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1

Premedication with Montelukast Reduces Local Reactions of Allergen Immunotherapy  

Microsoft Academic Search

Background: Local reactions (LRs) are a very frequent side effect of specific immunotherapy with allergens and can impair patients’ adherence. Antihistamine pretreatment – originally introduced as a safety measure to reduce anaphylactic side effects – has been the only treatment option for LRs so far, although these swellings usually do not appear immediately but after hours. We were interested whether

Stefan Wöhrl; Simon Gamper; Wolfgang Hemmer; Georg Heinze; Georg Stingl; Tamar Kinaciyan

2007-01-01

2

Aldehyde modification and alum coadjuvancy enhance anti-TNF-? autovaccination and mitigate arthritis in rat.  

PubMed

Experimental vaccination to induce antibodies (Abs) capable of cytokine antagonism shows promise as a novel immunotherapy for chronic inflammatory disease. We prepared a hybrid antigen consisting of residues 141-235 of rat TNF-? fused to the C-terminus of glutathione-S-transferase (GST), chemically modified to incorporate aldehyde residues, for development of an auto-vaccine eliciting anti-rTNF-? Abs. In rat immunization the soluble aldehyde-modified fusion protein did not generate observable Ab responses. By contrast, vaccination with the aldehyde-modified fusion protein adsorbed on alum induced anti-TNF-? autoAbs with high titer and neutralizing activity. Induction of adjuvant arthritis in rats pre-immunized with unmodified fusion protein or a control protein in alum resulted in severe inflammation and joint damage, whereas the disease induced in rats immunized with the aldehyde-bearing fusion protein in alum was markedly attenuated. Similar results were obtained in a collagen-induced rat arthritis model. Anti-collagen II IgG Ab titers did not deviate significantly in groups pre-immunized with modified fusion protein and control protein, suggesting that anti-TNF vaccination did not skew the immune response related to disease induction. This study demonstrates synergy between particulate alum and protein bound carbonyl residues for enhancement of protein immunogenicity. The antigen-specific co-adjuvant system could prove advantageous for breaking tolerance in emerging auto-vaccination therapies targeting inflammatory cytokines as well as for enhancing a broader category of subunit vaccines. Aldehyde adduction introduces a minimal modification which, together with the established use of alum as a safe adjuvant for human use, could be favorable for further vaccine development. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd. PMID:25424319

Bavoso, Alfonso; Ostuni, Angela; De Vendel, Jolanda; Bracalello, Angelo; Shcheglova, Tatiana; Makker, Sudesh; Tramontano, Alfonso

2014-11-26

3

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 Dm; van Moorsel, Coline Hm; Korenromp, Ingrid He; Deneer, Vera Hm; Grutters, Jan C

2014-10-01

4

Anti-TNF therapy in Jordan: a focus on severe infections and tuberculosis  

PubMed Central

Background A high rate of infection has been reported in patients receiving treatment with anti-tumor necrosis factor (anti-TNF). This study describes the rate of and risk factors for serious infections in patients receiving anti-TNF agents in Jordan. Methods This retrospective observational study was conducted at a large tertiary referral center in the north of Jordan. Between January 2006 and January 2012, 199 patients who received an anti-TNF agent (infliximab, adalimumab, or etanercept) were included. Patients received the anti-TNF treatment for rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, or other conditions. A serious infection was defined as any bacterial, viral, or fungal infection that required hospitalization, administration of appropriate intravenous antimicrobial therapy, and temporary withholding of anti-TNF treatment. Results The mean duration of anti-TNF treatment was 26.2 months. Steroids were used in 29.1% of patients, while 54.8% were given additional immunosuppressant therapy (methotrexate or azathioprine). Only one anti-TNF agent was given in 70.4% of patients, while 29.6% received different anti-TNF agents for the duration of treatment. Serious infections were documented in 39 patients (19.6%), including respiratory tract infections (41%), urinary tract infections (30.8%), and skin infections (20.5%), and extrapulmonary tuberculosis in three patients (7.7%). Exposure to more than one anti-TNF agent was the only factor associated with a significant increase in the rate of infection (relative risk 1.9, 95% confidence interval 1.06–4.0, P=0.03). Conclusion Serious infections, including tuberculosis, were a common problem in patients receiving anti-TNF agents, and exposure to more than one anti-TNF agent increased the risk of serious infection. PMID:24790412

Alawneh, Khaldoon M; Ayesh, Mahmoud H; Khassawneh, Basheer Y; Saadeh, Salwa Shihadeh; Smadi, Mahmoud; Bashaireh, Khaldoun

2014-01-01

5

Clinical application and evaluation of anti-TNF-alpha agents for the treatment of rheumatoid arthritis  

PubMed Central

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease that dramatically impairs quality of life. A number of compounds are available to treat RA, but they vary in effectiveness. Thus, no optimal treatment strategy has been defined. Currently, disease-modifying anti-rheumatic drugs (DMARDs) and anti-tumor necrosis factor-alpha (anti-TNF-?) agents are considered the treatments of choice. For patients with inadequate responses to DMARD therapy, one recommended therapeutic alternative is anti-TNF-? therapy. Anti-TNF-? agents are effective and have rapid onset of action compared with DMARDs. Elucidating the differences in effectiveness of anti-TNF-? compounds has important clinical implications. By comparing the efficacy, safety and use principle of different treatment options, this review focuses on providing important information about three anti-TNF-? compounds (etanercept, infliximab, and adalimumab) to help define optimal treatments for RA patients. PMID:20711219

Jin, Juan; Chang, Yan; Wei, Wei

2010-01-01

6

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

7

Benefit of anti-TNF therapy in rheumatoid arthritis patients with moderate disease activity  

PubMed Central

Objectives. Anti-TNF therapy has improved outcomes for patients with highly active RA. Less is known about its effectiveness in patients with lower disease activity. The aim of this analysis is to compare the response to anti-TNF therapy between RA patients with high (DAS28 > 5.1) and moderate (DAS28 > 3.2–5.1) disease activity. Methods. A total of 4687 anti-TNF and 344 DMARD patients with high disease activity despite treatment with two standard DMARDs (including MTX) and 224 anti-TNF- and 300 DMARD-treated patients with moderate disease activity were selected from the British Society For Rheumatology Biologics Register. Mean change in HAQ over the first 12 months of enrolment was compared first between anti-TNF-treated and untreated patients in each DAS28 group, and then between anti-TNF-treated patients in the moderate and high DAS28 groups, using doubly robust estimates, adjusting for age, gender, disease duration, baseline HAQ and DAS28 score, number of previous DMARDs and steroid use. Results. Compared with anti-TNF-untreated patients within each DAS group, treated patients were younger, had higher DAS28 and HAQ and had failed a higher number of previous DMARDs. The mean adjusted change in HAQ over 12 months was similar in anti-TNF-treated patients with moderate and high disease activity at baseline: moderate ?0.26 (95% CI ?0.35, ?0.16), high ?0.28 (95% CI ?0.34, ?0.23) and mean difference ?0.03 (95% CI ?0.14, 0.08). Conclusions. Improvement in HAQ score 12 months after start of anti-TNF therapy was not dependent on baseline DAS28 scores, suggesting that substantial benefits may also be gained by treating those with moderately active disease despite standard DMARD therapy. PMID:19706737

Deighton, Chris; Watson, Kath D.; Symmons, Deborah P. M.; Lunt, Mark

2009-01-01

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

Onset of psoriasis in patients with inflammatory bowel disease treated with anti-TNF agents.  

PubMed

Anti-TNF agents are widely used in the treatment of some inflammatory diseases, such as inflammatory bowel disease and psoriasis. Their use has led to a significant advance in the treatment of these diseases. Paradoxically, the onset of psoriatic lesions has been observed in patients on anti-TNF treatment. The cause of this side effect has not yet been clearly identified. In recent years, an increasing number of cases of psoriasis related to anti-TNF therapy in inflammatory bowel disease patients have been reported. Although withdrawal of anti-TNF was usually implemented in the first reports, in more recent series the maintenance of the drug with topical therapy, with the exception of the most severe or extensive forms of skin lesions, appears to be the treatment of choice. This article summarizes the relevant literature, discusses the etiopathology, epidemiology, location and phenotypes of psoriatic lesions and the management of this side effect. PMID:23265148

Guerra, Iván; Gisbert, Javier P

2013-01-01

11

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

12

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

13

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

14

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

15

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

16

Diagnosis and Treatment of Latent Tuberculosis Infection due to Initiation of Anti-TNF Therapy  

PubMed Central

Patients with immune-mediated inflammatory diseases (IMIDs) are increasingly being treated with anti-tumor necrosis factor (TNF) agents and are at increased risk of developing tuberculosis (TB). Therefore, diagnosis and treatment of latent TB infection (LTBI) is recommended in these patients due to the initiation of anti-TNF therapy. Traditionally, LTBI has been diagnosed on the basis of clinical factors and a tuberculin skin test. Recently, interferon-gamma releasing assays (IGRAs) that can detect TB infection have become available. Considering the high-risk of developing TB in patients on anti-TNF therapy, the use of both a tuberculin skin test and an IGRA should be considered to detect and treat LTBI in patients with IMIDs. The traditional LTBI treatment regimen consisted of isoniazid monotherapy for 9 months. However, shorter regimens such as 4 months of rifampicin or 3 months of isoniazid/rifampicin are increasingly being used to improve treatment completion rates. In this review, the screening methods for diagnosing latent and active TB before anti-TNF therapy in patients with IMIDs will be briefly described, as well as the current LTBI treatment regimens, the recommendations for managing TB that develops during anti-TNF therapy, the necessity of regular monitoring to detect new TB infection, and the re-initiation of anti-TNF therapy in patients who develop TB. PMID:25024719

2014-01-01

17

Onset of lupus like syndrome in patients with spondyloarthritis treated with anti-TNF-?  

PubMed Central

Background The anti-TNF? therapy has been since its approval by the FDA, along with nonsteroidal antiinflammatory drugs (NSAIDs), one of the most important therapies for control of spondyloarthritis (SpA). The onset of Lupus Like Syndrome (LLS) has been described in patients with rheumatoid arthritis (RA) treated with anti-TNF? therapy but there is little literature on the occurrence of this entity in patients with SpA. Methods We studied 57 patients with SpA who received more than 1 year of anti-TNF? therapy (infliximab, adalimumab or etanercept). Patients were analyzed for the development of LLS, in addition to measuring ANA levels ? 1:160 and Anti-dsDNA (measured by IIF). Results In total, 7.01% of patients treated with anti-TNF? had titers of ANA ? 1:160, whereas 3.5% of patients had serum levels of dsDNA. However, only one patient (1.75%; n = 1) experienced clinical symptoms of LLS; this was a female patient with a history of psoriatic arthritis. Conclusions The presence of LLS secondary to anti-TNF? therapy in patients with SpA is observed less frequently compared with patients with RA. LLS was only detected in a patient with a history of psoriasis since youth, who developed psoriatic arthritis after 27 years of age and had received anti-TNF? therapy for > 2 years. This may be because LLS is an entity clearly associated with innate immunity, with little central role of B and T cells. PMID:22336076

2012-01-01

18

Anti-TNF? therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a Pilot Study  

PubMed Central

Background Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti-tumor necrosis factor-? (anti-TNF?) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. Methods Twenty-three RA patients starting on anti-TNF? treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3?months of treatment. Results Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2?weeks (p?Anti-TNF? therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function. PMID:22824166

2012-01-01

19

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

20

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 * the two authors contributed equally to the work Key words: anti-TNF-alpha, tuberculosis, safety, rheumatoid arthritis, inflammatory chronic diseases Running head: Tuberculosis complicating anti-TNF therapy

Paris-Sud XI, Université de

21

The impact of patient-perceived restricted access to anti-TNF therapy for rheumatoid arthritis: a qualitative study  

PubMed Central

Objective To explore rheumatoid arthritis patients’ experience of access to anti-TNF therapy in the UK, and of switching therapies after an initial failure. Methods Patients were asked about their experience of accessing, receiving and discontinuing anti-TNF therapy in face-to-face informal interviews, within the context of the larger study about treatment outcomes. 17 individuals with a diagnosis of rheumatoid arthritis and experience of receiving anti-TNF therapy were interviewed in one hospital trust in England. Results Different emotions (Theme 1) surrounded the process of accessing anti-TNF therapy: hope, desperation, apprehension, anxiety, and frustration. Experience of receiving anti-TNF therapy (Theme 2) included not only positive transformation, but also fear of failure and discontinuation. The subsequent value that patients placed on anti-TNF therapy (Theme 3) included having a right to receive therapy and being lucky. These three themes were underpinned by the core category of ‘willing to try anything’. Those switching therapies reported increased caution over the possibility of recurring side effects, but some suggestion of benefit. There was a perception that access to anti-TNF therapy was restricted by cost, rather than being recommended for those in clinical need. Conclusions Anti-TNF therapies may have a sudden and dramatic impact on RA patients’ lives that contrasts with other available medications. However, the stress of the patient’s journey through the need to “qualify” for anti-TNF therapy, and the fear of failing or discontinuation of therapy should not be underestimated by clinicians. PMID:19127529

Sanderson, Tessa; Calnan, Michael; Morris, Marianne; Richards, Pam; Hewlett, Sarah

2010-01-01

22

[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

23

Anti-TNF Treatment Reverts Increased Muscle Ubiquitin Gene Expression in Tumour-Bearing Rats  

Microsoft Academic Search

Implantation of the ascitic tumour Yoshida AH-130 hepatoma (a cachectic tumour) resulted in important increases in muscle ubiquitin gene expression. Administration of daily injections of 25 mg\\/kg b.w. polyclonal goat anti-murine TNF IgG preparation to tumour-bearing rats abolished the increase in muscle ubiquitin gene expression observed in the control (non-anti-TNF-treated) tumour-bearing rats. It is concluded that TNF can have an

Marta Llovera; Neus Carbó; Celia Garc??a-Mart??nez; Paola Costelli; Luciana Tessitore; Francesco M. Baccino; Neus Agell; Gregory J. Bagby; Francisco J. López-Soriano; Josep M. Argilés

1996-01-01

24

Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF?  

Microsoft Academic Search

OBJECTIVESTo evaluate the effect of anti-TNF? on the Th1 and Th2 cytokines in patients with spondyloarthropathy (SpA).METHODSPeripheral blood mononuclear cells (PBMC) were obtained from 20 patients with active SpA treated with infliximab (5 mg\\/kg). For comparison, PBMC were also obtained from 15 healthy controls and 19 patients with active rheumatoid arthritis (RA). After stimulation with PMA\\/ionomycin, the intracellular cytokines interleukin

D Baeten; N Van Damme; F Van den Bosch; E Kruithof; M De Vos; H Mielants; E M Veys; F De Keyser

2001-01-01

25

Characteristics and treatment responses of patients satisfying the BSR guidelines for anti-TNF in ankylosing spondylitis  

Microsoft Academic Search

Objective. We present the results of the response to anti-tumour necrosis factor (anti-TNF) of 30 ankylosing spondylitis (AS) patients where we have complied with the BSR guidelines. Method. All patients had pre-assessments of Bath AS Disease Activity Index (BASDAIs) at two points a month apart prior to commencing anti-TNF. They then had 2 week and 2 month assessments followed by

K. Gadsby; C. Deighton

2007-01-01

26

Measurement of Anti-TNF Agents and anti-Drug Antibodies Serum Levels in Patients with Inflammatory Bowel Disease.  

PubMed

Despite its undoubted benefit in patients with inflammatory bowel disease, anti-TNF therapy has some limitations including the lack of primary response and the loss of response to treatment in some patients. An empiric approach to these problems is frequently used, based on clinical outcome. The measurement of anti-TNF drug serum levels and anti-drug antibodies (ADAb) levels has been proposed for improving the management of anti-TNF drugs. Although their role in routine clinical practice has not been clearly defined, current data supports their relationship with clinical outcomes and suggests their clinical utility primarily in patients with loss of response to anti-TNF agents. The presence of pre-existing ADAb before starting the anti-TNF therapy has recently been described. Transient ADAb, non-neutralizing ADAb and some cut-offs points have been proposed, extending the knowledge about this topic. A standardized and widely available test with cut-offs points for each anti-TNF agent and the definition of the most appropriate actions to be taken given the serum concentration of the drugs and ADAb are needed before recommending their routine use. PMID:25373884

Guerra, Iván; Chaparro, María; Bermejo, Fernando; Gisbert, Javier P

2014-11-01

27

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

28

Anti-TNF treatment reverts increased muscle ubiquitin gene expression in tumour-bearing rats.  

PubMed

Implantation of the ascitic tumour Yoshida AH-130 hepatoma (a cachectic tumour) resulted in important increases in muscle ubiquitin gene expression. Administration of daily injections of 25 mg/kg b.w. polyclonal goat anti-murine TNF IgG preparation to tumour-bearing rats abolished the increase in muscle ubiquitin gene expression observed in the control (non-anti-TNF-treated) tumour-bearing rats. It is concluded that TNF can have an important role in the activation of the ubiquitin-dependent proteolytic system during tumour growth. PMID:8630016

Llovera, M; Carbó, N; García-Martínez, C; Costelli, P; Tessitore, L; Baccino, F M; Agell, N; Bagby, G J; López-Soriano, F J; Argilés, J M

1996-04-25

29

Pityriasis versicolor during anti-TNF-? monoclonal antibody therapy: therapeutic considerations.  

PubMed

Anecdotal reports have shown that tumour necrosis factor (TNF)-? inhibition may cause unchecked superficial infection with the microorganisms responsible for pityriasis versicolor (PV). We observed several cases of PV, which is frequently resistant to topical therapies, in psoriatic patients undergoing anti-TNF-? monoclonal antibody therapy. To evaluate the incidence and the therapeutic management of PV in this group of individuals, between 1 January and 27 December 2010, we examined 153 psoriatic patients for the hypopigmented/hyperpigmented macular and scaling lesions associated with PV. All patients positive for PV were given topical therapy with miconazole nitrate cream twice daily for 28 days, after which they were re-evaluated. In patients non-responsive to topical therapy, we started systemic therapy with fluconazole, 300 mg week(-1) for 3 weeks. We diagnosed seven cases of PV. At the end of topical treatment, complete healing of lesions was observed in only one patient. In the other six patients, systemic treatment led to complete resolution of the infection. Although the onset of PV during anti-TNF-? therapy is seldom reported, it is not likely to be rare, but rather under-reported because of its limited pathological significance. In our opinion, the therapeutic management of this condition deserves greater consideration, as the use of topical treatments alone is largely ineffective compared with systemic treatment. PMID:22283428

Balestri, Riccardo; Rech, Giulia; Piraccini, Bianca Maria; Antonucci, Angela; Ismaili, Alma; Patrizi, Annalisa; Bardazzi, Federico

2012-09-01

30

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

31

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

32

Radiation-Induced Astrogliosis and Blood-Brain Barrier Damage Can Be Abrogated Using Anti-TNF Treatment  

SciTech Connect

Purpose: In this article, we investigate the role of tumor necrosis factor-alpha (TNF) in the initiation of acute damage to the blood-brain barrier (BBB) and brain tissue following radiotherapy (RT) for CNS tumors. Methods and Materials: Intravital microscopy and a closed cranial window technique were used to measure quantitatively BBB permeability to FITC-dextran 4.4-kDa molecules, leukocyte adhesion (Rhodamine-6G) and vessel diameters before and after 20-Gy cranial radiation with and without treatment with anti-TNF. Immunohistochemistry was used to quantify astrogliosis post-RT and immunofluorescence was used to visualize protein expression of TNF and ICAM-1 post-RT. Recombinant TNF (rTNF) was used to elucidate the role of TNF in leukocyte adhesion and vessel diameter. Results: Mice treated with anti-TNF showed significantly lower permeability and leukocyte adhesion at 24 and 48 h post-RT vs. RT-only animals. We observed a significant decrease in arteriole diameters at 48 h post-RT that was inhibited in TNF-treated animals. We also saw a significant increase in activated astrocytes following RT that was significantly lower in the anti-TNF-treated group. In addition, immunofluorescence showed protein expression of TNF and ICAM-1 in the cerebral cortex that was inhibited with anti-TNF treatment. Finally, administration of rTNF induced a decrease in arteriole diameter and a significant increase in leukocyte adhesion in venules and arterioles. Conclusions: TNF plays a significant role in acute changes in BBB permeability, leukocyte adhesion, arteriole diameter, and astrocyte activation following cranial radiation. Treatment with anti-TNF protects the brain's microvascular network from the acute damage following RT.

Wilson, Christy M. [School of Biomedical Engineering and Imaging, University of Tennessee Health Science Center, Memphis, TN (United States); Gaber, M. Waleed [School of Biomedical Engineering and Imaging, University of Tennessee Health Science Center, Memphis, TN (United States)], E-mail: mwgaber@txccc.org; Sabek, Omaima M. [Department of Surgery, Methodist Hospital Research Institute, Houston, TX (United States); Zawaski, Janice A. [School of Biomedical Engineering and Imaging, University of Tennessee Health Science Center, Memphis, TN (United States); Merchant, Thomas E. [School of Biomedical Engineering and Imaging, University of Tennessee Health Science Center, Memphis, TN (United States); Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN (United States)

2009-07-01

33

ELISPOT-IFN-gamma assay instead of tuberculin skin test for detecting latent Mycobacterium tuberculosis infection in rheumatic patients candidate to anti-TNF-alpha treatment.  

PubMed

In rheumatic patients candidate to anti-TNF-alpha treatment, there is an increased risk of developing tuberculosis (TB). The tuberculin skin test (TST), the standard diagnostic test for latent tuberculosis infection (LTBI), suffers low specificity and sensitivity. Here, we compared the performance characteristics of an in-house ELISPOT-IFN-gamma assay (using a restricted pool of Mycobacterium tuberculosis-specific peptides or MTP) to TST for the diagnosis of LTBI in 69 rheumatic patients candidate to anti-TNF-alpha treatment and in 60 healthy LTBI individuals. Among the 69 patients enrolled, 17 (25%) had a positive TST response and 15 (22%) a positive ELISPOT-MTP response. Among the patients with a positive TST result, eight had a positive and nine a negative ELISPOT-MTP response, whereas among the 49 patients with a negative TST result, 42 were ELISPOT-MTP negative, but seven (14%) were ELISPOT-MTP positive, with three indeterminate results. The agreement between the two tests was poor (k = 0.341, 95% CI = 0.060 to 0.622) and the test of symmetry was not significant (P = 0.8). Considering the ELISPOT assay, rheumatic patients had a reduced number of spot-forming cells after stimulation of lymphocytes with PHA or PPD when compared with healthy LTBI individuals. Thus, the ELISPOT-IFN-gamma assay performs better than the TST in recognizing patients with LTBI, on one hand reducing the number of patients submitted to isoniazid prophylaxis, and on the other hand, since the assay is less biased by immunosuppressive regimens than TST, recognizing LTBI patients among those with a negative TST response. PMID:20645117

Girlanda, Stefania; Mantegani, Paola; Baldissera, Elena; Aiello, Patrizia; Ratti, Manuela; Sabbadini, Maria Grazia; Fortis, Claudio

2010-10-01

34

Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF?  

PubMed Central

OBJECTIVES—To evaluate the effect of anti-TNF? on the Th1 and Th2 cytokines in patients with spondyloarthropathy (SpA).?METHODS—Peripheral blood mononuclear cells (PBMC) were obtained from 20 patients with active SpA treated with infliximab (5 mg/kg). For comparison, PBMC were also obtained from 15 healthy controls and 19 patients with active rheumatoid arthritis (RA). After stimulation with PMA/ionomycin, the intracellular cytokines interleukin (IL)2, IL4, IL10, and interferon (IFN)? were determined in CD3+ T cells and in CD3+/CD56+ natural killer (NK) T cells by flow cytometry.?RESULTS—At baseline the percentage of T cells positive for IFN? (p=0.020) and IL2 (p=0.046) was decreased in patients with SpA compared with healthy controls, while IL10 (p=0.001) was increased. This cytokine profile, confirmed by the mean fluorescence intensities (MFI), was more pronounced in CD3+/CD8- cells and contrasted with higher IL2 production in RA. NK T cells, characterised by high IL4 and IL10 numbers, were also increased in patients with SpA (p=0.017). Treatment with infliximab induced a significant and persistent increase in IFN? and IL2 in patients with SpA. Moreover, there was a transient decrease in IL10 and NK T cells in patients with high baseline values, resulting in values comparable with those of healthy controls. This switch in cytokine profile was seen in both the CD3+/CD8- and CD3+/CD8+ subsets.?CONCLUSIONS—Before treatment patients with SpA had an impaired Th1 cytokine profile compared with healthy controls and patients with RA. TNF? blockade induced restoration of the Th1 cytokines, resulting in a normal cytokine balance. These data confirm the effect of anti-TNF? on the immune changes in SpA, and provide insights into the mechanisms involved in TNF? blockade.?? PMID:11454638

Baeten, D; Van Damme, N; Van den Bosch, F; Kruithof, E; De Vos, M; Mielants, H; Veys, E; De Keyser, F

2001-01-01

35

Nonmyeloablative stem cell transplantation: reduced-intensity conditioning for cancer immunotherapy--from bench to patient bedside.  

PubMed

Despite major progress in treating hematologic malignancies and, to a lesser extent, metastatic solid tumors, much work remains ahead. With the anticancer potential of immunotherapy not yet fully exploited, patients with leukemia, malignant lymphoma, and other hematologic malignancies for which high-dose chemoradiotherapy is frequently recommended in conjunction with stem cell transplantation (SCT) can now benefit from the advantages of immunotherapy mediated by cytokines or alloreactive donor lymphocytes, while minimizing procedure-related toxicity and mortality. The feasibility of applying allogeneic cell-mediated immunotherapy in conjunction with allogeneic SCT following reduced-intensity conditioning, with minimal toxicity and no serious transplant-related complications, makes it possible to undertake such procedures on an outpatient basis as well as to offer an option for cure to elderly individuals and patients with less than optimal performance status. Being well tolerated, reduced-intensity transplants also offer a chance for cure to patients with otherwise resistant leukemia and malignant lymphoma who have relapsed after autologous SCT. Thus, the traditional obstacle of very high transplant-related toxicity and mortality due to multiorgan failure from cumulative toxicity of multiple anticancer agents and radiation therapy is overcome. Although immunotherapy mediated by allogeneic lymphocytes can be most effective, the immune potential of donor lymphocytes should be maximized by nonspecific or specific activation in vitro or in vivo, or both, for more effective eradication of resistant tumor cells, including in patients with bulky disease. More important is the challenge to target donor lymphocytes to the tumor and minimize their capacity to induce responses against normal host tissues, which frequently results in severe acute and chronic graft-versus-host disease (GVHD). Alternatively, donor lymphocytes should be eliminated as soon as tumor eradication is completed, or as soon as severe GVHD becomes prohibitive. Based on available experience, clinical application of innovative therapy, especially at the stage of minimal residual disease (MRD), may open new horizons for the treatment of malignancies considered until recently to be incurable. The feasibility of controlling cancer by targeted chemotherapy, best illustrated by the phenomenal activity of imatinib in patients with chronic myelogenous leukemia and, more recently, in gastrointestinal stromal tumors (including in patients fully resistant to all known anticancer agents) suggests that in the future, tumor-specific chemotherapy may represent the ultimate goal for achieving a stage of MRD with minimal multiorgan toxicity. Together, the combination of immunotherapy and targeted chemotherapy may provide the most logical approach for making real progress in controlling resistant hematologic malignancies and metastatic solid tumors. PMID:14970932

Slavin, Shimon; Morecki, Shoshana; Weiss, Lola; Shapira, Michael Y; Resnick, Igor; Or, Reuven

2004-02-01

36

Immunity against Mycobacterium tuberculosis and the risk of biologic anti-TNF-? reagents.  

PubMed

A third of the world's population is exposed to Mycobacterium tuberculosis in their lifetime. Over eight million people develop a tuberculosis (TB) illness and 1.3 million people die from the disease every year. Acquired immunity (cytotoxic CD8+ T cells (CBT), Th1 CD4+ helper T cells) macrophages, and dendritic cells all play important roles in TB infection. Recently, it is well established that innate immunity as well plays a definitive role in the development of TB immunity under the effects of several cytokines, microbicidal proteins and Toll-like receptors. Meanwhile, the introduction and widespread use of biological disease-modifying anti-rheumatic reagents over the last 15 years worldwide has dramatically advanced and improved the standard care and prognosis of patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). However, as clinical experience with these drugs has grown, the risk of granulomatous infections, especially disseminated TB and fungal infections, has become apparent, especially because having RA or JIA may innately increase the risk of infection (bacterial, viral and fungal). The knowledge of basic immunology has also advanced over the past 10 years and adult and pediatric rheumatologists should increase their understanding of this dynamic between arthritis diseases, anti-TNF-? medications, and TB. This review will provide an up-to-date discussion of both the immunology of the TB organism in the human host and the pathophysiologic mechanisms of the TNF-? blockers in the development of secondary (disseminated) tuberculosis. PMID:25317081

Yasui, Kozo

2014-01-01

37

Antidepressants suppress neuropathic pain by a peripheral ?2-adrenoceptor mediated anti-TNF? mechanism.  

PubMed

Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through ?2-adrenoceptors (?2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor ? (TNF?) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on ?2-ARs expressed by non-neuronal satellite cells. This stimulation of ?2-ARs decreases the neuropathy-induced production of membrane-bound TNF?, resulting in relief of neuropathic allodynia. This indirect anti-TNF? action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the ?2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies. PMID:23978467

Bohren, Yohann; Tessier, Luc-Henri; Megat, Salim; Petitjean, Hugues; Hugel, Sylvain; Daniel, Dorothée; Kremer, Mélanie; Fournel, Sylvie; Hein, Lutz; Schlichter, Rémy; Freund-Mercier, Marie-José; Yalcin, Ipek; Barrot, Michel

2013-12-01

38

Off-Label Uses of Anti-TNF Therapy in Three Frequent Disorders: Behçet's Disease, Sarcoidosis, and Noninfectious Uveitis  

PubMed Central

Tumoral necrosis factor ? plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropatties, inflammatory bowel disease, and psoriasis. Nonetheless, theoretically, some other autoimmune disorders may benefit from these agents. Our aim is to review these off-label uses of anti-TNF blockers in three common conditions: Behçet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series. PMID:23983404

Sánchez-Cano, Daniel; Callejas-Rubio, José Luis; Ruiz-Villaverde, Ricardo; Ríos-Fernández, Raquel; Ortego-Centeno, Norberto

2013-01-01

39

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

E-print Network

etanercept was an independent risk factor for lymphoma in the case-control study: odds ratio=4.7 (1.3­ 17Lymphoma in patients treated with anti-TNF. Results of the 3-year prospective French RATIO registry Schaeverbeke T,9 Salmon D,10 Lemann M,11 Hermine, O 12 Raphael M,13 Ravaud P2 for the RATIO group. 1 Assistance

Paris-Sud XI, Université de

40

Immunotherapy targeting ?-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] ?-synuclein mice.  

PubMed

Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (?-synuclein) in the central nervous system (CNS) is an early pathogenic event in Parkinson's disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against ?-synuclein as a promising novel treatment strategy. Since large ?-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. In support of this, (Thy-1)-h[A30P] ?-synuclein transgenic mice with motor dysfunction symptoms were found to display increased levels of ?-synuclein protofibrils in the CNS. An ?-synuclein protofibril-selective monoclonal antibody (mAb47) was evaluated in this ?-synuclein transgenic mouse model. As measured by ELISA, 14month old mice treated for 14weeks with weekly intraperitoneal injections of mAb47 displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. Besides the lower levels of pathogenic ?-synuclein demonstrated, a reduction of motor dysfunction in transgenic mice upon peripheral administration of mAb47 was indicated. Thus, immunotherapy with antibodies targeting toxic ?-synuclein species holds promise as a future disease-modifying treatment in Parkinson's disease and related disorders. PMID:24851801

Lindström, Veronica; Fagerqvist, Therese; Nordström, Eva; Eriksson, Fredrik; Lord, Anna; Tucker, Stina; Andersson, Jessica; Johannesson, Malin; Schell, Heinrich; Kahle, Philipp J; Möller, Christer; Gellerfors, Pär; Bergström, Joakim; Lannfelt, Lars; Ingelsson, Martin

2014-09-01

41

Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register  

PubMed Central

Background Anti-tumour necrosis factor (anti-TNF) therapy has been associated with reports of rapid severe progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, reports also exist of favourable responses to anti-TNF therapy in patients with ILD. The aim of this study was to examine the influence of anti-TNF therapy on mortality in patients with pre-existing RA-ILD. Methods Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, 367 patients with pre-existing RA-ILD were identified (299 treated with anti-TNF therapy and 68 treated with traditional disease-modifying antirheumatic drugs (DMARDs)). Results 70/299 patients (23%) in the anti-TNF cohort died after a median follow-up of 3.8 years compared with 14/68 (21%) in the DMARD cohort after a median follow-up of 2.1 years. The mortality was 68 deaths/1000 person years (pyrs) (95% CI 53 to 86) in the anti-TNF cohort and 92/1000 pyrs (95% CI 50 to 155) in the DMARD cohort, generating an age- and sex-adjusted mortality rate ratio (aMRR) of 1.26 (95% CI 0.69 to 2.31). After further adjustment for potential confounders, the aMRR fell to 0.81 (95% CI 0.38 to 1.73) for the anti-TNF cohort compared with the DMARD cohort. RA-ILD was the underlying cause of death in 15/70 (21%) and 1/14 (7%) patients in the anti-TNF and DMARD cohorts, respectively. Conclusion The mortality in patients with RA-ILD is not increased following treatment with anti-TNF therapy compared with traditional DMARDs. The proportion of deaths attributable to RA-ILD is higher in patients treated with anti-TNF therapy, although reporting bias may exist. PMID:20444754

Dixon, W G; Hyrich, K L; Watson, K D; Lunt, M; Symmons, D P M

2010-01-01

42

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

43

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

44

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

45

Nonmyeloablative stem cell transplantation: reduced-intensity conditioning for cancer immunotherapy—from bench to patient bedside  

Microsoft Academic Search

Despite major progress in treating hematologic malignancies and, to a lesser extent, metastatic solid tumors, much work remains ahead. With the anticancer potential of immunotherapy not yet fully exploited, patients with leukemia, malignant lymphoma, and other hematologic malignancies for which high-dose chemoradiotherapy is frequently recommended in conjunction with stem cell transplantation (SCT) can now benefit from the advantages of immunotherapy

Shimon Slavin; Shoshana Morecki; Lola Weiss; Michael Y Shapira; Igor Resnick

2004-01-01

46

Anti-TNF-? therapy in the management of severe neurosarcoidosis: a report of five cases from a single centre and literature review.  

PubMed

Neurologic manifestations are found in 5-15 % of patients with sarcoidosis. This granulomatous disease may affect any part of the peripheral or the central nervous system, being potentially severe and difficult to treat. Corticosteroids are the cornerstone of therapy in sarcoidosis. However, some patients become resistant or experience side effects to corticosteroids. In these patients, second line therapies including immunosuppressive drugs such as methotrexate, azathioprine, mycophenolate, cyclophosphamide and leflunomide have been used. Anti-TNF-? drugs have been proposed as a therapeutic option for those who are refractory to immunosuppressive drugs or initially in cases of severe sarcoidosis. We report on 5 patients with neurosarcoidosis treated with anti-TNF-? drugs in our center. A literature review of patients with neurosarcoidosis treated with anti-TNF-? drugs was conducted. In our series successful response to anti-TNF-? therapy was achieved. However, the high frequency of relapses following anti-TNF-? discontinuation makes necessary a close follow-up of these patients when the biologic agent is stopped. PMID:24321604

Riancho-Zarrabeitia, L; Delgado-Alvarado, M; Riancho, J; Oterino, A; Sedano, M J; Rueda-Gotor, J; Pérez-Martín, I; González-Vela, M C; Berciano, J; González-Gay, M A; Blanco, R

2014-01-01

47

Treatment with anti-TNF alpha protects against the neuropathy induced by the proteasome inhibitor bortezomib in a mouse model.  

PubMed

Bortezomib (BTZ), a proteasome inhibitor, is an effective anti-neoplastic drug used in the treatment of multiple myeloma and mantle cell lymphoma. However, it can induce a reversible peripheral neuropathy that may lead to treatment discontinuation. The mechanism through which BTZ exerts toxic effects in peripheral neurons is not clear. Release of proinflammatory cytokines after nerve damage can induce neurodegeneration, but the effects of BTZ on cytokine expression in neurons are unknown, although BTZ modulates the expression of cytokines, such as TNF-? and IL-6, in tumor cells. The aim of this study was to evaluate the expression and the role of these cytokines on the course of BTZ induced neuropathy in mice. IL-6, TNF-?, TGF-?1 and IL-1? were up-regulated in dorsal root ganglia but TNF-? and IL-6 increased faster and higher. Then, we studied the potential neuroprotective effect of selective antibodies anti-TNF-? and anti-IL-6 on the evolution of the neuropathy. Treatment with anti-TNF-? but not with anti-IL-6 significantly prevented the decrease of sensory nerve action potentials amplitude and the loss of myelinated and unmyelinated fibers. We conclude that monoclonal antibodies directed against TNF-? may be a suitable neuroprotective therapy against the neurotoxicity induced by BTZ. PMID:24406455

Alé, Albert; Bruna, Jordi; Morell, Marta; van de Velde, Helgi; Monbaliu, Johan; Navarro, Xavier; Udina, Esther

2014-03-01

48

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

49

Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR)  

PubMed Central

Background The risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) is thought to be increased following anti-tumour necrosis factor (anti-TNF) therapy, with a proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA). Objective To compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity. Methods Data from the British Society for Rheumatology Biologics Register (BSRBR), a national prospective observational study, were used to compare TB rates in 10 712 anti-TNF treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active RA treated with traditional disease-modifying antirheumatic drugs. Results To April 2008, 40 cases of TB were reported, all in the anti-TNF cohort. The rate of TB was higher for the monoclonal antibodies ADA (144 events/100 000 person-years) and INF (136/100 000 person-years) than for ETA (39/100 000 person-years). After adjustment, the incidence rate ratio compared with ETA-treated patients was 3.1 (95% CI 1.0 to 9.5) for INF and 4.2 (1.4 to 12.4) for ADA. The median time to event was lowest for INF (5.5 months) compared with ETA (13.4 months) and ADA (18.5 months). 13/40 cases occurred after stopping treatment. 25/40 (62%) cases were extrapulmonary, of which 11 were disseminated. Patients of non-white ethnicity had a sixfold increased risk of TB compared with white patients treated with anti-TNF therapy. Conclusion The rate of TB in patients with RA treated with anti-TNF therapy was three- to fourfold higher in patients receiving INF and ADA than in those receiving ETA. PMID:19854715

Dixon, W G; Hyrich, K L; Watson, K D; Lunt, M; Galloway, J; Ustianowski, A; Symmons, D P M

2010-01-01

50

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

51

Immune Response to Influenza A/H1N1 Vaccine in Inflammatory Bowel Disease Patients Treated with Anti TNF-? Agents: Effects of Combined Therapy with Immunosuppressants  

PubMed Central

Background and Aims Our first objective was to evaluate the immune response to the adjuvanted 2009 A/H1N1 pandemic (pH1N1) vaccine in inflammatory bowel disease (IBD) patients treated with anti-TNF-? alone or combined with immunosuppressants (IS). Second and third aims were the safety of pH1N1 vaccine and the effects on IBD clinical activity. Methods 36 patients with Crohn's disease (CD) and 26 with ulcerative colitis (UC) and thirty-one healthy control subjects (HC) were enrolled. 47 patients were on anti TNF-? maintenance monotherapy and 15 on anti TNF-? combined with IS. Sera were collected at baseline (T0) and 4 weeks after the vaccination (T1) for antibody determination by hemagglutination inhibition (HAI Disease activity was monitored at T0 and T1. Results Seroprotective titers (? 1: 40) in patients were comparable to HC. Seroconvertion rate (? 4 fold increase in HAI titer) was lower than HC in IBD patients (p=0,009), either on anti TNF-? monotherapy (p=0,034) or combined with IS (p=0,011). Geometric mean titer (GMT) of antibodies at T1 was significantly lower in patients on combined therapy versus those on monotherapy (p=0,0017) and versus HC (p=0,011). The factor increase of GMT at T1 versus T0 was significantly lower in IBD patients versus HC (p=0,042), and in those on combined immunosuppression, both versus monotherapy (p=0,0048) and HC (p=0,0015). None of the patients experienced a disease flare. Conclusion Our study has shown a suboptimal response to pH1N1 vaccine in IBD patients on therapy with anti TNF-? and IS compared to those on anti-TNF-? monotherapy and HC. PMID:22673636

Andrisani, G.; Frasca, D.; Romero, M.; Armuzzi, A.; Felice, C.; Marzo, M.; Pugliese, D; Papa, A.; Mocci, G.; De Vitis, I.; Rapaccini, G.L.; Blomberg, B.B.; Guidi, L

2013-01-01

52

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

53

What effects might anti?TNF? treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNF? in cardiovascular pathophysiology  

PubMed Central

Patients with rheumatoid arthritis (RA) have an increased burden of atherosclerotic cardiovascular disease which cannot be explained by an increased prevalence of traditional cardiovascular risk factors alone. Atherosclerosis is now being viewed as an inflammatory condition and the cumulative inflammation experienced in RA may contribute to accelerated atherosclerosis. It has been hypothesised that treatment with anti?tumour necrosis factor (TNF) ? in RA may reduce both intra?articular inflammation and the inflammation associated with atherosclerosis. Thus, TNF? blockade may reduce the cardiovascular morbidity and mortality associated with RA. This review examines the pathophysiological role of TNF? in atherosclerosis and the evidence to date that anti?TNF? treatment modifies this process in RA. PMID:17251223

Dixon, W G

2007-01-01

54

Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis.  

PubMed

Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.The Pharmacogenomics Journal advance online publication, 18 November 2014; doi:10.1038/tpj.2014.71. PMID:25403996

Julià, A; Ferrándiz, C; Dauden, E; Fonseca, E; Fernández-López, E; Sanchez-Carazo, J L; Vanaclocha, F; Puig, L; Moreno-Ramírez, D; Lopez-Estebaranz, J L; Herrera, E; de la Cueva, P; Avila, G; Alonso, A; Tortosa, R; López-Lasanta, M; Marsal, S

2014-11-18

55

Severe Guillain-Barré syndrome in a patient receiving anti-TNF therapy. Consequence or coincidence. A case-based review.  

PubMed

The adverse effects of anti-tumour necrosis factor alpha (TNF?) drugs include an increase in the risk of infections, congestive heart failure, lupus-like syndrome, and the onset or worsening of various demyelinating diseases such as, multiple sclerosis, optic neuritis, and Guillain-Barrè syndrome (GBS), among others. We describe the case of a patient who developed GBS while she was on treatment with adalimumab. A 50-year-old woman with rheumatoid arthritis (RA) was admitted to the hospital due to progressive severe bilateral symmetric weakness of the legs, which quickly extended to the upper limbs and to the respiratory muscles. Adalimumab was started 13 months before. GBS was diagnosed and the anti-TNF? therapy discontinued. The serological test for Campylobacter jejuni was positive. She required invasive mechanical ventilatory support for 9 months. Twelve months later, the patient was using a wheelchair following a rehabilitation programme, and at 24 months she was walking a few steps with assistive devices. The relevant literature on the relationship between GBS and anti-TNF? is reviewed. Twenty three cases of GBS occurring during anti-TNF? therapy have been reported so far in the literature. In several cases, there was no clear temporal association, more than half had a possible previous infection, and in two cases the drug was reintroduced without recurrence of GBS. Our case, which is best explained by C. jejuni infection, as well as some of the cases described are probably not a direct result of anti-TNF? treatment, but an accidental coincidence. We also discuss the potential therapeutic options after anti-TNF? discontinuation. PMID:23666317

Alvarez-Lario, Bonifacio; Prieto-Tejedo, Rosa; Colazo-Burlato, María; Macarrón-Vicente, Jesús

2013-09-01

56

IGF-1 and ADMA Levels Are Inversely Correlated in Nondiabetic Ankylosing Spondylitis Patients Undergoing Anti-TNF-Alpha Therapy  

PubMed Central

Like rheumatoid arthritis, ankylosing spondylitis (AS) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome (MeS) features. AS patients often display osteoporosis as well as new bone formation. Insulin-like growth factor 1 (IGF-1) is a protein involved in both inflammation and bone metabolism. In the present study we assessed whether disease activity, systemic inflammation, MeS features, adipokines, and biomarkers of endothelial activation were associated with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels in a series of 30 nondiabetic AS patients without CV disease undergoing TNF-? antagonist-infliximab therapy. All determinations were made in the fasting state, immediately before an infliximab infusion. Although no association of IGF-1 and IGFBP-3 levels with angiopoietin-2 or osteopontin was found, an inverse correlation between IGF-1 levels and asymmetric dimethylarginine (ADMA), an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction, was found (r = ?0.397; P = 0.04). However, no significant association was found between IGF-1 and IGFBP-3 levels and disease activity, systemic inflammation, metabolic syndrome features, or adipokines. In conclusion, in nondiabetic patients with AS undergoing periodic anti-TNF-? therapy, IGF-1 and ADMA are inversely correlated. PMID:25295265

López-Mejías, Raquel; Rueda-Gotor, Javier; Miranda-Filloy, José A.; Villar-Bonet, Aurelia; Carnero-López, Beatriz; Gómez-Acebo, Inés; Blanco, Ricardo; Pina, Trinitario; González-Juanatey, Carlos; González-Gay, Miguel A.

2014-01-01

57

Short-course treatment of latent tuberculosis infection in patients with rheumatic conditions proposed for anti-TNF therapy.  

PubMed

Tuberculosis reactivation is a serious threat in patients treated with anti-tumour necrosis factor therapy. A 6-month regimen with isoniazid is considered as the standard of care, but patient adherence is a major shortcoming. We carried out an open-label, single-arm intervention study to assess the efficacy, the completion rate and the tolerability of a 3-month regimen with isoniazid plus rifampin. Seventy-eight patients with rheumatic conditions proposed for anti-tumour necrosis factor (TNF) therapy and at risk of tuberculosis reactivation were offered to participate in the study. Nine patients were excluded due to deficit of glucose-6-phosphate dehydrogenase (n?=?1), salicylate hypersensitivity (n?=?1), declining to participate (n?=?5) or preferring a 6-month isoniazid regimen (n?=?6). Sixty-nine patients were treated with a 3-month regimen with isoniazid and rifampin. No cases of tuberculosis were observed after a mean follow-up of 90 months (range from 66 to 121 months). Sixty (87 %) patients completed the therapy. Nine (13 %) patients discontinued the therapy due to rifampin hypersensitivity (n?=?1), symptomatic grade 3-4 hepatotoxicity (n?=?2), abdominal discomfort (n?=?2), pruritus (n?=?1), arthritis (n?=?1) and personal concerns (n?=?2). A short course treatment with isoniazid and rifampin provided efficacy, good tolerability and good completion rate in patients with rheumatic conditions proposed for anti-TNF therapy. PMID:24464437

Valls, Victoria; Ena, Javier

2015-01-01

58

Predictive factors for partial remission according to the Ankylosing Spondylitis Assessment Study working group in patients with ankylosing spondylitis treated with anti-TNF? drugs.  

PubMed

The objective of this study was to evaluate the predictive factors for achieving partial remission (PR) in patients with ankylosing spondylitis (AS) treated with anti-TNF?. We longitudinally enrolled in a multi-center study 214 AS patients, classified according to New York criteria, treated with anti-TNF? drugs adalimumab (ADA), etanercept (ETA) and infliximab (INF) with at least 12 months of follow up. PR was reached when the score was <20 mm (on a visual analogue scale of 0-100 mm) in each of the following 4 domains: 1) patient global assessment (in the last week); 2) pain (spinal pain); 3) function [measured by the bath ankylosing spondylitis functional index (BASFI)]; 4) inflammation [mean of intensity and duration of morning stiffness, from the bath ankylosing spondylitis disease activity index (BASDAI)]. Two hundred fourteen AS patients (M/F=160/54; median age/range=43.2/19-78 years; median disease duration/ range=96/36-189 months) were treated with ADA (15.8%), ETA (28.9%) and INF (55.1%). At 12 and 24 months, high serum level of C reactive protein (CRP) (?2 vs ?0.8 mg/dL) were associated with higher rate of PR in AS patients treated with anti-TNF? drugs. At 24 months, PR was associated with shorter disease duration (?36 vs ?189 months) and higher erythrosedimentation rate (ESR) values (?45 vs ?17 mm/h). In male patients lower bath ankylosing spondylitis metrology index (BASMI) (?2 vs ?6) and absence of psoriasis were associated with higher PR rate only at 12 months. Other parameters assessed before treatment, such as BASDAI, BASFI, peripheral arthritis, inflammatory bowel disease and uveitis were not associated with PR. Our long-term longitudinal study in a setting of clinical practice showed that inflammatory parameters (i.e. CRP, ESR) and disease duration represent the most important predictive variables to achieve PR with an anti-TNF? treatment. PMID:25376955

Perrotta, F M; Addimanda, O; Ramonda, R; D'Angelo, S; Lubrano, E; Marchesoni, A; Olivieri, I; Punzi, L; Salvarani, C; Spadaro, A

2014-01-01

59

Efficacy of combined anti-TNF-alpha and surgical therapy in perianal and enterocutaneous fistulizing Crohn's disease - clinical observations from a tertiary Eastern European center.  

PubMed

Abstract Background and aims. Recently, anti-TNF-alpha therapy has increasingly been used in the treatment of perianal Crohn's disease (PCD), but there is only limited data regarding its short- and long-term efficacy. Material and methods. The medical records of 68 patients treated with anti-TNF-alpha for PCD were assessed retrospectively. Rate of complex fistulas was 75%. Every patient received induction therapy, but in 20 cases the treatment was discontinued before week 52 due to funding regulations, an allergic reaction, or compliance problems. On week 12, the luminal activity decreased in more than 80% of the cases and the complete remission (CR) rate was about 60%; by the end of the first year, this ratio did not change substantially. Complete fistula closure was achieved in 26 cases (38.3%) and 53 patients (51.5%) showed a partial response during the 1-year period. Regarding both perianal and luminal activities, CR rate was achieved in 23 cases (33.8%). However, after the biological therapy was discontinued, recurrence of fistulas could be detected in every second patient. Additional surgical intervention was performed in 45% of patients during the 1-year period (seton drainage of fistulas and abscess drainage). Conclusion. The anti-TNF-alpha therapy combined with surgery is an effective treatment of PCD. Approximately every third patient revealed complete fistula closure, while half of the other cases showed a partial response. Due to the high rate of fistula recurrence after stopping the biological therapy, more than 1 year of anti-TNF-? treatment may be beneficial. PMID:25384713

Bor, Renáta; Farkas, Klaudia; Bálint, Anita; Sz?cs, Mónika; Ábrahám, Szabolcs; Baradnay, Gellért; Wittmann, Tibor; Szepes, Zoltán; Nagy, Ferenc; Molnár, Tamás

2015-02-01

60

Immunotherapy: rationale and mechanisms.  

PubMed

Immunotherapy is defined as the controlled exposure to known allergens to reduce the severity of the allergic response. Although available since 1910, its exact mechanisms of action is not known but may involve an increase in allergen-specific IgG antibodies, a decrease in IgE synthesis, and alteration in T-lymphocyte activity. Immunotherapy is indicated in patients with proven allergy who have significant symptoms. It may be used together with pharmacologic measures but is relatively contraindicated in patients receiving beta-blocker therapy. Immunotherapy may be continued during pregnancy and should not be initiated in patients with autoimmune diseases or in human immunodeficiency virus-positive patients. Selection of appropriate diagnostic tests is important. Before immunotherapy is considered, there are two recommended in vivo tests (combined prick and intradermal skin test, and skin end point titration) and two recommended in vitro tests (radioallergosorbent test [RAST] and enzyme-linked immunosorbent assays [ELISA]), all equally safe and sensitive. After appropriate test interpretation, treatment is initiated with slowly escalating doses of allergen. Effects are often apparent in 3 to 6 months and, after continuation for 3 to 5 years, patients usually achieve lasting benefit. PMID:1470467

Gordon, B R

1992-12-01

61

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

62

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

63

Is IL-6 an appropriate target to treat spondyloarthritis patients refractory to anti-TNF therapy? a multicentre retrospective observational study  

PubMed Central

Introduction The aim of this study was to evaluate, under real-life conditions, the safety and efficacy of tocilizumab in patients having failed anti-TNF? therapy for spondyloarthritis. Methods French rheumatologists and internal-medicine practitioners registered on the Club Rhumatismes et Inflammations website were asked to report on patients given tocilizumab (4 or 8 mg/kg) to treat active disease meeting Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis, after anti-TNF? treatment failure. Safety and efficacy after 3 and 6 months were assessed retrospectively using standardised questionnaires. Results Data were obtained for 21 patients, 13 with axial spondyloarthritis (46% men; median age, 42 years; disease duration, 11 years; HLA-B27-positive, 92.3%) and eight with peripheral spondyloarthritis (25% men; median age, 40 years; disease duration, 10 years; HLA-B27-positive, 62.5%). No patients with axial disease had at least a 20 mm decrease in the BASDAI, nor a BASDAI50 response or major ASAS-endorsed disease activity score improvements after 3 or 6 months; an ASAS-endorsed disease activity score clinically important improvement was noted at month 3 in five of 13 patients and at month 6 in one of four patients. A good DAS28 response was achieved in four patients with peripheral disease, including one in EULAR remission at month 3. Four patients were still taking tocilizumab at month 6, including one in EULAR remission and one with a good DAS28 response. Tocilizumab was well tolerated, with no serious adverse events. Initially elevated acute-phase reactants declined during tocilizumab therapy. Conclusion In patients having failed anti-TNF? therapy, tocilizumab decreased acute-phase reactants but failed to substantially improve axial spondyloarthritis and was inconsistently effective in peripheral spondyloarthritis. PMID:22404969

2012-01-01

64

CD11c as a transcriptional biomarker to predict response to anti-TNF monotherapy with adalimumab in patients with rheumatoid arthritis.  

PubMed

We performed transcription profiling using monocytes to identify predictive markers of response to anti-tumor necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA). Several potential predictors of response were identified, including CD11c. Validation in samples from independent cohorts (total of n = 27 patients) using reverse transcription-PCR confirmed increased expression of CD11c in responders to adalimumab (100% sensitivity; 91.7% specificity, power 99.6%; alpha = 0.01). Pretherapy CD11c levels significantly correlated with the response criteria as defined by the American College of Rheumatology (ACR) (r = 0.656, P < 0.0001). However, CD11c was neither predictive of response to methotrexate (MTX) alone (n = 34) nor to MTX in combination with adalimumab (n = 16). Clinical responders revealed a reset to a normal expression pattern of resident/inflammatory monocyte markers, which was absent in nonresponders. Therefore, an analysis of key cell types identifies potentially predictive biomarkers that may help to restrict the use of adalimumab to therapy responders. Larger studies, including studies of monotherapy with other drugs, are now needed to confirm and validate the specificity of CD11c for anti-TNF biologics. PMID:20032971

Stuhlmüller, B; Häupl, T; Hernandez, M M; Grützkau, A; Kuban, R-J; Tandon, N; Voss, J W; Salfeld, J; Kinne, R W; Burmester, G R

2010-03-01

65

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

66

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

67

Increased Plasma IL-17F Levels in Rheumatoid Arthritis Patients Are Responsive to Methotrexate, Anti-TNF, and T Cell Costimulatory Modulation.  

PubMed

The aims of this study are to compare plasma levels of IL17A, A/F, and F biomarkers in RA patients versus controls, and to determine responsiveness to methotrexate (MTX), anti-TNFs, and abatacept. We selected plasma samples from RA cohorts consisting of a cross-sectional RA cohort (N?=?78) not receiving DMARDs at the time of sampling, as well as from longitudinal drug start cohorts (N?=?71 patients) with pre/post samples including anti-TNF, abatacept, and MTX-treated patients. We assayed IL-17A, IL-17F, and IL17-A/F using a highly sensitive immunoassay system. Plasma levels of IL-17A, IL-17A/F, and IL-17F were all significantly increased in RA versus controls. The difference was largest in IL-17F, with median IL-17F levels in RA patients being approximately 18-fold higher than controls (81 pg/mL in RA vs. 4.4 pg/mL in controls, p?anti-TNF cohorts (p?=?0.02), whereas IL-17A and IL-17A/F were not significantly decreased for any of the three drug cohorts. Synovial fluid analysis demonstrated higher IL-17F levels in RA (p?=?0.016) than healthy controls. These results suggest a specific role for IL-17F in human RA pathogenesis and as a therapeutic target. PMID:25240765

Jain, Manish; Attur, Mukundan; Furer, Vika; Todd, John; Ramirez, Renita; Lock, Michael; Lu, Quynh A; Abramson, Steven B; Greenberg, Jeffrey D

2015-02-01

68

The comparative effectiveness of anti?TNF therapy and methotrexate in patients with psoriatic arthritis: 6 month results from a longitudinal, observational, multicentre study  

PubMed Central

Objectives To compare the response to treatment with tumour necrosis factor (TNF) inhibitors and methotrexate (MTX) monotherapy in patients with psoriatic arthritis (PsA) within a real?life clinical setting. Methods We analysed data from an ongoing longitudinal, observational multicentre study in Norway. Our data comprised 526 cases of patients with PsA who received either anti?TNF treatment (n?=?146) or MTX monotherapy (n?=?380) and were followed for at least 6?months with measures of disease activity, health status and utility scores. A propensity score was computed to adjust for channelling bias. The changes in measures of disease activity and health?related quality of life from baseline to 3? and 6?month follow?up were compared between the groups with adjustments for the baseline value of the dependent variable and the propensity score (analyses of covariance (ANCOVA)). Results The groups were significantly different at baseline with respect to demographic and disease activity measures. The variables included in the propensity score were age, sex, number of previous disease modifying anti?rheumatic drugs (DMARDs), presence of erosive disease, treatment centre and investigator's global assessment. The adjusted changes at 6?months were significantly larger in the anti?TNF group for ESR, DAS?28, M?HAQ, patient's assessments of pain, fatigue and global disease activity on a visual analogue scale (VAS) and 4 out of 8 SF?36 dimensions. Conclusions Clinical improvement was superior with TNF inhibitors compared to MTX monotherapy in patients with PsA, when assessed in this setting of daily clinical practice. PMID:17213251

Heiberg, M S; Kaufmann, C; Rødevand, E; Mikkelsen, K; Koldingsnes, W; Mowinckel, P; Kvien, T K

2007-01-01

69

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

70

Patient related outcomes in a real life prospective follow up study: Allergen immunotherapy increase quality of life and reduce sick days  

PubMed Central

Background One fourth of the adult population in Europe suffer from respiratory allergy. Subcutaneous-allergen-specific-immunotherapy (SCIT) has long-term disease modifying effect on disease specific Health-Related Quality of Life (HRQoL). The purpose of this study was to assess the effect of SCIT on alternative disease outcomes in patients with grass-pollen and/or house dust mite induced allergic rhino-conjunctivitis and/or an asthma diagnosis. Focus was on expressing outcomes in terms of generic quality of life (Quality-Adjusted-Life-Years (QALY)) and reductions in sick days. Methods The study was a multi-centre study with prospective follow-up. 248 patients were initiated on SCIT. The disease specific Rhino-conjunctivitis Quality of Life Questionnaire (RQLQ) and two generic (HRQoL) instruments 15D and EQ-5D were used at baseline and at follow-up. The outcome measures included change in; disease severity, RQLQ-scores, number of days with symptoms- and number of sick days per year and finally changes in generic HRQoL and thus, QALY. Disease severity was assessed by specialist doctors; severity of rhino-conjunctivitis was classified according to the Allergic Rhinitis and its Impact on Asthma (ARIA) and asthma severity according to the Global Initiative for Asthma (GINA guideline). The remaining outcome measures were assessed by the patients in questionnaires at baseline and at follow-up. An intension to treat approach was applied. For missing items imputation of sample mean base-line values or follow-up values were used after specified criteria. The effect of SCIT on rhino-conjunctivitis and/or asthma diagnoses was analysed at follow-up using three logistic regression models. Results The disease severity showed significantly improved disease control. Mean RQLQ-score was reduced from 3.02 at baseline to 2.00 at follow-up. Average annual days with symptoms were reduced from 189 to 145 days whilst annual sick days were reduced from 3.7 to 1.2 days. The 15D-score increased from 0.83 to 0.86 and the EQ-5D-score from 0.70 to 0.77, which indicated an annual gain per patient of 0.03-0.06 QALY. Conclusions Allergic patients suffering from rhino-conjunctivitis alone or rhino-conjunctivitis and asthma experience significantly increased HRQoL and they gain 0.03-0.06 QALY, when treated with SCIT for one year. Trial registration The study was registered at ClinicalTrials.gov with the identifier: NCT01486498. PMID:24229439

2013-01-01

71

Immunotherapy for mold allergy.  

PubMed

The objective of this article is to review the available studies regarding mold immunotherapy. A literature search was conducted in MEDLINE to identify peer-reviewed articles related to mold immunotherapy using the following keywords: mold, allergy, asthma, and immunotherapy. In addition, references cited within these articles were also reviewed. Articles were selected based on their relevance to the topic. Allergic responses to inhaled mold antigens are a recognized factor in allergic rhinitis and asthma. There are significant problems with respect to the production of relevant allergen material for the diagnosis and treatment of mold allergy with immunotherapy. Mold allergens contain proteases and should not be mixed with other allergens for immunotherapy. Most of the immunotherapy studies focus on two molds, Alternaria and Cladosporium. There is a lack of randomized placebo-controlled trials when evaluating the efficacy of mold immunotherapy with trials only focusing on immunotherapy to Alternaria and Cladosporium. Additional studies are needed regarding mold allergy and immunotherapy focusing on which molds are important for causing allergic disease. PMID:24057512

Coop, Christopher A

2014-12-01

72

PERIANAL COMPLETE REMISSION WITH COMBINED THERAPY (SETON PLACEMENT AND ANTI-TNF AGENTS) IN Crohn's DISEASE: a Brazilian multicenter observational study.  

PubMed

Background Perianal fistulizing Crohn's disease is one of the most severe phenotypes of inflammatory bowel diseases. Combined therapy with seton placement and anti-TNF therapy is the most common strategy for this condition Objectives The aim of this study was to analyze the rates of complete perianal remission after combined therapy for perianal fistulizing Crohn's disease. Methods This was a retrospective observational study with perianal fistulizing Crohn's disease patients submitted to combined therapy from four inflammatory bowel diseases referral centers. We analyzed patients' demographic characteristics, Montreal classification, concomitant medication, classification of the fistulae, occurrence of perianal complete remission and recurrence after remission. Complete perianal remission was defined as absence of drainage from the fistulae associated with seton removal. Discussion A total of 78 patients were included, 44 (55.8%) females with a mean age of 33.8 (±15) years. Most patients were treated with Infliximab, 66.2%, than with Adalimumab, 33.8%. Complex fistulae were found in 52/78 patients (66.7%). After a medium follow-up of 48.2 months, 41/78 patients (52.6%) had complete perianal remission (95% CI: 43.5%-63.6%). Recurrence occurred in four (9.8%) patients (95% CI: 0.7%-18.8%) in an average period of 74.8 months. Conclusions Combined therapy lead to favorable and durable results in perianal fistulizing Crohn's disease. PMID:25591155

Kotze, Paulo Gustavo; Albuquerque, Idblan Carvalho de; Moreira, André da Luz; Tonini, Wanessa Bertrami; Olandoski, Marcia; Coy, Claudio Saddy Rodrigues

2014-12-01

73

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

74

Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly  

PubMed Central

Objectives. To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages. Methods. Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11?798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients. Results. A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)]. Conclusions. These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments. PMID:20675706

Galloway, James B.; Hyrich, Kimme L.; Mercer, Louise K.; Dixon, William G.; Fu, Bo; Ustianowski, Andrew P.; Watson, Kath D.; Lunt, Mark

2011-01-01

75

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

76

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

77

The anti-TNF-? antibody infliximab indirectly regulates PECAM-1 gene expression in two models of in vitro blood cell activation.  

PubMed

Chronic inflammatory bowel diseases can be successfully treated with antibodies against the acute phase mediator TNF-?. The process of activation and of extravasation of inflammatory cells from the blood into the 'stressed' tissue site is controlled by cytokines and chemokines, which attract leukocytes and by adhesion molecules, which mediate their attachment and transmigration toward the affected cell(s). The changes in the gene expression of adhesion molecules taking place in those cells before attachment have been less investigated. Changes of PECAM-1, ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) gene expression were studied in phytohaemagglutinin (PHA)- and lipolysaccharide (LPS)-treated human peripheral blood leukocytes (PBLs), granulocytes and the human monocyte cell line U-937. Cells were treated either with PHA or with LPS in the presence or absence of infliximab and incubated with TNF-?, IFN-? and/or transforming growth factor beta (TGF-?) and treated as above. Activation of PBLs by PHA or LPS treatment triggered a sharp upregulation of ICAM-1, VCAM-1 gene expression and a time-dependent downregulation of PECAM-1 gene expression reaching a minimum 4?h from start of the experiment. The anti-TNF-? antibody infliximab, by neutralizing TNF-? and IFN-? production, completely reversed PECAM-1 mRNA downregulation and ICAM-1 and VCAM-1 upregulation. Immunostaining of PBLs cytospins with antibodies against PECAM-1 and ICAM-1 confirmed RT-PCR and western blot results. PBLs IFN-? or TNF-? treatment downregulated PECAM-1 in parallel with the upregulation of ICAM-1 and VCAM-1 gene expression, whereas TGF-? upregulated PECAM-1- and downregulated ICAM-1 and VCAM-1 gene expression counteracting the effect of TNF-? or IFN-?. Similar results were obtained in human U937 cells and in granulocyte cultures by TNF-? or IFN-? treatment. Taken together, these results suggest that infliximab, blocking TNF-? and IFN-? production, exerts its anti-inflammatory effect through inhibiting downregulation of PECAM-1 gene expression and upregulation of ICAM-1 and VCAM-1 expression in leukocytes of the peripheral blood. These results also suggest that TGF-? may thus be of therapeutic importance as an anti-inflammatory agent. PMID:22042082

Moriconi, Federico; Malik, Ihtzaz Ahmed; Amanzada, Ahmad; Blaschke, Martina; Raddatz, Dirk; Khan, Sajjad; Ramadori, Giuliano

2012-02-01

78

In vitro evaluation of effects of sustained anti-TNF release from MPEG-PCL-MPEG and PCL microspheres on human rheumatoid arthritis synoviocytes.  

PubMed

Anti-tumor necrosis factor ? (TNF?) drugs such as etanercept (ETN) have been mostly used in systemic treatment of rheumatoid arthritis. To eliminate the side effects in long-term treatments and to achieve a local sustained anti-inflammatory effect, a controlled drug delivery system is needed for anti-TNF? drugs. This study aims to develop novel injectable microcarriers of ETN that can provide long-term controlled release of this protein drug upon intra-articular application. In this study, poly(?-caprolactone) (PCL) and its copolymer with poly(ethylene glycol), methoxypoly(ethylene glycol)-poly(?-caprolactone)-methoxypoly(ethylene glycol) microspheres (MPEG-PCL-MPEG) were compared for their prospective success in rheumatoid arthritis treatment. Microspheres with smooth surface of a mean particle diameter of approximately 5??m were prepared with both polymers. MPEG-PCL-MPEG microspheres had higher encapsulation efficiency than PCL microspheres. The activity of encapsulated ETN within MPEG-PCL-MPEG microspheres also retained while 90% of the activity of ETN within PCL microspheres could retain during 90-day release. MPEG-PCL-MPEG microspheres showed faster ETN release compared to PCL microspheres in various release media. Cumulative amounts of ETN released from both types of microspheres were significantly lower in cell culture medium and in synovial fluids than in phosphate buffered saline. This was mainly due to protein adsorption onto microspheres. Hydrophilic MPEG segment enhanced ETN release while preventing protein adsorption on microspheres compared to PCL. Sustained ETN release from microspheres resulted with a significant decrease in pro-inflammatory cytokines (TNF?, IFN?, IL-6, IL-17) and MMP levels (MMP-3, MMP-13), while conserving viability of fibroblast-like synoviocytes compared to the free drug. Results suggest that MPEG-PCL-MPEG is a potential copolymer of PCL that can be used in development of biomedical materials for effective local treatment purposes in chronic inflammatory arthritis owing to enhanced hydrophilicity. Yet, PCL microspheres are also promising systems having good compatibility to synoviocytes and would be especially the choice for treatment approach requiring longer term and slower release. PMID:24854983

Erdemli, Özge; Özen, Seza; Keskin, Dilek; Usanmaz, Ali; Batu, Ezgi Deniz; Atilla, Bülent; Tezcaner, Ay?en

2014-10-01

79

Immunotherapies: The Blockade of Inhibitory Signals  

PubMed Central

T lymphocytes require signaling by the T cell receptor and by nonclonotypic cosignaling receptors. The costimulatory and inhibitory signals profoundly influence the course of immune responses by amplifying or reducing the transcriptional effects of T cell receptor triggering. The inhibitory receptors such as CTLA-4, PD-1, and BTLA have recently drawn much attention as potential targets for immunotherapies. This review focuses on the progress that has been made with the mentioned receptors in the field of immunotherapies for autoimmune diseases, malignancies, infectious diseases, and transplantation. PMID:23197939

Wu, Yan-Ling; Liang, Jing; Zhang, Wen; Tanaka, Yoshimasa; Sugiyama, Hiroshi

2012-01-01

80

A personalized view on cancer immunotherapy.  

PubMed

Recent progress in cancer immunotherapy has resulted in complete responses in patients refractory to current standard cancer therapies. However, due to tumor heterogeneity and inter-individual variations in anti-tumor immunity, only subsets of patients experience clinical benefit. This review highlights the implementation of a personalized approach to enhance treatment efficacy and reduce side effects, including the identification of tumor-specific antigens for cancer vaccination and adoptive T cell therapies. Furthermore, together with the current advances and promising clinical outcomes of combination cancer (immuno-)therapies, the screening for predictive biomarkers in a patient-specific manner is emphasized. PMID:24051308

Wayteck, Laura; Breckpot, Karine; Demeester, Jo; De Smedt, Stefaan C; Raemdonck, Koen

2014-09-28

81

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

82

Recent advances in immunotherapy for allergic diseases.  

PubMed

Allergic diseases are a major health problem worldwide. The therapeutic approaches to treat allergic rhinitis (AR) and allergic asthma (AA) fall in three major categories. The first step is allergen avoidance, or reduction of exposure to the offending allergen(s). The second and most widely used therapeutic practice is the prescription of relevant medication to reduce symptoms. The third therapeutic element is specific allergy vaccination, also known as allergen specific immunotherapy. Allergen-specific immunotherapy (SIT) is the only etiologic treatment of allergic disorders that can alter the natural course of the disease. In this review, recent advances in immunotherapy and relevant patents are presented. General vaccine modifications could be applied for any type of allergen. New specific modifications in allergic vaccines have been developed for a variety of allergies such as house dust mites, horse, cat, parvalbumin and from birch, ragweed and parietaria pollen. PMID:24237114

El-Qutob, David; Mencia, Gemma; Fernandez-Caldas, Enrique

2014-01-01

83

Immunotherapy in gastric cancer.  

PubMed

Gastric cancer is the second most common of cancer-related deaths worldwide. In the majority of cases gastric cancer is advanced at diagnosis and although medical and surgical treatments have improved, survival rates remain poor. Cancer immunotherapy has emerged as a powerful and promising clinical approach for treatment of cancer and has shown major success in breast cancer, prostate cancer and melanoma. Here, we provide an overview of concepts of modern cancer immunotherapy including the theory, current approaches, remaining hurdles to be overcome, and the future prospect of cancer immunotherapy in the treatment of gastric cancer. Adaptive cell therapies, cancer vaccines, gene therapies, monoclonal antibody therapies have all been used with some initial successes in gastric cancer. However, to date the results in gastric cancer have been disappointing as current approaches often do not stimulate immunity efficiently allowing tumors continue to grow despite the presence of a measurable immune response. Here, we discuss the identification of targets for immunotherapy and the role of biomarkers in prospectively identifying appropriate subjects or immunotherapy. We also discuss the molecular mechanisms by which tumor cells escape host immunosurveillance and produce an immunosuppressive tumor microenvironment. We show how advances have provided tools for overcoming the mechanisms of immunosuppression including the use of monoclonal antibodies to block negative regulators normally expressed on the surface of T cells which limit activation and proliferation of cytotoxic T cells. Immunotherapy has greatly improved and is becoming an important factor in such fields as medical care and welfare for human being. Progress has been rapid ensuring that the future of immunotherapy for gastric cancer is bright. PMID:24587645

Matsueda, Satoko; Graham, David Y

2014-02-21

84

Immunotherapy in gastric cancer  

PubMed Central

Gastric cancer is the second most common of cancer-related deaths worldwide. In the majority of cases gastric cancer is advanced at diagnosis and although medical and surgical treatments have improved, survival rates remain poor. Cancer immunotherapy has emerged as a powerful and promising clinical approach for treatment of cancer and has shown major success in breast cancer, prostate cancer and melanoma. Here, we provide an overview of concepts of modern cancer immunotherapy including the theory, current approaches, remaining hurdles to be overcome, and the future prospect of cancer immunotherapy in the treatment of gastric cancer. Adaptive cell therapies, cancer vaccines, gene therapies, monoclonal antibody therapies have all been used with some initial successes in gastric cancer. However, to date the results in gastric cancer have been disappointing as current approaches often do not stimulate immunity efficiently allowing tumors continue to grow despite the presence of a measurable immune response. Here, we discuss the identification of targets for immunotherapy and the role of biomarkers in prospectively identifying appropriate subjects or immunotherapy. We also discuss the molecular mechanisms by which tumor cells escape host immunosurveillance and produce an immunosuppressive tumor microenvironment. We show how advances have provided tools for overcoming the mechanisms of immunosuppression including the use of monoclonal antibodies to block negative regulators normally expressed on the surface of T cells which limit activation and proliferation of cytotoxic T cells. Immunotherapy has greatly improved and is becoming an important factor in such fields as medical care and welfare for human being. Progress has been rapid ensuring that the future of immunotherapy for gastric cancer is bright. PMID:24587645

Matsueda, Satoko; Graham, David Y

2014-01-01

85

The Impact of DMARD and Anti-TNF Therapy on Functional Characterization of Short-Term T-Cell Activation in Patients with Rheumatoid Arthritis – A Follow-Up Study  

PubMed Central

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a systemic dysfunction of T-cells. In this study we tested the impact of DMARD and anti-TNF agents on short-term activation characteristics of T-cells. We enrolled 12 patients with newly diagnosed RA (naïve RA) who were treated with methothrexate (MTX) and glucocorticsteroid (GCS) and 22 patients with established RA non responding to conventional DMARD therapy who were treated with different anti-TNF agents. Nine healthy volunteers served as controls. Blood samples were taken at baseline, then at 4th and 8th week of therapy. The characteristics of several intracellular activation processes during short-term activation of T-cells including cytoplasmic Ca2+ level, mitochondrial Ca2+ level, reactive oxygen species (ROS) and nitric oxide (NO) generation were determined by a novel flow-cytometry technique. At baseline, the tested processes were comparable to controls in naïve RA. During GCS therapy, cytoplasmic Ca2+ level and ROS generation decreased. After the addition of MTX to GCS cytoplasmic Ca2+ level became comparable to controls, while ROS generation decreased further. In DMARD non responders, cytoplasmic Ca2+ level was higher than controls at baseline. The cytoplasmic Ca2+ level became comparable to controls and ROS generation decreased during each of the three anti-TNF-? agent therapies. Mitochondrial Ca2+ level and NO generation were unaltered in all of the patient groups. These results indicate that intracellular machinery is affected in T-cells of RA patients. This may alter the behavior of T-cells during activation. Different therapeutic approaches may modulate the abnormal T-cell functions. PMID:25098248

Szalay, Balázs; Cseh, Áron; Mészáros, Gerg?; Kovács, László; Balog, Attila; Vásárhelyi, Barna

2014-01-01

86

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

87

Radiation and immunotherapy  

PubMed Central

Anticancer immunotherapy holds great promises, as long-term responses to interleukin-2 have been observed in metastatic melanoma and renal cell carcinoma patients. However, improving the relative low rates of such responses has constituted a great challenge. In our experience, high-dose radiation combined with interleukin-2 provided encouraging results that are worth exploring further. PMID:23264923

Seung, Steven K.; Curti, Brendan; Crittenden, Marka; Urba, Walter

2012-01-01

88

Immunotherapy - Vaccines for allergic diseases  

PubMed Central

Allergic diseases are some of the most commonly encountered problems in clinical practice. Drugs such as corticosteroids and antihistamines can provide effective symptomatic relief, but do not alter the course of the disease. Specific immunotherapy (SIT) was first used to treat pollen allergy in 1911, and has since evolved into an effective treatment for allergic rhinitis and asthma. SIT has been shown in clinical studies to reduce symptoms and medication use in patients with allergic rhinitis and asthma. Recent studies also showed that the therapeutic benefit is long-lasting after the completion of three to five years of treatment. SIT can also effectively reduce the risk of developing asthma and new allergic sensitizations in children with allergic rhinitis. PMID:22833826

2012-01-01

89

Immunotherapy for tularemia  

PubMed Central

Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (>30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia. PMID:23959031

Skyberg, Jerod A.

2013-01-01

90

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

91

Allergen specific immunotherapy induced multi-organ failure.  

PubMed

Allergen specific immunotherapy (ASI) is a well-documented treatment for allergic asthma, rhinitis and allergy to bee venoms. Immunotherapy with subcutaneous injections of allergens extracts has proved beneficial in reducing symptoms of allergic rhinitis and asthma. Side effects due to specific immunotherapy in short term have been largely documented. These effects were various but were usually mild. Fatal reactions are less frequent. We reported a case of a woman, with a history of allergic asthma under specific desensitization protocol who developed an acute multi-organ failure (MOF) consecutive to administration of ASI (Alustal(®) Stallergenes SA, France). This fatal reaction has never been described as adverse event of specific immunotherapy. We aimed to describe this dramatic reaction, expose the arguments to define the relationship between the administration of allergen extract and the occurrence of this fatal reaction. PMID:23785560

Sana, Aissa; Ben Salem, Chaker; Ahmed, Khedher; Abdelbeki, Azouzi; Jihed, Sehli; Imene, Ben Saida; Mohamed, Boussarsar

2013-01-01

92

Current perspectives on immunotherapy.  

PubMed

After many years of disappointments, the successful development and commercialization of the first immune checkpoint inhibitor, and regulatory approval of a dendritic cell (DC)-based cancer vaccine has led to renewed interest and enthusiasm for cancer immunotherapy. Approval of ipilimumab, an antibody targeting cytotoxic T-lymphocyte-associated antigen 4 for advanced melanoma, and sipuleucel-T, an autologous DC-based vaccine for advanced prostate cancer have brought immunotherapy to the forefront of cancer therapeutics and made the goal of long-term tumor control for patients with advanced metastatic disease seem achievable. Additionally, encouraging data from early clinical trials of other immune checkpoint inhibitors targeting programmed cell death 1 and programmed cell death ligand 1 and numerous therapeutic vaccines in development have further expanded interest in the potential of cancer immunotherapy. These recent developments represent the fruits of years of preclinical and clinical research to better understand the complex mechanisms of immune regulation and the ways in which tumors exploit those mechanisms to evade and avoid the antitumor immune response. PMID:25438996

Weber, Jeffrey S

2014-10-01

93

New types of immunotherapy in children  

Microsoft Academic Search

Injection immunotherapy has been shown to be particularly beneficial in treating allergic rhinitis, mild to moderate asthma,\\u000a and anaphylaxis caused by bee and wasp venom. It also produces a long-term, antigen-specific, protective immune effect and\\u000a is the only treatment that offers the possibility of reducing the risk of asthma development in children with allergic rhinitis.\\u000a Nonetheless, the potentially severe side

Noel Rodríguez-Pérez; Martin Penagos; Jay M. Portnoy

2008-01-01

94

Regulatory T cells as immunotherapy.  

PubMed

Regulatory T cells (Tregs) suppress exuberant immune system activation and promote immunologic tolerance. Because Tregs modulate both innate and adaptive immunity, the biomedical community has developed an intense interest in using Tregs for immunotherapy. Conditions that require clinical tolerance to improve outcomes - autoimmune disease, solid organ transplantation, and hematopoietic stem cell transplantation - may benefit from Treg immunotherapy. Investigators have designed ex vivo strategies to isolate, preserve, expand, and infuse Tregs. Protocols to manipulate Treg populations in vivo have also been considered. Barriers to clinically feasible Treg immunotherapy include Treg stability, off-cell effects, and demonstration of cell preparation purity and potency. Clinical trials involving Treg adoptive transfer to treat graft versus host disease preliminarily demonstrated the safety and efficacy of Treg immunotherapy in humans. Future work will need to confirm the safety of Treg immunotherapy and establish the efficacy of specific Treg subsets for the treatment of immune-mediated disease. PMID:24575095

Singer, Benjamin D; King, Landon S; D'Alessio, Franco R

2014-01-01

95

CCL21 Cancer Immunotherapy  

PubMed Central

Cancer, a major health problem, affects 12 million people worldwide every year. With surgery and chemo-radiation the long term survival rate for the majority of cancer patients is dismal. Thus novel treatments are urgently needed. Immunotherapy, the harnessing of the immune system to destroy cancer cells is an attractive option with potential for long term anti-tumor benefit. Cytokines are biological response modifiers that stimulate anti-tumor immune responses. In this review, we discuss the anti-tumor efficacy of the chemotactic cytokine CCL21 and its pre-clinical and clinical application in cancer. PMID:24810425

Lin, Yuan; Sharma, Sherven; John, Maie St.

2014-01-01

96

Immunotherapies in rheumatologic disorders.  

PubMed

Over the past several decades, rheumatology has directed its focus to understanding and countering the immune dysregulation underlying autoimmune diseases with rheumatologic manifestations. Older therapies, effective though poorly understood, are being scrutinized anew and are yielding the immune-modulating mechanisms behind their efficacy. New therapies, the "biologics," are drugs tailored to address specific immune defects and imbalances. This article discusses the current standard and biologic immunotherapies of the rheumatic diseases, correlating our current understanding of their mechanisms with dysfunctions believed to be present in the major autoimmune syndromes, especially rheumatoid arthritis and systemic lupus erythematosus. PMID:22703852

Miller, Anne V; Ranatunga, Sriya K M

2012-05-01

97

Keyhole Limpet Hemocyanin Immunotherapy of Bladder Cancer: Laboratory and Clinical Studies  

Microsoft Academic Search

Background: Since the serendipitous observation by Olsson in 1974 that patients immunized with 5 mg of keyhole limpet hemocyanin (KLH) had a marked reduction in recurrence of superficial bladder cancer, multiple laboratory and clinical studies have confirmed the efficacy of KLH immunotherapy. Results: In 1981, we reported that KLH immunotherapy reduced tumor growth and prolonged survival in the MBT-2 murine

Donald L. Lamm; Jean I. Dehaven; Dale R. Riggs

2000-01-01

98

Cancer immunotherapy and nanomedicine.  

PubMed

The immune system has the ability to recognize and kill pre-cancer and cancer cells. However, with the immune system's surveillance, the survival tumor cells learn how to escape the immune system after immunoselection. Cancer immunotherapy develops strategies to overcome these problems. Nanomedicine applications in cancer immunotherapy include the nanodiagnostics and nanobiopharmaceuticals. In cancer nanodiagnostics, it looks for specific "molecular signatures" in cancer cells or their microenvironment by using genomics and proteomics. Nanobiopharmaceuticals is the field that studies nanotechnology-based therapeutic agents and drug carriers. DNA, RNA, peptides, proteins and small molecules can all be used as cancer therapies when formulated in nanocarriers. Currently, cancer vaccines are applied in treatments with existing cancer or to prevent the development of cancer in certain high risk individuals. Most of the non-specific immune activation agents include adjuvants which enhance immunogenicity and accelerate and prolong the response of cancer vaccines. The carriers of vaccines, such as viruses and nanoparticles, have also been in clinical studies for many years. This review will discuss the relationships between the tumor and the immune system, and also will include topics covering the strategies used in eliminating tumors by using nanomedicine. PMID:20821040

Sheng, Wei-Yun; Huang, Leaf

2011-02-01

99

Sublingual immunotherapy in children: facts and needs  

PubMed Central

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 sometimes severe and - though very rarely - even fatal. This was the background to develop non injections routes for SIT and particularly sublingual immunotherapy (SLIT), that emerged as a real treatment option for respiratory allergy. A number of studies was conducted to evaluate efficacy and safety of SLIT, the first meta-analysis - including 22 placebo-controlled trials - concluded for positive results in both issues, but the number of studies on children was too low to draw definite conclusions. Since then, many other studies became available and make possible to analyze SLIT in children in its well defined aspects as well as in sides still requiring more solid data. PMID:19852795

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

2009-01-01

100

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

101

Chemo-immunotherapy and chemo-adoptive immunotherapy of cancer  

Microsoft Academic Search

The chemo-immunotherapy (CIT) and chemo-adoptive immunotherapy (CAIT) regimens tested in the past decade are summarized. From them we have learned a great deal about the interactions between various chemotherapeutic agents, immune modulating agents and effector cells. The most commonly reported result in multi-modality experiments with CAIT has been a synergistic enhancement in antitumor activity. Clinical trials usually demonstrated improvement in

G. G Gomez; R. B Hutchison; C. A Kruse

2001-01-01

102

Immunotherapy for Pediatric Leukemia  

PubMed Central

Substantial progress has been made in the treatment of leukemia in childhood. Despite this, leukemia remains a leading cause of pediatric cancer-related mortality and the prognosis is guarded for individuals with relapsed or refractory disease. Standard therapies are associated with a wide array of acute and long-term toxicities and further treatment intensification may not be tolerable or beneficial. The curative potential of allogeneic stem cell transplantation is due in part to the graft-versus-leukemia effect, which provides evidence for the therapeutic capacity of immune-based therapies. In recent years there have been significant advances in the development and application of immunotherapy in the treatment of leukemias, including the demonstration of activity in chemotherapy-resistant cases. This review summarizes immunotherapeutic approaches in the treatment of pediatric leukemia including current results and future directions. PMID:23847759

Shah, Nirali N.; Dave, Hema; Wayne, Alan S.

2013-01-01

103

Immunotherapy of cancer  

PubMed Central

Major advances have been made in the field of immunology in the past two decades. A better understanding of the molecular and cellular mechanisms controlling the immune system, has opened the door to many innovative and promising new cancer therapies that manipulate the immune response. For instance, toll-like receptor agonists have been shown to boost immune responses toward tumors. Also, a wide array of cell-based immunotherapies utilizing T cells, NK cells, and dendritic cells have been established. Furthermore, a rapidly expanding repertoire of monoclonal antibodies is being developed to treat tumors, and many of the available antibodies have demonstrated impressive clinical responses. Here, we examine some of these immunotherapeutic approaches currently in use or testing to treat cancer, and we examine available evidence with regards to mechanism and efficacy of these treatments. PMID:19837059

Borghaei, Hossein; Smith, Mitchell R.; Campbell, Kerry S.

2009-01-01

104

Cytokines in Cancer Immunotherapy  

PubMed Central

Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. The growing interest over the past two decades in harnessing the immune system to eradicate cancer has been accompanied by heightened efforts to characterize cytokines and exploit their vast signaling networks to develop cancer treatments. The goal of this paper is to review the major cytokines involved in cancer immunotherapy and discuss their basic biology and clinical applications. The paper will also describe new cytokines in pre-clinical development, combinations of biological agents, novel delivery mechanisms, and potential directions for future investigation using cytokines. PMID:24213115

Lee, Sylvia; Margolin, Kim

2011-01-01

105

Immunotherapy of allergic contact dermatitis.  

PubMed

The term 'immunotherapy' refers to treating diseases by inducing, enhancing or suppressing immune responses. As allergy is an excessive, detrimental immune reaction to otherwise harmless environmental substances, immunotherapy of allergic disease is aimed at the induction of tolerance toward sensitizing antigens. This article focuses on the historical developments, present state and future outlook for immunotherapy with haptens as a therapeutic modality for allergic contact dermatitis. Inspired by the effectiveness of immunotherapy in respiratory allergies, attempts were undertaken at curing allergic contact dermatitis by means of controlled administration of the sensitizing haptens. Animal and human experiments confirmed that tolerance to haptens can be induced most effectively when the induction of tolerance precedes attempted sensitization. In real life, however, therapy is sought by people who are already sensitized and an effective reversal of hypersensitivity seems more difficult to achieve. Decades of research on Rhus hypersensitivity led to a conclusion that immunotherapy can suppress Rhus dermatitis, however, only to a limited degree, for a short period of time, and at a high risk of side effects, which makes this method therapeutically unprofitable. Methodological problems with most available studies of immunotherapy of contact allergy to nickel make any definite conclusions impossible at this stage. PMID:21843085

Spiewak, Radoslaw

2011-08-01

106

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

107

Recombinant allergens for pollen immunotherapy.  

PubMed

Specific immunotherapy (IT) represents the only potentially curative therapeutic intervention of allergic diseases capable of suppressing allergy-associated symptoms not only during treatment, but also after its cessation. Presently, IT is performed with allergen extracts, which represent a heterogeneous mixture of allergenic, as well as nonallergenic, compounds of a given allergen source. To overcome many of the problems associated with extract-based IT, strategies based on the use of recombinant allergens or derivatives thereof have been developed. This review focuses on recombinant technologies to produce allergy therapeuticals, especially for allergies caused by tree, grass and weed pollen, as they are among the most prevalent allergic disorders affecting the population of industrialized societies. The reduction of IgE-binding of recombinant allergen derivatives appears to be mandatory to increase the safety profile of vaccine candidates. Moreover, increased immunogenicity is expected to reduce the dosage regimes of the presently cumbersome treatment. In this regard, it has been convincingly demonstrated in animal models that hypoallergenic molecules can be engineered to harbor inherent antiallergenic immunologic properties. Thus, strategies to modulate the allergenic and immunogenic properties of recombinant allergens will be discussed in detail. In recent years, several successful clinical studies using recombinant wild-type or hypoallergens as active ingredients have been published and, currently, novel treatment forms with higher safety and efficacy profiles are under investigation in clinical trials. These recent developments are summarized and discussed. PMID:24283843

Wallner, Michael; Pichler, Ulrike; Ferreira, Fatima

2013-12-01

108

IgE immunotherapy  

PubMed Central

The importance of antibodies in activating immune responses against tumors is now better appreciated with the emergence of checkpoint blockade antibodies and with engineered antibody Fc domains featuring enhanced capacity to focus potent effector cells against cancer cells. Antibodies designed with Fc regions of the IgE class can confer natural, potent, long-lived immune surveillance in tissues through tenacious engagement of high-affinity cognate Fc receptors on distinct, often tumor-resident immune effector cells, and through ability to activate these cells under tumor-induced Th2-biased conditions. Here, we review the properties that make IgE a contributor to the allergic response and a critical player in the protection against parasites, which also support IgE as a novel anti-cancer modality. We discuss IgE-based active and passive immunotherapeutic approaches in disparate in vitro and in vivo model systems, collectively suggesting the potential of IgE immunotherapies in oncology. Translation toward clinical application is now in progress. PMID:24423620

Josephs, Debra H; Spicer, James F; Karagiannis, Panagiotis; Gould, Hannah J; Karagiannis, Sophia N

2014-01-01

109

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

PubMed

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

110

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

111

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

112

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

113

The immunotherapy of Alzheimer's disease  

PubMed Central

Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations. PMID:15679923

Weksler, Marc E

2004-01-01

114

Active immunotherapy of multiple myeloma  

Microsoft Academic Search

Since myeloma cells express various potential target antigens, active immunotherapy is being investigated as a novel treatment modality for myeloma. Immunization against the clonal myeloma immunoglobulin (idiotype) elicits protective immunity in mouse models. Idiotype vaccination of myeloma patients can induce cellular immunity, albeit as yet without firm evidence for improved clinical outcome. Other tumour-associated antigens (including cancer\\/testis antigens) are expressed

Leonora Houet; Hendrik Veelken

2006-01-01

115

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

116

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

117

Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy  

PubMed Central

In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines. PMID:22496608

De Souza Rebouças, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, María Luisa; Irache, Juan Manuel; Gamazo, Carlos

2012-01-01

118

[Treatment perspectives: immunotherapy with latex].  

PubMed

Latex allergy currently constitutes a serious problem because of the severity of its symptoms and the at-risk groups it affects. Since complete avoidance of this substance is practically impossible, in the last few years intense efforts have been made to standardize a latex extract with the aim not only of improving clinical diagnosis but also of being able to offer other therapeutic alternatives, such as specific immunotherapy.Since 1998, reports of immunotherapy with oral (three patients) subcutaneous (one patient) and sublingual latex desensitization (one patient) have been published. In all cases, clinical improvement was evident. In 2000, Laynadier published the first pilot study, a phase IIB multicenter, randomized, double-blind, placebo-controlled trial that evaluated the efficacy and safety of specific immunotherapy with latex in patients with occupational allergy. Twenty health care workers without obvious latex exposure and with latex allergy-induced symptoms of rhinitis and/or asthma were included. Treatment started with a 2-day course of rush immunotherapy in hospital and maintenance therapy was continued for 1 year. Efficacy was assessed by symptom and medication scores and by variation in the conjunctival reactivity threshold. The safety of the extract was also evaluated. In the overall analysis of symptom score, the treated group showed a marked improvement and the medication score was significantly lower in patients in the active treatment group than in the placebo group. Concerning safety, almost half the patients receiving active treatment showed local reactions starting with the first injection and four of the nine patients in this group suffered moderate-to-severe systemic reactions. In view of this first clinical trial, it can be concluded that this treatment is effective but that its tolerance is low.A second clinical trial with the same characteristics and extract is currently underway. Its aim is to validate the previous protocol, confirm the efficacy of specific immunotherapy with latex, improve its safety and, if possible, determine the optimal dose.J. Sastre et al. have recently (Formigal 2002) presented the results of the first double-blind study with latex immunotherapy using an extract standardized by the ALK-Abelló-España group. The authors included 24 patients with latex sensitization and symptoms of occupational allergy. To diagnose respiratory allergy, an inhalation challenge was performed in a closed 7-m2 chamber and, in case of contact urticaria, glove-wearing and rubbing tests were performed, using a vinyl glove as negative control. Treatment consisted of a first phase of incremental doses for 14 weeks, with 18 injections, followed by maintenance doses for 6 months. Sixteen patients received active treatment and 8 received placebo. Of the 578 doses administered, adverse effects were observed in 41 (7.1 %). There were 21 immediate systemic reactions (5.7 % of the doses) and 10 delayed systemic reactions (2.6 % of the doses). Adverse effects were more frequent in patients with underlying respiratory disease (p < 0.05). After 6 months' treatment, a clear improvement in the cutaneous response index was found in the active treatment group and in the rubbing and glove-wearing tests. The authors conclude that the immunotherapy tested was a high-risk treatment and that the greatest clinical improvement was found in cutaneous symptoms.In conclusion, although effective, latex immunotherapy is currently a high-risk treatment. PMID:11988148

Tabar, A I; Anda, M; Gómez, B; García, B; Lizaso, Ma T; Echechipía, S; Arroabarren, E; Olaguibel, J Ma

2002-01-01

119

Radiation and immunotherapy: a synergistic combination  

PubMed Central

Immunotherapy can be an effective treatment for metastatic cancer, but a significant subpopulation will not respond, likely due to the lack of antigenic mutations or the immune-evasive properties of cancer. Likewise, radiation therapy (RT) is an established cancer treatment, but local failures still occur. Clinical observations suggest that RT may expand the therapeutic reach of immunotherapy. We examine the immunobiologic and clinical rationale for combining RT and immunotherapy, two modalities yet to be used in combination in routine practice. Preclinical data indicate that RT can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of RT. PMID:23863633

Kalbasi, Anusha; June, Carl H.; Haas, Naomi; Vapiwala, Neha

2013-01-01

120

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

121

The future of sublingual immunotherapy.  

PubMed

Sublingual immunotherapy (SLIT) is currently the most prescribed form of allergen immunotherapy in many European countries. Its use has been accepted in the international consensus publications, and recently also the scepticism of USA scientists is attenuated. Still, this treatment may be improved, and the possible developments consist of modification of the materials, use of adjuvants and use of recombinant allergens. Moreover, new applications of SLIT, such as food allergy, seem promising. Concerning materials, the future form of SLIT is likely to be represented by tablets, which were already tested for efficacy and safety with grass pollen extracts, and are likely to increase the convenience for the patient by the use of no-updosing schedule. Adjuvants fitting with the characteristics of SLIT seem to be CpG oligodeoxynucleotides (CpG), able to interact with the Toll-like receptor 9 (TLR9) whose activation induces a Th1-like pattern of cytokine release, combination of 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3-Dex), and Lactobacillus plantarum. The approach with recombinant allergens, named component-resolved diagnosis, offers the possibility to tailor immunotherapy, which was found to be effective in two randomized trials of subcutaneous SIT (16-17), while studies with SLIT are not yet available. Regarding food allergy, an important controlled study demonstrated that SLIT with hazelnut is able to increase patients tolerance over possible reactions from inadvertent assumption of the culprit food, and warrants for further trials with other foods. PMID:19944008

Marcucci, F; Duse, M; Frati, F; Incorvaia, C; Marseglia, G L; La Rosa, M

2009-01-01

122

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

123

Developments in HIV-1 immunotherapy and therapeutic vaccination  

PubMed Central

Since the human immunodeficiency virus (HIV-1) pandemic began, few prophylactic vaccines have reached phase III trials. Only one has shown partial efficacy in preventing HIV-1 infection. The introduction of antiretroviral therapy (ART) has had considerable success in controlling infection and reducing transmission but in so doing has changed the nature of HIV-1 infection for those with access to ART. Access, compliance, and toxicity alongside the emergence of serious non-AIDS morbidity and the sometimes poor immune reconstitution in ART-treated patients have emphasized the need for additional therapies. Such therapy is intended to contribute to control of HIV-1 infection, permit structured treatment interruptions, or even establish a functional cure of permanently suppressed and controlled infection. Both immunotherapy and therapeutic vaccination have the potential to reach these goals. In this review, the latest developments in immunotherapy and therapeutic vaccination are discussed. PMID:24991420

Tanner, Helen; Dalgleish, Angus

2014-01-01

124

Immunotherapy of distant metastatic disease  

PubMed Central

Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon ?, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed. PMID:19617297

Schadendorf, D.; Algarra, S. M.; Bastholt, L.; Cinat, G.; Dreno, B.; Eggermont, A. M. M.; Espinosa, E.; Guo, J.; Hauschild, A.; Petrella, T.; Schachter, J.; Hersey, P.

2009-01-01

125

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

126

Escalating immunotherapy of multiple sclerosis.  

PubMed

Basic disease-modifying treatment for relapsing forms of active multiple sclerosis (MS) is now available in many countries with high prevalence rates, for this chronic inflammatory disease of the central nervous system. Several lines of evidence support early immunomodulatory treatment with either recombinant interferon-beta or glatiramer acetate, and positive results from phase III trials encourage start of treatment even in patients with clinically isolated syndromes (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for effective escalating strategies. Patients with suboptimal treatment response to basic therapy have been treated with combination therapies, cytotoxic drugs (such as mitoxantrone and cyclophosphamide) or autologous hematopoietic stem cell transplantation. Recently, the monoclonal antibody, natalizumab, was added to this armamentarium. None of these strategies have been vigorously evaluated in large randomized, controlled phase III trials with patients who failed basic therapy. Therefore, the decision to escalate immunotherapy is still based on limited evidence. This article will review potential candidates for intensified immunosuppression and call for innovative study designs to better evaluate escalating immunotherapy in MS. PMID:21180576

Rieckmann, Peter; Traboulsee, Anthony; Devonshire, Virginia; Oger, Joel

2008-11-01

127

Improved Endpoints for Cancer Immunotherapy Trials  

PubMed Central

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

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

2010-01-01

128

PROSTVAC® targeted immunotherapy candidate for prostate cancer.  

PubMed

Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response. PMID:24762070

Shore, Neal D

2014-03-01

129

Local Nasal Specific Immunotherapy for Allergic Rhinitis  

PubMed Central

The possibility of producing local hyposensitization by administering allergens via mucosal routes was envisaged at the beginning of 1900, and local nasal immunotherapy has been extensively studied since the 1970s. Presently, there are 21 randomized controlled trials being conducted with the most common allergens, consistently showing the clinical efficacy of local nasal immunotherapy for rhinitis. Other advantages are that it has an optimal safety profile and can be self-administered at home by the patient. Moreover, there are several data from animal models and from humans that confirm the immunomodulatory effect of intranasally administered antigens. On the other hand, local nasal immunotherapy seems to be effective only on rhinitis symptoms and requires a particular technique of administration. For these reasons, its clinical use is progressively declining in favour of the sublingual route although nasal immunotherapy is validated in official documents and remains a viable alternative to injection. PMID:20525156

2006-01-01

130

Allergen immunotherapy for allergic respiratory diseases  

PubMed Central

Allergen specific immunotherapy involves the repeated administration of allergen products in order to induce clinical and immunologic tolerance to the offending allergen. Immunotherapy is the only etiology-based treatment that has the potential for disease modification, as reflected by longterm remission following its discontinuation and possibly prevention of disease progression and onset of new allergic sensitizations. Whereas subcutaneous immunotherapy is of proven value in allergic rhinitis and asthma there is a risk of untoward side effects including rarely anaphylaxis. Recently the sublingual route has emerged as an effective and safer alternative. Whereas the efficacy of SLIT in seasonal allergy is now well-documented in adults and children, the available data for perennial allergies and asthma is less reliable and particularly lacking in children. This review evaluates the efficacy, safety and longterm benefits of SCIT and SLIT and highlights new findings regarding mechanisms, potential biomarkers and recent novel approaches for allergen immunotherapy. PMID:23095870

Cappella, Antonio; Durham, Stephen R.

2012-01-01

131

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

132

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

133

Keyhole-limpet hemocyanin immunotherapy in the bilharzial bladder: a new treatment modality? Phase II trial: superficial bladder cancer.  

PubMed

The efficacy of immunotherapy with keyhole-limpet hemocyanin or bacillus Calmette-Guerin for superficial bladder cancer is well known. A strong similarity has been noted between keyhole-limpet hemocyanin antigen and schistosomal antigen. In regard to this finding, we investigated the mechanisms of specific immunotherapy with keyhole-limpet hemocyanin in schistosomal associated transitional cell carcinoma. Keyhole-limpet hemocyanin was used for its ability to prevent tumor recurrence and because of its similarity to schistosomal antigen for intravesical specific immunotherapy in 13 patients with superficial transitional cell bladder tumors (Ta, Tis, T1) associated with urinary schistosomiasis. Keyhole-limpet hemocyanin immunotherapy reduced the recurrence rate of superficial bladder tumors to 15.4% compared to 76.9% before therapy. PMID:7853576

Wishahi, M M; Ismail, I M; Ruebben, H; Otto, T

1995-03-01

134

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

135

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

136

IgE-based Immunotherapy of Cancer -A Comparative Oncology Approach.  

PubMed

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

2014-05-31

137

[Specific immunotherapy and relocation in occupational allergic bakers].  

PubMed

Occupational allergy to components of wheat flour is the main cause of rhinitis and asthma of workers in bakeries and similar activities. An immunological mechanism IgE-mediated is involved and the sensitising properties of some proteins of wheat where assessed. Nowadays it is possible to have an extract to be used for specific immunotherapy. The aim of this treatment should be a reduction of individual immunological reactivity and the possibility of going on the particular activity of allergic bakers, pastry makers or pizza makers. An observational crossectional retrospective study was performed on 41 sensitised workers that were diagnosed in the same occupational health unit. All underwent a subcutaneous specific immunotherapy (SCIT) with the same schedule and the same extract (Lofarma Allergeni, Milan) for 4 or more years, without avoiding their work activity. The outcome was investigated after five or ten years. Data were collected by a questionnaire. 34 subjects on 41 are still at work with an acceptable quality of life and a normal working efficiency, mainly in their small enterprises. In the "old" subgroup (19 cases), treated in the past, several bakers still at work stopped SCIT even from 4-10 years. In the "new" subgroup (15 cases), still in treatment, symptoms and drug use during the work activity resulted to be reduced or absent in the majority of cases. According to results of other immunotherapies by allergenic vaccines (pollens, mites) also for wheat flour occupational allergy a specific treatment seems to be possible and SCIT may be an useful tool to reduce and control the biological individual effects of allergy. By the occupational point of view wheat flour SCIT allows a relocation in many of cases and may be associated to other intervention of environmental prevention at workplaces, improving the relocation of occupational allergic subjects when requested. PMID:18409768

Cirla, A M; Lorenzini, R A; Cirla, P E

2007-01-01

138

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

139

Immunotherapy in acute myeloid leukemia.  

PubMed

Treatment of acute myeloid leukemia (AML) with current chemotherapy regimens is still disappointing, with overall survival rates of ? 40% at 5 years. It is now well established that AML cells can evade the immune system through multiple mechanisms, including the expression of the enzyme indoleamine 2,3 dioxygenase. Immunotherapeutic strategies, including both active, such as vaccination with leukemia-associated antigens, and passive, such as adoptive transfer of allogeneic natural killer cells, may overcome leukemia escape and lead to improved cure. Allogeneic hemopoeitic stem cell transplantation, the most effective treatment of AML, is the best known model of immunotherapy. Following transplant, recipient AML cells are eradicated by donor immune cells through the graft-versus-leukemia (GVL) effect. However, GVL is clinically associated with graft-versus-host disease, the major cause of mortality after transplant. GVL is mediated by donor T cells recognizing either leukemia-associated antigens or minor as well as major histocompatibility antigens. Several innovative strategies have been devised to generate leukemia reactive T cells so as to increase GVL responses with no or little graft-versus-host disease. PMID:24341888

Arpinati, Mario; Curti, Antonio

2014-01-01

140

Immunotherapy for acute myeloid leukemia.  

PubMed

Immunotherapeutic strategies have become part of standard cancer treatment. Chimeric and humanized antibodies have demonstrated activity against a variety of tumors. Although the humanized anti-CD33 antibody HuM195 has only modest activity against overt acute myeloid leukemia (AML), it can eliminate minimal residual disease in acute promyelocytic leukemia. High-dose radioimmunotherapy with b-particle-emitting isotopes targeting CD33, CD45, and CD66 can potentially allow intensification of antileukemic therapy before hematopoietic stem cell transplantation. Conversely, a-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumor cell kill while sparing surrounding normal tissues. Targeted chemotherapy with the anti-CD33- calicheamicin construct gemtuzumab ozogamicin has produced remissions in relapsed AML and appears promising when used in combination with standard chemotherapy for newly diagnosed AML. T-cell recognition of peptide antigens presented on the cell surface in combination with major histocompatibility complex antigen provides another potentially promising approach for the treatment of AML. PMID:16091194

Jurcic, Joseph G

2005-09-01

141

Current Studies of Immunotherapy on Glioblastoma  

PubMed Central

Glioblastoma is a form of brain tumor with a very high morbidity and mortality. Despite decades of research, the best treatments currently in clinical practice only extend survival by a number of months. A promising alternative to conventional treatment for glioblastomas is immunotherapy. Although proposed over a century ago, the field of cancer immunotherapy has historically struggled to translate it into effective clinical treatments. Better understanding is needed of the various regulatory and co-stimulatory factors in the glioblastoma patient for more efficient immunotherapy treatments. The tumor microenvironment is anatomically shielded from normal immune-surveillance by the blood-brain barrier, irregular lymphatic drainage system, and it’s in a potently immunosuppressive environment. Immunotherapy can potentially manipulate these forces effectively to enhance anti-tumor immune response and clinical benefit. New treatments utilizing the immune system show promise in terms of targeting and efficacy. This review article attempts to discuss current practices in glioblastoma treatment, the theory behind immunotherapy, and current research into various clinical trials. PMID:25346943

Agrawal, Neena Stephanie; Miller, Rickey; Lal, Richa; Mahanti, Harshini; Dixon-Mah, Yaenette N.; DeCandio, Michele L.; Vandergrift, W Alex; Varma, Abhay K.; Patel, Sunil J.; Banik, Naren L.; Lindhorst, Scott M.; Giglio, Pierre; Das, Arabinda

2014-01-01

142

Strategies of mucosal immunotherapy for allergic diseases  

PubMed Central

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 and lower side-effect profile. This study reviews recent progress in mucosal immunotherapy for allergic diseases. Administration routes, antigen quality and quantity, and adjuvants used are major considerations in this field. Also, direct uses of unique probiotics, or specific cytokines, have been discussed. Furthermore, some researchers have reported new therapeutic ideas that combine two or more strategies. The most important strategy for development of mucosal therapies for allergic diseases is the improvement of antigen formulation, which includes continuous searching for efficient adjuvants, collecting more information about dominant T-cell epitopes of allergens, and having the proper combination of each. In clinics, when compared to other mucosal routes, sublingual immunotherapy (SLIT) is a preferred choice for therapeutic administration, although local and systemic side effects have been reported. Additionally, not every allergen has the same beneficial effect. Further studies are needed to determine the benefits of mucosal immunotherapy for different allergic diseases after comparison of the different administration routes in children and adults. Data collected from large, well-designed, double-blind, placebo-controlled, and randomized trials, with post-treatment follow-up, can provide robust substantiation of current evidence. PMID:21666705

Ye, Yi-Ling; Chuang, Ya-Hui; Chiang, Bor-Luen

2011-01-01

143

Sublingual immunotherapy: administration, dosages, use.  

PubMed

Allergen extracts for sublingual immunotherapy (SLIT) are currently marketed by several manufacturers, with administration schedules and amount of allergen(s) quite variable in the different products, although almost all are standardized biologically or immunologically. The allergen extracts for SLIT are available in two main pharmaceutical forms: solution to be delivered by drop-counters, pre-dosed actuators (mini-pumps) or disposable single-dose vials; tablets with appropriate composition that allows a slow (1-2 minutes) dissolution in the mouth in contact with saliva. In Europe, SLIT is prescribed in general for one or a few allergens, and mixtures are less used, though there is no immunological contraindication to give multiple allergens. SLIT traditionally involves a build-up phase and a maintenance phase with the top dose. The build-up phase has usually the duration of 4 - 6 weeks. The patient must start with the lowest concentration and gradually increase, using the different dosage preparations, until the maintenance dose is reached. Rush and ultra-rush inductions have been introduced, based on the safety profile of SLIT that is very favorable. For these reasons it has been suggested that an updosing phase maybe even not necessary. The no-updosing approach would result in a treatment that is more patient-friendly and convenient to manage. Indeed, the most recent randomized trials were performed with the no-updosing regimen and their results in term of safety were as favorable as the studies performed with the traditional updosing approach. The currently recommended duration of SLIT is comprised between 3 and 4 years depending on the clinical response in single patients. PMID:19944004

Frati, F; La Grutta, S; Bernardini, R; Zampogna, S; Scurati, S; Puccinelli, P; Riario-Sforza, G G; Incorvaia, C

2009-01-01

144

Adoptive immunotherapy for cancer or viruses.  

PubMed

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

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

2014-01-01

145

Short-term efficacy of nasal immunotherapy.  

PubMed

The purpose of this study was to evaluate the efficacy of nasal immunotherapy in the management of allergic rhinitis. Sixteen patients (10 Female; 6 Male) aged 15-60 years (mean age--31.9) were selected on the bases of clinical history, skin prick tests and RAST positivity. Allergen extract is a "macronized" powder form (Allerkin), it was supplied by Laboratorio Farmaceutico Lofarma (Milano Italy) and administered for 12 months to 8 patients with perennial rhinitis (Dermatophagoides extract) and for 6 months to 8 patients with seasonal rhinitis (grass or Parietaria pollens extract). This treatment was carried out by self administration in two phases: the first one (3 months) consisted of administration of increasing doses; the second phase (maintenance period) was carried out 3 months in seasonal rhinitis and 9 months in perennial rhinitis. All the patients were evaluated before and after immunotherapy and scores from 0 to 3 were attributed according to the symptoms presented and need of drugs for symptomatic relief. Scores before and after immunotherapy were compared using the Wilcoxon Matched-Pairs Signed-Ranks Test and a significant decrease was observed for every symptom in seasonal and perennial rhinitis (p < 0.05). In conclusion, this trial shows that nasal immunotherapy in powder form can be a valuable short-term option in patients with allergic rhinitis. PMID:9503098

Palma-Carlos, A G; Santos, A S; Pregal, A

1998-01-01

146

Complement as effector system in cancer immunotherapy  

Microsoft Academic Search

The contribution of the complement system to the control of tumour growth has been neglected for a long time as the major emphasis has been put mainly on cell-mediated immune response against cancer. With the introduction of monoclonal antibodies in cancer immunotherapy complement has come into play with a great potential as effector system. Complement has a number of advantages

Paolo Macor; Francesco Tedesco

2007-01-01

147

Dosing and efficacy in specific immunotherapy.  

PubMed

Allergen-specific immunotherapy is used to treat allergic rhinoconjuctivitis and asthma worldwide. The clinical efficacy of the most common routes, subcutaneous (SCIT) and sublingual (SLIT) immunotherapy, is documented for respiratory allergy by double-blind, placebo-controlled, randomised clinical trials (DB PC RCT). However, dose-effect relationships are not available for all extracts. The 1998 WHO Consensus Report on Allergen Immunotherapy found SCIT ineffective at low doses, with high doses more likely to result in an unacceptably high level of systemic reactions. Recent large well-designed DB PC RCTs using SLIT grass pollen tablets have undergone phase II-III studies in adults with allergic rhinitis, yielding proper dose-response studies. These were analysed by the European Academy of Allergy and Clinical Immunology Immunotherapy Interest Group task force on dose effect. In general, low doses (5-7 ?g of allergen Phl p 5 per day) are ineffective. Daily doses of 15-25 ?g of the major allergen protein are required for significant clinical improvement measured by symptom scores. A higher dose (33-40 ?g of Phl p 5 per day) was not more effective than 15-25 ?g. Optimization of the allergen/adjuvant ratio may allow for lower allergen doses, increase the safety/efficacy profile and allow for shorter updosing. However, our analysis of the available studies concluded that every product requires its own dose-response relationship study. PMID:21668851

Demoly, P; Calderon, M A

2011-07-01

148

Therapeutic strategies in multiple sclerosis. I. Immunotherapy.  

PubMed Central

This review first addresses several general aspects of the immunotherapy of multiple sclerosis. Next, two approved immunomodulatory treatments, interferon-beta and copolymer-1 (glatiramer acetate), are reviewed in more detail. Finally, other immunosuppressive therapies and experimental strategies are briefly discussed. PMID:10603621

Hohlfeld, R

1999-01-01

149

Checkpoint inhibitors in immunotherapy of ovarian cancer.  

PubMed

The treatment of ovarian cancer is a major challenge in oncology as mortality from ovarian cancer remains very high. The immune system plays a critical role in controlling cancer through a dynamic relationship with cancer cells. Immunotherapy can establish a sustained immune system response against recurring cancer cells leading to long-term remissions for ovarian cancer patient. The use of immune checkpoint inhibitors, which work by targeting molecules that serve as checks and balances in the regulation of immune responses, might be a promising avenue of immunotherapeutic research in ovarian cancer. In this review, we have focused on the potential of certain immune checkpoint inhibitors, such as anti-cytotoxic T lymphocyte antigens, anti-programmed death agents, and anti-program death ligands against ovarian cancer, with their mechanism of actions. Also, the problems arising due to checkpoint inhibitor immunotherapy have been discussed in this review. Checkpoint inhibitor immunotherapy is still in early-phase testing for ovarian cancer. Understanding the pivotal role of the tumor microenvironment in suppressing anticancer immunity, the unique adverse effects profiles of these agents, and the exploration of combinatorial treatment regimens will ultimately lead to enhance the efficacy of ovarian cancer immunotherapies and improved patient care. PMID:25409618

Wang, Dong-Hui; Guo, Liang; Wu, Xiao-Hua

2014-11-20

150

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

151

[Transcutaneous applications for vaccination and immunotherapy].  

PubMed

Although Edward Jenner applied the first vaccines by scratching cow pox material into the skin, the profound immunological properties of the skin have become evident through research and discoveries only in the last 20 years. The immunological cells in the epidermis and the dermis are suitable targets for transcutaneous vaccination and immunotherapy. However, as the skin represents a natural barrier for topically administered large molecules, novel methods to overcome this barrier function have been described. There are chemical, biochemical and physical methods, many of which are pain-free and therefore especially suitable for children. Also for adults non-invasive methods of vaccination and immunotherapy are attractive as self-administration is feasible. Future products are currently undergoing clinical tests which provide promising results. PMID:25305116

Krämer, Isabel; Zabel, Franziska; Kündig, Thomas M; Johansen, Pål

2014-10-15

152

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

153

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

154

Breast cancer gene therapy: transgenic immunotherapy  

Microsoft Academic Search

A number of studies have demonstrated that potent anti-tumor immunity can be induced using cytokine gene transfer, a strategy termed transgenic immunotherapy. Our aim is to express cytokine genes in the vicinity of tumor cells, either by transducing tumor cells themselves, or by delivering cytokine-expressing endothelial cells to tumor sites. We compared the ability of cytokine-expressing tumor cells or endothelial

Ning Su; John O. Ojeifo; Alexander MacPherson; James A. Zwiebel

1994-01-01

155

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

156

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

157

Sublingual vs Oral Immunotherapy for Food Allergy  

PubMed Central

The incidence of food allergy in developed countries has increased in recent years, escalating the need to find a suitable form of treatment as an alternative to current management, which includes strict avoidance and ready availability of injectable epinephrine (adrenaline). Allergen immunotherapy is currently being studied for use in the treatment of IgE-mediated food allergy to the most common foods, including peanut, tree nut, milk and egg. Two modalities, oral immunotherapy (OIT) and sublingual immunotherapy (SLIT), have shown great promise. Both OIT and SLIT have been able to desensitize subjects to varying degrees, but the two treatment methods differ in doses that can be achieved, duration of treatment, safety profile and ease of use outside the research setting, among other aspects. More research is needed to conclude which mode of treatment is more effective in inducing long-term tolerance with the least amount of serious adverse reactions. However, OIT and SLIT show great promise, and a widespread treatment for food allergy may be within reach. PMID:23009174

Narisety, Satya D.; Keet, Corinne A.

2013-01-01

158

[Review on immunotherapies for lung cancer].  

PubMed

Lung cancer is a highly malignant disease with poor prognosis, most cases are diagnosed at a very late stage. More effective medications or therapies should be developed to improve its prognosis. The advancement of tumor immunity and tumor immunosuppression facilitated the feasibility of immunotherapies for lung cancer. Ipilimumab, antibody to Programmed death-1 (PD-1), Toll-like receptor agonists, liposomal BLP25 (L- BLP25), belagenpumatucel-L, melanoma-associated antigen A3 (MAGE-A3) vaccine and talactoferrin have been proved to be effective for lung cancer through early clinical trials, most of the drugs have moved forward to phase III trials, so as to collect much higher level evidence to support the immunotherapies incorporated into the multidisciplinary treatment of lung cancer. The selection of target patients at appropriate stages, breaking down of tumor immunosuppression as well as the objective measurement of tumor response to the therapy are major challenges for the development of immunotherapies for lung cancer. The clarifying of the mechanism of immune escape led to the above drug development, and immune-senescence has already become the hotspot in this field. PMID:23075686

Jin, Sha; Tian, Jianhui

2012-10-01

159

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.

160

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 of these `false beliefs.' Discussion: 1. The symptoms of allergic rhinitis can be more heterogeneous, more severe

Paris-Sud XI, Université de

161

Immunotherapy for Guillain-Barré syndrome: A systematic review  

Microsoft Academic Search

Guillain-Barré syndrome (GBS) is an acute inflammatory disorder of the peripheral nervous system thought to be due to autoimmunity for which immunotherapy is usually prescribed. To provide the best evidence on which to base clinical practice, we systematically reviewed the results of randomized trials of immunotherapy for GBS. We searched the Cochrane Library, MEDLINE and EMBASE in July 2006 and

R. A. C. Hughes; A. V. Swan; J.-C. Raphaël; D. Annane; R. van Koningsveld; Doorn van P. A

2007-01-01

162

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

163

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

164

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

165

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

166

Sublingual immunotherapy: World Allergy Organization position paper 2013 update.  

PubMed

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

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

2014-01-01

167

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

168

[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

169

Immunotherapy and Immune Evasion in Prostate Cancer  

PubMed Central

Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies. PMID:24216992

Thakur, Archana; Vaishampayan, Ulka; Lum, Lawrence G.

2013-01-01

170

Immunotherapy and immune evasion in prostate cancer.  

PubMed

Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies. PMID:24216992

Thakur, Archana; Vaishampayan, Ulka; Lum, Lawrence G

2013-01-01

171

Anti-TNF? domain antibody construct CEP-37247  

PubMed Central

We report preclinical data for CEP-37247, the first human framework domain antibody construct to enter the clinic. At approximately 11–13 kDa, domain antibodies or dAbs are the smallest antibody domain able to demonstrate the antigen-recognition function of an antibody, e.g., high selectivity and affinity for target antigen. CEP-37247 is a bivalent anti-tumor necrosis factor (TNF)? domain antibody protein construct combining the antigen-recognition function of a dAb with the pharmacological advantages of an antibody Fc region. As a homodimer, with each chain comprising VL dAb, truncated CH1, hinge, CH2 and CH3 domains, CEP-37247 has a molecular mass of approximately 78 kDa, which is about half the size of a conventional IgG molecule. Surface plasmon resonance data demonstrate that CEP-37247 possesses high selectivity and affinity for TNF?. CEP-37247 is a potent neutralizer of TNF? activity in vitro in the L929 TNF mediated cytotoxicity assay. In a human TNF?-overexpressing mouse model of polyarthritis, CEP-37247 prevents development of disease and is at least as effective as the marketed product etanercept. Fc functionality is intact—CEP-37247 is capable of mediating antibody-dependent cell-mediated cytotoxicity and has a circulating half-life of approximately 4.5 days in cynomolgus macaques. Given the favorable properties outlined above and its high expression levels (approaching 7 g/L) in a CHOK1 based-expression system, CEP-37247 is progressing into the clinic where other potential advantages, such as enhanced efficacy due to improved tissue distribution and beneficial immunogenicity profile, will be evaluated. PMID:20930515

Clarke, Adam W.; Elgundi, Zehra; Domagala, Teresa; Simpson, Raina J.; Le, Nga B.

2010-01-01

172

Immunotherapy for prion diseases: opportunities and obstacles.  

PubMed

Transmissible spongiform encephalopathies (TSEs) represent a unique form of infectious disease based on the misfolding of a self-protein into a pathological conformation. While other human diseases are also attributed to protein misfolding, the TSEs are unique in their zoonotic potential and iatrogenic infectivity. These characteristics are of particular importance in the aftermath of the UK bovine spongiform encephalopathy (BSE) outbreak due to the dual concerns that a subpopulation of individuals exposed to the infectious agent may be serving as asymptomatic carriers, and that TSEs of other food animals may also threaten human health. These potentials, in addition to the ongoing baseline of familial and sporadic human prion diseases, necessitate development of effective treatment options. While TSEs represent a novel paradigm of infection, there is nevertheless the opportunity to apply traditional approaches of medicine for disease treatment and prevention, including vaccines for immunotherapy and immunoprophylaxis. However, vaccine development for TSEs is complicated by the challenges and potential dangers associated with induction of immune responses to a self-epitope, as well as the obstacles to treatment of a chronic infection through immunotherapy. The ongoing threat of TSEs to human health, together with the opportunity to apply information emerging from these investigations to other protein misfolding disorders, justifies the efforts required to overcome these obstacles. PMID:20635933

Li, Li; Napper, Scott; Cashman, Neil R

2010-03-01

173

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

174

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

175

Allergen-specific immunotherapy with recombinant allergens.  

PubMed

Subcutaneous immunotherapy is a well-documented treatment of allergic rhinitis and asthma. The major limitation is the risk of anaphylactic side effects. The documentation of clinical efficacy is based on crude allergenic extracts sometimes containing varying amounts of individual allergens including allergens to which the patient may not be sensitized. The introduction of recombinant allergens offer a possibility to use well-defined molecules with consistent pharmaceutical quality defined in mass units. The proof-of-concept of the clinical efficacy of recombinant allergens is based on two studies published as full articles. One study applied a mixture of five Phleum pratense major allergens in a maximum dose of 40 ?g protein. The clinical efficacy showed a significant efficacy with about 40% reduction in disease severity. The second study compared a commercial birch extract with both recombinant Bet v 1 and purified Bet v 1 in dosages of 15 ?g allergen. The clinical effect was around 60% additional efficacy. Systemic side effects occurred more frequently with grass allergens. A third study used hypoallergenic fragments and a trimer of Bet v 1. The study did not show efficacy and a rather high frequency of systemic side effects. The advantages of using recombinant allergens for immunotherapy are obvious but more large-scale clinical studies are needed before the overall value in terms of efficacy and safety can be determined. PMID:21404096

Pauli, G; Malling, Hans-Jørgen

2011-01-01

176

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

177

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

178

An extract of Timothy-grass pollen used as sublingual immunotherapy for summer hay fever.  

PubMed

Grazax is a lyophilisate of an extract of Timothy-grass pollen (Phleum pratense) administered by the sublingual route to induce desensitization (or hyposensitization) to grass pollen in subjects with hay fever. Since allergen avoidance measures are limited in hay fever sufferers, present treatment, at least in the United Kingdom, is almost always by symptomatic medication. The effectiveness of symptomatic treatment in hay fever is variable and depends on patient compliance and the judicious prescribing of antihistamines and anti-inflammatory preparations either alone or in combination. Desensitization (hyposensitization or specific immunotherapy) by subcutaneous injection has been shown to be very efficacious and is used for patients who do not adequately respond to drug treatment. A rare side effect of desensitizing injections is anaphylaxis, and so use is limited to specialized centers. For these reasons there has been considerable interest in specific immunotherapy by the sublingual route. Grazax has recently been approved in the United Kingdom. It is commenced at least four months prior to the expected start of the grass pollen season and in line with injection immunotherapy treatment will be recommended for a period of three years with annual reviews to assess patient outcomes. Grazax grass allergen tablets are well tolerated in patients with grass pollen allergy with most adverse events being mild local reactions. There have been no instances of anaphylaxis. In randomized double-blind placebo controlled trials Grazax reduces symptoms and medication scores in adults with hay fever. The long-term effects of Grazax are currently being investigated. PMID:18174969

Kay, A B

2007-12-01

179

Immunotherapy for the management of advanced melanoma: the next steps.  

PubMed

Melanoma is an immunogenic tumor that can induce a natural immune response. A number of immunotherapy-based approaches have been developed over the past decades, and certain degrees of effectiveness were achieved by the use of cytokines, adoptive cell transfer and T-cell immune modulators. Currently, interleukin-2 and the immune stimulatory antibody, ipilimumab, are the only two approved immunotherapies for metastatic melanoma, but various new therapies are in promising developmental stages. This comprehensive review will discuss the latest achievements of immunotherapy and emerging directions for the management of advanced melanoma. PMID:23516145

Zikich, Dragoslav; Schachter, Jacob; Besser, Michal J

2013-08-01

180

Nanoparticle-Based Vaccine Delivery for Cancer Immunotherapy  

PubMed Central

Development of nano-sized carriers including nanoparticles, nanoemulsions or liposomes holds great potential for advanced delivery systems for cancer immunotherapy, as such nanostructures can be used to more effectively manipulate or deliver immunologically active components to specific target sites. Successful development of nanotechnology based platform in the field of immunotherapy will allow the application of vaccines, adjuvants and immunomodulatory drugs that improve clinical outcomes for immunological diseases. Here, we review current nanoparticle-based platforms in the efficacious delivery of vaccines in cancer immunotherapy. PMID:24198742

Park, Yeong-Min; Lee, Seung Jun; Kim, Young Seob; Lee, Moon Hee; Cha, Gil Sun

2013-01-01

181

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

182

Engineering better immunotherapies via RNA interference.  

PubMed

The therapeutic potential of dendritic cell (DC) cancer vaccines has gained momentum in recent years. However, clinical data indicate that antitumor immune responses generally fail to translate into measurable tumor regression. This has been ascribed to a variety of tolerance mechanisms, one of which is the expression of immunosuppressive factors by DCs and T cells. With respect to cancer immunotherapies, these factors antagonise the ability to induce robust and sustained immunity required for tumor cell eradication. Gene silencing of immunosuppressive factors in either DCs or adoptive transferred T cells enhanced anti-tumor immune responses and significantly inhibited tumor growth. Therefore, engineered next generation of DC vaccines or adoptive T-cell therapy should include immunomodulatory siRNAs to release the "brakes" imposed by the immune system. Moreover, the combination of gene silencing, antigen targeting to DCs and cytoplasmic cargo delivery will improve clinical benefits. PMID:25483669

Sioud, Mouldy

2014-11-01

183

Dendritic cell-based cancer immunotherapies.  

PubMed

Because of their unique role in linking the innate and adaptive immune systems, dendritic cells (DCs) have been a logical focus for novel immunotherapies. However, strategies employing active immunization with ex vivo generated and antigen-pulsed DCs have shown limited efficacy in clinical trials. These past approaches did not take into account the complex interactions between cells of the innate immune system and DCs during DC maturation, antigen processing, and presentation to naïve T cells. By better understanding the natural sequence of events occurring in vivo during an effective immune response, we can tailor antitumor immunotherapeutic strategies to augment aspects of this response from the activation of innate immune cells to antigen uptake and DC maturation to priming of naïve T cells and, ultimately, to the establishment of antitumor immunity. Current DC vaccination strategies utilize a number of methods to recapitulate the cascade of events that culminate in a protective antitumor immune response. PMID:19479202

Fujii, Shin-ichiro; Takayama, Takuya; Asakura, Miki; Aki, Kaori; Fujimoto, Koji; Shimizu, Kanako

2009-01-01

184

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

185

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

186

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

187

Immunotherapies for non-small-cell lung cancer and mesothelioma.  

PubMed

Non-small-cell lung cancer and mesothelioma are thoracic malignancies, which in their advanced stages are incurable and have poor prognosis. Advances in our understanding of immune responses to tumours, tumour immunosuppression mechanisms, and tumour-specific shared antigens enabled successful early clinical trials of several specific and non-specific immunotherapies. For non-small-cell lung cancer, phase 3 clinical trial results of Toll-like receptor agonists show little promise. However, ongoing phase 3 trials are assessing melanoma-associated antigen A3 vaccine, liposomal BLP25, belagenpumatucel-L, and talactoferrin. In mesothelioma, immunotherapies being investigated include dendritic cell-based and Listeria-based vaccines, and allogeneic tumour cell and WT1 analogue peptide vaccines. Selection of appropriate patients and disease stages for immunotherapy, measurement of tumour-specific immune responses, and understanding the association between immune and clinical responses are some of the major challenges for the development of immunotherapies for these malignancies. PMID:22748269

Thomas, Anish; Hassan, Raffit

2012-07-01

188

Bacteria and their toxins tamed for immunotherapy.  

PubMed

Bacterial toxins share the ability to enter host cells to target various intracellular proteins and to modulate host immune responses. Over the last 20 years, toxins and their mutated variants, as well as live attenuated bacteria, have been exploited for vaccination and immunotherapy of various infectious, malignant and autoimmune diseases. The ability of Bordetella pertussis adenylate cyclase toxin to translocate its adenylate cyclase domain across the host cell membrane, as well as the pathways of intracellular trafficking of Bacillus anthracis lethal and edema toxins, Shigella dysenteriae shiga toxin or Escherichia coli shiga-like toxin, have been repeatedly exploited for the delivery of antigenic epitopes into host cells and for stimulation of antigen-specific T cell responses. Similarly, E. coli ?-hemolysin, or effector proteins of Yersinia and Salmonella secreted by the type III secretion systems, were used to facilitate the delivery of fused heterologous proteins or peptides for antigenic presentation. Vibrio cholerae cholera toxin, E. coli heat-labile enterotoxin, B. pertussis pertussis toxin or the Cry1A protein of Bacillus thuringiensis have shown a great potential to act as adjuvants and to stimulate mucosal as well as systemic immune responses. The immunotherapeutic potential of some toxins, like Clostridium perfringens perfringolysin O, Streptococcus intermedius intermedilysin, or Streptococcus pneumoniae pneumolysin needs to be evaluated further. The Bordetella adenylate cyclase toxoid used as a vaccine delivery tool, or Corynebacterium diphtheriae diphtheria toxin and Pseudomonas aeruginosa exotoxin A-based immunotoxins, are currently in various phases of clinical trials for cancer immunotherapy, as are some antigen-delivering Salmonella and Listeria monocytogenes strains. PMID:22339216

Adkins, Irena; Holubova, Jana; Kosova, Martina; Sadilkova, Lenka

2012-06-01

189

Complement as effector system in cancer immunotherapy.  

PubMed

The contribution of the complement system to the control of tumour growth has been neglected for a long time as the major emphasis has been put mainly on cell-mediated immune response against cancer. With the introduction of monoclonal antibodies in cancer immunotherapy complement has come into play with a great potential as effector system. Complement has a number of advantages over other effector systems in that it is made of molecules that can easily penetrate the tumour tissue and a large majority, if not all, of the components of this system can be supplied locally by many cells at tissue site. Further advances are being made to increase the anti-tumour efficiency of the complements system using C-fixing antibodies that are modified in the Fc portion to be more active in complement activation. Another strategy currently investigated is essentially based on the use of a combination of two antibodies directed against different molecules or different epitopes of the same molecule expressed on the cell surface in order to increase the number of the binding sites for the antibodies on the tumor cells and the chance for them to activate complement more efficiently. One of the problems to solve in exploiting complement as an effector system in cancer immunotherapy is to neutralize the inhibitory effect of complement regulatory proteins which are often over-expressed on tumour cells and represent a mechanism of evasion of these cells from complement attack. This situation can be overcome using neutralizing antibodies to target onto tumour cells together with the specific antibodies directed against tumor specific antigens. This is an area of active investigation and the initial data that start to be available from animal models seem to be promising. PMID:17572509

Macor, Paolo; Tedesco, Francesco

2007-07-31

190

Specific immunotherapy-induced Sjögren’s syndrome  

Microsoft Academic Search

Background: Allergen-specific immunotherapy (SIT) is a well-documented treatment for allergic rhinitis, asthma, and allergy to bee venoms. Side-effects of SIT in long-term have not been well documented yet. Herein, we report a case of Sjögren’s syndrome following SIT. Case: The patient, a 25-year-old Caucasian woman, was started on subcutaneous grass-pollen immunotherapy. The patient’s autoantibodies before the SIT screening tests were

N. Turkcapar; G. Kinikli; S. Dizbay Sak; M. Duman

2005-01-01

191

Allergen hybrids – next generation vaccines for Fagales pollen immunotherapy  

PubMed Central

Summary Background Trees belonging to the order of Fagales show a distinct geographical distribution. While alder and birch are endemic in the temperate zones of the Northern Hemisphere, hazel, hornbeam and oak prefer a warmer climate. However, specific immunotherapy of Fagales pollen-allergic patients is mainly performed using birch pollen extracts, thus limiting the success of this intervention in birch-free areas. Objectives T cells are considered key players in the modification of an allergic immune response during specific immunotherapy (SIT), therefore we thought to combine linear T cell epitope-containing stretches of the five most important Fagales allergens from birch, hazel, alder, oak and hornbeam resulting in a Fagales pollen hybrid (FPH) molecule applicable for SIT. Methods A Fagales pollen hybrid was generated by PCR-based recombination of low IgE-binding allergen epitopes. Moreover, a structural-variant FPH4 was calculated by in silico mutagenesis, rendering the protein unable to adopt the Bet v 1-like fold. Both molecules were produced in Escherichia coli, characterized physico-chemically as well as immunologically, and tested in mouse models of allergic sensitization as well as allergy prophylaxis. Results Using spectroscopic analyses, both proteins were monomeric, and the secondary structure elements of FPH resemble the ones typical for Bet v 1-like proteins, whereas FPH4 showed increased amounts of unordered structure. Both molecules displayed reduced binding capacities of Bet v 1-specific IgE antibodies. However, in a mouse model, the proteins were able to induce high IgG titres cross-reactive with all parental allergens. Moreover, prophylactic treatment with the hybrid proteins prevented pollen extract-induced allergic lung inflammation in vivo. Conclusion The hybrid molecules showed a more efficient uptake and processing by dendritic cells resulting in a modified T cell response. The proteins had a lower IgE-binding capacity compared with the parental allergens, thus the high safety profile and increased efficacy emphasize clinical application for the treatment of Fagales multi-sensitization. PMID:24330218

Pichler, U; Hauser, M; Hofer, H; Himly, M; Hoflehner, E; Steiner, M; Mutschlechner, S; Hufnagl, K; Ebner, C; Mari, A; Briza, P; Bohle, B; Wiedermann, U; Ferreira, F; Wallner, M

2013-01-01

192

Emerging immunotherapies in older adults with acute myeloid leukemia  

PubMed Central

Purpose of review We summarize recent advances for acute myeloid leukemia (AML) in older patients, with a focus on immunotherapeutics. Although the recently updated US SEER data still show that the majority of older AML patients do not receive any therapy, this reality is slowly changing. Advances in our understanding of the biology of AML and in the field of immunology are facilitating the development of alternative therapeutic options for patients, affording more and novel opportunities for potentially curative treatment. Recent findings Data from multiple cooperative groups show that older patients benefit from the incorporation of gemtuzumab ozogamicin, an anti-CD33 mAb toxin, into induction regimens. The first prospective study for Reduced-intensity conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplantation in older AML patients was reported at ASH 2012; the approach was feasible and improved Disease-Free Survival over conventional chemotherapy. Proof-of-concept trials targeting specific antigens such as WT1 or novel unique leukemia-associated antigens are currently underway, as well as other trials using chimeric antigen receptor T cells or (Natural Killer NK/effector cells in nontransplantation settings. Summary Wider application of immunotherapies such as allogeneic hematopoietic stem cell transplantation with RIC have altered the landscape and offer potential for cure of an increasing number of older AML patients. PMID:23334192

Vasu, Sumithira; Blum, William

2014-01-01

193

Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy  

PubMed Central

Background Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. Objective We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. Methods The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. Results Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4 levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4+CD25highCD127lowCD45RO+ forkhead box protein 3 (Foxp3)+ memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. Conclusion The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells. PMID:22677046

Swamy, Ravi S.; Reshamwala, Neha; Hunter, Tessa; Vissamsetti, Soujanya; Santos, Carah B.; Baroody, Fuad M.; Hwang, Peter H.; Hoyte, Elisabeth G.; Garcia, Marco A.; Nadeau, Kari C.

2014-01-01

194

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

195

Engineering Dendritic Cells to Enhance Cancer Immunotherapy  

PubMed Central

Cancer immunotherapy aims to establish immune-mediated control of tumor growth by priming T-cell responses to target tumor-associated antigens. Three signals are required for T-cell activation: (i) presentation of cognate antigen in self MHC molecules; (ii) costimulation by membrane-bound receptor-ligand pairs; and (iii) soluble factors to direct polarization of the ensuing immune response. The ability of dendritic cells (DCs) to provide all three signals required for T-cell activation makes them an ideal cancer vaccine platform. Several strategies have been developed to enhance and control antigen presentation, costimulation, and cytokine production. In this review, we discuss progress toward developing DC-based cancer vaccines by genetic modification using RNA, DNA, and recombinant viruses. Furthermore, the ability of DC-based vaccines to activate natural killer (NK) and B-cells, and the impact of gene modification strategies on these populations is described. Clinical trials using gene-modified DCs have shown modest results, therefore, further considerations for DC manipulation to enhance their clinical efficacy are also discussed. PMID:21468005

Boudreau, Jeanette E; Bonehill, Aude; Thielemans, Kris; Wan, Yonghong

2011-01-01

196

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

197

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

198

Mitigating the toxic effects of anticancer immunotherapy.  

PubMed

Advances in our understanding of the regulatory mechanisms of the immune system have led to the development of novel approaches for cancer therapy, including inhibition of immune checkpoints with anti-CTLA-4 and anti-PD-1 antibodies. An increasing number of immunomodulatory treatments are under investigation, and are beginning to show promise in clinical trials. As more-effective therapies become available based on modulation of the immune system in order to trigger or enhance antitumour immune responses, clinicians will need to become familiar with recognizing and controlling the adverse effects arising from immune therapy. This Review describes the toxicity profiles for various anticancer therapies based on the use of agents that block immune checkpoints, immunostimulatory agents, and adoptive T-cell therapy (that is, infusion of modified autologous T cells). The management of patients receiving these treatments presents unique challenges for clinicians. Nevertheless, many of the adverse effects associated with these treatments are reversible and can be managed with supportive care either with or without cessation of therapy. This final point is extremely important given the continued development of new cancer immunotherapies, and the importance of safe and effective use of existing effective FDA-approved agents. PMID:24445516

Gangadhar, Tara C; Vonderheide, Robert H

2014-02-01

199

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

200

Immune-checkpoint blockade and active immunotherapy for glioma.  

PubMed

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

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

2013-01-01

201

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

2014-09-28

202

Statins are Associated with Reduced Use of Steroids in Inflammatory Bowel Disease: a Retrospective Cohort Study  

PubMed Central

Introduction Statin medications have anti-inflammatory effects. We sought to determine whether statin use in persons with inflammatory bowel disease (IBD) was associated with reduced rates of steroid use or other markers of disease activity. Methods We performed a retrospective cohort study using administrative data. Statin users with IBD were compared to statin-unexposed IBD subjects. The primary outcome was an oral steroid prescription; secondary outcomes included anti-TNF initiation, hospitalization, or abdominal surgery. Cox proportional hazard models were used to estimate hazard ratios (HR) adjusted for potential confounders. Results The study cohort included 1,986 statin-exposed and 9,871 unexposed subjects. Statin use was associated with an 18% reduction in the rate of steroid initiation [HR 0.82 (95% CI 0.71, 0.94)]. A statistically significant result was seen with atorvastatin only [HR 0.76 (95% CI 0.60, 0.96)]. Statins were associated with a reduced rate of steroids in ulcerative colitis [HRs 0.75 (95% CI 0.62, 0.91)], but not in Crohn’s disease [HR 0.91 (95% CI 0.74, 1.12)]. Statin use was associated with reduced hazard of anti-TNF use [HR 0.72 (95% CI 0.46, 1.11)], abdominal surgery [HR 0.80 (95% CI 0.63, 1.02)], and hospitalization [HR 0.88 (95% CI 0.74, 1.05)], but these results did not reach statistical significance. Conclusion In this large retrospective cohort study, statin use amongst persons with IBD was associated with reduced use of oral steroids, particularly for UC. Prospective clinical trials are needed to confirm whether adjuvant treatment of IBD with statin drugs may spare immunosuppressant therapy or ameliorate flares. PMID:21826766

Crockett, Seth D.; Hansen, Richard A.; Stürmer, Til; Schectman, Robin; Darter, Jane; Sandler, Robert S.; Kappelman, Michael D.

2011-01-01

203

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

204

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

205

Possible role of laser phototherapy in laser immunotherapy  

NASA Astrophysics Data System (ADS)

Laser immunotherapy is a promising cancer treatment method that induces antitumor immunity and appears to be effective both locally and systemically. In this context, an important factor is the overall state of the immune system, both locally and systemically. The success of any immunotherapy treatment depends on the balance between the local immunosuppressive forces induced by the tumor and the immune response of the host organism. Factors that influence this balance include heat-shock proteins (for example HSP70), transforming growth factor ? (TGF-?), tumor necrosis factor ? (TNF-?), interleukins, and more. Laser phototherapy, which is based on non-thermal photobiological processes, has been shown to modulate the body's own immune response, both locally and systemically, with a strong influence on for example cytokine production and heat-shock protein synthesis. Laser phototherapy may therefore be an important component in the overall efficacy of laser immunotherapy, and may tip the balance between the immunosuppressive and immunostimulatory forces in favor of immunostimulation.

Hode, Tomas; Hode, Lars

2009-02-01

206

Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy  

PubMed Central

There is much promise in the use of immunotherapy for the treatment of cancer. Approaches such as those using antibodies or adoptive cell transfer can mediate complete tumor regression in a proportion of patients. However, the tumor microenvironment can inhibit immune responses leading to ineffective or suboptimal responses of tumors to immunotherapy in the majority of cases. As our knowledge of the tumor microenvironment increases, many strategies are emerging for changing the immunosuppressive nature of the tumor toward a microenvironment able to support immunity. These strategies aim to enhance the ability of immunotherapies to initiate effective immune responses able to destroy tumors. In this article, we review approaches that use immunomodulators specifically to modify the tumor microenvironment, and their use in combination with other immune-based strategies for cancer therapy. PMID:24083084

Devaud, Christel; John, Liza B; Westwood, Jennifer A; Darcy, Phillip K; Kershaw, Michael H

2013-01-01

207

Interleukin-13 receptor alpha 2-targeted glioblastoma immunotherapy.  

PubMed

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

Sengupta, Sadhak; Thaci, Bart; Crawford, Andrew C; Sampath, Prakash

2014-01-01

208

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

209

Treatment planning for radio-immunotherapy  

NASA Astrophysics Data System (ADS)

To foster the success of clinical trials in radio-immunotherapy (RIT), one needs to determine (i) the quantity and spatial distribution of the administered radionuclide carrier in the patient over time, (ii) the absorbed dose in the tumour sites and critical organs based on this distribution and (iii) the volume of tumour mass(es) and normal organs from computerized tomography or magnetic resonance imaging and appropriately correlated with nuclear medicine imaging techniques (such as planar, single-photon emission computerized tomography or positron-emission tomography). Treatment planning for RIT has become an important tool in predicting the relative benefit of therapy based on individualized dosimetry as derived from diagnostic, pre-therapy administration of the radiolabelled antibody. This allows the investigator to pre-select those patients who have `favourable' dosimetry characteristics (high time-averaged target: non-target ratios) so that the chances for treatment success may be more accurately quantified before placing the patient at risk for treatment-related organ toxicities. The future prospects for RIT treatment planning may yield a more accurate correlation of response and critical organ toxicity with computed absorbed dose, and the compilation of dose - volume histogram information for tumour(s) and normal organ(s) such that computing tumour control probabilities and normal tissue complication probabilities becomes possible for heterogeneous distributions of the radiolabelled antibody. Additionally, radiobiological consequences of depositing absorbed doses from exponentially decaying sources must be factored into the interpretation when trying to compute the effects of standard external beam isodose display patterns combined with those associated with RIT.

Erdi, Alev K.; Erdi, Yusuf E.; Yorke, Ellen D.; Wessels, Barry W.

1996-10-01

210

Fever and the use of paracetamol during IL-2-based immunotherapy in metastatic melanoma.  

PubMed

Fever is frequently observed in conjunction with interleukin-2 (IL-2)-based immunotherapy. Traditionally, fever has been regarded as an undesirable side effect and treated with fever-lowering drugs. However, new insights in tumor immunology suggest that elevated temperature may facilitate a more effective antitumor immune response. The purpose of this retrospective study was to examine the potential role of the IL-2-induced fever in melanoma patients treated with or without paracetamol in two consecutive cohorts. One hundred and seventy-nine patients with metastatic melanoma treated with a modified decrescendo regimen of IL-2 and Interferon (IFN) between 2004 and 2010 were retrospectively studied. 87 patients treated before 2007 received paracetamol as part of the treatment schedule, and 92 patients treated after 2007 did not receive paracetamol routinely. Body temperature was analyzed as dichotomized and continuous variables and correlated to objective tumor response and overall survival using logistic regression and Cox proportional hazard analysis. Patients experiencing peak temperature of ?39.5 °C had a median OS of 15.2 months compared to 8.7 months among patients with lower temperatures (P = 0.01). In the multivariate analysis, peak temperature of ?39.5 °C (HR 0.53; P = 0.026) and high mean temperature (HR 0.56; P = 0.004) were independent prognostic factors for improved survival. We suggest high fever as a biomarker for improved survival in melanoma patients treated with IL-2/IFN. The routine use of fever-reducing drugs during immunotherapy can therefore be questioned. More studies are needed to evaluate the role of fever and the use of antipyretics during cytokine-based immunotherapy. PMID:25445814

Køstner, Anne Helene; Ellegaard, Mai-Britt Bjørklund; Christensen, Ib Jarle; Bastholt, Lars; Schmidt, Henrik

2014-12-01

211

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

212

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

213

Factors influencing the prescription of allergen immunotherapy: the allergen immunotherapy decision analysis (AIDA) study.  

PubMed

The evidence of efficacy of allergen immunotherapy (AIT) for respiratory allergy has been demonstrated by a number of meta-analyses. However, the daily practice of AIT is quite different from controlled trials, facing challenges in terms of selection of patients, practical performance, and, of particular importance, use of allergen extracts of inadequate quality. We here performed a survey, named the Allergen Immunotherapy Decision Analysis (AIDA), to evaluate which criteria are used by specialists to choose a product for sublingual immunotherapy (SLIT) in patients with respiratory allergy. A questionnaire composed of 14 items to be ranked by each participant according to the importance attributed when choosing SLIT products was submitted to 444 Italian specialists. The responses of the 169 (38.1%) physicians, who answered all questions, were analysed. Most of the respondents were allergists (79%), followed by pulmonologists (10.8%), both allergists and pulmonologists (4.8%), and otorhinolaryngologists (3%); 59.8% of the respondents were males and 40.2% were females. The age distribution showed that 89.9% of the respondents were aged between 35 and 64 years. All respondents usually prescribed AIT products in their clinical practice: 31.4% used only SLIT, whereas 69.2% used both subcutaneous and sublingual administration. The rankings, expressed as means, attributed by physicians for each of the 14 items were as follows: level of evidence-based medicine (EBM ) validation of efficacy (3.44), level of EBM validation of safety (4.30), standardization of the product (5.37), efficacy based on personal experience (5.82), defined content(s) of the major allergen(s) in micrograms (5.96), scientific evidence for each single allergen (6.17), safety based on personal experience (6.32), ease of administration protocol (8.08), cost and terms of payment (e.g. instalments) (9.17), dose personalization (9.24), patient preference (9.25), ease of product storage (9.93), reimbursement (10.12), and availability of a helpline or on-line assistance from the manufacturer (11.89). These attitudes need to be taken into consideration by regulatory agencies as well as by producers. PMID:24129083

Frati, F; Incorvaia, C; Cadario, G; Fiocchi, A; Senna, G E; Rossi, O; Romano, A; Scala, E; Romano, C; Ingrassia, A; Zambito, M; Dell'albani, I; Scurati, S; Passalacqua, G; Canonica, G W

2013-01-01

214

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

215

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

216

Cancer immunotherapy: are we there yet?  

PubMed Central

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

2013-01-01

217

Tumor stroma-associated antigens for anti-cancer immunotherapy  

Microsoft Academic Search

Immunotherapy has been widely investigated for its potential use in cancer therapy and it becomes more and more apparent that the selection of target antigens is essential for its efficacy. Indeed, limited clinical efficacy is partly due to immune evasion mechanisms of neoplastic cells, e.g. downregulation of expression or presentation of the respective antigens. Consequently, antigens contributing to tumor cell

Valeska Hofmeister; Claudia Vetter; David Schrama; Eva-B. Bröcker; Jürgen C. Becker

2006-01-01

218

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

219

Sublingual immunotherapy in allergic rhinitis: efficacy, safety, adherence and guidelines.  

PubMed

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

Aboshady, Omar Ali; Elghanam, Karim Mohamed

2014-12-01

220

Systemic and local reactions of bee venom immunotherapy in Iran.  

PubMed

Severe allergic reactions during specific immunotherapy may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during specific immunotherapy in patients with allergy towards hymenoptera venom in the Iranian population. A prospective study was performed using the clinical reports of 27 patients with anaphylaxis to bee venom (Apis melifera, Geupes vespula and Geupes Polites). Ten patients treated with Cluster protocol during 2002 and 2006 After diagnosis of hymenoptera sting allergy according to history and intradermal tests, the patient were treated with Cluster protocol immunotherapy. The protocol lasted 6 weeks with an increase in the concentration of venom from 0.01 microg/ml to 100 microg/ml. None of the patient received premedication. All patients with hymenoptera venom allergy received 120 injections. Anaphylactic reactions were classified according to the Mueller-classification. The frequencies of systemic reactions during Cluster protocol were 8.33% and 5% for yellow jacket and honey bee venom respectively. No patient experienced severe systemic reaction. Cluster protocol for hymenoptera immunotherapy is a reliable method for the treatment of anaphylactic reactions to bee venom. It is safe with low cost and do not need hospitalization. PMID:18094443

Bemanian, Mohammad Hassan; Farhoudi, Abolhassan; Pourpak, Zahra; Gharagozlou, Mohammad; Movahedi, Masoud; Nabavi, Mohammad; Mozafari, Habibeh; Mohammadzadeh, Iraj; Chavoshzadeh, Zahra; Shirkhoda, Zahra

2007-12-01

221

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

222

Preseasonal intranasal immunotherapy in birch-alder allergic rhinitis. A double-blind study.  

PubMed

A double-blind, placebo-controlled study was carried out to test the clinical efficacy and safety of local nasal immunotherapy (LNIT) in powder form. Twenty-two patients suffering from allergic rhinitis strictly associated with early spring symptoms, with positive skin prick tests and RAST for birch-alder, all responders to a specific nasal provocation test (NPT), received randomly active or placebo treatment for 4 months. Immunotherapy consisted of administration of a set of capsules containing progressively increasing amounts of birch (Betula pendula) and speckled alder (Alnus incana) allergens in powder form with controlled granulometry. The active (birch-alder) and placebo (lactose) group completed the treatment according to a similar schedule. During the pollen season (March-April), the patients who took the active treatment reported less sneezing and rhinorrhea than the placebo group, on the basis of a symptoms score, and the differences were statistically significant; the need for drugs (terfenadine) was also significantly reduced. These findings agreed well with the results of specific NPT after the treatment; only patients in the active group had a higher threshold dose of nasal specific reactivity to birch-alder allergens than in tests before the LNIT. PMID:8836333

Cirla, A M; Sforza, N; Roffi, G P; Alessandrini, A; Stanizzi, R; Dorigo, N; Sala, E; Della Torre, F

1996-05-01

223

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

224

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

PubMed Central

Asthma and rhinitis are often co-morbid conditions. As rhinitis often precedes asthma it is possible that effective treatment of allergic rhinitis may reduce asthma progression. The aim of our study is to investigate history of allergic rhinitis as a risk factor for asthma and the potential effect of allergen immunotherapy in attenuating the incidence of asthma. Hospital-referred non-asthmatic adults, aged 18–40 years between 1990 and 1991, were retrospectively followed up until January and April 2000. At the end of follow up, available subjects were clinically examined for asthma diagnosis and history of allergen specific immunotherapy, second-hand smoking and the presence of pets in the household. A total of 436 non-asthmatic adults (332 subjects with allergic rhinitis and 104 with no allergic rhinitis nor history of atopy) were available for final analyses. The highest OR (odds ratio) associated with a diagnosis of asthma at the end of follow-up was for the diagnosis of allergic rhinitis at baseline (OR, 7.8; 95%CI, 3.1–20.0 in the model containing the covariates of rhinitis diagnosis, sex, second-hand smoke exposure, presence of pets at home, family history of allergic disorders, sensitization to Parietaria judaica; grass pollen; house dust mites; Olea europea: orchard; perennial rye; and cat allergens). Female sex, sensitization to Parietaria judaica and the presence of pets in the home were also significantly predictive of new onset asthma in the same model. Treatment with allergen immunotherapy was significantly and inversely related to the development of new onset asthma (OR, 0.53; 95%CI, 0.32–0.86). In the present study we found that allergic rhinitis is an important independent risk factor for asthma. Moreover, treatment with allergen immunotherapy lowers the risk of the development of new asthma cases in adults with allergic rhinitis. PMID:16381607

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

2005-01-01

225

Systems biology applied to vaccine and immunotherapy development  

PubMed Central

Immunotherapies, including vaccines, represent a potent tool to prevent or contain disease with high morbidity or mortality such as infections and cancer. However, despite their widespread use, we still have a limited understanding of the mechanisms underlying the induction of protective immune responses. Immunity is made of a multifaceted set of integrated responses involving a dynamic interaction of thousands of molecules; among those is a growing appreciation for the role the innate immunity (i.e. pathogen recognition receptors - PRRs) plays in determining the nature and duration (immune memory) of adaptive T and B cell immunity. The complex network of interactions between immune manipulation of the host (immunotherapy) on one side and innate and adaptive responses on the other might be fully understood only employing the global level of investigation provided by systems biology. In this framework, the advancement of high-throughput technologies, together with the extensive identification of new genes, proteins and other biomolecules in the "omics" era, facilitate large-scale biological measurements. Moreover, recent development of new computational tools enables the comprehensive and quantitative analysis of the interactions between all of the components of immunity over time. Here, we review recent progress in using systems biology to study and evaluate immunotherapy and vaccine strategies for infectious and neoplastic diseases. Multi-parametric data provide novel and often unsuspected mechanistic insights while enabling the identification of common immune signatures relevant to human investigation such as the prediction of immune responsiveness that could lead to the improvement of the design of future immunotherapy trials. Thus, the paradigm switch from "empirical" to "knowledge-based" conduct of medicine and immunotherapy in particular, leading to patient-tailored treatment. PMID:21933421

2011-01-01

226

[Hymenoptera venom allergy. Analysis of double sensitization to wasp and bee venom in own material--diagnosis and classification for immunotherapy].  

PubMed

According to scientific societies guidelines the indication for venom immunotherapy is based on the clinical history of the patient. Diagnostic tests, like skin prick test or specific IgE serum estimation are conduct to prove IgE dependent mechanism of allergy and insect identification. Recent guidelines indicates for group of patients with severe systemic reactions as a candidates for diagnostic testing and in consequence for immunotherapy. In some countries diagnostic tests are also performed in patient who have a history of large local reactions, if they are considered as a candidates for immunotherapy. Double sensitization in cases of patients unable to identify the culprit insect is a diagnostic and therapeutic problem. In our group of patients (n = 113) we confirmed the double sensitization in 30% cases. The addition of a major allergen labeling reduced the number of people actually double-sensitized to 8.84%. It was observed that in patients who are not able to identify insect double sensitization phenomenon is particularly frequent as much as 45.5% and in the determination of the major allergens in 18.2%. Such patients needed detailed diagnosis and in many cases the use of two vaccines to conduct immunotherapy. PMID:24720122

Stobiecki, Marcin; Dyga, Wojciech; Czarnobilska, Ewa

2013-01-01

227

Job Description: Research Associate I for Cancer Immunotherapy Lab The Tumor Immunology Laboratory in the Animal Cancer Center (ACC) is seeking a Research  

E-print Network

Job Description: Research Associate I for Cancer Immunotherapy Lab The Tumor Immunology Laboratory in tumor immunology and immunotherapy. The studies will involve investigations of tumor immunotherapy training and expertise in immunological assays and methodologies. Particular preference will be given

Birner, Thomas

228

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

229

Immunotherapy of acute radiation syndromes with antiradiation gamma G globulin.  

NASA Astrophysics Data System (ADS)

Introduction: If an immunotherapy treatment approach to treatment of acute radiation syndromes (ARS) were to be developed; consideration could be given to neutralization of radiation toxins (Specific Radiation Determinants- SRD) by specific antiradiation antibodies. To accomplish this objective, irradiated animals were injected with a preparation of antiradiation immunoglobulin G (IgG) obtained from hyperimmune donors. Radiation-indeced toxins that we call Specific Radiation Determinants (SRD) possess toxic (neurotoxic, haemotoxic and enterotoxic) characteristics as well as specific antigenic properties that combined with the direct physiochemical direct radiation damage, induce the development of many of the pathological processes associated with ARS. We tested several specific hyperimmune IgG preparations against these radiation toxins and observed that their toxic properties were neutralized by specific antiradiation IgGs. Material and Methods: Rabbits were inoculated with SRD radiation toxins to induce hyperimmune serum. The hyperimmune serum was pooled from several animals, purified, and concentrated. Enzyme-linked immunosorbent assays of the hyperimmune serum revealed high titers of IgG with specific binding to radiation toxins. The antiradiation IgG preparation was injected into laboratory animals one hour before and three hours after irradiation, and was evaluated for its ability to protect inoculated animals against the development of acute radiation syndromes. Results: Animals that were inoculated with specific antiradiation antibodies before receiving lethal irradiation at LD 100/30 exhibited 60-75% survival rate at 30 days, whereas all control animals expired by 30 days following exposure. These inoculated animals also exhibited markedly reduced clinical symptoms of ARS, even those that did not survive irradiation. Discussion: The results of our experiments demonstrate that rabbit hyperimmune serum directed against SRD toxins afford significant, albeit incomplete, protection against high doses of radiation. In comparison, the mortality rate of irradiated control animals was 100% in the same time period. The mortality rates of hyperimmune serum-treated animals varied in different groups of animals and different forms of ARS; however, significant radioprotection was observed in each group treated with IgGs activated against specific radiation toxins.

Popov, Dmitri; Maliev, Vecheslav; Casey, Rachael; Jones, Jeffrey; Kedar, Prasad

230

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

231

Molecular imaging of cell-based cancer immunotherapy  

PubMed Central

Cell-based cancer immunotherapy represents a new and powerful weapon in the arsenal of anticancer treatments. Non-invasive monitoring of the disposition, migration and destination of therapeutic cells will facilitate the development of cell based therapy. The therapeutic cells can be modified intrinsically by a reporter gene or labeled extrinsically by introducing imaging probes into the cells or on the cell surface before transplant. Various advanced non-invasive molecular imaging techniques are playing important roles in optimizing cellular therapy by tracking cells and monitoring the therapeutic effects of transplanted cells in vivo. This review will summarize the application of multiple molecular imaging modalities in cell-based cancer immunotherapy. PMID:21308113

Liu, Gang; Swierczewska, Magdalena; Zhang, Xiaoming

2011-01-01

232

Novel approaches and mechanisms of immunotherapy for glioblastoma.  

PubMed

Glioblastoma (GBM) is the most aggressive primary brain tumor. Combination therapy with surgery, radiation, and chemotherapy is not curative at present and carries a significant risk of toxicity. Advancements in the knowledge of tumor biology and tumor microenvironment have led to the development of novel targeted therapies for glioblastoma. In the past 15 years, a vast amount of pre-clinical data has been generated for glioblastoma immunotherapy. Translating these promising results into the clinic is, however, still an evolving process. Early clinical trials have demonstrated the feasibility and safety of several such approaches in patients with recurrent as well as newly diagnosed glioblastoma. Both passive as well as active immunotherapeutic modalities have also shown potential clinical benefit in at least a subset of these patients. This brief review discusses 'why' and 'how' various types of immunotherapies are being employed to treat glioblastoma. PMID:24641957

Hegde, Meenakshi; Bielamowicz, Kevin J; Ahmed, Nabil

2014-03-01

233

Current role of immunotherapy for the treatment of prostate cancer.  

PubMed

Chemotherapy is the conventional treatment for castration-resistant prostate cancer (CRPC) which provides only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer. Several characteristics of prostate cancer make it an ideal target for immunotherapy, and FDA approved recently sipuleucel-T based on improvement in overall survival (OS) in patients with CRPC. Current trials investigate the role of various immunological approaches in the treatment of prostate cancer, as far as the clinical benefit they provide is concerned and also deal with the issue of the measurability of this benefit. Future studies will focus on the combination of immunotherapeutic agents with conventional treatments in an effort to optimize patient outcomes. PMID:24344002

Porfyris, O; Kalomoiris, P

2013-01-01

234

Monitoring Regulatory Immune Responses in Tumor Immunotherapy Clinical Trials  

PubMed Central

While immune monitoring of tumor immunotherapy often focuses on the generation of productive Th1-type inflammatory immune responses, the importance of regulatory immune responses is often overlooked, despite the well-documented effects of regulatory immune responses in suppressing anti-tumor immunity. In a variety of malignancies, the frequency of regulatory cell populations has been shown to correlate with disease progression and a poor prognosis, further emphasizing the importance of characterizing the effects of immunotherapy on these populations. This review focuses on the role of suppressive immune populations (regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) in inhibiting anti-tumor immunity, how these populations have been used in the immune monitoring of clinical trials, the prognostic value of these responses, and how the monitoring of these regulatory responses can be improved in the future. PMID:23653893

Olson, Brian M.; McNeel, Douglas G.

2013-01-01

235

Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms  

PubMed Central

The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles. PMID:22778766

Sapoznik, Sivan; Hammer, Ohad; Ortenberg, Rona; Besser, Michal J.; Ben-Moshe, Tehila; Schachter, Jacob; Markel, Gal

2012-01-01

236

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

237

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

238

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

239

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

240

Is Sublingual Immunotherapy the Final Answer? Implications for the Allergist  

PubMed Central

Sublingual immunotherapy (SLIT) is now accepted as a viable alternative to the traditional injection route based on more than 40 clinical trials and several meta-analyses of efficacy. In addition, the safety profile is very favorable, also in younger children. Although some aspects need to be further clarified (eg, optimal doses, patient selection, and mechanisms of action), SLIT can be currently regarded as an additional therapeutic option that allergists have available. The main distinctive feature of SLIT is certainly its tolerability, safety, and convenience for the patient. Nonetheless, as happens with injection immunotherapy, it is mandatory that the prescription of SLIT is made by a trained specialist, and that a detailed diagnosis is made before prescribing it. PMID:23283394

2008-01-01

241

Immunotherapy with B cell epitopes ameliorates inflammatory responses in Balb/c mice.  

PubMed

Osmotin, a protein from the pathogenesis-related family (PR-5), has been identified as an allergen based on in-silico and in-vitro studies. In the present study, three B cell epitopes of osmotin with single and double amino acid modifications were studied for immunotherapy in a murine model. The single-modification peptides (P-1-1, P-2-1 and P-3-1) and double-modification peptides (P-1-2, P-2-2 and P-3-2) showed significantly lower immunoglobulin (Ig)E binding with patients' sera compared to osmotin (P < 0·01). These peptides showed reduced IgE binding compared to the unmodified peptides (B cell epitopes) P-1, P-2 and P-3. Among the modified peptides, P-2-1, P-3-1, P-2-2 and P-3-2 showed significant reduction in IgE binding and were used for immunotherapy in mice. The sera of mice group treated with peptides showed a significant increase in IgG2a level and a significant decrease in IgE and IgG1 levels (P < 0·05). The mice that received peptide immunotherapy showed a shift from a T helper type 2 (Th2) to Th1 type where interferon (IFN)-? and interleukin (IL)-10 levels were elevated, with a significant increase in groups treated with peptides P-3-1 and P-3-2 (P < 0·05). There was a reduction in the IL-4 and IL-5 levels in bronchoalveolar lavage fluid (BALF) in the peptide-treated mice groups. Total cell count and eosinophil count in BALF of the peptide-treated groups was also reduced compared to the phosphate-buffered saline (PBS)-treated group. Lung histology showed a significant reduction in cellular infiltrate in mice treated with P-2-2 and P-3-2 compared to PBS. In conclusion, peptides P-2-2 and P-3-2 lowered inflammatory responses and induced a Th1 response in mice. PMID:25142552

Sharma, P; Gaur, S N; Arora, N

2015-01-01

242

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  

PubMed Central

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, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. Results After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse A? immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. Conclusions The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage. PMID:15588287

Wilcock, Donna M; Rojiani, Amyn; Rosenthal, Arnon; Subbarao, Sangeetha; Freeman, Melissa J; Gordon, Marcia N; Morgan, Dave

2004-01-01

243

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

PubMed

BACKGROUND: Anti-Abeta 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-Abeta antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Abeta antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Abeta immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage. PMID:15588287

Wilcock, Donna M; Rojiani, Amyn; Rosenthal, Arnon; Subbarao, Sangeetha; Freeman, Melissa J; Gordon, Marcia N; Morgan, Dave

2004-12-01

244

Bacillary prostatitis after intravesical immunotherapy: a rare adverse effect.  

PubMed

Nowadays, the most efficient form of intravesical immunotherapy for superficial transitional cell carcinoma of the urinary bladder is the instillation of bacillus Calmette-Guérin (BCG), proceeding from an attenuated strain of Mycobacterium bovis. In up to 40% of cases, its instillation is associated with significantly elevated prostate-specific antigen (PSA) levels. In these cases, prostate biopsy should be withheld for 3 months and PSA should be monitored. Bacillary prostatitis is a rare occurrence in patients treated with intravesical BCG immunotherapy. Although symptomatic bacillary prostatitis is even rarer, it is the worst type of this condition. The aims of this study are to report a case of bacillary prostatitis as a rare adverse effect of intravesical BCG immunotherapy and to make a theoretical review about how to manage this complication. A 58-year-old man, former smoker, underwent a transurethral resection of the bladder in February 2004 because of a papillary transitional cell carcinoma of the bladder (pT1G2N0M0). After surgery, BCG instillation therapy was given in a total of 15 instillations, the last one in March 2007. In the last 3 months of therapy, until May 2007, a progressive increase in his PSA level was registered, and he underwent a prostate biopsy revealing granulomatous prostatitis of bacillary etiology. The semen culture was positive for M. bovis. After 3 months of a two-drug (isoniazid and rifampin) antituberculous regimen, the semen culture became negative and the PSA level decreased. The early identification of intravesical BCG immunotherapy complications allows their effective treatment. However, when a histological diagnosis of asymptomatic granulomatous prostatitis is made, the execution and type of treatment are controversial. PMID:22539919

Joaquim, Ana; Custódio, Sandra; Pimentel, Francisco Luís; Matos, José Fidalgo; Peixoto, Vânia; Faria, Ana Luísa; Macedo, Joana Espiga; Macias, Emílio; Rego, Sónia; Araújo, António

2012-01-01

245

Adoptive T-cell transfer in cancer immunotherapy  

Microsoft Academic Search

Adoptive T-cell therapy has definite clinical benefit in relapsed leukaemia after allogeneic transplant and in Epstein–Barr virus-associated post-transplant lymphoproliferative disease. However, the majority of tumour targets are weakly immunogenic self-antigens and success has been limited in part by inadequate persistence and expansion of transferred T cells and by tumour-evasion strategies. Adoptive immunotherapy presents the opportunity to activate, expand and genetically

Siok-Keen Tey; Catherine M Bollard; Helen E Heslop

2006-01-01

246

Cancer Immunotherapy and Aging: Lessons From the Mouse  

Microsoft Academic Search

Cancer is a disease of the elderly. Since demographic trends indicate that over the next decades the number of elderly people\\u000a will increase substantially, strategies for cancer prevention and therapy need to be optimized to older patients. Immunotherapy,\\u000a either through passive or active immunization is a highly targeted type of therapy that is potentially less toxic than chemotherapy\\u000a or radiation

Claudia Gravekamp

247

Peptide-Mediated Immune Responses in Specific Immunotherapy  

Microsoft Academic Search

Conventional immunotherapy using whole allergen extracts has been shown to be an effective, disease-modifying treatment in carefully selected patients with allergic conjunctivo-rhinitis, asthma and bee and wasp venom hypersensitivity. However, this form of therapy is associated with the risk of systemic anaphylaxis, which, when severe, can be life threatening. A potentially significant reduction in the incidence of IgE-mediated events during

Brigitte M. Haselden; A. Barry Kay; Mark Larché

2000-01-01

248

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

249

Mechanistic Basis of Immunotherapies for Type 1 Diabetes Mellitus  

PubMed Central

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. In order 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

2013-01-01

250

Keyhole limpet hemocyanin immunotherapy of murine bladder cancer  

Microsoft Academic Search

The current treatment of choice for superficial bladder cancer, bacillus Calmette-Guérin, has significant adverse side effects. We have compared two alternative immunotherapies—crude keyhole limpet hemocyanin (KLH) and Immucothel, a KLH modified for clinical use (Biosyn)-in an intralesional mouse model of bladder cancer (MBT2). Crude KLH required either immunization before tumor transplant or frequent intralesional therapy after transplantation to be effective.

Donald L. Lamm; Jean I. DeHaven; Dale R. Riggs; Catalina Delgra; Robert Burrell

1993-01-01

251

New trends in immunotherapy to prevent atopic diseases  

Microsoft Academic Search

Advances in the understanding of the molecular and cellular immunological mechanism of atopy have led to the development of new therapies for allergic diseases. However, only a few new drugs have reached the clinic and none provides long-term immunomodulatory effects. Immunotherapy, through its capacity to produce a long-term, antigen-specific, protective immune response, is the only aetiologic treatment that offers the

Christoph Walker; Claudia Zuany-Amorim

2001-01-01

252

Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome.  

PubMed

Non-small cell lung cancer (NSCLC) is found worldwide with high incidence and poor prognoses. Nowadays, insights in the interaction between tumors and immune system have led to the development of immunotherapy as a fundamentally new concept for the treatment of NSCLC. Adoptive cell transfer represents an important advancement in cancer immunotherapy such as cytokine-induced killer and ?? T-cells. Recent clinical research studies provide evidence for the positive effects of adoptive immunotherapy, which is probably associated with levels of cytokines, cell doses, and immune microenvironment. This review summarizes the current condition of adoptive immunotherapy in NSCLC and the long-standing confusion in this field. PMID:23477587

Zheng, Ya-Wen; Li, Run-Mei; Zhang, Xin-Wei; Ren, Xiu-Bao

2013-03-01

253

Combination treatment with comprehensive cryoablation and immunotherapy in metastatic hepatocellular cancer  

PubMed Central

AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intra- and extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immunotherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryo-immunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy. PMID:23801841

Niu, Li-Zhi; Li, Jia-Liang; Zeng, Jian-Ying; Mu, Feng; Liao, Meng-Tian; Yao, Fei; Li, Li; Liu, Chun-Yan; Chen, Ji-Bing; Zuo, Jian-Sheng; Xu, Ke-Cheng

2013-01-01

254

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

255

Immunotherapy for prostate cancer: recent developments and future challenges.  

PubMed

Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug development in this area has focused primarily on antigen-specific (i.e. cancer vaccines and antibody based therapies) or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved in advanced melanoma and two phase III trials evaluating ipilimumab in men with metastatic castrate-resistant prostate cancer are underway. A phase III trial evaluating ProstVac-VF, a poxvirus-based therapeutic prostate cancer vaccine, is also underway. While there has been reason for encouragement over the past few years, many questions regarding the use of immunotherapies remain. Namely, it is unclear what stage of disease is most likely to benefit from these approaches, how best to incorporate said treatments with each other and into our current treatment regimens and which therapy is most appropriate for which disease. Herein we review some of the recent advances in immunotherapy as related to the treatment of prostate cancer and outline some of the challenges that lie ahead. PMID:24477411

Schweizer, Michael T; Drake, Charles G

2014-09-01

256

Immunotherapy for brain cancer: recent progress and future promise.  

PubMed

Immunotherapy is emerging as the newest pillar of cancer treatment, with the potential to assume a place alongside surgical debulking, radiotherapy, and chemotherapy. Early experiences with antitumor vaccines demonstrated the feasibility and potential efficacy of this approach, and newer agents, such as immune checkpoint blocking antibodies and modern vaccine platforms, have ushered in a new era. These efforts are headlined by work in melanoma, prostate cancer, and renal cell carcinoma; however, substantial progress has been achieved in a variety of other cancers, including high-grade gliomas. A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiotherapy and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also use an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas, and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology. PMID:24771646

Jackson, Christopher M; Lim, Michael; Drake, Charles G

2014-07-15

257

The Immune Response to Tumors as a Tool toward Immunotherapy  

PubMed Central

Until recently cancer medical therapy was limited to chemotherapy that could not differentiate cancer cells from normal cells. More recently with the remarkable mushroom of immunology, newer tools became available, resulting in the novel possibility to attack cancer with the specificity of the immune system. Herein we will review some of the recent achievement of immunotherapy in such aggressive cancers as melanoma, prostatic cancer, colorectal carcinoma, and hematologic malignancies. Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs) derived from tumor infiltrating lymphocytes (TILs). The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes. PMID:22190975

Pandolfi, F.; Cianci, R.; Pagliari, D.; Casciano, F.; Bagalà, C.; Astone, A.; Landolfi, R.; Barone, C.

2011-01-01

258

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

259

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

260

Specific immunotherapy by the sublingual route for respiratory allergy  

PubMed Central

Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes. PMID:21062481

2010-01-01

261

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

262

Peptide immunotherapies in Type 1 diabetes: lessons from animal models.  

PubMed

Insulin dependent diabetes mellitus (Type 1 diabetes, T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells by proinflammatory autoreactive T cells. In the past, several therapeutic approaches have been exploited by immunologists aiming to regulate the autoimmune response; this can occur by deleting lymphocyte subsets and/or re-establishing immune tolerance via activation of regulatory T cells. The use of broad immunosuppressive drugs was the first approach to be explored. Subsequently, antibody-based immunotherapies failed to discriminate between autoreactive versus non-autoimmune effectors. Antigen-based immunotherapy is a third approach developed to manipulate beta cell autoimmunity. This approach allows the selective targeting of disease-relevant T cells, while leaving the remainder of the immune system intact. Animal models have been successfully employed to prevent or treat T1D by injection of either the self proteins or peptides derived from them. Peptide immunotherapies have been mainly experimented in the NOD mouse spontaneous model of disease. In this review we therefore report the main approaches that rely on the use of peptides obtained from relevant autoantigens such as glutamic acid decarboxylase, isoform 65 (GAD65), insulin, proinsulin and islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP). Protective peptides have proven to be effective in treating or delaying the diabetic process. We also highlight the main difficulties encountered in extrapolating data to guide clinical translational investigations in humans. PMID:21143110

Fierabracci, A

2011-01-01

263

IgE-based immunotherapy of cancer: challenges and chances.  

PubMed

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

2014-02-01

264

Effect of Pollen-Specific Sublingual Immunotherapy on Oral Allergy Syndrome: An Observational Study  

PubMed Central

Background Oral allergy syndrome (OAS) triggered by fruit and vegetables often occurs in patients with pollen-induced rhinoconjunctivitis because of cross-reactive epitopes in pollen and associated foods. This open observational study examined the effect of pollen-specific sublingual immunotherapy ([SLIT] B. U. Pangramin or SLITone involving birch/alder/hazel, grasses/rye, and/or mugwort) on OAS triggered by several foods in patients treated in standard practice. Very few studies have examined SLIT use in this situation. Methods Patients (n = 102) had pollen-induced rhinoconjunctivitis and OAS and were followed for up to 12 months. Baseline OAS (triggers, symptoms, and symptom severity) was assessed by questionnaire and patient history. Change in OAS was assessed using oral challenge test with 1 or 2 dominant food triggers (and compared with the sum score calculated from the OAS questionnaire at baseline) and clinician ratings of change. Pollen-induced rhinoconjunctivitis symptoms and medication use were also measured. Results In the oral challenge test, 77.0% of patients were considered responders (decrease in sum score of ? 50%; no difference in patients receiving B. U. Pangramin or SLITone). At baseline, investigators rated OAS severity as at least moderate in 94.9% of patients compared with 36.9% after 12 months of treatment. After 12 months, OAS was rated as much or very much improved in 72.9% of patients. Sublingual immunotherapy significantly reduced rhinoconjunctivitis symptoms and medication use. Only 10% of patients experienced adverse drug reactions. Conclusion This study supplements the sparse literature on this topic and suggests that pollen-specific SLIT can reduce OAS triggered by pollen-associated foods in patients with pollen-induced rhinoconjunctivitis. PMID:23282323

2008-01-01

265

Advances in upper airway diseases and allergen immunotherapy.  

PubMed

The purpose of this review is to highlight important articles on upper airway disease and immunotherapy that appeared in the Journal of Allergy and Clinical Immunology and elsewhere during 2005. In recent studies of tissue from patients with chronic hypertrophic eosinophilic sinusitis, increased leukotriene C4 synthase and 5-lipoxygenase activity and increased levels of cysteinyl leukotriene production were demonstrated that correlated with disease severity but not with whether the patient was aspirin sensitive. However, the cysteinyl leukotriene 1 receptor was increased in leukocytes in the sinus tissue only in those patients with aspirin sensitivity. Major basic protein, released by eosinophils into the mucus in the paranasal sinus lumen, was found to reach concentrations capable of damaging the sinus epithelium, predisposing to bacterial infections. Testing the hypothesis that chronic hypertrophic eosinophilic sinusitis represents a reaction to common fungi, a double-blind trial of intranasal instillation of amphotericin B was conducted. There were marginal but significant differences in favor of amphotericin B treatment for sinus mucosal thickening on the basis of computed tomography and the evidence of eosinophilic inflammation in the sinus mucus. The effectiveness of topical nasal corticosteroids for treatment of nasal polyps was confirmed in 2 large studies. Improvement in sleep quality and daytime drowsiness in patients with allergic rhinitis treated with nasal corticosteroids was reported to correlate with reduction in nasal obstruction. The statistical analysis behind studies that reported a decrease in asthma exacerbations with nasal corticosteroids or oral antihistamines has been questioned. It appears that the results of at least one of these studies are indeed too good to be true. Although caution is still indicated in administering immunotherapy to patients receiving beta-adrenergic blocking agents, the prohibition might not be absolute. A study in patients with Hymenoptera sensitivity given venom immunotherapy revealed no increase in serious adverse reactions to venom injections and no greater incidence of reactions to insect stings in those taking beta-blocking agents. Sublingual immunotherapy for 8 to 12 weeks in patients with hazelnut sensitivity significantly increased their tolerance to hazelnut in double-blind, placebo-controlled challenges while inducing increased IgG4 and IL-10 levels, indicating induction of regulatory T cells. There were a number of articles in the Journal of Allergy and Clinical Immunology in 2005 that addressed the entity of chronic hypertrophic eosinophilic sinusitis. In addition, an update of the "Practice parameters on sinusitis" was published. The major focus in allergen immunotherapy continues to be sublingual administration. PMID:16675331

Nelson, Harold S

2006-05-01

266

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

267

Venom immunotherapy for stinging insect allergy  

Microsoft Academic Search

Generalized reactions to insect stings were recognized as hypersensitivity phenomena in the early part of this century. 1 Attempts at reducing human hypersensitivity with specific immunologic treatment were reported in the 1920s and 1930s. 2-4 In part because Benson 4 concluded that \\

David F. Graft

1987-01-01

268

New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer's Disease  

PubMed Central

There are an estimated 18 million Alzheimer's disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterized by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterized by deposits of amyloid beta (A?), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against A? leads to the clearance of deposits in transgenic mice expressing human A?. This clearance is associated with reversal of associated cognitive deficits, but these results have not translated to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-A? antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (Fc?R) are a family of immunoglobulin-like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking Fc?R by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that Fc?R expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. Therefore, we propose that increased expression and ligation of Fc?R in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of Fc?R in the healthy and diseased brain. Here we review the literature on Fc?R expression, function and proposed roles in multiple age-related neurological diseases. Lessons can be learnt from therapeutic antibodies used for the treatment of cancer where antibodies have been engineered for optimal efficacy. PMID:25191216

Fuller, James P.; Stavenhagen, Jeffrey B.; Teeling, Jessica L.

2014-01-01

269

X:\\Original Source Version\\Informed Consent to Receive Allergy Immunotherapy.doc 08/2010 Patient Name: _______________________________________ Date: _____________________  

E-print Network

X:\\Original Source Version\\Informed Consent to Receive Allergy Immunotherapy.doc 08/2010 Patient: ______________________________________________ MR#: _____________________ Duke Student Health Allergy Clinic (DSHAC) Informed Consent to Receive Allergy Immunotherapy I request to receive my allergy immunotherapy at the Duke Student Health Allergy

270

The value of an in-hospital insect sting challenge as a criterion for application or omission of venom immunotherapy  

Microsoft Academic Search

Background: Venom immunotherapy is a generally accepted treatment for serious allergy to bee and yellow jacket venom. However, it is not precisely known to whom venom immunotherapy should be offered. Objective: The purpose of this study was to determine whether an in-hospital insect sting challenge (IHC) can be used as a criterion for application or omission of venom immunotherapy. Methods:

Pieter J. Blaauw; Otto L. M. J. Smithuis; Armin R. W. Elbers

1996-01-01

271

Malignancy and Specific Allergen Immunotherapy: The Results of a Case Series  

Microsoft Academic Search

Background: Specific immunotherapy with allergen is the only causative treatment for IgE-mediated allergies such as stinging insect allergy or hay fever and works by the induction of blocking antibodies and regulatory T lymphocytes. Objective: Does a hypothetical obstruction of tumor surveillance presupposing the induction of regulatory T cells really justify detaining immunotherapy to oncologic patients as suggested by recent guidelines?

Stefan Wöhrl; Tamar Kinaciyan; Ahmad Jalili; Georg Stingl; Katharina B. Moritz

2011-01-01

272

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

273

Inmunoterapias para las adicciones a las drogas Immunotherapies for Drug Addictions  

Microsoft Academic Search

Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful

Iván D. Montoya

274

Rush Hymenoptera venom immunotherapy: A safe and practical protocol for high-risk patients  

Microsoft Academic Search

Background: Hymenoptera venom immunotherapy in allergic patients is a well-established treatment modality for the prevention of systemic anaphylactic reactions caused by insect stings. A variety of therapy regimens exists, from conventional to rush and ultrarush modalities that operate on continuous or intermittent schedules. Objective: The aim of this study was to report the 8-year experience with our rush venom immunotherapy

Gunter Sturm; Birger Kränke; Christina Rudolph; Werner Aberer

2002-01-01

275

Severe Anaphylaxis to Bee Venom Immunotherapy: Effi cacy of Pretreatment and Concurrent Treatment With Omalizumab  

Microsoft Academic Search

? Abstract Immunotherapy is an established mode of treatment for Hymenoptera venom anaphylaxis, although adverse reactions may occur. We report the case of a 33-year-old woman, the wife of a beekeeper, who experienced a systemic allergic reaction following a bee sting. Initial specifi c immunotherapy had to be stopped due to anaphylaxis (multiple immediate cardiovascular reactions). We looked for an

C Galera; N Soohun; N Zankar; S Caimmi; C Gallen; P Demoly

276

Early predictive value of multifunctional skin-infiltrating lymphocytes in anticancer immunotherapy  

PubMed Central

Bioassays that predict clinical outcome are essential to optimize cellular anticancer immunotherapy. We have recently developed a robust and simple skin test to evaluate the capacity of tumor-specific T cells to migrate, recognize their targets and exert effector functions. This bioassay detects T cells with an elevated antineoplastic potential and hence rapidly identifies patients responding to immunotherapy. PMID:24653961

Wimmers, Florian; Aarntzen, Erik HJG; Schreibelt, Gerty; Jacobs, Joannes FM; JA Punt, Cornelis; Figdor, Carl G; de Vries, I Jolanda M

2014-01-01

277

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 cancer patients, 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 co-injected 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, Mike J; Miles, Kiersten Marie; Celander, Mona; Adelaiye, Remi; Orillion, Ashley; Ciamporcero, Eric; Ramakrishnan, Swathi; Ellis, Leigh; Fenstermaker, Robert A; Abrams, Scott I; Eriksson, Helena; Leanderson, Tomas; Olson, Anders; Pili, Roberto

2014-11-01

278

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

279

[Current status and prospects of immunotherapy for castration-resistant prostate cancer].  

PubMed

Surgery, radiation and chemotherapy are three major therapies for cancer. But now, hope is being gathered in immunotherapy as a treatment for fourth. Immunotherapy has been done than before, but they are non-specific immunotherapy. Those that have become hot topics are specific immunotherapies targeting certain molecules or antigens. In this chapter, current status and prospects of immunotherapy for castration-resistant prostate cancer (CRPC) are described. As concrete examples, Sipuleucel-T(Provenge), GVAX, PROSTVAC-VF, Ipilimumab (anti-CTLA-4 mAb), anti-PD-1 mAb and anti-PSMA mAb are cited. As a result, it is not obtained results which therapy also satisfactory at present. Because of its uncertainties we are in the developmental stages of this therapy and improved outcomes might be achievable. PMID:25518354

Yatsuda, Junji; Eto, Masatoshi

2014-12-01

280

Vitiligo in patients with melanoma: normal tissue antigens can be targets for cancer immunotherapy.  

PubMed

Patients with metastatic renal cell cancer and metastatic melanoma treated with high-dose interleukin-2-based immunotherapy were prospectively evaluated for the development of vitiligo. All patients seen in the Surgery Branch, NCI Immunotherapy Clinic, who had been followed for at least 1 year were evaluated. Of 104 patients with metastatic renal cancer none developed vitiligo, though vitiligo was seen in 11 of 74 (15%) patients with metastatic melanoma (p2 = 0.0001). No vitiligo was seen in 27 patients who did not respond to immunotherapy, although vitiligo was seen in 11 of 43 (26%) melanoma patients who had an objective response to IL-2-based immunotherapy (p2 = 0.0002). These findings provide further evidence that the presence of a growing melanoma can sensitize patients to melanocyte-differentiation antigens and that the immune response against these antigens is associated with cancer regression in patients undergoing immunotherapy. PMID:8859727

Rosenberg, S A; White, D E

1996-01-01

281

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

2014-12-01

282

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

283

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

284

Targeted alpha-particle immunotherapy for acute myeloid leukemia.  

PubMed

Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ((213)Bi)-labeled lintuzumab. In a subsequent study, (213)Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of (213)Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ((225)Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that (225)Ac-lintuzumab is safe at doses of 3 ?Ci/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose (225)Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using (213)Bi- and astatine-211 ((211)At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios. PMID:24857092

Jurcic, Joseph G; Rosenblat, Todd L

2014-01-01

285

Passive immunotherapy - a viable treatment for Alzheimer's disease.  

PubMed

Passive immunotherapy is one of the most exciting and extensively researched areas in the field of Alzheimer's disease (AD) today, harbouring the potential to become the first disease-modifying treatment for the disease. The interest in immunotherapy as a treatment stemmed from the significant dangers of toxic side-effects and major obstacles in selectivity for currently pursued therapies against amyloid beta (A?) proteins and neurofibrillary tangles. Passive immunotherapy especially, has received much limelight, seen as having the potential to be the safer alternative to active immunisation which encountered a significant setback with the notorious AN-1972 trial in which 6% of the vaccinated patients developed meningoencephalitis. At present, passive immunisation research in animal models have exclusively focused on targeting A? proteins, a widely accepted pathology of AD. Following on from this, the preliminary results of phase II trials of three distinct passive immunisation strategies were demonstrated at the 2008 International Conference on Alzheimer's Disease (ICAD). The three therapeutic strategies each targeted the N-terminal of A?, the central epitope or utilised a polyclonal approach. The results demonstrated potential as well as caution. Efficacy was undoubtedly present but not to the extent that was hoped and side-effects, most notably vasogenic oedema occurred in the N-terminal targeting antibody, bapineuzimab. Lessons have been learnt by identifying the possible cause of the problems and have been taken on board to nurture the proven efficacious results. Key points to be addressed currently are dosage of the agent to ensure that high enough concentrations enter the central nervous system to be available to cause effect and early enough time of administration to cause effect. The results of the efficacy and safety phase III trials and the development of newer passive immunotherapeutic agents addressing the problems are eagerly awaited in the hope of finally yielding a disease modifying therapy of AD. PMID:25413550

Yi, Keonwoo

2014-11-01

286

Venom immunotherapy in patients with mastocytosis and hymenoptera venom anaphylaxis.  

PubMed

Systemic mastocytosis (SM) is typically suspected in patients with cutaneous mastocytosis (CM). In recent years, the presence of clonal mast cells (MCs) in a subset of patients with systemic symptoms associated with MC activation in the absence of CM has been reported and termed monoclonal MC activation syndromes or clonal systemic MC activation syndromes. In these cases, bone marrow (BM) MC numbers are usually lower than in SM with CM, there are no detectable BM MC aggregates, and serum baseline tryptase is often <20 µg/l; thus, diagnosis of SM in these patients should be based on careful evaluation of other minor WHO criteria for SM in reference centers, where highly sensitive techniques for immunophenotypic analysis and investigation of KIT mutations on fluorescence-activated cell sorter-purified BM MCs are routinely performed. The prevalence of hymenoptera venom anaphylaxis (HVA) among SM patients is higher than among the normal population and it has been reported to be approximately 5%. In SM patients with IgE-mediated HVA, venom immunotherapy is safe and effective and it should be prescribed lifelong. Severe adverse reactions to hymenoptera stings or venom immunotherapy have been associated with increased serum baseline tryptase; however, presence of clonal MC has not been ruled out in most reports and thus both SM and clonal MC activation syndrome might be underdiagnosed in such patients. In fact, clonal BM MC appears to be a relevant risk factor for both HVA and severe reactions to venom immunotherapy, while the increase in serum baseline tryptase by itself should be considered as a powerful surrogate marker for anaphylaxis. The Spanish Network on Mastocytosis has developed a scoring system based on patient gender, the clinical symptoms observed during anaphylaxis and serum baseline tryptase to predict for the presence of both MC clonality and SM among individuals who suffer from anaphylaxis. PMID:21554093

González-de-Olano, David; Alvarez-Twose, Iván; Vega, Arantza; Orfao, Alberto; Escribano, Luis

2011-05-01

287

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

PubMed

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

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

2014-11-01

288

Lymph Node-Targeted Immunotherapy Mediates Potent Immunity Resulting in Regression of Isolated or Metastatic HPV-Transformed Tumors  

PubMed Central

Purpose The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic HPV 16-transformed murine tumors. Experimental design Animals bearing E7-expressing tumors were co-immunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and anti-tumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease. Results In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen-specific T lymphocytes in the range of 1/10 CD8+ T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with anti-tumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization. Conclusions This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells. PMID:19789304

Smith, Kent A.; Meisenburg, Brenna L.; Tam, Victor L.; Pagarigan, Robb R.; Wong, Raymond; Joea, Diljeet K.; Lantzy, Liz; Carrillo, Mayra A.; Gross, Todd M.; Malyankar, Uriel M.; Chiang, Chih-Sheng; Da Silva, Diane M.; Kündig, Thomas M.; Kast, W. Martin; Qiu, Zhiyong; Bot, Adrian

2009-01-01

289

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

290

Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm  

PubMed Central

Metastatic melanoma is one of the most challenging malignancies to treat and often has a poor outcome. Until recently, systemic treatment options were limited, with poor response rates and no survival advantage. However, the treatment of metastatic melanoma has been revolutionized by developments in targeted therapy and immunotherapy; the BRAF inhibitor, vemurafenib, and anticytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, are the first agents to demonstrate a survival benefit. Despite the success of these treatments, most patients eventually progress, and research into response and resistance mechanisms, rationally designed combination therapies and evaluation of the role of these agents in the adjuvant setting is critically important. PMID:23450149

Khattak, Muhammad; Fisher, Rosalie; Turajlic, Samra

2013-01-01

291

Brain tumor immunotherapy: seeing the brain in the body.  

PubMed

Brain tumor immunotherapy is often interpreted in terms of immune privilege and the blood-brain barrier (BBB), but a broader view is warranted. The delicate regulatory balance of the immune system is relevant at any site, as are the heterogeneity and plasticity of tumor growth. Criteria for tumor antigens, and often the antigens themselves, cut across tumor types. Here, this broader view, complemented by current understanding of privilege and the BBB, provides the context for review. Future success is likely to exploit simplified methods, used in combination; and similarities - more than differences - between the brain and other sites. PMID:23195329

Lampson, Lois A

2013-04-01

292

Immunotherapy applications of carbon nanotubes: from design to safe applications.  

PubMed

Carbon nanotubes (CNTs) have the potential to overcome significant challenges related to vaccine development and immunotherapy. Central to these applications is an improved understanding of CNT interactions with the immune system. Unique properties such as high aspect ratio, flexible surface chemistry, and control over structure and morphology may allow for enhanced target specificity and transport of antigens across cell membranes. Although recent work has demonstrated the potential of CNTs to amplify the immune response as adjuvants, other results have also linked their proinflammatory properties to harmful health effects. Here, we review the recent advances of CNT-based immunological research, focusing on current understandings of therapeutic efficacy and mechanisms of immunotoxicology. PMID:24630474

Fadel, Tarek R; Fahmy, Tarek M

2014-04-01

293

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

294

Current Clinical Trials Testing Combinations of Immunotherapy and Radiation.  

PubMed

Preclinical evidence of successful combinations of ionizing radiation with immunotherapy has inspired testing the translation of these results to the clinic. Interestingly, the preclinical work has consistently predicted the responses encountered in clinical trials. The first example came from a proof-of-principle trial started in 2001 that tested the concept that growth factors acting on antigen-presenting cells improve presentation of tumor antigens released by radiation and induce an abscopal effect. Granulocyte-macrophage colony-stimulating factor was administered during radiotherapy to a metastatic site in patients with metastatic solid tumors to translate evidence obtained in a murine model of syngeneic mammary carcinoma treated with cytokine FLT-3L and radiation. Subsequent clinical availability of vaccines and immune checkpoint inhibitors has triggered a wave of enthusiasm for testing them in combination with radiotherapy. Examples of ongoing clinical trials are described in this report. Importantly, most of these trials include careful immune monitoring of the patients enrolled and will generate important data about the proimmunogenic effects of radiation in combination with a variety of immune modulators, in different disease settings. Results of these studies are building a platform of evidence for radiotherapy as an adjuvant to immunotherapy and encourage the growth of this novel field of radiation oncology. PMID:25481267

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

2015-01-01

295

Use of lectin-functionalized particles for oral immunotherapy.  

PubMed

Immunotherapy, in recent times, has found its application in a variety of immunologically mediated diseases. Oral immunotherapy may not only increase patient compliance but may, in particular, also induce both systemic as well as mucosal immune responses, due to mucosal application of active agents. To improve the bioavailability and to trigger strong immunological responses, recent research projects focused on the encapsulation of drugs and antigens into polymer particles. These particles protect the loaded antigen from the harsh conditions in the GI tract. Furthermore, modification of the surface of particles by the use of lectins, such as Aleuria aurantia lectin, wheatgerm agglutinin or Ulex europaeus-I, enhances the binding to epithelial cells, in particular to membranous cells, of the mucosa-associated lymphoid tissue. Membranous cell-specific targeting leads to an improved transepithelial transport of the particle carriers. Thus, enhanced uptake and presentation of the encapsulated antigen by antigen-presenting cells favor strong systemic, but also local, mucosal immune responses. PMID:22834202

Diesner, Susanne C; Wang, Xue-Yan; Jensen-Jarolim, Erika; Untersmayr, Eva; Gabor, Franz

2012-02-01

296

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

297

[Biotherapies, immunotherapies, targeted therapies, biopharmaceuticals… which word should be used?].  

PubMed

The ability to accurately describe and name medical advances is a prerequisite to foster public debates with scientists and physicians, and favour faith over fear among patients and citizens. Therapeutic antibodies are a good example of a medical breakthrough which has met with considerable clinical success, and which terminology has changed over the years. If the appellation serotherapy was appropriate a century ago, it has become obsolete. Recent names such as biotherapy, immunotherapy, targeted therapy, biopharmaceuticals have been introduced and are now commonly used, each of those can apply to therapeutic antibodies. It is thus interesting to question the real meaning of these different appellations. Our goal in this manuscript is to analyse the genesis of these terms but also to suggest how to simplify the terminology: biotherapy or targeted therapy need to be eliminated, as well as immunotherapy when communicating with non scientific public. It is recommended to favour the term biopharmaceuticals (biomédicaments in French), which clearly indicates the origin of these molecules, intermediate between chemical drugs and living biologics, whose borders need to be accurately defined also. PMID:24939545

Watier, Hervé

2014-05-01

298

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

299

Immunotherapy for head and neck cancer: advances and deficiencies  

PubMed Central

The concept of immunotherapy as a treatment for cancer patients has been in existence for decades. However, more recent immune therapeutic approaches have involved targeting of tumor-specific antigens. While improvements have been made in using such immune stimulatory treatment strategies for a variety of solid cancers, the use of these strategies for patients with head and neck squamous cell carcinoma (HNSCC) is lagging behind. Immunotherapeutic approaches for HNSCC are particularly complicated by the profound immune suppression that is induced by HNSCC, which potentially lessens the effectiveness of immune stimulatory efforts. Trials involving patients with various solid cancers have shown the enhanced effectiveness of combining various immunotherapeutic approaches or combining immunotherapy with chemotherapy or radiation therapy. Treatment of HNSCC with such combination approaches has not been extensively investigated and has the added challenge of the need to overcome the HNSCC-induced immune suppression. This review focuses on clinical trials that have tested immunotherapeutic approaches for HNSCC patients and the challenges associated with such approaches. In addition, it will call attention to immunotherapeutic strategies that have been demonstrated as successful in the treatment of other solid cancers in order to identify potential strategies that may apply to the treatment of HNSCC. PMID:21037467

De Costa, Anna-Maria A.; Young, M. Rita I.

2010-01-01

300

HDAC inhibitors and immunotherapy; a double edged sword?  

PubMed Central

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; Armandari, Inna; Hoogerbrugge, Peter M.; Adema, Gosse J.

2014-01-01

301

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

2014-06-01

302

Immune complex formation impairs the elimination of solutes from the brain: implications for immunotherapy in Alzheimer’s disease  

PubMed Central

Background Basement membranes in the walls of cerebral capillaries and arteries form a major lymphatic drainage pathway for fluid and solutes from the brain. Amyloid-? (A?) draining from the brain is deposited in such perivascular pathways as cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). CAA increases in severity when A? is removed from the brain parenchyma by immunotherapy for AD. In this study we investigated the consequences of immune complexes in artery walls upon drainage of solutes similar to soluble A?. We tested the hypothesis that, following active immunization with ovalbumin, immune complexes form within the walls of cerebral arteries and impair the perivascular drainage of solutes from the brain. Mice were immunized against ovalbumin and then challenged by intracerebral microinjection of ovalbumin. Perivascular drainage of solutes was quantified following intracerebral microinjection of soluble fluorescent 3kDa dextran into the brain at different time intervals after intracerebral challenge with ovalbumin. Results Ovalbumin, IgG and complement C3 co-localized in basement membranes of artery walls 24 hrs after challenge with antigen; this was associated with significantly reduced drainage of dextran in immunized mice. Conclusions Perivascular drainage along artery walls returned to normal by 7 days. These results indicate that immune complexes form in association with basement membranes of cerebral arteries and interfere transiently with perivascular drainage of solutes from the brain. Immune complexes formed during immunotherapy for AD may similarly impair perivascular drainage of soluble A? and increase severity of CAA. PMID:24252464

2013-01-01

303

Timing Is Critical for an Effective Anti-Metastatic Immunotherapy: The Decisive Role of IFN?/STAT1-Mediated Activation of Autophagy  

PubMed Central

Background Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown. Methods and Findings Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFN?/STAT1 activation and attenuated tumor metastasis. IFN? neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFN?/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis. Conclusion and Significance Our studies suggest that activation of IFN?/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis. PMID:21931823

Yan, Jun; Wang, Zi-Yan; Yang, Hong-Zhen; Liu, Han-Zhi; Mi, Su; Lv, Xiao-Xi; Fu, Xiao-Ming; Yan, Hui-Min; Zhang, Xiao-Wei; Zhan, Qi-Min; Hu, Zhuo-Wei

2011-01-01

304

Macrophage-directed immunotherapy as adjuvant to photodynamic therapy of cancer.  

PubMed Central

The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours. PMID:9010027

Korbelik, M.; Naraparaju, V. R.; Yamamoto, N.

1997-01-01

305

Novel strategy to create hypoallergenic peanut protein-polyphenol edible matrices for oral immunotherapy.  

PubMed

Peanut allergy is an IgE-mediated hypersensitivity. Upon peanut consumption by an allergic individual, epitopes on peanut proteins bind and cross-link peanut-specific IgE on mast cell and basophil surfaces triggering the cells to release inflammatory mediators responsible for allergic reactions. Polyphenolic phytochemicals have high affinity to bind proteins and form soluble and insoluble complexes with unique functionality. This study investigated the allergenicity of polyphenol-fortified peanut matrices prepared by complexing various polyphenol-rich plant juices and extracts with peanut flour. Polyphenol-fortified peanut matrices reduced IgE binding to one or more peanut allergens (Ara h 1, Ara h 2, Ara h 3, and Ara h 6). Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) suggested changes in secondary protein structure. Peanut protein-cranberry polyphenol fortified matrices triggered significantly less basophil degranulation than unmodified flour in an ex vivo assay using human blood and less mast cell degranulation when used to orally challenge peanut-allergic mice. Polyphenol fortification of peanut flour resulted in a hypoallergenic matrix with reduced IgE binding and degranulation capacity, likely due to changes in protein secondary structure or masking of epitopes, suggesting potential applications for oral immunotherapy. PMID:24758688

Plundrich, Nathalie J; Kulis, Mike; White, Brittany L; Grace, Mary H; Guo, Rishu; Burks, A Wesley; Davis, Jack P; Lila, Mary Ann

2014-07-23

306

Penile tuberculosis following intravesical Bacille Calmette-Guérin immunotherapy  

PubMed Central

Bacille Calmette-Guérin (BCG) is an effective treatment for patients with superficial bladder cancer and bladder carcinoma in situ (CIS). It may cause side effects usually due to local and systemic inflammatory effects. We report a case of a male patient with non-invasive urothelial carcinoma of urinary bladder (Stage T1) who developed caseating granulomas on his glans penis as a complication of intravesical BCG immunotherapy. Though there are other reported cases of BCG dissemination noted in the literature, penile granuloma is rare. The first reported case was published in 1992 and since then only eleven cases are reported. It appears that both direct infectious processes and hypersensitivity reactions contribute to the clinical manifestations of a systemic BCG infection. Our case possibly represents a local infection of M bovis involving the glans penis. PMID:23671370

Chowdhury, Anadi Roy; Dey, Ranjan Kumar

2013-01-01

307

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

308

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

309

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

310

Use of allogeneic NK cells for cancer immunotherapy  

PubMed Central

Controversy exists as to the role that the immune system plays in cancer therapy. While the immune system has been proposed to scavenge the body to prevent microscopic transformation from forming cancer, it has been difficult to mount its potential of shrinking established tumors. NK cells are components of the innate immune system. They can recognize targets without prior sensitization, making them ideal candidates to manipulate for therapeutic use against cancer. Initially, autologous NK cells were directed against tumors but it was realized that NK cells that recognize self cells are inhibited. More encouraging advances have been made with allogeneic NK cell therapy in clinical trials to overcome this limitation. In this article, we present developments in NK cell adoptive immunotherapy for hematologic and solid tumor malignancies. PMID:22091681

Geller, Melissa A; Miller, Jeffrey S

2012-01-01

311

New strategies in lung cancer: translating immunotherapy into clinical practice.  

PubMed

Recent breakthroughs in translating the early development of immunomodulatory antibodies into the clinic, notably with the anti-cytotoxic T-lymphocyte antigen-4 antibody, ipilimumab, have led to durable benefits and prolonged survival for a subgroup of patients with advanced melanoma. Subsequent studies have shown that related immune checkpoint antibodies, specifically those targeting the programmed death-1 pathway, have activity in non-small cell lung cancer. Non-small cell lung cancer is the commonest cause of cancer death worldwide and this exciting avenue of clinical investigation carries with it great promise and new challenges. In this article, we discuss recent developments in lung cancer immunotherapy, reviewing recent findings from therapeutic vaccine studies and in particular we focus on the refinement of immunomodulation as a therapeutic strategy in this challenging disease. PMID:24470514

Forde, Patrick M; Kelly, Ronan J; Brahmer, Julie R

2014-03-01

312

A mathematical model of the dynamics of antitumor laser immunotherapy  

NASA Astrophysics Data System (ADS)

We use a mathematical model to describe and predict the population dynamics of tumor cells, immune cells, and other immune components in a host undergoing laser immunotherapy treatment against metastatic cancer. We incorporate key elements of the treatment into the model: a function describing the laser-induced primary tumor cell death and parameters capturing the role and strength of the primary immunoadjuvant, glycated chitosan. We focus on identifying conditions that ensure a successful treatment. In particular, we study the patient response (i.e., anti-tumor immune dynamics and treatment outcome) in two different but related mathematical models as we vary quantitative features of the immune system (supply, proliferation, death, and interaction rates). We compare immune dynamics of a `baseline' immune model against an `augmented' model (with additional cell types and antibodies) and in both, we find that using strong immunoadjuvants, like glycated chitosan, that enhance dendritic cell activity yields more promising patient outcomes.

Dawkins, Bryan A.; Laverty, Sean M.

2014-02-01

313

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.

314

Immunotherapy of Brain Cancers: The Past, the Present, and Future Directions  

PubMed Central

Treatment of brain cancers, especially high grade gliomas (WHO stage III and IV) is slowly making progress, but not as fast as medical researchers and the patients would like. Immunotherapy offers the opportunity to allow the patient's own immune system a chance to help eliminate the cancer. Immunotherapy's strength is that it efficiently treats relatively small tumors in experimental animal models. For some patients, immunotherapy has worked for them while not showing long-term toxicity. In this paper, we will trace the history of immunotherapy for brain cancers. We will also highlight some of the possible directions that this field may be taking in the immediate future for improving this therapeutic option. PMID:21437175

Ge, Lisheng; Hoa, Neil; Bota, Daniela A.; Natividad, Josephine; Howat, Andrew; Jadus, Martin R.

2010-01-01

315

The evolution of allergen and non-specific immunotherapy: past achievements, current applications and future outlook.  

PubMed

Recent epidemiological studies estimated that more than 30% of European suffer from allergic rhinitis or conjunctivitis, while up to 20% suffer from asthma and 15% from allergic skin conditions, while for many other regions the prevalence is increasing. Allergen immunotherapy represents the only available treatment that can modify the allergic disease process, and thus is worth considering as a treatment in affected individuals. A beneficial effect of allergen immunotherapy has been shown in both adults and children affected by allergic rhinitis, allergic conjunctivitis, allergic asthma and hymenoptera venom allergy. The present study represents an overview on allergen immunotherapy, focusing on the principal aspects of the use of immunotherapy in the past, its recent clinical applications and future outlook. PMID:25454510

Pajno, Giovanni B; Nadeau, Kari C; Passalacqua, Giovanni; Caminiti, Lucia; Hobson, Ben; Jay, David C; Arasi, Stefania; Chiera, Fernanda; Salzano, Giuseppina

2015-01-01

316

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

317

Immunotherapy: What It Is and How It Can Help Fight Cancer  

MedlinePLUS

... skin) or systemic (taken by pill, injection, or infusion). Topical Immunotherapy In mid-2004, a topical medication ... alpha is administered . Following one month of intravenous infusion, interferon-alpha is usually given as a shot ...

318

Safety of home-based and office allergy immunotherapy: A multicenter prospective study.  

PubMed

During a 1-year period, 27 otolaryngic allergy practices recorded all systemic reactions to immunotherapy resulting from 635,600 patient visits and 1,144,000 injections. Sixty percent of injections were given at home. Major systemic reactions were observed after 0. 005% of injections. There were no hospitalizations or deaths. Eighty-seven percent of major reactions began within 20 minutes of injection. Frequently observed risk factors for major reactions were buildup phase of immunotherapy, active asthma, and first injection from a treatment vial. Home and office injections had similar rates of total systemic reactions, but home-based immunotherapy had far fewer major reactions. Home-based immunotherapy was found to be safe. The methods and precautions used to treat patients with this degree of safety are specified and discussed. PMID:10547469

Hurst, D S; Gordon, B R; Fornadley, J A; Hunsaker, D H

1999-11-01

319

Regulatory T cells in children undergoing rush venom immunotherapy.  

PubMed

Venom immunotherapy (VIT) induces immune tolerance to Hymenoptera venom but the underlying mechanisms are not clarified. Regulatory T cells are thought to play an important role in tolerance induction during specific immunotherapy. Our objective was to determine the effects of rush VIT on the percentage of regulatory T cells and immunosuppressive cytokines interleukin (IL)-10 and transforming growth factor beta (TGF-beta) in children. Blood samples were collected from 18 children with a previous systemic allergic reaction to a Hymenoptera sting, with a positive skin test and positive specific IgE, before rush VIT, after 6 weeks and 6 months of rush VIT. Ten children with no history of venom allergy were studied as controls. Isolated peripheral blood mononuclear cells were stained with specific markers for regulatory T cells and analyzed by flow cytometry. The percentage of regulatory T cells did not change during rush VIT in children. No change was noticed in the percentage of IL-10 and TGF-beta secreting cells after 6 weeks or 6 months of VIT. No difference in expression of cytotoxic T-lymphocyte antigen 4 on CD4(+)CD25(+high) was found. Rush VIT is a safe and effective treatment for patients allergic to Hymenoptera venom. Although regulatory T cells are considered to be responsible for this effect; no significant changes in the percentage of these cells or immunosuppressive cytokines were noticed during rush VIT in children. Additional investigations are needed to clarify the role of regulatory T cells in the induction of tolerance during rush VIT in children. PMID:23394512

Ajduk, Jakov; Turkalj, Mirjana; Gagro, Alenka

2012-01-01

320

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

321

Enhancement of interleukin-2 immunotherapy with L-arginine.  

PubMed Central

Nutrient substrates have been shown to enhance cell-mediated immunity, but their role as adjuvants to immunotherapy has not been previously determined. This study evaluated L-arginine as an essential substrate for optimal generation of lymphokine-activated killer (LAK) cells. This experiment also assessed supplemental dietary L-arginine as a means to potentiate the host antitumor response to interleukin-2 (IL-2) in a murine neuroblastoma (NRB) model. A/J mice received 1% arginine or isonitrogenous 1.7% glycine in addition to a regular diet 14 days before subcutaneous inoculation with C1300 NRB cells. Twenty-four hours later, animals received low (1 x 10(6) U/kg three times a day) or high (3 x 10(6) U/kg three times a day) doses of IL-2 or saline intraperitoneally for 4 days. On days 4 and 10 post-C1300 NRB inoculation, mice were killed for assessment of natural killer cell and tumor specific cytotoxicity. Remaining animals were followed for tumor incidence, tumor growth, and duration of host survival. Interleukin-2 therapy in mice receiving dietary arginine compared with those receiving glycine resulted in significantly augmented natural killer cell cytotoxicity (day 4) and generation of specific tumoricidal mechanisms (day 10). The addition of dietary arginine to low-dose IL-2 therapy significantly diminished C1300 NRB engraftment (p less than 0.05) and growth (p less than 0.001) and prolonged the duration of host survival (p less than 0.05) compared with the glycine treatment group. In vitro studies demonstrated that L-arginine is an essential substrate for optimal generation of LAK cells. Thus, supplemental dietary L-arginine enhances lymphocyte cytotoxic mechanisms and potentiates IL-2 immunotherapy. PMID:1546902

Lieberman, M D; Nishioka, K; Redmond, H P; Daly, J M

1992-01-01

322

GM-CSF-secreting cancer immunotherapies: preclinical analysis of the mechanism of action  

Microsoft Academic Search

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapies have demonstrated long-lasting,\\u000a and specific anti-tumor immune responses in animal models. The studies reported here specifically evaluate two aspects of\\u000a the immune response generated by such immunotherapies: the persistence of irradiated tumor cells at the immunization site,\\u000a and the breadth of the immune response elicited to tumor associated antigens (TAA) derived from the

Andrew D. Simmons; Betty Li; Melissa Gonzalez-Edick; Carol Lin; Marina Moskalenko; Thomas Du; Jennifer Creson; Melinda J. VanRoey; Karin Jooss

2007-01-01

323

Changes in IgG and IgE Antibody Levels to Bee Venom during Immunotherapy  

Microsoft Academic Search

IgE and IgG antibodies to bee venom were measured in sera of patients receiving bee venom immunotherapy. All patients selected for therapy had suffered severe reactions to bee stings. The results showed that within 2–3 months from the commencement of immunotherapy there was a marked rise in IgG antibodies and a slight but not significant rise in IgE antibodies. After

Antonio Ferrante; Frances Mocatta; David H. B. Goh

1986-01-01

324

Role of immunotherapy in the prevention of recurrence and invasion of urothelial bladder tumors: a review  

Microsoft Academic Search

Although many different chemotherapeutic regimens for the treatment of superficial bladder cancer have been used, none are considered ideal. This has stimulated investigations of alternative forms of therapy, including immunotherapy. Contained within this therapeutic category are bacterial agents such as Bacille Calmette-Guerin, Corynebacterium parvum and a streptococcal preparation, OK-432, as well as the interferon inducer polyriboinosinic acid-polyribocytidylic and passive immunotherapy

Eric O. Haff; Steven M. Dresner; David R. Kelley; Timothy L. Ratliff; Amos Shapiro; William J. Catalona

1985-01-01

325

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

NASA Astrophysics Data System (ADS)

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

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

2006-08-01

326

Immunoediting and Antigen Loss: Overcoming the Achilles Heel of Immunotherapy with Antigen Non-Specific Therapies  

PubMed Central

Cancer immunotherapy has emerged as a mainstream therapy option in the battle against cancer. Pre-clinical data demonstrates the ability of immunotherapy to harness the immune system to fight disseminated malignancy. Clinical translation has failed to recapitulate the promising results of pre-clinical studies although there have been some successes. In this review we explore some of the short-comings of cancer immunotherapy that have limited successful clinical translation. We will give special consideration to what we consider the most formidable hurdle to successful cancer immunotherapy: tumor-induced immune suppression and immune escape. We will discuss the need for antigen-specific immune responses for successful immunotherapy but also consider the need for antigen specificity as an Achilles heel of immunotherapy given tumor heterogeneity, immune editing, and antigen loss. Finally, we will discuss how combinatorial strategies may overcome some of the pitfalls of antigen specificity and highlight recent studies from our lab which suggest that the induction of antigen non-specific immune responses may also produce robust anti-tumor effects and bypass the need for antigen specificity. PMID:23898464

Monjazeb, Arta Monir; Zamora, Anthony E.; Grossenbacher, Steven K.; Mirsoian, Annie; Sckisel, Gail D.; Murphy, William J.

2013-01-01

327

rBet v 1 immunotherapy of sensitized mice with Streptococcus thermophilus as vehicle and adjuvant.  

PubMed

Lactobacilli are able to induce upregulation of co-stimulatory molecules in DCs with Th1 cytokines production and increase in Treg activity. This could explain the observed effectiveness of the prolonged administration of lactobacilli in the prevention of allergic disorders in infants and envisage the possible use of bacteria expressing the allergen for the specific immunotherapy of allergic diseases. Hence, we evaluated Streptococcus thermophilus (ST) expressing rBet v 1 as allergen delivery tool and adjuvant factor for immunotherapy in Betv1-sensitized mice. rBet v 1 gene was introduced and expressed in ST (ST[rBet v 1]). BALB/c mice were sensitized with rBet v 1 and then treated with either ST alone, ST[rBet v 1], or the combination of ST and rBet v 1, for 20 days. After 2 aerosol challenges, Treg frequency, in vitro allergen-induced cytokines, rBet v 1-specific IgE and IgG2a, and bronchial histology were made in harvested spleen, sera, and lung. Results were compared with those obtained from not-treated/sensitized mice. ST[rBet v 1] induced immunological and histological changes typical of successful SIT: increased frequency of Tregs and expression of Foxp3; decreased allergen-specific IgE/IgG2a ratio; decrease of in vitro rBet v 1-induced IL-4 from spleen cells; increased allergen-induced IL-10 and IFN-?; drop of bronchial eosinophilia. ST and ST+rBet v 1 combination, even though induced a slight increase in the frequency of Tregs and moderate allergen-induced IL-10, were ineffective in reducing bronchial eosinophilia, allergen induced IL-4 and rBet v 1-specific IgE/IgG2a ratio. ST[rBet v 1] has tolerogenic and Th-1 skewing properties and efficiently delivers the allergen to the gut immune-system restraining and readdressing the established specific Th2 response toward the allergen in mice. PMID:24603094

Petrarca, Claudia; Clemente, Emanuela; Toto, Valentina; Iezzi, Manuela; Rossi, Cosmo; Zanotta, Stefania; Mistrello, Gianni; Zanoni, Ivan; Granucci, Francesca; Arioli, Stefania; Mora, Diego; Guglielmetti, Simone; Paganelli, Roberto; Di Gioacchino, Mario

2014-05-01

328

Paradoxical Increase of IgE Binding Components during Allergen-Specific Immunotherapy in Pollinosis Patients  

PubMed Central

Allergen-specific immunotherapy (SIT) reduces allergen specific IgE (sIgE) levels and achieves clinical and immunological tolerance by modulating innate and adaptive immunological responses. Increased temperature and CO2 concentrations caused by climate changes contribute to an increase of pollen count and allergenicity that influences clinical SIT outcomes. In this study, we investigated the changes of IgE binding components to tree and weed pollens in pollinosis patients who showed a paradoxical increase of serum sIgE level during pollen-SIT. We enrolled nine patients who showed an increasing pattern of serum sIgE level to alder, birch, ragweed and mugwort pollens by enzyme-linked immunosorbant assay. IgE immunoblot analysis confirmed the intensification or new generation of major IgE binding components that could be induced by climate change. The findings suggest that the regular monitoring of sIgE levels and symptom changes is required to improve the clinical outcomes of SIT in patients undergoing SIT for tree and weed pollens. Graphical Abstract PMID:25045240

Kim, Mi-Ae; Yoon, Moon-Gyung; Jin, Hyun-Jung; Shin, Yoo-Seob

2014-01-01

329

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

330

Antigen-Specific Tolerance in Immunotherapy of Th2-Associated Allergic Diseases  

PubMed Central

Allergic diseases are an increasing health concern, particularly in the developed world. The standard clinical approach to treatment of allergic disease focuses on allergen avoidance and symptom control but does little to address the underlying Th2 bias of disease. Specific immunotherapy (SIT) consisting of controlled administration of allergen, however, has been demonstrated to successfully induce desensitization and tolerance in an antigen-specific manner for a variety of Th2-mediated diseases. This review focuses on the mechanisms by which current SIT approaches induce tolerance as well as discussing attempts to modify the safety and efficacy of SIT. These refinements focus on three major aspects of SIT: the route of antigen administration, modification of the antigen to remove allergenic epitopes and reduce adverse events and choice of adjuvant used to induce tolerance and/or immune deviation from Th2 to Th1 and regulatory T cell (Treg) phenotypes. Synthesis of these recent developments in SIT provides considerable promise for more robust therapies with improved safety profiles to improve resolution of allergic disease and its associated costs. PMID:24099300

Smarr, Charles B.; Bryce, Paul J.; Miller, Stephen D.

2013-01-01

331

Clinical effects of immunotherapy on Japanese cedar pollinosis in the season of cedar and cypress pollination.  

PubMed

Because of cross-allergenicity between Cryptomeria japonica (Japanese cedar) and Chamaecyparis obtusa (Japanese cypress) pollens, many Japanese cedar pollinosis patients have symptoms during the cypress pollination season. Therefore, the effect of immunotherapy (IT) specific for Japanese cedar pollinosis must be evaluated not only in the cedar season but also in the cypress season. Eight out of 16 patients with cedar pollinosis who received IT and the same number not receiving IT (non-IT) was studied. Nasal and ocular symptoms and medication(s) prescribed were classified from score 0 to 4 and score 0 to 3, respectively. The sum of these scores was used as the symptom-medication score (SMS). IT with Japanese cedar pollen extract reduced the daily SMS not only in cedar but also in the cypress pollination season, but not significantly. However, after the season, the mean SMS in the IT group tended to be lower than that in the non-IT group (P < 0.1). In conclusion, IT was useful as well as concomitant medications also in the cypress season, and considered to shorten the long-drawn symptoms persisting after the season. PMID:9134139

Ito, Y; Takahashi, Y; Fujita, T; Fukuyama, S

1997-04-01

332

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

333

Bystander immunotherapy as a strategy to control allergen-driven airway inflammation.  

PubMed

Allergic asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), lung infiltration of Th2 cells, and high levels of IgE. To date, allergen-specific immunotherapy (SIT) is the only treatment that effectively alleviates clinical symptoms and has a long-term effect after termination. Unfortunately, SIT is unsuitable for plurisensitized patients, and highly immunogenic allergens cannot be used. To overcome these hurdles, we sought to induce regulatory CD4(+) T cells (Treg) specific to an exogenous antigen that could be later activated as needed in vivo to control allergic responses. We have established an experimental approach in which mice tolerized to ovalbumin (OVA) were sensitized to the Leishmania homolog of receptors for activated c kinase (LACK) antigen, and subsequently challenged with aerosols of LACK alone or LACK and OVA together. Upon OVA administration, AHR and allergic airway responses were strongly reduced. OVA-induced suppression was mediated by CD25(+) Treg, required CTLA-4 and ICOS signaling and resulted in decreased numbers of migrating airway dendritic cells leading to a strong impairment in the proliferation of allergen-specific Th2 cells. Therefore, inducing Treg specific to a therapeutic antigen that could be further activated in vivo may represent a safe and novel curative approach for allergic asthma.Mucosal Immunology advance online publication, 26 November 2014; doi:10.1038/mi.2014.115. PMID:25425267

Navarro, S; Lazzari, A; Kanda, A; Fleury, S; Dombrowicz, D; Glaichenhaus, N; Julia, V

2014-11-26

334

NK cells in hepatitis B virus infection: a potent target for immunotherapy.  

PubMed

Viruses, including hepatitis B virus (HBV), are the most prevalent and infectious agents that lead to liver disease in humans. Hepatocellular carcinoma (HCC) and cirrhosis of the liver are the most serious complications arising from prolonged forms of hepatitis B. Previous studies demonstrated that patients suffering from long-term HBV infections are unable to eradicate HBV from hepatocytes completely. The mechanisms responsible for progression of these forms of infection have not yet been clarified. However, it seems that there are differences in genetic and immunological parameters when comparing patients to subjects who successfully clear HBV infections, and these may represent the causes of long-term infection. Natural killer (NK) cells, the main innate immune cells that target viral infections, play important roles in the eradication of HBV from hepatocytes. NK cells carry several stimulatory and inhibitor receptors, and binding of receptors with their ligands results in activation and suppression of NK cells, respectively. The aim of this review is to address the recent information regarding NK cell phenotype, functions and modifications in hepatitis B. This review addresses the recent data regarding the roles of NK cells as novel targets for immunotherapies that target hepatitis B infection. It also discusses the potential to reduce the risk of HCC or cirrhosis of the liver by targeting NK cells. PMID:24445811

Shabani, Ziba; Bagheri, Masomeh; Zare-Bidaki, Mohammad; Hassanshahi, Gholamhossein; Arababadi, Mohammad Kazemi; Mohammadi Nejad, Mozafar; Kennedy, Derek

2014-07-01

335

Surgical management of melanoma brain metastases in patients treated with immunotherapy  

PubMed Central

Object Despite the increasing use of immunotherapy in the treatment of metastatic melanoma, the effects of this therapy on the management of patients with associated brain metastases are not completely defined. The authors undertook this study to determine the effectiveness of resection and the effects of immunotherapy on brain metastasis management. Methods The authors analyzed data pertaining to consecutive patients with metastatic melanoma treated with immunotherapy within 3 months of discovery of brain metastases that were surgically resected. Results Forty-one patients (median age 44.4 years, range 19.2–63.1 years) underwent resection of 53 brain metastases (median number of metastases 1, range 1–4). The median metastasis volume was 2.5 cm3. Fifteen patients underwent whole-brain radiation therapy (WBRT) and 26 patients did not. Duration of survival from brain metastasis diagnosis was not significantly different between patients who received WBRT (mean 24.9 months) and those who did not (mean 23.3 months) (p > 0.05). Local and distant brain recurrence rates were not statistically different between the WBRT (7.1% and 28.6%, respectively) and non-WBRT (7.7% and 41.0%) groups for the duration of follow-up (p > 0.05). An objective systemic response to immunotherapy was associated with increased duration of survival (p < 0.05). Conclusions Resection of melanoma brain metastases in patients treated with immunotherapy provides excellent local control with low morbidity. An objective response to systemic immunotherapy is associated with a prolonged survival in patients who have undergone resection of melanoma brain metastases. Moreover, adjuvant WBRT in melanoma immunotherapy patients with limited metastatic disease to the brain does not appear to provide a significant survival benefit. PMID:21476810

Lonser, Russell R.; Song, Debbie K.; Klapper, Jacob; Hagan, Marygrace; Auh, Sungyoung; Kerr, P. Benjamin; Citrin, Deborah E.; Heiss, John D.; Camphausen, Kevin; Rosenberg, Steven A.

2014-01-01

336

Harnessing the exosome-induced immune response for cancer immunotherapy.  

PubMed

In recent years exosomes have emerged as potent stimulators of immune responses and as agents for cancer therapy. Exosomes can carry a broad variety of immunostimulatory molecules depending on the cell of origin and in vitro culture conditions. Dendritic cell-derived exosomes (dexosomes) have been shown to carry NK cell activating ligands and can be loaded with antigen to activate invariant NKT cells and to induce antigen-specific T and B cell responses. Dexosomes have been investigated as therapeutic agents against cancer in two phase I clinical trials, with a phase II clinical trial currently ongoing. Dexosomes were well tolerated but therapeutic success and immune activation were limited. Several reports suggest that multiple factors need to be considered in order to improve exosomal immunogenicity for cancer immunotherapy. These include antigen-loading strategies, exosome composition and exosomal trafficking in vivo. Hence, a better understanding of how to engineer and deliver exosomes to specific cells is crucial to generate strong immune responses and to improve the immunotherapeutic potential of exosomes. PMID:24859748

Gehrmann, Ulf; Näslund, Tanja I; Hiltbrunner, Stefanie; Larssen, Pia; Gabrielsson, Susanne

2014-10-01

337

Topical immunotherapy in alopecia areata. What, how, and why?  

PubMed

At present the induction and elicitation of an ACD with potent contact allergens such as DCP appear to be the most effective, but still not definitively curative, approach in treating extensive forms of AA. Experimental data suggest that cytokines and growth factors such as IL 1 beta are involved in the pathogenesis of AA as well as the therapeutic effect mediated by contact sensitizers. It seems reasonable to assume that factors inherent in the late phase of ACD modulate a T-cell mediated mechanism responsible for AA, thus inducing hair regrowth. Such counteracting activities are most likely mediated by proinflammatory cytokines such as TNF-alpha, IL-10, or TGF-beta 1. This hypothesis may oversimplify the underlying immunologic mechanisms, but the effectiveness of topical immunotherapy in AA would be compatible with this concept. This mode of treatment is, however, a rather rough approach and recurrences are possible. It is hoped that advances in basic science will eventually allow us to find a more specific mode of treatment. PMID:9238332

Hoffmann, R; Happle, R

1996-10-01

338

Role of immunotherapy in castration-resistant prostate cancer (CRPC).  

PubMed

Initial therapy for metastatic prostate cancer consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that usually lasts 12-24 months. Historically, castration-resistant prostate cancer (CRPC) had been considered a chemoresistant tumour. In 2004, docetaxel received USA Food and Drug Administration approval as a first-line treatment for metastatic prostate cancer, after two independent phase III trials showed an increased survival benefit. Recently, five new drugs have shown increased survival in CRPC: sipuleucel-T (assymptomatic or minimally symptomatic), abiraterone acetate (before and after docetaxel), cabazitaxel (after docetaxel), MDV3100 (after docetaxel) and radium-223 (not suitable for docetaxel or after docetaxel). The identification of antigens in normal prostate tissue or prostate cancer that are recognised by immune effectors cells has resulted in several new studies based on immunotherapy. Prostate cancer disease provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only with biochemical progression), there is a biological marker that can predict prognosis and outcome (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti-androgen therapy, chemotherapy, or radiotherapy. Here we provide a review of the main important immune treatments in CRPC. PMID:23650874

Suárez, Cristina; Morales-Barrera, Rafael; Ramos, Victor; Núñez, Isaac; Valverde, Claudia; Planas, Jacques; Morote, Juan; Maldonado, Xavier; Carles, Joan

2014-03-01

339

Vaccine immunotherapy for prostate cancer: from mice to men.  

PubMed

Preclinical studies demonstrated the ability of an adenovirus/PSA (Ad/PSA) vaccine to induce strong anti-PSA immune responses, and these responses were capable of destroying prostate-specific antigen (PSA)-secreting mouse prostate tumors. A series of preclinical studies have demonstrated the superiority of the Ad/PSA vaccine to other PSA vaccines for the induction of anti-PSA immune responses, the ability of Ad/PSA vaccination combined with cytokine gene therapy and the TLR9 agonist CpG to enhance the anti-prostate tumor immunotherapy, and the reduction of negative regulatory elements when the vaccine was combined with 5-fluoruracil administration. A phase I clinical trial of the Ad/PSA vaccine in men with metastatic castrate-resistant prostate cancer demonstrated the safety of the vaccine even at the highest single dose permitted by the FDA. Currently, a phase II trial of the Ad/PSA vaccine is underway treating patients in two protocols. Thus far 81 patients have been enrolled and vaccinated. Early results from the patients evaluated to date demonstrated the induction of anti-PSA T cell responses, and the majority of patients evaluated at this time had demonstrated an increase in PSA doubling times. PMID:24847764

Lubaroff, David M; Vaena, Daniel; Brown, James A; Zehr, Pamela; Griffith, Karen C; Brown, Erica; Eastman, Julie; Nepple, Kenneth; Kattula, Ambika; Williams, Richard D

2014-08-01

340

Scientific foundations of allergen-specific immunotherapy for allergic disease.  

PubMed

Allergen-specific immunotherapy (AIT) was described as a therapeutic option for the treatment of allergies > 100 years ago. It is based on administration of allergen extracts and leads to the development of clinical allergen tolerance in selected patients. According to current knowledge, AIT results in the restoration of immune tolerance toward the allergen of interest. It is mainly accompanied by the induction of regulatory and suppressive subsets of T and B cells, the production of IgG4 isotype allergen-specific blocking antibodies, and decreased inflammatory responses to allergens by effector cells in inflamed tissues. Currently, AIT is mainly applied subcutaneously or sublingually and is suitable for both children and adults for pollen, pet dander, house dust mite, and venom allergies. It not only affects rhinoconjunctival symptoms but also has documented short- and long-term benefits in asthma treatment. Clinically, a fast onset of tolerance is achieved during desensitization, with a tolerable amount of side effects. The disease modification effect leads to decreased disease severity, less drug usage, prevention of future allergen sensitizations, and a long-term curative effect. Increasing safety while maintaining or even augmenting efficiency is the main goal of research for novel vaccine development and improvement of treatment schemes in AIT. This article reviews the principles of allergen-specific immune tolerance development and the effects of AIT in the clinical context. PMID:25367471

Soyka, Michael B; van de Veen, Willem; Holzmann, David; Akdis, Mübeccel; Akdis, Cezmi A

2014-11-01

341

Antitumor immune responses induced by photodynamic immunotherapy in rats  

NASA Astrophysics Data System (ADS)

A new laser immunotherapy was used to treat metastatic mammary rat tumors. This new modality consists of three components: a near-infrared diode laser, a photosensitizer, and an immunoadjuvant. The sensitizer-adjuvant solution was injected directly to the tumor, followed by a non-invasive laser application. The new method resulted in total eradication of the treated primary tumors and eradication of untreated metastases at remote sites. Observed was the long-term survival of treated tumor-bearing rats: up to 120 days after tumor inoculation, a 300% increase in survival length compared with untreated control tumor-bearing rats. In addition, the successfully treated rats were refractory to tumor rechallenge with 10 times of the original tumor dose. Fluorescein and peroxidase immunochemical assays were also performed using sera from cured rats as the primary antibody. Strong antibody binding to both live and preserved tumor cells was observed. Western blot analysis, using the cured rat serum as primary antibody also showed distinctive protein binding, suggesting the induction of tumor-specific humoral immune response. These results indicated that an immune response was induced by the treatment of laser, photosensitizer and immunoadjuvant.

Chen, Wei R.; Robinson, Karen E.; Adams, Robert L.; Singhal, Anil K.; Nordquist, Robert E.

1998-05-01

342

Single-chain fragment variable passive immunotherapies for neurodegenerative diseases.  

PubMed

Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including A?, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action. PMID:24048248

Huang, Liang; Su, Xiaomin; Federoff, Howard J

2013-01-01

343

A new take on comparative immunology; Relevance to immunotherapy  

PubMed Central

Summary It is becoming increasingly recognized that experimental animal models, while useful to address monothematic biological questions, bear unpredictable relevance to human disease. Several reasons have been proposed. However, the uncontrollable nature of human genetics and the heterogeneity of disease that with difficulty can be replicated experimentally play a leading role. Comparative immunology is a term that generally refers to the analysis of shared or diverging facets of immunology among species; these comparisons are carried according to the principle that evolutionarily conserved themes outline biologic functions universally relevant for survival. We propose that a similar strategy could be applied searching for themes shared by distinct immune pathologies within our own species. Identification of common patterns may outline pathways necessary for a particular determinism to occur such as tissue-specific rejection or tolerance. This approach is founded on the unproven but sensible presumption that Nature does not require an infinite plethora of redundant mechanisms to reach its purposes. Thus, immune pathologies must follow, at least in part, common means that determine their onset and maintenance. Commonalities among diseases can, in turn, be segregated from disease-specific patterns uncovering essential mechanisms that may represent universal targets for immunotherapy. PMID:20635956

Wang, Ena; Albini, Adriana; Stroncek, David F; Marincola, Francesco M

2012-01-01

344

Mast cells as targets for immunotherapy of solid tumors.  

PubMed

Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells. PMID:24698842

Oldford, Sharon A; Marshall, Jean S

2015-01-01

345

Seed-based oral vaccines as allergen-specific immunotherapies.  

PubMed

Plant-based vaccines have advantages over conventional vaccines in terms of scalability, lack of requirement for cold chain logistics, stability, safety, cost-effectiveness and needle-free administration. In particular, when antigen is expressed in seeds, high production is possible and immunogenicity is not lost even if stocked at ambient temperature for several years. Induction of immune tolerance (desensitization) to allergen is a principle strategy for controlling allergic diseases, and is generally carried out by subcutaneous injection. Seed-based oral administration offers a straightforward and inexpensive alternative approach to deliver vaccines effectively to the GALT without loss of activity. Consumption of transgenic seeds containing modified hypo-allergenic tolerogen or T-cell epitope peptides derived from allergens has no or very few severe side effects and can induce immune tolerance leading to reduction of allergen-specific IgE production, T-cell proliferation and release of histamine. Suppression of allergen-specific clinical symptoms results. Thus, seed-based allergy vaccines offer an innovative and convenient allergen-specific immunotherapeutic approach as an alternative to conventional allergen-specific immunotherapy. PMID:21358268

Takaiwa, Fumio

2011-03-01

346

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

347

New Roads Open Up for Implementing Immunotherapy in Mesothelioma  

PubMed Central

Treatment options for malignant mesothelioma are limited, and the results with conventional therapies have been rather disappointing to this date. Chemotherapy is the only evidence-based treatment for mesothelioma patients in good clinical condition, with an increase in median survival of only 2 months. Therefore, there is urgent need for a different approach to battle this malignancy. As chronic inflammation precedes mesothelioma, the immune system plays a key role in the initiation of this type of tumour. Also, many immunological cell types can be found within the tumour at different stages of the disease. However, mesothelioma cells can evade the surveillance capacity of the immune system. They build a protective tumour microenvironment to harness themselves against the immune system's attacks, in which they even abuse immune cells to act against the antitumour immune response. In our opinion, modulating the immune system simultaneously with the targeting of mesothelioma tumour cells might prove to be a superior treatment. However, this strategy is challenging since the tumour microenvironment possesses numerous forms of defence strategies. In this paper, we will discuss the interplay between immunological cells that can either inhibit or stimulate tumour growth and the challenges associated with immunotherapy. We will provide possible strategies and discuss opportunities to overcome these problems. PMID:22778767

Cornelissen, R.; Heuvers, M. E.; Maat, A. P.; Hendriks, R. W.; Hoogsteden, H. C.; Aerts, J. G. J. V.; Hegmans, J. P. J. J.

2012-01-01

348

Immunotherapy for Alzheimer’s disease: past, present and future  

PubMed Central

Alzheimer’s disease (AD) is an incurable, progressive, neurodegenerative disorder affecting over 5 million people in the US alone. This neurological disorder is characterized by widespread neurodegeneration throughout the association cortex and limbic system caused by deposition of A? resulting in the formation of plaques and tau resulting in the formation of neurofibrillary tangles. Active immunization for A? showed promise in animal models of AD; however, the models were unable to predict the off-target immune effects in human patients. A few patients in the initial trial suffered cerebral meningoencephalitis. Recently, passive immunization has shown promise in the lab with less chance of off-target immune effects. Several trials have attempted using passive immunization for A?, but again, positive end points have been elusive. The next generation of immunotherapy for AD may involve the marriage of anti-A? antibodies with technology aimed at improving transport across the blood-brain barrier (BBB). Receptor mediated transport of antibodies may increase CNS exposure and improve the therapeutic index in the clinic. PMID:24959143

Spencer, Brian; Masliah, Eliezer

2014-01-01

349

Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy  

PubMed Central

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice. PMID:24081947

Bouchlaka, Myriam N.; Sckisel, Gail D.; Chen, Mingyi; Mirsoian, Annie; Zamora, Anthony E.; Maverakis, Emanual; Wilkins, Danice E.C.; Alderson, Kory L.; Hsiao, Hui-Hua; Weiss, Jonathan M.; Monjazeb, Arta M.; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L.; Blazar, Bruce R.; Wiltrout, Robert H.; Redelman, Doug; Taub, Dennis D.

2013-01-01

350

Single-Chain Fragment Variable Passive Immunotherapies for Neurodegenerative Diseases  

PubMed Central

Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including A?, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action. PMID:24048248

Huang, Liang; Su, Xiaomin; Federoff, Howard J.

2013-01-01

351

T Cell Coinhibition and Immunotherapy in Human Breast Cancer  

PubMed Central

Costimulation and coinhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T lymphocyte activation and tolerance. These pathways are very attractive therapeutic targets for human cancers including breast cancer. Gene polymorphisms of B7x (B7-H4/B7S1), PD-1 (CD279), and CTLA-4 (CD152) are associated with increased risk of developing breast cancer although the underlying mechanisms are unclear. In human breast cancer microenvironment, up-regulation of coinhibitory B7/CD28 members B7x, B7-H3 (CD276), and PD-L1 (B7-H1/CD274) on tumor cells as well as PD-1 and PD-L1 on tumor-infiltrating immune cells are emerging as immune evasion pathways. Chemotherapy can affect the expression of these molecules, and therefore may dampen the immune response against breast cancer. Immunotherapy targeting T cell coinhibition as monotherapy or combined with standard therapies are in early stages of clinical development, but hold great promise for treatment of human breast cancer. PMID:23114578

Janakiram, Murali; Abadi, Yael M.; Sparano, Joseph A.; Zang, Xingxing

2014-01-01

352

Anti-metastatic immunotherapy based on mucosal administration of flagellin and immunomodulatory P10.  

PubMed

Current therapies against malignant melanoma generally fail to increase survival in most patients, and immunotherapy is a promising approach as it could reduce the dosage of toxic therapeutic drugs. In the present study, we show that an immunotherapeutic approach based on the use of the Toll-like receptor (TLR)-5 ligand flagellin (Salmonella Typhimurium FliCi) combined with the major histocompatibility complex class II-restricted P10 peptide, derived from the Paracoccidioides brasiliensis gp43 major surface protein, reduced the number of lung metastasis in a murine melanoma model. Compounds were administered intranasally into C57Bl/6 mice intravenously challenged with syngeneic B16F10-Nex2 melanoma cells, aiming at the local (pulmonary) immune response modulation. Along with a marked reduction in the number of lung nodules, a significant increase in survival was observed. The immunization regimen induced both local and systemic proinflammatory responses. Lung macrophages were polarized towards a M1 phenotype, lymph node cells, and splenocytes secreted higher interleukin-12p40 and interferon (IFN)-? levels when re-stimulated with tumor antigens. The protective effect of the FliCi+P10 formulation required TLR-5, myeloid differentiation primary response gene 88 and IFN-? expression, but caspase-1 knockout mice were only partially protected, suggesting that intracellular flagellin receptors are not involved with the anti-tumor effect. The immune therapy resulted in the activation of tumor-specific CD4(+) T lymphocytes, which conferred protection to metastatic melanoma growth after adoptive transfer. Taken together, our results report a new immunotherapeutic approach based on TLR-5 activation and IFN-? production capable to control the metastatic growth of B16F10-Nex2 melanoma, being a promising alternative to be associated with chemotherapeutic drugs for an effective anti-tumor responses. PMID:25223833

de Melo, Filipe M; Braga, Catarina Jm; Pereira, Felipe V; Maricato, Juliana T; Origassa, Clarice St; Souza, Mariana F; Melo, Amanda C; Silva, Priscila; Tomaz, Samanta L; Gimenes, Karina P; Scutti, Jorge Ab; Juliano, Maria A; Zamboni, Dario S; Câmara, Niels O; Travassos, Luiz R; Ferreira, Luis Cs; Rodrigues, Elaine G

2015-01-01

353

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

354

Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy.  

PubMed

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

Exley, Christopher

2014-01-01

355

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

356

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

PubMed Central

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

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

2011-01-01

357

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

358

Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models  

PubMed Central

Introduction Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. Methods We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Results Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Conclusions Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer. PMID:23799045

Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

2013-01-01

359

A cough conundrum in a patient with a previous history of BCG immunotherapy for bladder cancer.  

PubMed

We describe a non-smoker who presented with a persistent cough, weight loss and general malaise, and had a medical history of bladder carcinoma that had been successfully treated with intravesical BCG immunotherapy. Radiology revealed hilar lymphadenopathy, a predominantly mid-zone and lower-zone lung parenchymal nodular pattern with a perilymphatic distribution, a few thickened interlobular septae, and small pleural effusions bilaterally. The T-SPOT.TB blood test was negative. Video-assisted thoracoscopic surgery showed multiple pleural nodules, the histopathology of which showed multiple well-defined non-caseating granulomata. The patient was started on antituberculosis medication for presumed BCGosis--a systemic complication of previous BCG immunotherapy--and the patient showed an excellent clinical and radiological response. This case further adds to previous reports and reinforces the recommendation that all patients should be made fully aware of the potential systemic and delayed complications of BCG immunotherapy when they are consented for treatment. PMID:23097577

Mehta, Arpan R; Mehta, Puja R; Mehta, Rajesh L

2012-01-01

360

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

PubMed Central

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

Luevano, Martha; Madrigal, Alejandro; Saudemont, Aurore

2012-01-01

361

Coexisting Crohn's Disease and Takayasu's Arteritis in Two Patients Treated with Anti-TNF-? Therapies  

PubMed Central

Crohn's disease (CD) and Takayasu's arteritis (TA) are inflammatory granulomatous autoimmune disorders. Simultaneous occurrence of CD and TA in the same individual is rare. We report two cases treated with biologic agents. Case 1: A 16-year-old male presented with abdominal pain, nausea, vomiting. CT angiogram showed thickening of the terminal ileum, wall thickening and narrowing of multiple large and medium arteries including aorta and left common carotid. Colonoscopy with biopsy of the stenotic ileocecal valve confirmed CD. Resected carotid artery pathology was consistent with TA. Treatment was initially begun with prednisone, then methotrexate was started followed by infliximab. Due to side effects, methotrexate was switched to azathioprine. He remained asymptomatic. Case 2: A 38-year-old male with well-characterized Crohn's ileocolitis for 15 years, who had been treated with prednisone, mesalamine, sulfasalazine, and azathioprine presented with chest, upper back and abdominal pain. CT angiogram showed vasculitis of large and medium arteries, with stenosis of the right renal artery, and wall thickening of the sigmoid colon. He was diagnosed with TA. He underwent treatment with infliximab and adalumimab on different occasions, which were later discontinued due to fever, bacteremia and complications from sepsis. He remained on prednisone and azathioprine. In these two patients with both CD and TA the diagnoses were confirmed by imaging and pathologic findings. Both patients developed vascular complications. Tumor necrosis factor inhibitor therapy was effective in one patient but discontinued in the other due to infection. Further research into the association of CD and TA may provide clues to their etiologies and guide effective interventions. PMID:21103225

Ratuapli, S.; Mazlumzadeh, M.; Gurudu, S.; Money, S.; Heigh, R.

2010-01-01

362

Rapid immunodiagnosis of tuberculosis in a woman receiving anti-TNF therapy  

Microsoft Academic Search

Background A 63-year-old German woman with a 24-year history of Crohn's disease and associated polyarthralgias presented with severe malaise, dyspnea, fever, night sweats, dry cough and an extensive right-sided pleural effusion. The patient had begun treatment with bi-weekly subcutaneous injections of adalimumab 5 weeks earlier.Investigations Physical examination, chest X-ray, transthoracic ultrasonography, pleural tap and drainage, bacterial and cytological analyses of

Christoph Lange; Bernhard Hellmich; Martin Ernst; Stefan Ehlers

2007-01-01

363

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

PubMed Central

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS)1, it has been difficult to demonstrate which variants are causal and what role they play in disease. Moreover, the modest contribution these variants make to disease risk has raised questions regarding their medical relevance2. We have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes TNF receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS)3,4, but not with other autoimmune conditions such as rheumatoid arthritis (RA)5, psoriasis6 and Crohn’s disease7. By analyzing MS GWAS3,4 data in conjunction with the 1000 Genomes Project data8 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 MS9-11, 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

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

2014-01-01

364

Anti-TNF? therapy in the treatment of rheumatoid arthritis, spondyloarthropathies and juvenile idiopathic arthritis.  

E-print Network

??LL Tiina Levälammen väitöskirja "TNF-salpaajat reumatautien hoidossa" tarkastetaan Tampereen yliopiston lääketieteen laitoksella perjantaina 11.12.2009. Tutkimus on tehty osana Tampereen yliopiston Farmakologian yksikön ja Tampereen yliopistollisen… (more)

Levälampi, Tiina

2009-01-01

365

Hidradenitis suppurativa associated with Crohn’s disease and spondyloarthropathy: response to anti-TNF therapy  

Microsoft Academic Search

An association of hidradenitis suppurativa with Crohn’s disease is supported by previous repent. We here report a patient with hidradenitis suppurativa who subsequently developed peripheral arthritis, sacroiliitis, and Crohn’s disease. A significant attenuation of bowel, cutaneous, and joint symptoms was achieved after treatment with monoclonal antibody against tumor necrosis factor (TNF). The pathogenetic aspects according to the literature and response

Maria Roussomoustakaki; Philippos Dimoulios; Constantinos Chatzicostas; Heraklis D. Kritikos; John Romanos; John G. Panayiotides; Elias A. Kouroumalis

2003-01-01

366

Successful treatment of resistant SAPHO syndrome with anti-TNF therapy  

PubMed Central

A 42-year-old Caucasian woman with SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) refractory to non-steroidal anti-inflammatory drugs, sulfasalzine, methotrexate, bisphosphonates and steroids was successfully treated with antitumour necrosis factor therapy (infliximab). This case was a diagnostic challenge leading to extensive investigations for infection and malignancy and delayed diagnosis for several years. We report the significant improvement in clinical, radiological and laboratory markers of disease activity on infliximab and the steroid sparing effect of such therapy. PMID:23355559

Hampton, Shayma Lamya; Youssef, Hazem

2013-01-01

367

Cerebral tuberculoma in a patient receiving anti-TNF alpha (adalimumab) treatment  

Microsoft Academic Search

We report a case of a cerebral tuberculoma in a 60-year-old woman with rheumatoid arthritis while receiving the anti-tumor\\u000a necrosis factor alpha monoclonal antibody, adalimumab (Humira), for active disease. MR brain imaging for dyspraxia revealed\\u000a a left parietal ring-enhancing lesion, which on resection was shown to be a necrotizing granuloma. There were no associated\\u000a pulmonary lesions, and the patient was

Karen Lynch; Michael Farrell

2010-01-01

368

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

369

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

370

In vitro Natural Killer Cell Immunotherapy for Medulloblastoma  

PubMed Central

How the immune system attacks medulloblastoma (MB) tumors effectively is unclear, although natural killer (NK) cells play an important role in immune defense against tumor cells. Interactions between receptors on NK cells and ligands expressed by tumor cells are critical for tumor control by immunotherapy. In this study, we analyzed tumor samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA) and UL16 binding protein (ULPB-2), which are ligands for the NK group 2 member D activatory receptor (NKG2D). The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a MB cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently killed tumor cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo. PMID:23626949

Fernández, Lucia; Portugal, Raquel; Valentín, Jaime; Martín, Roberto; Maxwell, Hannah; González-Vicent, Marta; Díaz, Miguel Ángel; de Prada, Inmaculada; Pérez-Martínez, Antonio

2013-01-01

371

Induced pluripotent stem cells: challenges and opportunities for cancer immunotherapy.  

PubMed

Despite recent advances in cancer treatment over the past 30?years, therapeutic options remain limited and do not always offer a cure for malignancy. Given that tumor-associated antigens (TAA) are, by definition, self-proteins, the need to productively engage autoreactive T cells remains at the heart of strategies for cancer immunotherapy. These have traditionally focused on the administration of autologous monocyte-derived dendritic cells (moDC) pulsed with TAA, or the ex vivo expansion and adoptive transfer of tumor-infiltrating lymphocytes (TIL) as a source of TAA-specific cytotoxic T cells (CTL). Although such approaches have shown some efficacy, success has been limited by the poor capacity of moDC to cross present exogenous TAA to the CD8(+) T-cell repertoire and the potential for exhaustion of CTL expanded ex vivo. Recent advances in induced pluripotency offer opportunities to generate patient-specific stem cell lines with the potential to differentiate in vitro into cell types whose properties may help address these issues. Here, we review recent success in the differentiation of NK cells from human induced pluripotent stem (iPS) cells as well as minor subsets of dendritic cells (DCs) with therapeutic potential, including CD141(+)XCR1(+) DC, capable of cross presenting TAA to naïve CD8(+) T cells. Furthermore, we review recent progress in the use of TIL as the starting material for the derivation of iPSC lines, thereby capturing their antigen specificity in a self-renewing stem cell line, from which potentially unlimited numbers of naïve TAA-specific T cells may be differentiated, free of the risks of exhaustion. PMID:24860566

Sachamitr, Patty; Hackett, Simon; Fairchild, Paul Jonathan

2014-01-01

372

Regulatory Dendritic Cells for Immunotherapy in Immunologic Diseases  

PubMed Central

We recognize well the abilities of dendritic cells to activate effector T cell (Teff cell) responses to an array of antigens and think of these cells in this context as pre-eminent antigen-presenting cells, but dendritic cells are also critical to the induction of immunologic tolerance. Herein, we review our knowledge on the different kinds of tolerogenic or regulatory dendritic cells that are present or can be induced in experimental settings and humans, how they operate, and the diseases in which they are effective, from allergic to autoimmune diseases and transplant tolerance. The primary conclusions that arise from these cumulative studies clearly indicate that the agent(s) used to induce the tolerogenic phenotype and the status of the dendritic cell at the time of induction influence not only the phenotype of the dendritic cell, but also that of the regulatory T cell responses that they in turn mobilize. For example, while many, if not most, types of induced regulatory dendritic cells lead CD4+ naïve or Teff cells to adopt a CD25+Foxp3+ Treg phenotype, exposure of Langerhans cells or dermal dendritic cells to vitamin D leads in one case to the downstream induction of CD25+Foxp3+ regulatory T cell responses, while in the other to Foxp3? type 1 regulatory T cells (Tr1) responses. Similarly, exposure of human immature versus semi-mature dendritic cells to IL-10 leads to distinct regulatory T cell outcomes. Thus, it should be possible to shape our dendritic cell immunotherapy approaches for selective induction of different types of T cell tolerance or to simultaneously induce multiple types of regulatory T cell responses. This may prove to be an important option as we target diseases in different anatomic compartments or with divergent pathologies in the clinic. Finally, we provide an overview of the use and potential use of these cells clinically, highlighting their potential as tools in an array of settings. PMID:24550907

Gordon, John R.; Ma, Yanna; Churchman, Laura; Gordon, Sara A.; Dawicki, Wojciech

2013-01-01

373

Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment  

PubMed Central

The tumor microenvironment is a complex assortment of cells that includes a variety of leukocytes. The overall effect of the microenvironment is to support the growth of tumors and suppress immune responses. Immunotherapy is a highly promising form of cancer treatment, but its efficacy can be severely compromised by an immunosuppressive tumor microenvironment. Chemotherapy and radiation treatment can mediate tumor reduction through cytotoxic effects, but it is becoming increasingly clear that these forms of treatment can be used to modify the tumor microenvironment to liberate tumor antigens and decrease immunosuppression. Chemotherapy and radiotherapy can be used to modulate the tumor microenvironment to enhance immunotherapy. PMID:24327938

Kershaw, Michael H; Devaud, Christel; John, Liza B; Westwood, Jennifer A; Darcy, Phillip K

2013-01-01

374

Chimerism and minimal residual disease monitoring after reduced intensity conditioning (RIC) allogeneic transplantation  

Microsoft Academic Search

Since graft-versus-leukemia (GVL) is the main weapon for disease eradication after reduced intensity conditioning (RIC) allogeneic SCT, the availability of sensitive and specific techniques to monitor changes in tumor load after transplant are especially helpful. These minimal residual disease techniques would allow an early intervention in the event of low tumor burden, for which immunotherapy is highly effective. Some authors

JA Pérez-Simón; D Caballero; M Diez-Campelo; R Lopez-Pérez; G Mateos; C Cañizo; L Vazquez; B Vidriales; MV Mateos; M Gonzalez; JF San Miguel

2002-01-01

375

Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma.  

PubMed

The adaptive immune system is clearly capable of recognizing and attacking malignant plasma cells in patients with multiple myeloma (MM). However, MM patients evidence severe defects of humoral and cellular immunity, and it is likely that the profound immune dysregulation typical for this malignancy contributes to its eventual escape from natural immune control. One of the factors responsible for the immune dysfunction in MM might be the programmed death 1 (PD-1) protein. The physiological role of PD-1 is to guarantee T-cell homeostasis by limiting T-cell activation and proliferation. Accordingly, binding of the ligand PD-L1 to PD-1 expressed on the surface of activated T cells delivers an inhibitory signal, reducing cytokine production and proliferation. Using the same mechanism, PD-L1/PD-1 interactions have been shown in a number of animal models to confer tumor escape from immune control. Recently, clinical trials have suggested a significant therapeutic impact of PD-1/PD-L inhibition on a variety of solid tumors-for example, by the application of monoclonal antibodies. We show here that based on (1) the broad expression of PD-1 and its ligands in the microenvironment of myeloma, (2) data indicating an important role of the PD-1 pathway in the immune evasion by MM cells and (3) preclinical results providing a strong rationale for therapeutic PD-1/PD-L inhibition in this malignancy, MM may be very well suited for immunotherapy, for example, a monoclonal antibody, targeting PD-1 and/or its ligands. PMID:24153012

Atanackovic, D; Luetkens, T; Kröger, N

2014-05-01

376

Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration  

NASA Astrophysics Data System (ADS)

Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 in the industrialized world. Severe loss of central vision frequently occurs with the exudative (wet) form of AMD, as a result of the formation of a pathological choroidal neovasculature (CNV) that damages the macular region of the retina. We tested the effect of an immunotherapy procedure, which had been shown to destroy the pathological neovasculature in solid tumors, on the formation of laser-induced CNV in a mouse model simulating exudative AMD in humans. The procedure involves administering an Icon molecule that binds with high affinity and specificity to tissue factor (TF), resulting in the activation of a potent cytolytic immune response against cells expressing TF. The Icon binds selectively to TF on the vascular endothelium of a CNV in the mouse and pig models and also on the CNV of patients with exudative AMD. Here we show that the Icon dramatically reduces the frequency of CNV formation in the mouse model. After laser treatment to induce CNV formation, the mice were injected either with an adenoviral vector encoding the Icon, resulting in synthesis of the Icon by vector-infected mouse cells, or with the Icon protein. The route of injection was i.v. or intraocular. The efficacy of the Icon in preventing formation of laser-induced CNV depends on binding selectively to the CNV. Because the Icon binds selectively to the CNV in exudative AMD as well as to laser-induced CNV, the Icon might also be efficacious for treating patients with exudative AMD.

Bora, Puran S.; Hu, Zhiwei; Tezel, Tongalp H.; Sohn, Jeong-Hyeon; Kang, Shin Goo; Cruz, Jose M. C.; Bora, Nalini S.; Garen, Alan; Kaplan, Henry J.

2003-03-01

377

Intratumoral temozolomide synergizes with immunotherapy in a T cell-dependent fashion.  

PubMed

Despite temozolomide (TMZ) treatment, the prognosis for patients with glioblastoma multiforme is still dismal. As dose escalation of TMZ is limited by systemic toxicity, intratumoral delivery emerges as an attractive treatment modality, which may sustain cytotoxic drug concentrations intratumorally and induce immunogenic cell death. Both clinical and experimental gliomas have responded to immunotherapy, but the benefit of simultaneous chemo- and immunotherapy is inadequately studied. Here, we monitored survival of GL261-bearing C57BL/6 mice following a 3-day treatment with either intratumoral TMZ (micro-osmotic pump, 4.2 mg/kg/day) or systemic TMZ (i.p. injections, 50 mg/kg/day) alone, or combined with immunization using GM-CSF secreting GL261 cells. Peripheral and intratumoral leukocytes were analyzed by flow cytometry and immunohistochemistry. Intratumoral TMZ induced higher survival rate than systemic TMZ (45 vs. 8%). When T cells were depleted following intratumoral TMZ, the therapeutic effect was completely abrogated (0 % survival). Intratumoral TMZ synergistically increased survival rate of immunized mice (from 25 to 83%), while systemic TMZ failed (0%). While systemic TMZ induced a transient leukopenia, intratumoral TMZ and immunotherapy sustained the proliferation of CD8+ T cells and decreased the number of intratumoral immunosuppressive cells. In conclusion, intratumoral TMZ alone or in combination with immunotherapy could cure glioma-bearing mice, due to attenuation of local immunosuppression and increase in potential effector immune cells. PMID:23775421

Fritzell, Sara; Sandén, Emma; Eberstål, Sofia; Visse, Edward; Darabi, Anna; Siesjö, Peter

2013-09-01

378

The use of bispecific antibodies in tumor cell and tumor vasculature directed immunotherapy  

Microsoft Academic Search

To overcome dose limiting toxicities and to increase efficacy of immunotherapy of cancer, a number of strategies are under development for selectively redirecting effector cells\\/molecules towards tumor cells. Many of these strategies exploit the specificity of tumor associated antigen recognition by monoclonal antibodies. Using either hybridoma fusion, chemical derivatization or molecular biology technology, antibodies with dual specificity can be constructed.

Grietje Molema; Bart Jan Kroesen; Wijnand Helfrich; Dirk K. F. Meijer

2000-01-01

379

Which Patients Will Benefit from Immunotherapy for Cancer? Some Hints Emerge  

Cancer.gov

Researchers have identified a “genetic signature” in the tumors of patients with advanced melanoma who responded to a form of immunotherapy called checkpoint blockade. The results could be the basis for a test that identifies likely responders to this treatment as well as for developing new treatments.

380

The Potential of Enzymatic Hydrolysis to Improve Immunotherapy and Ingredient Applications of peanut flour.  

Technology Transfer Automated Retrieval System (TEKTRAN)

Peanut flour is currently being used as the active ingredient in oral immunotherapy applications designed to desensitize peanut allergic patients. This strategy for treating peanut allergy is proving quite promising; however, there is a risk for adverse reactions using this approach. In the curren...

381

Enhancement of Cancer Immunotherapy Using Immune Modulating Peptides Hua-Chen Chang1, 4  

E-print Network

Enhancement of Cancer Immunotherapy Using Immune Modulating Peptides Hua-Chen Chang1, 4 , Ling Han1 of cancer patients. Lunasin, a synthetic 43-amino acid peptide, was originally isolated from soybeans. Our cells from chemotherapy-treated Non-Hodgkin's Lymphoma (NHL) patients who are immunocompromised

Zhou, Yaoqi

382

Activation of matrix metalloproteinases following anti-A? immunotherapy; implications for microhemorrhage occurrence  

PubMed Central

Background Anti-A? immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur. Methods We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-A? immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-A? antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with A? vaccination for 4 months. Results There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-A? immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity. Conclusions Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence. PMID:21906275

2011-01-01

383

Specific Immunotherapy with Standardized Latex Extract versus Placebo in Latex-Allergic Patients  

Microsoft Academic Search

Background: Allergy to natural rubber latex proteins continues to be an important medical problem among health care professionals, but also in multioperated children. Clinical manifestations range from urticaria to angioedema, rhinoconjunctivitis, bronchial asthma and anaphylactic shock. Methods: The aim of this study was to investigate the efficacy and safety of a 12-month latex-specific immunotherapy in sensitized patients, most often health

Ana Isabel Tabar; Marta Anda; Floriano Bonifazi; Maria Beatrice Bilò; Francisque Leynadier; Thomas Fuchs; Johannes Ring; Sylvie Galvain; Claude André

2006-01-01

384

Cancer immunotherapy in children: How does it differ from approaches in adults?  

Cancer.gov

More often than not, cancer immunotherapies that work in adults are used in modified ways in children. Seldom are new therapies developed just for children, primarily because of the small number of pediatric patients relative to the adult cancer patient population. Depicted are members of NCI’s Pediatric Oncology Branch. From left: Drs. Crystal Mackall, Daniel Lee, and Alan Wayne

385

Different patterns of antigen-induced histamine release during immunotherapy in insect venom and pollen allergy  

Microsoft Academic Search

Antigen-induced histamine release from whole blood was shown to be a suitable parameter for the diagnosis of hypersensitivity in both patients allergic to bee or wasp venom as well as in patients suffering from seasonal tree pollen allergy. Although both groups were treated successfully by specific immunotherapy, only in patients with insect allergy venom induced histamine release decreased significantly during

H. G. Nüsslein; M. Kleinlein; B. Hemmerlein; J. R. Kalden

1986-01-01

386

Monitoring of Antibodies in Patients on Immunotherapy with Insect Venoms by Immunoblotting  

Microsoft Academic Search

A rapid nitrocellulose immunoblotting procedure based upon electrophoretic transfer has been used to monitor patient specific IgE and IgG antibodies before and after specific Hymenoptera insect venom therapy. The patients followed a conventional schedule for immunotherapy with Pharmalgen® bee and yellow jacket venoms. The allergenic profiles of the patients before and after treatment were qualitatively similar in many patients, but

R. Einarsson

1987-01-01

387

Optimal control in a model of dendritic cell transfection cancer immunotherapy  

E-print Network

as immunotherapeutic agent. Keywords. Optimal control, necessary conditions, cancer, immuno-therapy, autologous system to react against something specific. For example, for people which are allergic to bee sting, doctors repeat to inject small doses of venom until the immune system "changes" its way if reacting

Piccoli, Benedetto

388

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

SciTech Connect

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

Wada, Satoshi [Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Harris, Timothy J.; Tryggestad, Erik [Department of Radiation Oncology and Molecular Radiation Sciences, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Yoshimura, Kiyoshi [Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Zeng, Jing [Department of Radiation Oncology and Molecular Radiation Sciences, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Yen, Hung-Rong; Getnet, Derese; Grosso, Joseph F.; Bruno, Tullia C. [Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); De Marzo, Angelo M. [Department of Pathology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); and others

2013-11-15

389

Effects of birch pollen-specific immunotherapy on apple allergy in birch pollen-hypersensitive patients  

Microsoft Academic Search

Summary Background Most patients with birch pollen allergy report oral allergy symptoms after eating fresh apples and other vegetable foods. Major birch pollen and apple allergens, Bet v 1 and Mal d 1, are highly homologous; as a consequence, pollen-specific immunotherapy (SIT) might be expected to improve apple hypersensitivity. Objective To evaluate the clinical and immunological effects of birch pollen

Asero

1998-01-01

390

Immunotherapy as a strategy for the treatment of non-small-cell lung cancer  

PubMed Central

Positive modulation of a patient’s immune system to produce antitumor immunity is an attractive strategy that may improve the dismal outcomes typically associated with non-small-cell lung cancer (NSCLC). Using methods that either augment specific antitumor immunity or positively influence the patient’s immune system to allow the de novo generation of immunity to encompass current strategies used in recent clinical trials of NSCLC. Encouraging results of Phase II trials in antigen-specific immunotherapy have led to three subsequent Phase III trials, which are currently enrolling. Results of these trials will improve our understanding of the role that immunotherapy plays in the treatment of NSCLC. Successful application of a humoral vaccine in Cuba led to its approval for the treatment of advanced NSCLC patients in that country. To date, trials involving nonspecific immunotherapeutic interventions have failed to improve outcomes in NSCLC and may indicate a need to combine them with antigen-specific vaccines. Although these trials will greatly advance our knowledge of NSCLC immunotherapy, we believe truly efficacious immunotherapy may only result from implementation of strategies to both augment antitumor immunity and counteract tumor-mediated immunosuppression. PMID:21359153

Holt, Gregory E; Podack, Eckhard R; Raez, Luis E

2011-01-01

391

The anti-vaccination movement and resistance to allergen-immunotherapy: a guide for clinical allergists  

PubMed Central

Despite over a century of clinical use and a well-documented record of efficacy and safety, a growing minority in society questions the validity of vaccination and fear that this common public health intervention is the root-cause of severe health problems. This article questions whether growing public anti-vaccine sentiments might have the potential to spill-over into other therapies distinct from vaccination, namely allergen-immunotherapy. Allergen-immunotherapy shares certain medical vernacular with vaccination (e.g., allergy shots, allergy vaccines), and thus may become "guilty by association" due to these similarities. Indeed, this article demonstrates that anti-vaccine websites have begun unduly discrediting this allergy treatment regimen. Following an explanation of the anti-vaccine movement, the article aims to provide guidance on how clinicians can respond to patient fears towards allergen-immunotherapy in the clinical setting. This guide focuses on the provision of reliable information to patients in order to dispel misconceived associations between vaccination and allergen-immunotherapy, and the discussion of the risks and benefits of both therapies in order to assist patients in making autonomous decisions about their choice of allergy treatment. PMID:20843332

2010-01-01

392

The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy  

PubMed Central

The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care. PMID:25268164

Patel, Mira A.; Kim, Jennifer E.; Ruzevick, Jacob; Li, Gordon; Lim, Michael

2014-01-01

393

NCI Researchers Confirm the Effectiveness of Immunotherapy Approach to Treating Melanoma  

Cancer.gov

A team of researchers, led by Steven A. Rosenberg, M.D., at the National Cancer Institute, part of the National Institutes of Health, have found that patients with advanced melanoma who had not responded to previous therapies experienced a significant reduction in the size of their cancers as a result of receiving a new immunotherapy.

394

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

PubMed

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

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

2014-10-01

395

Once-daily sublingual allergen-specific immunotherapy improves quality of life in patients with grass pollen-induced allergic rhinoconjunctivitis: a double-blind, randomised study.  

PubMed

The effect of sublingual immunotherapy on quality of life (QoL) was examined in patients with grass pollen-induced rhinoconjunctivitis. Patients (n = 855) were randomised to once-daily grass allergen tablets (2,500; 25,000; or 75,000 SQ-T Phleum pratense extract; GRAZAX or placebo. Treatment was initiated 8 weeks before the start of the grass pollen season and continued throughout. If symptoms were present, patients received loratadine or placebo rescue medication. There were three major findings: in patients using loratadine, grass allergen tablets provided QOL benefits over placebo; Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score was 17% (p = 0.006) and 20% (p = 0.020) greater with 75,000 SQ-T tablet than with placebo at first and second seasonal visit, respectively; in patients not using loratadine, grass allergen tablets improved QoL more than placebo; RQLQ score was 21% greater (p = 0.021) with 75,000 SQ-T tablet at second seasonal visit; grass tablets (without loratadine) had a greater effect on QoL than loratadine alone. RQLQ score was 26% (p = 0.014) greater with 75,000 SQ-T tablets than loratadine at second seasonal visit. These data show that sublingual immunotherapy with grass allergen tablets improves QOL in allergic rhinoconjunctivitis, reduces symptoms, and that this effect is greater than rescue antihistamine alone. PMID:17033900

Rak, Sabina; Yang, William H; Pedersen, Martin R; Durham, Stephen R

2007-03-01

396

Humoral and Cellular Immunotherapy in ALL in Children, Adolescents, and Young Adults.  

PubMed

Although the event-free survival for children and adolescents with acute lymphoblastic leukemia (ALL) has dramatically improved over the past half century, it has plateaued over the past decade. Children and adolescents with refractory/relapsed ALL continue to have a dismal prognosis with hematopoietic stem cell transplant being their most viable option for cure. There is an obvious need for the development of novel agents to further enhance overall outcomes. In this review we focus on the development of humoral and cellular immunotherapeutic agents in the treatment of childhood, adolescent, and young adult ALL. Immunotherapy in various forms has shown immense promise. To date we have seen numerous safety studies using monoclonal antibody therapy, antibody conjugates, bispecific T cell and bispecific natural killer (NK) cell antibodies and genetically reengineered T and NK cells expressing targeted chimeric antigen receptors. Initial success has been found with the anti-CD20 monoclonal antibodies followed by promising results using anti-CD22 and anti-CD19 therapies alone or in combination. Genetic modification of T and NK cells to express targeted chimeric antigen receptors offers a novel immunotherapy option that demonstrates enhanced cytotoxicity in otherwise resistant tumor cells. There is great potential to combine immunotherapies to further improve overall cure rates in children, adolescents, and young adults with poor-risk ALL. A number of humoral and cellular immunotherapy strategies have been investigated and found to be effective, safe, and well tolerated. Ideally, the targeted approach of immunotherapy will result in an overall decrease in toxicities experienced by patients. Future studies are required to determine when in the course of treatment with humoral and cellular therapy will have the safest and optimal effect in ALL. PMID:25486958

Hochberg, Jessica; El-Mallawany, Nader Kim; Cairo, Mitchell S

2014-09-01

397

Attenuated Listeria monocytogenes: a powerful and versatile vector for the future of tumor immunotherapy  

PubMed Central

For over a century, inactivated or attenuated bacteria have been employed in the clinic as immunotherapies to treat cancer, starting with the Coley's vaccines in the 19th century and leading to the currently approved bacillus Calmette-Guérin vaccine for bladder cancer. While effective, the inflammation induced by these therapies is transient and not designed to induce long-lasting tumor-specific cytolytic T lymphocyte (CTL) responses that have proven so adept at eradicating tumors. Therefore, in order to maintain the benefits of bacteria-induced acute inflammation but gain long-lasting anti-tumor immunity, many groups have constructed recombinant bacteria expressing tumor-associated antigens (TAAs) for the purpose of activating tumor-specific CTLs. One bacterium has proven particularly adept at inducing powerful anti-tumor immunity, Listeria monocytogenes (Lm). Lm is a gram-positive bacterium that selectively infects antigen-presenting cells wherein it is able to efficiently deliver tumor antigens to both the MHC Class I and II antigen presentation pathways for activation of tumor-targeting CTL-mediated immunity. Lm is a versatile bacterial vector as evidenced by its ability to induce therapeutic immunity against a wide-array of TAAs and specifically infect and kill tumor cells directly. It is for these reasons, among others, that Lm-based immunotherapies have delivered impressive therapeutic efficacy in preclinical models of cancer for two decades and are now showing promise clinically. In this review, we will provide an overview of the history leading up to the development of current Lm-based immunotherapies, the advantages and mechanisms of Lm as a therapeutic vaccine vector, the preclinical experience with Lm-based immunotherapies targeting a number of malignancies, and the recent findings from clinical trials along with concluding remarks on the future of Lm-based tumor immunotherapies. PMID:24860789

Wood, Laurence M.; Paterson, Yvonne

2014-01-01

398

Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape  

PubMed Central

Malignant melanoma is on the rise. There have been recent advances in targeted agents and immunotherapies that have improved the management and treatment of patients with advanced melanoma. This review discusses the clinical efficacy and unique side effects of targeted immunotherapy and the role of predictive biomarkers in better selection of patients who would derive most benefit from specific treatments. Additionally, this review addresses concerns about the best sequencing algorithms for the currently available targeted agents. By thoroughly and extensively researching through PubMed and the American Society of Clinical Oncology, 69 published articles and abstracts were identified as addressing topics related to malignant melanoma and immunotherapy. The research was divided into subcategories discussing cytokine-based therapy, immunotherapy, molecularly targeted agents, other novel targeted agents, and combination regimens for malignant melanoma. New immune checkpoint inhibitors and targeted agents are able to improve immune-mediated regulatory effects against tumors and, specifically in advanced melanoma, are associated with improvement in overall survival. These new agents have distinct side effects that are often controlled and reversed with dose reductions and/or use of corticosteroids. Currently, there are clinical trials underway to assess the role of combination therapy, whereas other trials are focusing on devising algorithms to delineate how best to sequentially administer these drugs. Although there has been tremendous progress in the management of advanced melanoma with immunotherapy and targeted agents, there is still much to be learned about clinically useful predictive biomarkers and combination therapies as well as how to administer these agents safely. PMID:25018651

Srivastava, Neeharika; McDermott, David

2014-01-01

399

Allergy immunotherapy tablet: Grazax® for the treatment of grass pollen allergy.  

PubMed

Immunotherapy is the only treatment for allergy that alters the natural course of this disease. Sublingual immunotherapy has been developed to make immunotherapy more suitable for allergic patients. In the largest clinical program ever conducted with grass allergen-specific immunotherapy, over 2000 adults and more than 500 children have been exposed to Grazax(®) (ALK-Abello A/S, Hoersholm, Denmark). Grazax is an oral lyophilisate tablet (allergy immunotherapy tablet [AIT]) for sublingual administration, containing 75,000 standardized quality tablet units of allergen extract of grass pollen (Phleum pratense). Grazax is indicated for treatment of grass pollen-induced rhinitis and conjunctivitis in adult and pediatric patients. Results from the GT-08 trial (first, second and third treatment years) showed a reduction of 31, 36 and 29%, respectively, in symptom scores and a reduction of 38, 45 and 40% of medication scores, respectively, compared with placebo. Subjects treated with Grazax also had an increased number of well days and a relevant improvement in quality of life. More subjects experienced excellent and complete rhinoconjunctivitis control in comparison with patients treated with symptomatic medications only. Grazax treatment is also associated with a sustained and relevant increase of specific IgG4. This increase is also observed after stopping AIT treatment. The most common adverse events related to Grazax treatment are local reactions, such as oral itch, edema of the mouth, ear pruritus, throat irritation and sneezing. Clinical efficacy of Grazax is observed also after 1 and 2 years of follow-up after stopping the AIT treatment. Grazax is efficacious and safe for treatment of grass-pollen rhinoconjunctivitis in both adults and children. Grazax is the first AIT showing a disease-modifying effect on grass pollen-induced allergic rhinoconjuctivitis. PMID:21162646

Senna, Gian Enrico; Calderon, Moises; Milani, Massimo

2011-01-01

400

Leishmania donovani Nucleoside Hydrolase Terminal Domains in Cross-Protective Immunotherapy Against Leishmania amazonensis Murine Infection  

PubMed Central

Nucleoside hydrolases of the Leishmania genus are vital enzymes for the replication of the DNA and conserved phylogenetic markers of the parasites. Leishmania donovani nucleoside hydrolase (NH36) induced a main CD4+ T cell driven protective response against L. chagasi infection in mice which is directed against its C-terminal domain. In this study, we used the three recombinant domains of NH36: N-terminal domain (F1, amino acids 1–103), central domain (F2 aminoacids 104–198), and C-terminal domain (F3 amino acids 199–314) in combination with saponin and assayed their immunotherapeutic effect on Balb/c mice previously infected with L. amazonensis. We identified that the F1 and F3 peptides determined strong cross-immunotherapeutic effects, reducing the size of footpad lesions to 48 and 64%, and the parasite load in footpads to 82.6 and 81%, respectively. The F3 peptide induced the strongest anti-NH36 antibody response and intradermal response (IDR) against L. amazonenis and a high secretion of IFN-? and TNF-? with reduced levels of IL-10. The F1 vaccine, induced similar increases of IgG2b antibodies and IFN-? and TNF-? levels, but no IDR and no reduction of IL-10. The multiparameter flow cytometry analysis was used to assess the immune response after immunotherapy and disclosed that the degree of the immunotherapeutic effect is predicted by the frequencies of the CD4+ and CD8+ T cells producing IL-2 or TNF-? or both. Total frequencies and frequencies of double-cytokine CD4 T cell producers were enhanced by F1 and F3 vaccines. Collectively, our multifunctional analysis disclosed that immunotherapeutic protection improved as the CD4 responses progressed from 1+ to 2+, in the case of the F1 and F3 vaccines, and as the CD8 responses changed qualitatively from 1+ to 3+, mainly in the case of the F1 vaccine, providing new correlates of immunotherapeutic protection against cutaneous leishmaniasis in mice based on T-helper TH1 and CD8+ mediated immune responses. PMID:24966857

Nico, Dirlei; Gomes, Daniele Crespo; Palatnik-de-Sousa, Iam; Morrot, Alexandre; Palatnik, Marcos; Palatnik-de-Sousa, Clarisa Beatriz

2014-01-01