumor cells and can thus compliment radiotherapy, leading to synergistic killing. PMID:23772032

Weng, Desheng; Song, Baizheng; Koido, Shigeo; Calderwood, Stuart K.; Gong, Jianlin

2014-01-01

394

Mite-specific induction of interleukin-2 receptor on T lymphocytes from children with mite-sensitive asthma: Modified immune response with immunotherapy  

Microsoft Academic Search

BACKGROUND: The efficacy of immunotherapy is still controversial. To elucidate the mechanisms of immunotherapy, we studied mite-specific induction of IL-2 receptor (IL-2R) expression on T lymphocytes from children with mite-sensitive asthma. METHODS: Peripheral blood mononuclear cells were obtained from 28 children with mite-sensitive asthma: 13 had never received house dust immunotherapy (nonimmunotherapy group), 15 had been receiving house dust immunotherapy

Motoki Bonno; Takao Fujisawa; Kousei Iguchi; Yukinori Uchida; Hitoshi Kamiya; Yoshihiro Komada; Minoru Sakurai

1996-01-01

395

Oral immunotherapy for food allergy: clinical and preclinical studies.  

PubMed

Food allergies affect approximately 5% of the U.S. population and have increased in the last decade. In recent years, oral immunotherapy (OIT) has been tested in clinical trials for peanut, milk, and egg allergies in young children. OIT appears to be fairly well tolerated by most subjects and leads to desensitization with a greatly increased threshold of allergen required to induce reactions. Further approaches being investigated in preclinical studies in mouse models indicate the potential for using adjuvants, such as TLR9 agonists in combination with OIT; peptide OIT; and non-allergen specific applications such as herbal formulations. Further questions about OIT remain, including the optimal dosing and length of treatment; whether tolerance can be developed; and the exact cellular mechanisms resulting in protection following OIT. With many clinical trials underway across the United States and other countries, and a growing pipeline of preclinical research with translational potential, there is great hope for a widely applicable food allergy treatment. PMID:23099276

Kulis, Mike; Wesley Burks, A

2013-06-15

396

Oral immunotherapy for peanut allergy in clinical practice is ready.  

PubMed

Oral immunotherapy (OIT) for peanut allergy is ready for clinical allergy practice. Some physicians, particularly at academic centers, believe that OIT is not ready for clinical practice. The shortcomings of the present general recommendations of food avoidance and provision of epinephrine autoinjectors for a select number of patients demand a different approach. In peanut-allergic patients, the rate of accidental reactions is ~10% annually. Between 1 and 2% of these reactions require epinephrine or emergency department visits. Food allergy and peanut allergy, specifically, have a large negative impact on the quality of life (QOL) for patients and their families, which can be psychosocially debilitating. These decreases in health-related QOL continue into adulthood. There is only an ~20% chance of spontaneous remission in peanut allergy. Given this climate, three private allergy practices have begun providing OIT to 150 patients with peanut anaphylaxis. One hundred eleven (74%) patients were able to tolerate eight peanuts (8 g, ~2 g of protein). During outpatient dosing, epinephrine was used at a rate of 8 per 10,000 doses. To date, there have been no long-term (>24-36 months) unexpected reactions. OIT decreases risk and in one study, conducted in a practice setting, it was shown to improve QOL. OIT is a meaningful clinical procedure that can help our patients. PMID:23676569

Mansfield, Lyndon E

2013-01-01

397

Active DNA A?42 vaccination as immunotherapy for Alzheimer disease  

PubMed Central

As a neurodegenerative disorder, Alzheimer disease (AD) is the most common form of dementia found in the aging population. Immunotherapy with passive or active immunizations targeting amyloid beta (A?) build-up in the brain may provide a possible treatment option and may help prevent AD from progressing. A number of passive immunizations with anti-A?42 antibodies are in different phases of clinical trials. One active immunization approach, AN-1792, was stopped after the development of autoimmune encephalitis in 6% of patients and a second one, CAD106, in which a small A? epitope is used, is currently in safety and tolerability studies. Besides active immunizations with proteins or peptides, active immunizations using DNA which codes for the protein against which the immune response will be directed, so called genetic immunizations, provide additional safety as the immune response in DNA immunizations differs quantitatively and qualitatively from the response elicited by peptide immunizations. In this review, we summarize our data using DNA A?42 immunizations in mouse models and discuss the results together with the results presented by other groups working on a DNA vaccine as treatment option for AD. PMID:23741624

Lambracht-Washington, Doris; Rosenberg, Roger N.

2013-01-01

398

Advances in chimeric antigen receptor immunotherapy for chronic lymphocytic leukemia.  

PubMed

Despite the recent advances with targeted therapies in chronic lymphocytic leukemia (CLL), allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. However, this procedure is associated with significant morbidity and mortality due to high rates of infection and the toxicity of graft versus host disease (GVHD). One of the principle aims of cellular immunotherapy is to target the malignant cells without damaging the other tissues of the body. T lymphocytes offer the opportunity to do this, due to the exquisite specificity that they exhibit as part of the adaptive immune response. Chimeric antigen receptor (CAR) T cells are lymphocytes that have been genetically modified to express the antigen binding component of an immunoglobulin molecule coupled to T-cell signaling domains. The use of an immunoglobulin molecule eliminates MHC restriction, enabling the same CAR to be used for several different patients and increasing the feasibility of widespread clinical use. They can be constructed to target a huge range of antigens, allowing the targeting of cancer cells with unprecedented levels of specificity. The addition of co-stimulatory domains to the CAR construct has enhanced the efficacy and durability of these T cells, which are under investigation in several clinical trials. The early results from these trials have been very encouraging with dramatic responses being observed in heavily pre-treated patients with otherwise poor risk disease. PMID:24333409

Riches, John C; Gribben, John G

2013-12-01

399

Harnessing the power of V?2 cells in cancer immunotherapy.  

PubMed

?? T cells are a subset of T lymphocytes that have been implicated in immunosurveillance against infections and tumours. In the peripheral blood of humans the ?? T cell pool is made up predominantly of V?2 cells, which can detect both foreign and self-metabolites of the isoprenoid biosynthesis pathway. This unique axis of antigen recognition enables V?2 cells to respond to a range of pathogenic infections as well as perturbations in endogenous isoprenoid biosynthesis that can occur during cell stress and malignant transformation. There has been growing interest in V?2 cells as a potential avenue for cancer immunotherapy, and a number of strategies have been utilized in an attempt to boost the anti-tumour response of V?2 cells in patients. In this review we discuss critically the evidence that V?2 cells contribute to the cytotoxic response against tumours and evaluate current immunotherapeutic approaches that target these cells in cancer patients, with specific focus on their shortcomings and how they may be improved. PMID:25469879

Fowler, D W; Bodman-Smith, M D

2015-04-01

400

Cellular immune responses to hepatocellular carcinoma: lessons for immunotherapy.  

PubMed

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with a continuously high mortality. Thus, the development of new therapeutic strategies is crucial to decrease recurrence rates and to improve the overall survival rates of HCC patients. The rationale for immunotherapy is based on the findings of several studies showing specific CD8(+) T-cell responses against various tumor-associated antigens (TAAs) in HCC patients and a clinical benefit of T-cell infiltration in the tumor tissue. However, the impact of TAA-specific CD8(+) T-cell responses on tumor control seems to be rather weak. Several different mechanisms contribute to the failure of the cellular immune response and will be summarized in this review. The aim of immune-based therapies is to overcome these mechanisms of T-cell failure and to induce or boost TAA-specific CD8(+) and CD4(+) T-cell responses. Several preclinical and clinical studies of immune-based therapeutic approaches show encouraging results and will be discussed in this review. PMID:23108304

Schmidt, Nathalie; Neumann-Haefelin, Christoph; Thimme, Robert

2012-01-01

401

Enhanced Cellular Immunity in Macaques following a Novel Peptide Immunotherapy  

PubMed Central

Advances in treating and preventing AIDS depend on understanding how human immunodeficiency virus (HIV) is eliminated in vivo and on the manipulation of effective immune responses to HIV. During the development of assays quantifying the elimination of fluorescent autologous cells coated with overlapping 15-mer simian immunodeficiency virus (SIV) or HIV-1 peptides, we made a remarkable observation: the reinfusion of macaque peripheral blood mononuclear cells, or even whole blood, pulsed with SIV and/or HIV peptides generated sharply enhanced SIV- and HIV-1-specific T-cell immunity. Strong, broad CD4+- and CD8+-T-cell responses could be enhanced simultaneously against peptide pools spanning 87% of all SIV- and HIV-1-expressed proteins—highly desirable characteristics of HIV-specific immunity. De novo hepatitis C virus-specific CD4+- and CD8+-T-cell responses were generated in macaques by the same method. This simple technique holds promise for the immunotherapy of HIV and other chronic viral infections. PMID:15731268

Chea, S.; Dale, C. J.; De Rose, R.; Ramshaw, I. A.; Kent, S. J.

2005-01-01

402

Modulation of CTLA-4 and GITR for cancer immunotherapy.  

PubMed

The rational manipulation of antigen-specific T cells to reignite a tumor-specific immune response in cancer patients is a challenge for cancer immunotherapy. Targeting coinhibitory and costimulatory T cell receptors with specific antibodies in cancer patients is an emerging approach to T cell manipulation, namely "immune modulation." Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor family receptor (GITR) are potential targets for immune modulation through anti-CTLA-4 blocking antibodies and anti-GITR agonistic antibodies, respectively. In this review, we first discuss preclinical findings key to the understanding of the mechanisms of action of these immunomodulatory antibodies and the preclinical evidence of antitumor activity which preceded translation into the clinic. We next describe the outcomes and immune related adverse effects associated with anti-CTLA-4 based clinical trials with particular emphasis on specific biomarkers used to elucidate the mechanisms of tumor immunity in patients. The experience with anti-CTLA-4 therapy and the durable clinical benefit observed provide proof of principle to effective antitumor immune modulation and the promise of future clinical immune modulatory antibodies. PMID:20563707

Avogadri, Francesca; Yuan, Jianda; Yang, Arvin; Schaer, David; Wolchok, Jedd D

2011-01-01

403

Nanoscale Artificial Antigen Presenting Cells for T Cell Immunotherapy  

PubMed Central

Artificial antigen presenting cells (aAPC), which deliver stimulatory signals to cytotoxic lymphocytes, are a powerful tool for both adoptive and active immunotherapy. Thus far, aAPC have been synthesized by coupling T cell activating proteins such as CD3 or MHC-peptide to micron-sized beads. Nanoscale platforms have different trafficking and biophysical interaction properties and may allow development of new immunotherapeutic strategies. We therefore manufactured aAPC based on two types of nanoscale particle platforms: biocompatible iron-dextran paramagnetic particles (50–100 nm in diameter) and avidin-coated quantum dot nanocrystals, (~30 nm). Nanoscale aAPC induced antigen-specific T cell proliferation from mouse splenocytes and human peripheral blood T cells. When injected in vivo, both iron-dextran particles and quantum dot nanocrystals enhanced tumor rejection in a subcutaneous mouse melanoma model. This is the first description of nanoscale aAPC that induce antigen-specific T cell proliferation in vitro and lead to effective T cell stimulation and inhibition of tumor growth in vivo. PMID:23891987

Perica, Karlo; De León Medero, Andrés; Durai, Malarvizhi; Chiu, Yen Ling; Bieler, Joan Glick; Sibener, Leah; Niemöller, Michaela; Assenmacher, Mario; Richter, Anne; Edidin, Michael; Oelke, Mathias; Schneck, Jonathan

2014-01-01

404

Vaccine-mediated immunotherapy directed against a transcription factor driving the metastatic process.  

PubMed

Numerous reports have now demonstrated that the epithelial-to-mesenchymal transition (EMT) process is involved in solid tumor progression, metastasis, and drug resistance. Several transcription factors have been implicated as drivers of EMT and metastatic progression, including Twist. Overexpression of Twist has been shown to be associated with poor prognosis and drug resistance for many carcinomas and other tumor types. The role of Twist in experimental cancer metastases has been principally studied in the 4T1 mammary tumor model, where silencing of Twist in vitro has been shown to greatly reduce in vivo metastatic spread. Transcription factors such as Twist are generally believed to be "undruggable" because of their nuclear location and lack of a specific groove for tight binding of a small molecule inhibitor. An alternative approach to drug therapy targeting transcription factors driving the metastatic process is T-cell-mediated immunotherapy. A therapeutic vaccine platform that has been previously characterized consists of heat-killed recombinant Saccharomyces cerevisiae (yeast) capable of expressing tumor-associated antigen protein. We report here the construction and characterization of a recombinant yeast expressing the entire Twist protein, which is capable of inducing both CD8(+) and CD4(+) Twist-specific T-cell responses in vivo. Vaccination of mice reduced the size of primary transplanted 4T1 tumors and had an even greater antitumor effect on lung metastases of the same mice, which was dependent on Twist-specific CD8(+) T cells. These studies provide the rationale for vaccine-induced T-cell-mediated therapy of transcription factors involved in driving the metastatic process. PMID:24520078

Ardiani, Andressa; Gameiro, Sofia R; Palena, Claudia; Hamilton, Duane H; Kwilas, Anna; King, Thomas H; Schlom, Jeffrey; Hodge, James W

2014-04-01

405

The effect of multiple allergen immunotherapy on exhaled nitric oxide in adults with allergic rhinitis  

PubMed Central

Background There is a lack of objective measures of the clinical efficacy of allergen immunotherapy which relies on patients’ perception about the effect of this treatment. We studied whether the fraction of exhaled nitric oxide is affected by multiple allergen immunotherapy in polysensitized adult subjects with allergic rhinitis. We also looked for associations between exhaled nitric oxide and subjects’ demographics, symptom scores, and pulmonary function tests. Methods Twenty adult, polysensitized subjects with seasonal and perennial allergic rhinitis who chose to undergo allergen immunotherapy were enrolled. They were evaluated at baseline, and 4, 8, 12, 24, and 52 weeks later. Exhaled nitric oxide was reported as the mean of triplicate determinations. Findings Our results indicate that multiple allergen immunotherapy did not affect exhaled nitric oxide levels and such levels did not correlate with subjects’ demographics and pulmonary function tests. However, exhaled nitric oxide was associated with rhinoconjuctivitis and asthma symptom scores at the end of the study. Conclusions In polysensitized adult subjects with allergic rhinitis, exhaled nitric oxide levels are unaffected by multiple allergen immunotherapy. PMID:23958488

2013-01-01

406

Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy  

PubMed Central

Sub-cutaneous immunotherapy is an effective treatment for allergy. It works by helping to modify or re-balance an individual’s immune response to allergens and its efficacy is greatly improved by the use of adjuvants, most commonly, aluminium hydroxide. Aluminium salts have been used in allergy therapy for many decades and are assumed to be safe with few established side-effects. This assumption belies their potency as adjuvants and their potential for biological reactivity both at injection sites and elsewhere in the body. There are very few data purporting to the safety of aluminium adjuvants in allergy immunotherapy and particularly so in relation to longer term health effects. There are, if only few, published reports of adverse events following allergy immunotherapy and aluminium adjuvants are the prime suspects in the majority of such incidents. Aluminium adjuvants are clearly capable of initiating unwanted side effects in recipients of immunotherapy and while there is as yet no evidence that such are commonplace it is complacent to consider aluminium salts as harmless constituents of allergy therapies. Future research should establish the safety of the use of aluminium adjuvants in sub-cutaneous allergy immunotherapy. PMID:24444186

2014-01-01

407

Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom  

Microsoft Academic Search

Background: Specific immunotherapy with honeybee venom (BV) is highly effective, but allergic side effects can occur during treatment. Immunotherapy with peptides containing major T-cell epitopes of the relevant allergen or allergens provides an alternative strategy without these problems. Objective: The study investigates the immunologic mechanisms and clinical effects of immunotherapy with T-cell epitope peptides of the major BV allergen, the

Ulrich Müller; Cezmi A. Akdis; Michael Fricker; Mübeccel Akdis; Thorsten Blesken; Florence Bettens; Kurt Blaser

1998-01-01

408

Anti-TNF Therapy in Ankylosing Spondylitis: Insights for the Clinician  

PubMed Central

The introduction of tumour necrosis factor (TNF)-blocking therapy has revolutionized the management of ankylosing spondylitis (AS) over the last decade. This review highlights the current evidence relating to the use of TNF-blocking therapy in AS. International guidelines for the use of TNF blockers in AS are summarized. An outline of the evidence for efficacy and safety of these drugs is included, highlighting recent data from registries and real-life observational studies. Such cohort data is also reviewed highlighting the evidence for ‘switching’ TNF blockers in AS in the case of non-response or adverse events. The potential new application of TNF blockers in preradiographic axial spondyloarthropathy (SpA) or ‘early AS’ is discussed with reviews of two recent studies in this area. Finally research into the possible additional impacts of TNF therapies is reviewed. The question of whether TNF blockers are truly disease modifying in AS remains unanswered with conflicting reports. The additional burden of AS in terms of cardiovascular disease is now becoming understood. Recent data from basic science studies highlights the potential impact of TNF blockers on this excess cardiovascular morbidity and mortality. Future studies and registry data will be able to assess whether TNF blockers have an additional role in controlling systemic inflammation and its associated cardiovascular risk. PMID:22870436

Coates, Laura C.; Marzo-Ortega, Helena; Bennett, Alexander N.; Emery, Paul

2010-01-01

409

Mycobacterium poriferae infection in a psoriasis patient on anti-TNF-? therapy.  

PubMed

Psoriasis is a chronic, auto-inflammatory disease affecting millions of individuals worldwide. In addition to classic cutaneous manifestations, the condition is linked to significant co-morbidities including cardiovascular disease, metabolic syndrome, melanoma and non-melanoma skin cancer, and psychiatric disease. Therefore, more aggressive treatment and multi-disciplinary care is critical. Measures of disease burden (quantified by anatomic location, body surface area (BSA) of involvement, and impact on daily life) assist in determining the severity of disease and have been integral in objective assessment of treatment regimens and new drug therapies. Biologic agents have entered the clinical armamentarium as treatment options for patients with moderate-to-severe psoriasis who have failed traditional systemic therapies. Three of the four FDA-approved biologic agents for psoriasis suppress TNF-? mediated pathways, which are essential for granuloma formation and maintenance, key components of host defenses against intracellular pathogens. Subsequently, the increased use of these agents is accompanied by increased reporting of granulomatous infectious diseases such as tuberculosis, histoplasmosis, nocardia, and nontuberculous mycobacteria. Report of any unusual infection is therefore vitally important in the care of this immune suppressed patient population. PMID:24050284

Laquer, Vivian; Ta, Tuan; Nguyen, Tien; Tan, Belinda

2013-09-01

410

Ulcerative Necrobiosis Lipoidica: Is There a Place for Anti-TNF? Treatment?  

PubMed

Necrobiosis lipoidica is a rare granulomatous and inflammatory disease. Its management is particularly difficult when ulceration is present. The authors describe the clinical case of a 65-year-old female patient with necrobiosis lipoidica, who had been submitted in the past to several topical and systemic treatments with little or no improvement. She started treatment with subcutaneous etanercept and showed significant improvement without adverse events until today. The aim of this article is to report a valid and efficient alternative treatment to recalcitrant cases. PMID:22675367

Guedes, Rita; Leite, Inês; Baptista, Armando; Rocha, Natividade

2012-01-01

411

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.  

PubMed

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation. PMID:22801493

Gregory, Adam P; Dendrou, Calliope A; Attfield, Kathrine E; Haghikia, Aiden; Xifara, Dionysia K; Butter, Falk; Poschmann, Gereon; Kaur, Gurman; Lambert, Lydia; Leach, Oliver A; Prömel, Simone; Punwani, Divya; Felce, James H; Davis, Simon J; Gold, Ralf; Nielsen, Finn C; Siegel, Richard M; Mann, Matthias; Bell, John I; McVean, Gil; Fugger, Lars

2012-08-23

412

PTPRC rheumatoid arthritis risk allele is also associated with response to anti-TNF therapy  

E-print Network

. Karlson1 , and Robert M. Plenge1,3 1. Brigham and Women's Hospital, Division of Rheumatology, Immunology and Allergy, Boston, MA USA. 2. Rheumatology Unit, Department of Medicine, Karolinska Institutet of Rheumatology, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands. 5. Rosalind Russell Medical

Raychaudhuri, Soumya

413

Amelioration of Psoriasis by Anti-TNF-? RNAi in the Xenograft Transplantation Model  

Microsoft Academic Search

Tumor necrosis factor-? (TNF-?) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-?-encoding mRNA, however, is not increased in psoriatic skin, and it remains unclear whether intervention strategies based on RNA interference (RNAi) are therapeutically relevant. To test this hypothesis the present study describes first the in vitro functional screening of a

Maria Jakobsen; Karin Stenderup; Cecilia Rosada; Brian Moldt; Søren Kamp; Tomas N Dam; Thomas G Jensen; Jacob Giehm Mikkelsen

2009-01-01

414

Economic evaluation of anti-TNF agents for patients with rheumatoid arthritis in Greece  

PubMed Central

Objectives We aimed to estimate the total mean annual treatment cost of different therapy options for patients with moderate-to-severe rheumatoid arthritis (RA) in Greece. Methods A cost-minimization approach was adopted. An economic model was developed to estimate the direct costs of the three widely used treatments within a 1-year time horizon, from a health care payer perspective, either for new or for existing patients. Data on resource use, dose escalation, and frequency of therapy were based on a nationwide field survey of rheumatologists. Other analyses were also undertaken based on evidence from the literature. Total cost comprised the cost of drugs, administration, and hospital day care visits. Unit cost data were obtained from the price bulletin and the government gazettes issued by the Ministry of Health. Due to the short time horizon of the study, the cost was not discounted. Results The mean annual total cost per new (or per existing) responder patient on etanercept was estimated at €9,845 (€9,840), and the total cost on etanercept/methotrexate (MTX) was estimated at €9,857 (€9,852). Therapy with etanercept had lower annual cost relative to adalimumab and infliximab. On an annual basis, it was estimated that the difference between etanercept monotherapy and adalimumab monotherapy was €544 (€1,323). Similarly, the difference between etanercept/MTX and infliximab/MTX was €1,871 (€1,490) and €543 (€1,323), respectively, relative to adalimumab/MTX. Results remained constant under other scenario analyses undertaken. Conclusion In the real-life practice setting in Greece, where dose intensity and frequency differences occur, etanercept alone or in combination with MTX, if prescribed as per label, represents the option with lower annual cost per patient when compared with adalimumab or infliximab in patients with RA. These results hold true as long as the assumptions and data used in the analysis remain stable and may alter if any of the underlying parameters, such as drug price, change. PMID:25653545

Fragoulakis, Vasilis; Vitsou, Elli; Hernandez, Ana Cristina; Maniadakis, Nikolaos

2015-01-01

415

FOCUS on FOCIS: Combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer  

Microsoft Academic Search

Immunotherapy has emerged as another treatment modality in cancer. The goal of immunotherapy in advanced cancer patients does not have to be the complete eradication of tumor cells but rather the restoration of a dynamic balance between tumor cells and the immune response. Appropriate combination of tumor mass reduction (by surgery and\\/or chemotherapy) and neutralization of tumor-induced immunosuppression might set

Daniela Rožková; Hana Tišerová; Jitka Fu?íková; Jan Lašt'ovi?ka; Michal Podrazil; Hana Ul?ová; Vít Budínský; Jana Prausová; Zden?k Linke; Ivo Minárik; Anna Šedivá; Radek Špíšek; Ji?ina Bart??ková

2009-01-01

416

Modulation of IgE reactivity of allergens by site-directed mutagenesis: potential use of hypoallergenic variants for immunotherapy  

Microsoft Academic Search

Specific immunotherapy is an efficient treatment for patients suffering from type I allergy. The mechanisms underlying successful immunother- apy are assumed to operate at the level of T helper cells, leading to a modulation of the immune re- sponse to allergens. During immunotherapy, increas- ing doses of allergens are given on a regular basis, and the beneficial effects for the

FATIMA FERREIRA; CHRISTOF EBNER; BETTINA KRAMER; GEORG CASARI; PETER BRIZA; ANDREAS J. KUNGL; RUDOLF GRIMM; H BEATRICE JAHN-SCHMID; HEIMO BREITENEDER; DIETRICH KRAFT; MICHAEL BREITENBACH; HANS-JORG RHEINBERGER; OTTO SCHEINER

417

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

PubMed

IgE-mediated food allergy is a global health problem that affects millions of persons and affects every aspect of life for the patient. Developing effective treatment strategies to augment current practice standards of strict dietary avoidance of antigens and availability of self-injectable epinephrine has been a major focus of research teams, advocacy groups, funding agencies, and patients and their families. Significant progress has been made through the development of allergen-specific immunotherapy encompassing 3 major forms of treatment: oral, sublingual, and epicutaneous immunotherapy. These therapies are in various stages of clinical investigation, with some successes noted in clinical outcomes and modulation of immune mechanisms toward effective therapy. Here we review recent progress and areas of concern for the role of these forms of immunotherapy as an emerging treatment for food allergy. PMID:24636471

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

2014-02-01

418

Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer.  

PubMed

The immunity is dual host-protective and tumor-promoting in cancer development and progression. Many immune suppressive cells and cytokines in microenvironment can prevent cytotoxic T lymphocytes (CTL) and natural killer cells (NK) from killing tumor cells. Chemotherapy drugs and irradiation have been reported helpful in breaking immune tolerance and creating microenvironment for adoptive cell therapy. Low-dose cyclophosphamide or gemcitabine therapy can selectively deplete T regulatory cells (Treg). Paclitaxel can alter cytokine network at the tumor site, and 5-fluorouracil shows a pronounced effect on myeloid-derived suppressor cells (MDSC) depletion. Local tumor irradiation and total body irradiation (TBI) can also affect tumor microenvironment and facilitate immunotherapy. In this review, we summarize the particular effects of these agents and methods on immunomodulation, as well as their potential values in immunotherap