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  1. Selective inhibition of TNFR1 reduces osteoclast numbers and is differentiated from anti-TNF in a LPS-driven model of inflammatory bone loss.

    PubMed

    Espirito Santo, A I; Ersek, A; Freidin, A; Feldmann, M; Stoop, A A; Horwood, N J

    2015-09-01

    The treatment of autoimmune disorders has been revolutionised by the introduction of biologics such as anti-tumour necrosis factor (anti-TNF). Although in rheumatoid arthritis patients a bone sparing effect of anti-TNF has been shown, the mechanism is not fully understood. Anti-TNF molecules block tumour necrosis factor (TNF) and prevent signalling via both TNF receptor 1 (TNFR1; p55) and TNF receptor 2 (TNFR2; p75). However, signalling via TNFR2 is reported to have protective effects in a number of cell and organ systems. Hence we set out to investigate if pharmacological inhibition of TNFR1 had differential effects compared to pan-TNF inhibition in both an in vitro cell-based model of human osteoclast activity and an in vivo mouse model of lipopolysaccharide (LPS)-induced osteolysis. For the in vitro experiments the anti-human TNFR1 domain antibody (dAb) DMS5541 was used, whereas for the in vivo mouse experiments the anti-mouse TNFR1 dAb DMS5540 was used. We show that selective blocking of TNFR1 signalling reduced osteoclast formation in the presence of TNF. Subcutaneous LPS injection over the calvaria leads to the development of osteolytic lesions within days due to inflammation driven osteoclast formation. In this model, murine TNFR2 genetically fused with mouse IgG1 Fc domain (mTNFR2.Fc), an anti-TNF, did not protect from bone loss in contrast to anti-TNFR1, which significantly reduced lesion development, inflammatory infiltrate, and osteoclast number and size. These results support further exploring the use of TNFR1-selective inhibition in inflammatory bone loss disorders such as osteomyelitis and peri-prosthetic aseptic loosening. PMID:26208457

  2. Implementable strategies and exploratory considerations to reduce costs associated with anti-TNF therapy in inflammatory bowel disease.

    PubMed

    Park, K T; Crandall, Wallace V; Fridge, Jacqueline; Leibowitz, Ian H; Tsou, Marc; Dykes, Dana M H; Hoffenberg, Edward J; Kappelman, Michael D; Colletti, Richard B

    2014-05-01

    A health care system is needed where care is based on the best available evidence and is delivered reliably, efficiently, and less expensively (best care at lower cost). In gastroenterology, anti-tumor necrosis factor agents represent the most effective medical therapeutic option for patients with moderate-to-severe inflammatory bowel disease (IBD), but are very expensive and account for nearly a quarter of the cost of IBD care, representing a major area of present and future impact in direct health care costs. The ImproveCareNow Network, consisting of over 55 pediatric IBD centers, seeks ways to improve the value of care in IBD, curtailing unnecessary costs and promoting better health outcomes through systematic and incremental quality improvement initiatives. This report summarizes the key evidence to facilitate the cost-effective use of anti-tumor necrosis factor agents for patients with IBD. Our review outlines the scientific rationale for initiating cost-reducing measures in anti-tumor necrosis factor use and focuses on 3 implementable strategies and 4 exploratory considerations through practical clinical guidelines, as supported by existing evidence. Implementable strategies can be readily integrated into today's daily practice, whereas exploratory considerations can guide research to support future implementation. PMID:24451222

  3. Alternative for Anti-TNF Antibodies for Arthritis Treatment

    PubMed Central

    Paquet, Joseph; Henrionnet, Christel; Pinzano, Astrid; Vincourt, Jean-Baptiste; Gillet, Pierre; Netter, Patrick; Chary-Valckenaere, Isabelle; Loeuille, Damien; Pourel, Jacques; Grossin, Laurent

    2011-01-01

    Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a key role in the pathogenesis of many inflammatory diseases, including arthritis. Neutralization of this cytokine by anti-TNF-α antibodies has shown its efficacy in rheumatoid arthritis (RA) and is now widely used. Nevertheless, some patients currently treated with anti-TNF-α remain refractory or become nonresponder to these treatments. In this context, there is a need for new or complementary therapeutic strategies. In this study, we investigated in vitro and in vivo anti-inflammatory potentialities of an anti-TNF-α triplex-forming oligonucleotide (TFO), as judged from effects on two rat arthritis models. The inhibitory activity of this TFO on articular cells (synoviocytes and chondrocytes) was verified and compared to that of small interfering RNA (siRNA) in vitro. The use of the anti-TNF-α TFO as a preventive and local treatment in both acute and chronic arthritis models significantly reduced disease development. Furthermore, the TFO efficiently blocked synovitis and cartilage and bone destruction in the joints. The results presented here provide the first evidence that gene targeting by anti-TNF-α TFO modulates arthritis in vivo, thus providing proof-of-concept that it could be used as therapeutic tool for TNF-α-dependent inflammatory disorders. PMID:21811249

  4. Reduced numbers of mucosal DR(int) macrophages and increased numbers of CD103(+) dendritic cells during anti-TNF-α treatment in patients with Crohn's disease.

    PubMed

    Dige, Anders; Magnusson, Maria K; Öhman, Lena; Hvas, Christian Lodberg; Kelsen, Jens; Wick, Mary Jo; Agnholt, Jørgen

    2016-06-01

    Objective Anti-TNF-α treatment constitutes a mainstay in the treatment of Crohn's disease (CD), but its mechanisms of action are not fully understood. We aimed to investigate the effects of adalimumab, a human monoclonal TNF-α antibody, on macrophage (MQ) and dendritic cell (DC) subsets in mucosal biopsies and peripheral blood. Material and methods Intestinal biopsies and blood samples were obtained from 12 different CD patients both before and 4 weeks after the initiation of the induction of adalimumab treatment. Endoscopic disease activity was estimated by the Simple Endoscopic Score for Crohn's Disease. Biopsies were obtained from inflamed and non-inflamed areas. The numbers of lamina propria CD14 (+) DR(int) and CD14 (+) DR(hi) MQs, CD141(+), CD141(-) and CD103(+ )DCs subsets, and circulating monocytes and DCs were analyzed using flow cytometry. Results At baseline, we observed higher numbers of DR(int) MQs and lower numbers of CD103(+ )DCs in inflamed versus non-inflamed mucosa [843 vs. 391/10(5) lamina propria mononuclear cells (LPMCs) (p < 0.05) and 9 vs. 19 × 10(5) LPMCs (p = 0.01), respectively]. After four weeks of adalimumab treatment, the numbers of DR(int) MQs decreased [843 to 379/10(5) LPMCs (p = 0.03)], whereas the numbers of CD103(+ )DCs increased [9-20 × 10(5) LPMCs (p = 0.003)] compared with baseline. In peripheral blood, no alterations were observed in monocyte or DC numbers between baseline and week 4. Conclusions In CD, mucosal inflammation is associated with high numbers of DR(int) MQs and low numbers of CD103(+ )DCs. This composition of intestinal myeloid subsets is reversed by anti-TNF-α treatment. These results suggest that DR(int) MQs play a pivotal role in CD inflammation. PMID:26784676

  5. Influence of Anti-TNF and Disease Modifying Antirheumatic Drugs Therapy on Pulmonary Forced Vital Capacity Associated to Ankylosing Spondylitis: A 2-Year Follow-Up Observational Study

    PubMed Central

    Rocha-Muñoz, Alberto Daniel; Brambila-Tapia, Aniel Jessica Leticia; Zavala-Cerna, María Guadalupe; Vásquez-Jiménez, José Clemente; De la Cerda-Trujillo, Liliana Faviola; Vázquez-Del Mercado, Mónica; Rodriguez-Jimenez, Norma Alejandra; Díaz-Rizo, Valeria; Díaz-González, Viviana; Cardona-Muñoz, Ernesto German; Dávalos-Rodríguez, Ingrid Patricia; Salazar-Paramo, Mario; Gamez-Nava, Jorge Ivan; Nava-Zavala, Arnulfo Hernan; Gonzalez-Lopez, Laura

    2015-01-01

    Objective. To evaluate the effect of anti-TNF agents plus synthetic disease modifying antirheumatic drugs (DMARDs) versus DMARDs alone for ankylosing spondylitis (AS) with reduced pulmonary function vital capacity (FVC%). Methods. In an observational study, we included AS who had FVC% <80% at baseline. Twenty patients were taking DMARDs and 16 received anti-TNF + DMARDs. Outcome measures: changes in FVC%, BASDAI, BASFI, 6-minute walk test (6MWT), Borg scale after 6MWT, and St. George's Respiratory Questionnaire at 24 months. Results. Both DMARDs and anti-TNF + DMARDs groups had similar baseline values in FVC%. Significant improvement was achieved with anti-TNF + DMARDs in FVC%, at 24 months, when compared to DMARDs alone (P = 0.04). Similarly, patients in anti-TNF + DMARDs group had greater improvement in BASDAI, BASFI, Borg scale, and 6MWT when compared to DMARDs alone. After 2 years of follow-up, 14/16 (87.5%) in the anti-TNF + DMARDs group achieved the primary outcome: FVC% ≥80%, compared with 11/20 (55%) in the DMARDs group (P = 0.04). Conclusions. Patients with anti-TNF + DMARDs had a greater improvement in FVC% and cardiopulmonary scales at 24 months compared with DMARDs. This preliminary study supports the fact that anti-TNF agents may offer additional benefits compared to DMARDs in patients with AS who have reduced FVC%. PMID:26078986

  6. Whole cell-based surface plasmon resonance measurement to assess binding of anti-TNF agents to transmembrane target.

    PubMed

    Ogura, Takeharu; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2016-09-01

    We developed a technique for the measurement of surface plasmon resonance (SPR) to detect interactions of anti-tumor necrosis factor (TNF) agents with transmembrane TNF-α (mTNF-α) on living whole cells. The injection of a suspension of mTNF-α expressing Jurkat cells, used as an analyte, gave a clear binding response to anti-TNF agents, such as etanercept, infliximab and adalimumab, immobilized on sensorchip. The binding response of the analyte cells increased in a concentration-dependent manner and was competitively reduced by adding soluble TNF receptors to the analyte cell suspension. Treatment of analyte cells with free anti-TNF agent before injection reduced the binding response between the analyte cells and immobilized-etanercept on sensorchip, and the inhibitory effect of free anti-TNF agent was concordant with the affinity of anti-TNF agent for soluble TNF-α. These findings indicate that the SPR response arises from specific binding between anti-TNF agent and its target on cell membrane. PMID:27349512

  7. Tocilizumab: is there life beyond anti-TNF blockade?

    PubMed

    Alves, J D; Marinho, A; Serra, M J

    2011-04-01

    Anti-TNF-α therapy has become the most effective biological treatment for rheumatoid arthritis. Despite having changed the prognosis of the disease establishing new targets for treatment strategy, there are several aspects that still remain unmatched. About 30% of the patients with rheumatoid arthritis have a less than satisfactory response to anti-TNF therapy, which has led the way for the pursuit of new targets and approaches to treatment. IL-6 is one of these alternative targets and data from the more recent clinical trials involving tocilizumab (an anti-IL-6 soluble receptor antibody) suggest advantages in relation to some clinical aspects which are not addressed by anti-TNF-α treatment. PMID:21272164

  8. Anti-TNF-α monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis.

    PubMed

    Liu, Yu; Yang, Guoyou; Zhang, Junfeng; Xing, Kaiyan; Dai, Lei; Cheng, Lin; Liu, Junli; Deng, Jie; Shi, Gang; Li, Chunlei; Su, Xiaolan; Zhang, Shuang; Yang, Yang; Li, Jia; Yu, Dechao; Xiang, Rong; Wei, Yuquan; Deng, Hongxin

    2015-09-01

    Tumor necrosis factor-alpha (TNF-α) antagonists have shown remarkable efficacy in psoriasis; however, the precise mechanisms of action of TNF-α blocking agents mainly focus on their neutralizing TNF-α and its anti-inflammatory effects. In this study, we generated a humanized anti-TNF-α monoclonal antibody (IBI303) and suggested a potential mechanism of anti-TNF-α therapy for psoriasis. The results of SPR and ELISA indicated that IBI303 has a good affinity to TNF-α. In vitro, it could suppress TNF-α-induced cytotoxicity in WEHI164 cells. In vivo, administration of IBI303 to K14-VEGF transgenic mice led to a significant treatment efficiency in psoriasis in a dose-dependent manner. IHC staining and cytokines-ELISA indicated that TNF-α inhibition strongly reduced inflammatory cells infiltration and pro-inflammatory cytokines release, accompanied by suppression of inflamed dermal blood vessels. Mechanistically, in order to explain the anti-angiogenesis effect of anti-TNF-α antibody, the production of cytokine in macrophage conditional medium was measured by ELISA. The result indicated that the massive secretion of TNF-α stimulated by LPS in RAW264.7 cell supernatant was markedly neutralized in a dose-response manner by IBI303, moreover, the expression of NF-κB p65 was down-regulated. Mouse endothelial cell tube formation assay showed that anti-TNF-α could inhibit blood vessels formation directly and indirectly. Collectively, our study suggested a kind of antipsoriatic mechanism of TNF-α inhibitors that is the dual inhibition of inflammation and angiogenesis. PMID:26263167

  9. Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease.

    PubMed

    Levin, Alon D; Wildenberg, Manon E; van den Brink, Gijs R

    2016-08-01

    Several anti-tumour necrosis factor [TNF] blocking strategies have been evaluated in patients with Crohn's disease. Compounds that have been tested included the full monoclonal IgG1 antibodies infliximab and adalimumab, the pegylated anti-TNF F[ab']2 fragment certolizumab, an IgG4 anti-TNF CDP571 with reduced affinity for the Fc receptor, the soluble TNF receptor I onercept, and the TNF receptor II-Fc fusion protein etanercept. The endpoints of these studies suggest that not all methods of blocking TNF are equal. Here we will review the differences in the clinical, biochemical, and endoscopic endpoints of the major clinical studies. Collectively the data suggest that only IgG1 monoclonal antibodies have the ability to induce complete clinical, biochemical, and endoscopic remission. We discuss the potential multiple modes of action that may contribute to the response to full IgG1 anti-TNFs, focusing on the rapid induction of lamina propria T cell apoptosis and Fc receptor-dependent induction of M2-type wound-healing macrophages. We discuss how novel insights into the mechanism of action of anti-TNFs in Crohn's disease may contribute to the development of novel anti-TNFs with improved efficacy. PMID:26896086

  10. Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis.

    PubMed

    Sieberts, Solveig K; Zhu, Fan; García-García, Javier; Stahl, Eli; Pratap, Abhishek; Pandey, Gaurav; Pappas, Dimitrios; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Eksi, Ridvan; Fornés, Oriol; Guney, Emre; Li, Hongdong; Marín, Manuel Alejandro; Panwar, Bharat; Planas-Iglesias, Joan; Poglayen, Daniel; Cui, Jing; Falcao, Andre O; Suver, Christine; Hoff, Bruce; Balagurusamy, Venkat S K; Dillenberger, Donna; Neto, Elias Chaibub; Norman, Thea; Aittokallio, Tero; Ammad-Ud-Din, Muhammad; Azencott, Chloe-Agathe; Bellón, Víctor; Boeva, Valentina; Bunte, Kerstin; Chheda, Himanshu; Cheng, Lu; Corander, Jukka; Dumontier, Michel; Goldenberg, Anna; Gopalacharyulu, Peddinti; Hajiloo, Mohsen; Hidru, Daniel; Jaiswal, Alok; Kaski, Samuel; Khalfaoui, Beyrem; Khan, Suleiman Ali; Kramer, Eric R; Marttinen, Pekka; Mezlini, Aziz M; Molparia, Bhuvan; Pirinen, Matti; Saarela, Janna; Samwald, Matthias; Stoven, Véronique; Tang, Hao; Tang, Jing; Torkamani, Ali; Vert, Jean-Phillipe; Wang, Bo; Wang, Tao; Wennerberg, Krister; Wineinger, Nathan E; Xiao, Guanghua; Xie, Yang; Yeung, Rae; Zhan, Xiaowei; Zhao, Cheng; Greenberg, Jeff; Kremer, Joel; Michaud, Kaleb; Barton, Anne; Coenen, Marieke; Mariette, Xavier; Miceli, Corinne; Shadick, Nancy; Weinblatt, Michael; de Vries, Niek; Tak, Paul P; Gerlag, Danielle; Huizinga, Tom W J; Kurreeman, Fina; Allaart, Cornelia F; Louis Bridges, S; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M; Bridges, S Louis; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M

    2016-01-01

    Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2)=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data. PMID:27549343

  11. Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis

    PubMed Central

    Sieberts, Solveig K.; Zhu, Fan; García-García, Javier; Stahl, Eli; Pratap, Abhishek; Pandey, Gaurav; Pappas, Dimitrios; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Eksi, Ridvan; Fornés, Oriol; Guney, Emre; Li, Hongdong; Marín, Manuel Alejandro; Panwar, Bharat; Planas-Iglesias, Joan; Poglayen, Daniel; Cui, Jing; Falcao, Andre O.; Suver, Christine; Hoff, Bruce; Balagurusamy, Venkat S. K.; Dillenberger, Donna; Neto, Elias Chaibub; Norman, Thea; Aittokallio, Tero; Ammad-ud-din, Muhammad; Azencott, Chloe-Agathe; Bellón, Víctor; Boeva, Valentina; Bunte, Kerstin; Chheda, Himanshu; Cheng, Lu; Corander, Jukka; Dumontier, Michel; Goldenberg, Anna; Gopalacharyulu, Peddinti; Hajiloo, Mohsen; Hidru, Daniel; Jaiswal, Alok; Kaski, Samuel; Khalfaoui, Beyrem; Khan, Suleiman Ali; Kramer, Eric R.; Marttinen, Pekka; Mezlini, Aziz M.; Molparia, Bhuvan; Pirinen, Matti; Saarela, Janna; Samwald, Matthias; Stoven, Véronique; Tang, Hao; Tang, Jing; Torkamani, Ali; Vert, Jean-Phillipe; Wang, Bo; Wang, Tao; Wennerberg, Krister; Wineinger, Nathan E.; Xiao, Guanghua; Xie, Yang; Yeung, Rae; Zhan, Xiaowei; Zhao, Cheng; Calaza, Manuel; Elmarakeby, Haitham; Heath, Lenwood S.; Long, Quan; Moore, Jonathan D.; Opiyo, Stephen Obol; Savage, Richard S.; Zhu, Jun; Greenberg, Jeff; Kremer, Joel; Michaud, Kaleb; Barton, Anne; Coenen, Marieke; Mariette, Xavier; Miceli, Corinne; Shadick, Nancy; Weinblatt, Michael; de Vries, Niek; Tak, Paul P.; Gerlag, Danielle; Huizinga, Tom W. J.; Kurreeman, Fina; Allaart, Cornelia F.; Louis Bridges Jr., S.; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K.; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M.; Bridges, S. Louis; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K.; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M.

    2016-01-01

    Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data. PMID:27549343

  12. Effect of Anti-TNF Antibodies on Clinical Response in Rheumatoid Arthritis Patients: A Meta-Analysis

    PubMed Central

    Wang, Shengxu; Xian, Peifeng; Mo, Xianjie

    2016-01-01

    Background. Antitumor necrosis factor (anti-TNF) drugs have been applied for rheumatoid arthritis (RA) treatment; however, patients having anti-drug antibodies (ADAbs) do not benefit from these drugs. The meta-analysis aims to comprehensively assess the relationship between ADAb positive (ADAb+) and anti-TNF response in RA patients. Methods. Observational studies comparing different clinical response between ADAb+ and ADAb negative groups were included. Odds ratio (OR) with its corresponding 95% confidence interval (CI) was used as effect size. Subgroup analyses stratified by TNF inhibitor types and assay methods for ADAb detection were performed. Results. Totally, 10 eligible studies containing 1806 subjects were included. ADAb+ was significantly associated with reduced anti-TNF response to RA at all the time points after follow-up (P < 0.001). Subgroup analysis also supported this significant association (P < 0.05), except for enzyme-linked immunosorbent assay (ELISA) group at 3 months, infliximab (INF) and enzyme-linked immunosorbent assay (ELISA) groups at 6 months, and Immunological Multi-Parameter Chip Technology (IMPACT) group at 12 months. Conclusion. ADAb+ was significantly associated with reduced clinical response in RA patients, and other alternatives should be considered in RA patients presenting ADAb+. PMID:27556040

  13. Anti-TNF therapy: past, present and future

    PubMed Central

    Monaco, Claudia; Nanchahal, Jagdeep; Taylor, Peter

    2015-01-01

    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

  14. Assessment of Anti-TNF-α Activities in Keratinocytes Expressing Inducible TNF- α: A Novel Tool for Anti-TNF-α Drug Screening

    PubMed Central

    Udommethaporn, Sutthirat; Tencomnao, Tewin; McGowan, Eileen M.

    2016-01-01

    Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine important in normal and pathological biological processes. Newly synthesized pro-TNF-α is expressed on the plasma membrane and cleaved to release soluble TNF-α protein: both are biologically active. Secreted TNF-α signals through TNF receptors and the membrane-bound TNF-α acts by cell contact-dependent signaling. Anti-TNF-α antibodies have been used effectively for treatment of chronic inflammation, however with adverse side effects. Thus, there is a need for new anti-TNF-α small molecule compounds. Anti-TNF-α activity assays involve treatment of keratinocytes with exogenous TNF-α before or after anti-TNF-α incubation. However, this model fails to address the dual signaling of TNF-α. Here we describe a Doxycycline (Dox)-inducible TNF-α (HaCaT-TNF-α) expression system in keratinocytes. Using this in-vitro model, we show cell inhibition and induced expression of pro-inflammatory cytokines and markers, including IL-1β, IL-6, IL-8, NF-κB1, and KRT-16, similar to cells treated with exogenous TNF-α. Sufficient secreted TNF-α produced also activated IL-1β and IL-8 expression in wt HaCaT cells. Importantly, stimulated expression of IL-1β and IL-8 in HaCaT-TNF-α were blocked by Quercetin, a flavanol shown to possess anti-TNF-α activities. This novel in vitro cell model provides an efficient tool to investigate the dual signaling of TNF-α. Importantly, this model provides an effective, fast, and simple screening for compounds with anti-TNF-α activities for chronic inflammatory disease therapies. PMID:27415000

  15. Expression of recombinant human anti-TNF-α scFv-Fc in Arabidopsis thaliana seeds.

    PubMed

    Yao, N; Ai, L; Dong, Y Y; Liu, X M; Wang, D Z; Wang, N; Li, X W; Wang, F W; Li, Xk; Li, H Y; Jiang, C

    2016-01-01

    Recombinant human anti-tumor necrosis factor (TNF)-α scFv-Fc was expressed in TKO mutant Arabidopsis thaliana seeds using plant-specific codons. Immunoblotting using a human IgG1 antibody detected the expression of anti-TNF-α proteins in plants. Results from qRT-PCR analysis demonstrated that the time of harvest significantly affected the protein yield and quality. Our results indicate that the Phaseolus vulgaris β-phaseolin promoter directed anti-TNF-α scFv-Fc expression in A. thaliana seeds, with a maximum yield obtained at 20-days of development. Although the yield of anti-TNF-α scFv-Fc protein was not very high, accumulation of recombinant proteins in seeds is an attractive and simple method that can be used to purify biologically active anti-TNF-α scFv-Fc. PMID:27420937

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

    PubMed Central

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

    2013-01-01

    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

  17. Applying Pharmacokinetics to Optimize Dosing of Anti-TNF Biologics in Acute Severe Ulcerative Colitis

    PubMed Central

    Rosen, Michael J.; Minar, Philip; Vinks, Alexander A.

    2015-01-01

    Background Acute severe ulcerative colitis (ASUC), the most aggressive presentation ulcerative colitis (UC), occurs in 15 percent of adults and children with UC. First line therapy with intravenous corticosteroids is ineffective in half of adults and one third of children. Therapeutic monoclonal antibodies against TNF (anti-TNF therapy) are emerging as a common treatment for ASUC due to their similar efficacy to calcineurin inhibitors and more favorable adverse effect profile. Aim To comprehensively review the evidence for anti-TNF therapy for ASUC in children and adults with regard to outcomes and pharmacokinetics. Methods PubMed and recent conference proceedings were searched using the terms “ulcerative colitis”, “acute severe ulcerative colitis”, “anti-TNF”, “pharmacokinetics”, and the generic names of specific anti-TNF agents. Results Outcomes after anti-TNF therapy for ASUC remain suboptimal with aboutone half of children and adults undergoing colectomy. While several randomized controlled trials have demonstrated the efficacy of anti-TNF therapy for ambulatory patients with moderate to severely active UC, patients in these studies were less ill than those with ASUC. Patients with ASUC may exhibit more rapid clearance of anti-TNF biologics due pharmacokinetic mechanisms influenced by disease severity. Conclusions Conventional weight-based dosing effective in patients with moderately to severely active UC, may not be equally effective in those with ASUC. Personalized anti-TNF dosing strategies that integratepatient factors and early measures of pharmacokinetics and response hold promise for ensuring sustained drug exposure and maximizing early mucosal healing in patients with ASUC. PMID:25809869

  18. A guide to prepare patients with inflammatory bowel diseases for anti-TNF-α therapy.

    PubMed

    Chebli, Júlio Maria Fonseca; Gaburri, Pedro Duarte; Chebli, Liliana Andrade; da Rocha Ribeiro, Tarsila Campanha; Pinto, André Luiz Tavares; Ambrogini Júnior, Orlando; Damião, Adérson Omar Mourão Cintra

    2014-01-01

    Current therapy of moderate-to-severe inflammatory bowel disease (IBD) often involves the use of anti-tumor necrosis factor alpha (TNF-α) 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-α therapy. A thorough history to rule-out contraindications of this therapy and emphasis on monitoring guidelines are important steps preceding administration of anti-TNF-α 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-α agents have been considered to present a globally favorable benefit/risk ratio. However, it is important that in routine practice, initiation of anti-TNF-α therapy be carefully discussed with the patient, extensively explaining the potential benefits and risks of such treatment. Prior to starting anti-TNF-α 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-α 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-α therapy. PMID:24667275

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

    PubMed Central

    Aberer, Werner; Massone, Cesare

    2014-01-01

    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-α therapy. We retrieved 13 publications describing 20 patients where the new onset of DM/PM after anti-TNF-α 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-α 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-α 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-α blocking agents may trigger the onset of PM/DM or antisynthetase syndrome or may aggravate/trigger the lung disease. PMID:24600322

  20. Thyroid involvement in ankylosing spondylitis and relationship of thyroid dysfunction with anti-TNF α treatment.

    PubMed

    Tarhan, Figen; Orük, Gonca; Niflioğlu, Ozgür; Ozer, Serhat

    2013-04-01

    Association between rheumatological and autoimmune thyroid disorders has been demonstrated by many studies. However, a few data exist indicating the association between thyroid disorders and ankylosing spondylitis (AS). In this study, the frequency of thyroid disorders in patients with AS and the impact of anti-TNF α therapy on this were investigated. Data of 108 patients (female/male (F/M) 27/81) were analyzed. Data on free T3, free T4, thyroid-stimulating hormone, anti-thyroid peroxidase antibodies (TPO), anti-thyroglobulin antibodies, and thyroid ultrasound were assessed retrospectively. 44 (F/M 15/29) patients were receiving anti-TNF α, while 64 (F/M 12/52) were receiving other drugs [(sulfasalazine, anti-inflammatory drug (NSAIDs)]. Among those not receiving anti-TNF α therapy, TPO level was high in 23 patients (mean TPO value 86.69 ± 65.28 U/ml), while it was high only in nine receiving anti-TNF α (mean TPO 36.61 ± 14.02 U/ml) (p < 0.05). Investigating the data regarding gender in both populations, autoimmune thyroid disease frequency was found to be lower in the patient group receiving anti-TNF α treatment. Subclinical hyperthyroidism was discovered in three patients (one female two male), and subclinical hypothyroidism in two (two male). Thyroid nodule was detected in 29 patients. It was concluded that the frequency of thyroid autoimmune disease was higher in our study than that reported in the literature, and the frequency of thyroid disorder in patients with AS was lower in those receiving anti-TNF α compared to those not. This may arise from the role of TNF α on pathogenesis of thyroid disorders. PMID:22614219

  1. Effect of 1-year anti-TNF-α therapy on aortic stiffness, carotid atherosclerosis, and calprotectin in inflammatory arthropathies: a controlled study

    PubMed Central

    Angel, Kristin

    2012-01-01

    Background Premature arterial stiffening and atherosclerosis are increased in patients with inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The proinflammatory protein calprotectin is associated with inflammatory arthropathies, vascular pathology, and acute coronary events. We examined the long-term effects of treatment with tumor necrosis factor (TNF)-α antagonists on aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies, and the relationships to the levels of calprotectin. Methods Fifty-five patients with RA, AS, or PsA and a clinical indication for anti-TNF-α therapy were included and followed with regular examinations for 1 year. Thirty-six patients starting with anti-TNF-α therapy were compared with a nontreatment group of 19 patients. Examinations included assessments of aortic stiffness (aortic pulse wave velocity, aPWV), CIMT, and plasma calprotectin. Results After 1 year, aPWV (mean (s.d.)) was improved in the treatment group, but not in the control group (−0.54 [0.79] m/s vs. 0.06 [0.61] m/s, respectively; P = 0.004), and CIMT progression (median (quartile cut-points, 25th and 75th percentiles)) was reduced in the treatment group compared to the control group (−0.002 [–0.038, 0.030] mm vs. 0.030 [0.011, 0.043] mm, respectively; P = 0.01). In multivariable analyses, anti-TNF-α therapy over time was associated with improved aPWV (P = 0.02) and reduced CIMT progression (P = 0.04), and calprotectin was longitudinally associated with aPWV (P = 0.02). Conclusions Long-term anti-TNF-α therapy improved aortic stiffness and CIMT progression in patients with inflammatory arthropathies. Calprotectin may be a soluble biomarker reflecting aortic stiffening in these patients. PMID:22378036

  2. The influence of anti-TNF agents on hemoglobin levels of patients with inflammatory bowel disease

    PubMed Central

    Koutroubakis, Ioannis E.; Ramos–Rivers, Claudia; Regueiro, Miguel; Koutroumpakis, Efstratios; Click, Benjamin; Schwartz, Marc; Swoger, Jason; Baidoo, Leonard; Hashash, Jana G.; Barrie, Arthur; Dunn, Michael A.; Binion, David G.

    2015-01-01

    Background Anti-tumor necrosis factor (TNF) agents are an important component of inflammatory bowel disease (IBD) treatment but data on their influence on anemia, a frequent complication of IBD is limited. The aim of this study was to evaluate the effect of anti-TNF agents on hemoglobin (Hb) levels in a large IBD cohort. Methods Prospectively collected demographic, clinical, laboratory and treatment data from IBD patients who started anti-TNF treatment at a tertiary referral center during the years 2010–2012 were analyzed. Follow-up data including disease activity scores (Harvey-Bradshaw Index or ulcerative colitis activity index), quality of life scores [short IBD questionnaire (SIBDQ)] completed at each visit, and laboratory data were analyzed. Data from the year of anti-TNF initiation (year 0) and the following year (year 1) were compared. Results A total of 430 IBD patients (324 with Crohn’s disease, 51.6% females) started anti-TNF treatment. The prevalence of anemia and median Hb levels did not change between year 0 and year 1. Median SIBDQ was significantly improved at year 1 (p=0.002). IBD patients with anemia had significantly higher median Hb levels at year 1 compared to year 0 (p=0.0009). Hematopoietic response (increase of Hb ≥2 g/dL) was observed in only 33.6 % of the 134 anemic IBD patients, despite iron replacement being administered in 126 anemic patients (oral 77 %). Improvement in Hb levels was independently significantly correlated with change of CRP levels (p=0.04) and immunomodulators use (p=0.03). Conclusion Anemia remains a significant manifestation of IBD one year after treatment with anti-TNF agents. PMID:25933393

  3. Do patients with active RA have differences in disease activity and perceptions if anti-TNF naïve versus anti-TNF experienced? Baseline results of the optimization of adalimumab trial

    PubMed Central

    Pope, Janet; Thorne, J. Carter; Haraoui, Boulos Paul; Psaradellis, Eliofotisti; Sampalis, John

    2012-01-01

    Summary Background The chance of a good response in RA is attenuated in previous anti-TNF users who start new anti-TNF therapy compared to biologic naïve patients. In active RA, those with previous anti-TNF exposure compared to anti-TNF naïve may have different baseline disease activity and patient perceptions when starting a new anti-TNF treatment that could explain the observed response differences. Material/Methods The aim of this study was a post hoc analysis of baseline characteristics of patients enrolled in the Optimization of Adalimumab study that was a treat to target vs. routine care study in patients initiating adalimumab. As per the protocol, a maximum of 20% anti-TNF experienced patients were enrolled in the 300 patient trial. Twelve (4.0%) were excluded who previously used other biologics. Baseline characteristics including age, gender, tender and swollen joint counts, disease activity (DAS28), function (HAQ-DI), patient global assessment, patient satisfaction with current treatment, and inflammatory markers (CRP, ESR), were compared between previously anti-TNF experienced [etanercept or infliximab (EXP)], and anti-TNF naïve patients (NAÏVE). Results The mean (SD) age was 54.8 (13.3) years; 81.0% were female, and 237 (79.0%) were anti-TNF naïve while 51 (17.0%) patients were anti-TNF experienced (29 with etanercept, 16 with infliximab, and 6 for both). The mean (SD) baseline in EXP versus NAÏVE groups respectively was: CRP=21.7(32.9) vs. 17.5(20.7); ESR=28.7(22.5) vs. 29.8(20.4); SJC=10.5(6.0) vs. 10.7(5.6); TJC=12.8(7.1) vs. 12.3(7.3); and DAS28=6.0(1.2) vs. 5.8(1.1). None of the between-group differences were statistically significant, however, the HAQ-DI in EXP was 1.7(0.6) compared to 1.5(0.7) for the NAÏVE (P=0.021). Additionally, EXP patients had a higher patient global score [71.3(26.1) vs. 61.9(26.2), P=0.021]. Conclusions Although anti-TNF naïve and experienced patients who initiated adalimumab were similar, with respect to several

  4. Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents.

    PubMed

    Clark, Ian A; Vissel, Bryce

    2016-01-01

    The basic mechanism of the major neurodegenerative diseases, including neurogenic pain, needs to be agreed upon before rational treatments can be determined, but this knowledge is still in a state of flux. Most have agreed for decades that these disease states, both infectious and non-infectious, share arguments incriminating excitotoxicity induced by excessive extracellular cerebral glutamate. Excess cerebral levels of tumor necrosis factor (TNF) are also documented in the same group of disease states. However, no agreement exists on overarching mechanism for the harmful effects of excess TNF, nor, indeed how extracellular cerebral glutamate reaches toxic levels in these conditions. Here, we link the two, collecting and arguing the evidence that, across the range of neurodegenerative diseases, excessive TNF harms the central nervous system largely through causing extracellular glutamate to accumulate to levels high enough to inhibit synaptic activity or kill neurons and therefore their associated synapses as well. TNF can be predicted from the broader literature to cause this glutamate accumulation not only by increasing glutamate production by enhancing glutaminase, but in addition simultaneously reducing glutamate clearance by inhibiting re-uptake proteins. We also discuss the effects of a TNF receptor biological fusion protein (etanercept) and the indirect anti-TNF agents dithio-thalidomides, nilotinab, and cannabinoids on these neurological conditions. The therapeutic effects of 6-diazo-5-oxo-norleucine, ceptriaxone, and riluzole, agents unrelated to TNF but which either inhibit glutaminase or enhance re-uptake proteins, but do not do both, as would anti-TNF agents, are also discussed in this context. By pointing to excess extracellular glutamate as the target, these arguments greatly strengthen the case, put now for many years, to test appropriately delivered ant-TNF agents to treat neurodegenerative diseases in randomly controlled trials. PMID:27596607

  5. Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis.

    PubMed

    Spinelli, Francesca Romana; Di Franco, Manuela; Metere, Alessio; Conti, Fabrizio; Iannuccelli, Cristina; Agati, Luciano; Valesini, Guido

    2014-11-01

    Chronic inflammatory diseases such as rheumatoid arthritis (RA) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to the impairment of endothelial function, the earlier and reversible stage of atherosclerotic plaque formation. Since tumor necrosis factor (TNF) inhibits enzymatic degradation of ADMA, anti-TNF agents could restore its physiological level. The aim of this study was to investigate the effect of TNF inhibitors on ADMA serum levels in patients with RA. Our results suggest a possible effect of anti-TNF drugs on ADMA serum levels; longer studies would be necessary to confirm the role ADMA in assessing cardiovascular risk in RA. PMID:25381982

  6. Effects of Anti-Tumor Necrosis Factor α (anti-TNF) agents on Bone

    PubMed Central

    Kawai, Vivian K.; Stein, C. Michael; Perrien, Daniel S.; Griffin, Marie R.

    2013-01-01

    Purpose of the review TNF inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established. Recent findings There are many studies of the effects of TNF inhibitors on markers of bone turnover; however few have measured bone mineral density (BMD) or fractures. Most of these studies have small sample sizes and a minority had a placebo control group. Overall these studies suggest that the anti-resorptive effects of anti-TNF therapy are related to control of disease activity. Summary The antiresorptive effects of TNF inhibitors are likely related to their anti-inflammatory properties. Studies to date have not demonstrated any advantages of TNF inhibitors over traditional non biologic therapies in the prevention of bone loss and fractures. PMID:22810364

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

    PubMed

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

    2012-10-01

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

  8. Production and Purification of a Novel Anti-TNF-α Single Chain Fragment Variable Antibody

    PubMed Central

    Alizadeh, Ali Akbar; Hamzeh-Mivehroud, Maryam; Dastmalchi, Siavoush

    2015-01-01

    Purpose: TNF-α is an inflammatory cytokine with a key role in initiation of inflammatory responses. Anti-TNF-α antibodies are being used in clinic for the purpose of diagnosis and treatment due to their high specificity. The objective of the current study was to express and purify an anti-TNF-α scFv antibody identified by phage display technology. Methods: The DNA coding sequence of the identified scFv was cloned into pET28a vector and the corresponding protein was expressed as 6×His tagged using E.coli BL21 (DE3) pLysS expression system followed by affinity purification on Ni-Sepharose affinity column. Results: The J44 scFv antibody was cloned into the expression vector and successfully expressed and purified. The purity of the scFv fraction was confirmed using SDS-PAGE analysis. Western blotting technique was used to detect expression of 6×His tagged protein. Conclusion: In the current study an anti-TNF-α scFv antibody was successfully expressed in bacterial expression system and purified on affinity column. The purified protein can be used in different in vitro and in vivo experiments in order to elucidate its functionality. PMID:26793614

  9. Effects of hyaluronic acid conjugation on anti-TNF-α inhibition of inflammation in burns.

    PubMed

    Friedrich, Emily E; Sun, Liang Tso; Natesan, Shanmugasundaram; Zamora, David O; Christy, Robert J; Washburn, Newell R

    2014-05-01

    Biomaterials capable of neutralizing specific cytokines could form the basis for treating a broad range of conditions characterized by intense, local inflammation. Severe burns, spanning partial- to full-thickness of the dermis, can result in complications due to acute inflammation that contributes to burn progression, and early mediation may be a key factor in rescuing thermally injured tissue from secondary necrosis to improve healing outcomes. In this work, we examined the effects on burn progression and influence on the inflammatory microenvironment of topical application of anti-tumor necrosis factor-α (anti-TNF-α) alone, mixed with hyaluronic acid (HA) or conjugated to HA. We found that non-conjugated anti-TNF-α decreased macrophage infiltration to a greater extent than that conjugated to HA; however, there was little effect on the degree of progression or IL-1β levels. A simple transport model is proposed to analyze the results, which predicts qualitative and quantitative differences between untreated burn sites and those treated with the conjugates. Our results indicate that conjugation of anti-TNF-α to high molecular weight HA provides sustained, local modulation of the post-injury inflammatory responses compared to direct administration of non-conjugated antibodies. PMID:23765644

  10. Paradoxical effects of anti-TNF-α agents in inflammatory diseases.

    PubMed

    Wendling, Daniel; Prati, Clément

    2014-01-01

    Anti-TNF agents represent a major breakthrough in the management of inflammatory diseases. Among the side effects of these agents are the so-called paradoxical effects described in this review. They represent new onset or exacerbation of a condition (symptom/disease), usually improved with TNF blockers. These paradoxical effects are mainly psoriasiform skin reactions, uveitis and granulomatous diseases (such as sarcoidosis and Crohn's disease). Infrequent and probably underreported, they should be discussed from the viewpoint of spontaneous features of the underlying disease (e.g., uveitis or psoriasis in a case of spondyloarthritis). The causal mechanism of occurrence is still a matter of debate, but may implicate an imbalance of cytokines toward interferons, chemokines and probably IL-17. These reactions may raise differential diagnosis problems. Symptoms resolve, most of the time, due to the discontinuation of the anti-TNF agent or sometimes a switch to another TNF blocker; but in some cases, it is a class effect that could lead to the withdrawal of all anti-TNF agents. PMID:24325385

  11. Specific immunotherapy with mugwort pollen allergoid reduce bradykinin release into the nasal fluid

    PubMed Central

    Grzanka, Alicja; Jawor, Barbara; Czecior, Eugeniusz

    2016-01-01

    Introduction A pathomechanism of allergic rhinitis is complex. A neurogenic mechanism seems to play a significant role in this phenomenon. Aim The evaluation of influence of specific immunotherapy of mugwort pollen allergic patients on the bradykinin concentration in the nasal lavage fluid. Material and methods The study included 22 seasonal allergic rhinitis patients. Thirty persons with monovalent allergy to mugwort pollen, confirmed with skin prick tests and allergen-specific immunoglobulin E, underwent a 3-year-long allergen immunotherapy with the mugwort extract (Allergovit, Allergopharma, Germany). The control group was composed of 9 persons with polyvalent sensitivity to pollen, who were treated with pharmacotherapy. Before the allergen-specific immunotherapy (AIT) and in subsequent years before the pollen seasons, a provocation allergen test with the mugwort extract was performed, together with collection of nasal fluids, where bradykinin concentration was determined according to Proud method. Results There were similar levels of bradykinin in both groups at baseline prior to therapy (AIT group: 584.0 ±87.2 vs. controls 606.3 ±106.5 pg/ml) and changes after allergen challenge 1112.4 ±334.8 vs. 1013.3 ±305.9 pg/ml as well. The bradykinin concentration in nasal lavage fluid after mugwort challenge in 1 year was lower in the AIT group (824.1 ±184.2 pg/ml vs. 1000.4 ±411.5 pg/l; p < 005) with a further significant decrease after the 2nd and 3rd year of specific immunotherapy. Significant reduction of symptoms and medications use was observed in hyposensitized patients. Conclusions A decreased level of bradykinin as a result of AIT suggests that some of the symptomatic benefits of AIT may be related to the reduced release of bradykinin into nasal secretions. These values correlate with clinical improvement within the course of treatment. PMID:27605897

  12. CDP 571: anti-TNF monoclonal antibody, BAY 103356, BAY W 3356, Humicade.

    PubMed

    2003-01-01

    CDP 571 [anti-TNF monoclonal antibody, BAY 103356, BAY W 3356, Humicade] is a recombinant humanised antibody directed against tumour necrosis factor (TNF). CDP 571 has an advantage over the mouse/human chimera anti-TNF-alpha antibody, nerelimomab, in that it is suitable for multiple dosing as it is not so immunogenic. Celltech constructed CDP 571 by grafting the section of mouse antibody that recognises TNF onto a human IgG4 antibody. In the third quarter of 1999, Celltech merged with Chiroscience to form Celltech Chiroscience. In January 2000, Medeva was merged into Celltech Chiroscience, which was renamed as Celltech Group. The research division of Celltech Group is now called Celltech R&D (formerly Celltech Chiroscience Discovery) and the manufacturing and marketing division is called Celltech Pharmaceuticals (formerly Celltech Medeva Pharma). Celltech has completed two phase III trials, involving around 670 patients with moderate-to-severe Crohn's disease; however, both these trials failed to meet their primary endpoints. Biogen and Celltech group will review the scope of their collaboration following additional analysis of the phase III data and discussions with regulatory authorities. The Celltech Group intends to devote significant resources towards enhancing the capability of Celltech Pharmaceuticals to market CDP 571 and other new drugs (such as CDP 860 and CDP 870) as specialised hospital products. Phase II trials were underway in the United Kingdom for use of the drug in the treatment of type 2 diabetes mellitus. However, these trials have also been discontinued. Celltech Group is no longer developing CDP 571 for septic shock, based on negative results with the related compound nerelimomab. The compound was in phase III trials for septic shock in France, Belgium, the United Kingdom, Germany and the US. Celltech also plans to investigate the use of CDP 571 in psoriasis via a collaboration with Biogen (USA). In January 2002, AFX (Agence France-Presse and

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

    PubMed Central

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

    2014-01-01

    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

  14. [How to optimize the antiTNF alpha therapy in spondylitis?].

    PubMed

    Castro Villegas, Maria del Carmen; Escudero Contreras, Alejandro; Miranda García, Maria Dolores; Collantes Estévez, Eduardo

    2012-03-01

    TNFalpha inhibitors have been a major advance in the treatment of spondyloarthropathies, having demonstrated their safety and efficacy, with higher response and survival rates than those observed in patients with rheumatoid arthritis. The fact that disease modifying anti-arthritic drugs (DMARD) have shown utility in the treatment of this disease, especially in the axial forms, gives them greater importance, since it is known that up to 30%of patients do not respond to treatment with non-steroidal anti-inflammatory drugs. However, we must take into account that these drugs are expensive and not without side effects, so it is necessary to optimize their use. We intend to review the use of antiTNF alpha in spondyloarthropathies and review the available evidence on strategies that can help with their rational use. PMID:22418285

  15. DISSEMINATED GRANULOMA ANNULARE: A CUTANEOUS ADVERSE EFFECT OF ANTI-TNF AGENTS

    PubMed Central

    Ratnarathorn, Mondhipa; Raychaudhuri, Siba P; Naguwa, Stanley

    2011-01-01

    Tumor necrosis factor-alpha (TNF-α) inhibitors, such as etanercept, infliximab, and adalimumab, bind to TNF-α and thereby act as anti-inflammatory agents. This group of drugs has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, moderate to severe plaque psoriasis, ankylosing spodylitis, Crohn disease, and juvenile idiopathic arthritis. We describe a 56-year-old woman who developed an erythematous pruritic rash on both arms—diagnosed as granuloma annulare by skin biopsy—approximately 22 months after initiating adalimumab for treatment of rheumatoid arthritis. On stopping adalimumab there was total clearance of the skin lesions, but a similar rash developed again when her treatment was switched to another anti-TNF agent (etanercept). This clinical observation supports a link between TNF inhibition and the development of granuloma annulare. PMID:22345789

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

    SciTech Connect

    Wilson, Christy M.; Gaber, M. Waleed Sabek, Omaima M.; Zawaski, Janice A.; Merchant, Thomas E.

    2009-07-01

    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.

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

    PubMed Central

    Mariette, Xavier; Tubach, Florence; Bagheri, Haleh; Bardet, Michel; Berthelot, Jean-Marie; Gaudin, Philippe; Heresbach, Denis; Martin, Antoine; Schaeverbeke, Thierry; Salmon, Dominique; Lemann, Marc; Hermine, Olivier; Raphael, Martine; Ravaud, Philippe

    2010-01-01

    Objective To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare risks for different anti-TNF agents. Methods We designed a national prospective registry (RATIO) from 2004 to 2006, for collecting all cases of lymphoma in French patients receiving anti-TNF therapy, whatever the indication. We conducted a case-control analysis including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population used as reference.. Results We collected 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B-cell and 5 T-cell), 5 Hodgkin’s lymphoma (HL) and 2 Hodgkin’s-like lymphoma. Epstein-Barr virus (EBV) was detected in 2 of 2 Hodgkin’s-like lymphoma, 3 of 5 HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: SIR = 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4– 1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case-control study: odds ratio=4.7 (1.3– 17.7) and 4.1 (1.4–12.5), respectively. The sex and age- adjusted incidence rate of lymphoma was 42.1 per 100,000 patient-years. The standardized incidence ratio (SIR) was 2.4 (95% confidence interval [CI] 1.7–3.2). Conclusion Some lymphomas associated with immunosuppression may occur in patients receiving anti TNF therapy, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy. PMID:19828563

  18. Gastrointestinal stability of therapeutic anti-TNF α IgG1 monoclonal antibodies.

    PubMed

    Yadav, Vipul; Varum, Felipe; Bravo, Roberto; Furrer, Esther; Basit, Abdul W

    2016-04-11

    Monoclonal antibodies (mAbs) are highly effective therapeutic agents, administered exclusively by the parenteral route owing to their previously-documented instability in the gastrointestinal (GI) tract when delivered orally. To investigate the extent of the validity of this assumption, the stability of the tumor necrosis factor alpha (TNF-α) neutralizing IgG1 mAbs, infliximab and adalimumab, was studied in human GI conditions. In gastric fluid, infliximab and adalimumab degraded rapidly, with complete degradation occurring within 1min. In small intestinal fluid, the molecules were shown to be more stable, but nonetheless degraded within a short time frame of 30min. Investigations into the mechanisms responsible for infliximab and adalimumab instability in the small intestine revealed that the proteolytic enzyme elastase, and to a lesser extent the enzymes trypsin and chymotrypsin, was responsible for their degradation. By contrast, in the human colon, 75% and 50% of the dose of infliximab and adalimumab, respectively, were intact after 60min, with conversion of mAbs into F(ab')2 Fab and Fc fragments detected in colonic conditions. These data indicate that therapeutic IgG1 antibodies are more stable in the colon than in the upper GI tract, therefore highlighting the potential for oral delivery of anti-TNF-α mAbs targeted to the colon. PMID:26892815

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

    PubMed Central

    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

    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-) α, interleukin- (IL-) 1β, and IL-6. However, although biological treatment with anti-TNF-α 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-α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium. PMID:25061259

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

    PubMed

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

    2014-12-01

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

  1. Diffuse sclerosing osteomyelitis (DSO) of the mandible in SAPHO syndrome: a novel approach with anti-TNF therapy. Systematic review.

    PubMed

    Marí, Antonio; Morla, Arnaud; Melero, Mireia; Schiavone, Rocio; Rodríguez, Jesus

    2014-12-01

    Diffuse sclerosing osteomyelitis of the mandible is now considered a local manifestation of SAPHO syndrome. This rare condition is thought to be of auto-inflammatory origin. The myriad of treatments shown in the literature, are basically empirical and reflect its unknown origin. We present a clinical case of refractory DSO treated with an anti-TNF drug (etanercept) with complete clinical remission. We advise against radical surgery and an interdisciplinary approach is recommended. A systematic literature review was also conducted. PMID:25441866

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

    PubMed

    Laharie, David

    2014-01-01

    Management of patients with IBD and a past or current malignancy has become more frequent in daily practice. As trends in IBD therapy are moving to more immunomodulators, administered earlier and for longer periods than ever, an increasing number of IBD patients with a prior malignancy may receive conventional immunosuppressants (IS) and/or anti-TNF. However, few data are available for managing this IBD subpopulation due to three main reasons: (1) previous cancer is usually an exclusion criterion from all clinical trials, (2) guidelines do not recommend any immunomodulator use in patients who have had a malignancy within the last 5 years, and (3) physicians are reluctant to use immunomodulators which could reactivate dormant micrometastasis. However, there is a lack of scientific evidence for avoiding immunomodulators in IBD patients with previous cancer. In a recently published cohort of patients with previous cancer, no excess incidence of incident cancer was associated with exposure to IS. Data with anti-TNF are lacking in IBD. Recently in a registry including 79 patients with refractory IBD who started an anti-TNF therapy while having had a prior malignancy within the past 5 years, survival rates without incident cancer were 96 and 72% at 1 and 5 years, respectively. Thus, evidence to not start IS and/or anti-TNF therapy in IBD patients who have had a previous cancer is weak. Pending larger studies, a case-by-case joint decision taken with the oncologist and the patient is recommended, and should take IBD and the cancer risk-benefit ratio for using immunomodulators to treat refractory disease into consideration. PMID:25531363

  3. Dose modifications of anti-TNF drugs in rheumatoid arthritis patients under real-world settings: a systematic review.

    PubMed

    Ferriols-Lisart, Rafael; Ferriols-Lisart, Francisco

    2015-07-01

    Anti-TNF dose modifications in rheumatoid arthritis have implications on healthcare resource utilization. The objective was to systematically review the dose modifications, both escalations and reductions, of currently available anti-TNF drugs (adalimumab, certolizumab, etanercept, golimumab and infliximab) in the real-world setting. We performed a systematic literature search of MEDLINE, ISI Web of Science, EMBASE, Indice Médico Español databases and American College of Rheumatology and European League Against Rheumatism annual congresses databases. PRISMA and MOOSE guidelines were followed. Only observational studies were included. Clinical trials were excluded since they do not reflect routine clinical practice. Dose escalations and reductions of the anti-TNF drug and their magnitude were collected. Thirty-four studies fulfill the inclusion criteria. Etanercept was associated with the lower percentage of patients under dose escalation (4.5 %; range 0-22 %), both in naïve (4.9 %) and non-naïve patients (1.3 %). Adalimumab and infliximab were associated with significantly higher percentages. Dose modification magnitude in those patients compared to basal dose was significantly different between treatments; 7.1 % (95 % CI 6.3-7.9 %) in etanercept, 30.4 % (95 % CI 28.3-32.5 %) in adalimumab and 21 % (95 % CI 20.3-21.7 %) in infliximab. Adalimumab and infliximab were associated with a higher risk of dose escalation relative to etanercept. There were no significant differences in the dose reduction percentages for the whole group of patients between treatments. In rheumatoid arthritis, etanercept is associated with a significantly lower percentage of dose-escalated patients and a lower magnitude of dose modification. Significant differences in the dose reduction between anti-TNF drugs evaluated were not observed. PMID:25638015

  4. 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis.

    PubMed

    van der Heijde, Désirée; Sieper, Joachim; Maksymowych, Walter P; Dougados, Maxime; Burgos-Vargas, Rubén; Landewé, Robert; Rudwaleit, Martin; Braun, Jürgen

    2011-06-01

    This paper presents the second update of the Assessment in SpondyloArthritis international Society (ASAS) consensus statement on the use of anti-tumour necrosis factor (anti-TNF) agents in patients with axial spondyloarthritis (SpA). A major change from the previous recommendations is that patients fulfilling the ASAS axial SpA criteria, which also include patients fulfilling the modified New York criteria for ankylosing spondylitis, can be treated with anti-TNF agents. This makes an earlier start in the disease process possible. A second major change is the mandatory pretreatment before anti-TNF agents can be started. All patients should have tried a minimum of two non-steroidal anti-inflammatory drugs for a minimum of 4 weeks in total. This is significantly shorter than the previous requirement of 3 months. As previously, patients with axial symptoms require no further pretreatment. Patients with symptomatic peripheral symptoms should normally have had an adequate therapeutic trial of a disease-modifying antirheumatic drug, preferably sulfasalazine. Sulfasalazine is no longer mandatory in this group of patients. Finally, efficacy should be evaluated after at least 12 weeks. The remaining recommendations stayed largely unchanged. PMID:21540200

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

    PubMed

    Marquette, S; Peerboom, C; Yates, A; Denis, L; Langer, I; Amighi, K; Goole, J

    2014-08-15

    Antibodies (Abs) require the development of stable formulations and specific delivery strategies given their susceptibility to a variety of physical and chemical degradation pathways. In this study, the encapsulation of an antibody into polylactide-co-glycolide (PLGA) based microspheres was explored to obtain a controlled-release of the incorporated drug. In order to avoid stability issues, a solid-in-oil-in-water (s/o/w) method was preferred. The solid phase was made of anti-TNF alpha monoclonal antibody (MAb) spray-dried microparticles, and the PLGA microspheres were produced using two different polymers (i.e., Resomer(®) RG505 and Resomer(®) RG755S). The stability of the MAb incorporated into the microspheres was investigated under three conditions (5 ± 3°C, 25 ± 2°C/60% RH and 40 ± 2°C/75% RH) for 12 weeks. During this stability study, it was demonstrated that the MAb loaded PLGA microspheres were stable when stored at 5 ± 3°C and that the Resomer(®) RG755S, composed of 75%(w/w) lactic acid as PLGA, was preferred to preserve the stability of the system. Storage at temperatures higher than 5°C led to antibody stability issues such as aggregation, fragmentation and loss of activity. The release profiles were also altered. Physical ageing of the system associated with changes in the glass transition temperature and enthalpy of relaxation was noticed during the storage of the MAb loaded PLGA microspheres. PMID:24792974

  6. Genetic Variations in Pattern Recognition Receptor Loci Are Associated with Anti-TNF Response in Patients with Rheumatoid Arthritis

    PubMed Central

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

    2015-01-01

    Objectives To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA). Methods In a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes. We included 538 anti-TNF naïve Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses. False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status. Results Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1–2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1–7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4–1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response. The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4–16.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association. Conclusions We reproduced previously reported associations between

  7. Differential effects of anti-TNF-α and anti-IL-12/23 agents on human leukocyte-endothelial cell interactions.

    PubMed

    Ríos-Navarro, Cesar; de Pablo, Carmen; Collado-Diaz, Víctor; Orden, Samuel; Blas-Garcia, Ana; Martínez-Cuesta, María Ángeles; Esplugues, Juan V; Alvarez, Angeles

    2015-10-15

    Enhanced leukocyte recruitment is an inflammatory process that occurs during early phases of the vascular dysfunction that characterises atherosclerosis. We evaluated the impact of anti-TNF-α (adalimumab, infliximab and etanercept) and anti-IL-12/23 (ustekinumab) on interactions between human leukocytes and endothelial cells in a flow chamber that reproduced in vivo conditions. Clinical concentrations of anti-TNF-α were evaluated on the leukocyte recruitment induced by a variety of endothelial (TNF-α, interleukin-1β, lymphotoxin-α and angiotensin-II) and leukocyte (PAF, IL-12 and IL-23) stimuli related to inflammation and atherosclerosis. Treatment with anti-TNF-α, even before or after establishing the inflammatory situation induced by TNF-α, diminished leukocyte-endothelial cell interactions induced by this stimuli. Our results also implicated adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in the actions of anti-TNF-α in terms of leukocyte adhesion to endothelium. However, anti-TNF-α drugs did not influence the actions of interleukin-1β, but prevented those of lymphotoxin-α and angiotensin-II. However, once established, inflammatory response elicited by the latter three stimuli could not be reversed. Pre-treatment with anti-TNF-α, also prevented leukocyte actions induced by IL-23 on PBMC rolling flux and rolling velocity and by IL-12 on PMN adhesion. Ustekinumab exhibited a more discreet profile, having no effect on leukocyte recruitment induced by any of the endothelial stimuli, while blocking the effects of IL-23 on leukocyte activation and those of IL-12 on PMN adhesion and PAF on PBMC rolling velocity. These findings endorse the idea that biological anti-inflammatory drugs, in particular anti-TNF-α, have the capacity to influence cardiovascular risk accompanying psoriasis and rheumatoid arthritis by ameliorating vascular inflammation. PMID:26344475

  8. Candidate's single-nucleotide polymorphism predictors of treatment nonresponse to the first anti-TNF inhibitor in ankylosing spondylitis.

    PubMed

    Schiotis, Ruxandra; Sánchez, Alejandra; Escudero, Alejandro; Bartolomé, Nerea; Szczypiorska, Magdalena; Font, Pilar; Martínez, Antonio; Tejedor, Diego; Artieda, Marta; Mulero, Juan; Buzoianu, Anca; Collantes-Estévez, Eduardo

    2014-06-01

    The objective of this study is to identify single-nucleotide polymorphisms (SNPs) predictors of treatment nonresponse to the first anti-TNF-alpha agent in ankylosing spondylitis (AS). Patients were classified as "nonresponders" if they failed to achieve improvement ≥50 % of the initial BASDAI. We selected candidate SNPs previously reported, associated with susceptibility or pathogenesis of AS and with other spondylarthropaties (SpAs). The predictors of nonresponse were modeled with multiple logistic regression. The predictive power of the genetic model of nonresponse to treatment was tested with AUC-ROC. One hundred and twenty-one (121) AS patients fulfilled the inclusion criteria. Of the candidate SNPs tested for association with treatment effectiveness, five independent predictors were identified: rs917997, rs755622, rs1800896, rs3740691, and rs1061622. The genetic model of nonresponse to treatment had a predictive power of 0.77 (95 % CI 0.68-0.86). Our study identified several polymorphisms which could be the useful genetic biomarkers in predicting nonresponse to anti-TNF-alpha therapy. PMID:24337767

  9. Successful Treatment of Primary Cutaneous Mucormycosis Complicating Anti-TNF Therapy with a Combination of Surgical Debridement and Oral Posaconazole.

    PubMed

    Camargo, Jose F; Yakoub, Danny; Cho-Vega, Jeong Hee

    2015-10-01

    Lipid formulations of amphotericin B remain the first-line antifungal therapy for invasive mucormycosis. Posaconazole is an alternative for salvage therapy, but its use as primary therapy is not recommended due to the paucity of clinical data. Here we describe the case of a 57-year-old diabetic woman receiving etanercept and prednisone for the treatment of psoriatic arthritis who developed primary cutaneous mucormycosis after a minor gardening injury. Infection was successfully treated with aggressive surgical debridement followed by a 6-week course of the new delayed-release tablet formulation of posaconazole and temporary withholding of anti-TNF treatment. Primary antifungal therapy with posaconazole can be considered in selected cases of cutaneous mucormycosis. PMID:26112998

  10. Optimal Doses of Methotrexate Combined with Anti-TNF Therapy to Maintain Clinical Remission in Inflammatory Bowel Disease

    PubMed Central

    Rubin, David T

    2015-01-01

    Background and aims: Methotrexate (MTX) is sometimes used as part of combination therapy for the treatment of inflammatory bowel disease [IBD]; however, the optimal MTX dose for combination therapy has not been established. This study compared the efficacy of lower-dose and higher-dose MTX with anti tumor necrosis factor alpha (anti-TNF) therapy among IBD patients. Methods: Retrospective chart review was performed of 88 IBD patients at our center between 2010 and 2013. Low-dose MTX was defined as ≤ 12.5mg/week and high-dose MTX as 15–25mg/week. Patients who met the criteria for clinical remission [Harvey-Bradshaw Index ≤ 4, Simple Clinical Colitis Activity Index ≤ 2] at baseline were followed for up to 42 months. Chart review occurred in 6-month intervals. The primary outcome was consecutive months in remission prior to relapse. Secondary outcomes included other indicators of worsening disease [endoscopic inflammation, steroid use, therapy escalation/addition, or surgery] and adverse events. Regression analysis and Kaplan–Meier survival analysis were completed. Results: We identified 73 [83%] dual-therapy patients, of whom 32 low-dose and 14 high-dose individuals achieved remission. When compared with high-dose patients, low-dose patients were more likely to relapse [log-rank test, p < 0.01]. Secondary indicators of worsening disease occurred during 34.4% of low-dose review periods and 31.4% of high-dose review periods [p = 0.67]; 3/52 [6%] low-dose patients and 3/21 [14%] high-dose patients [p = 0.34] discontinued MTX therapy due to adverse events. Conclusions: When combined with anti-TNF therapy, MTX at doses of >12.5mg/week was more effective at maintaining clinical remission than lower doses. These findings will guide management of combination therapy in IBD patients. PMID:25616487

  11. Impact of 24 months of anti-TNF therapy versus methotrexate on body weight in patients with rheumatoid arthritis: a prospective observational study.

    PubMed

    Sfriso, Paolo; Caso, Francesco; Filardo, Giuseppe Sebastiano; Botsios, Costantino; Costa, Luisa; Scarpa, Raffaele; Todesco, Silvano; Spinella, Paolo; Oliviero, Francesca; Punzi, Leonardo

    2016-06-01

    To evaluate the impact of anti-TNF-α therapy on the body weight of rheumatoid arthritis (RA) patients following 24 months of treatment. Data were collected on all RA patients included in the Veneto Region's Registry of Biological Therapy from January 2007 to July 2012. Inclusion criteria were: start of monotherapy with adalimumab, etanercept, or methotrexate, no previous use of biologic therapy, and at least 24 months of treatment. At baseline, 12, and 24 months, each patient completed a questionnaire about physical activity, smoking, alcohol, and food habits. One hundred and thirty-one RA patients in monotherapy with etanercept (n = 47), adalimumab (n = 44), and methotrexate (n = 40) were enrolled for this study. After 24 months of therapy, there was an increase of weight only in patients treated with anti-TNF-α. Patients on etanercept and adalimumab therapy showed a risk to gain weight six times greater compared to those on methotrexate therapy. The results of present study show that the use of anti-TNF-α in RA patients can be associated to a significant increase of body weight. This increase is not shown in patients under treatment with methotrexate. A more careful evaluation of weight changes needs to be considered in RA patients under anti-TNF-α treatment. PMID:27048267

  12. The tumor necrosis factor receptor superfamily member 1B polymorphisms predict response to anti-TNF therapy in patients with autoimmune disease: A meta-analysis.

    PubMed

    Chen, Wenjuan; Xu, Hui; Wang, Xiuxiu; Gu, Junying; Xiong, Huizi; Shi, Yuling

    2015-09-01

    Numerous published data on the tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) gene polymorphisms are shown to be associated with response or non-response to anti-TNF therapy in autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and Crohn's Disease (CD). The aim of this study is to investigate whether the TNFRSF1B rs1061622 T/G or TNFRSF1A A/G rs767455 polymorphisms can predict the response to anti-TNF-based therapy in patients with autoimmune diseases. We conducted a meta-analysis of studies on the association between TNFRSF1B rs1061622 T/G polymorphism or TNFRSF1A A/G rs767455 polymorphism and non-responsiveness to anti-TNF therapy in autoimmune diseases. A total of 8 studies involving 929 subjects for TNFRSF1B rs1061622 and 564 subjects for TNFRSF1A rs767455 were finally considered. These studies consisted of seven studies on the TNFRSF1B polymorphism and four studies on the TNFRSF1A polymorphism. Meta-analysis showed significant association between the TNFRSF1B rs1061622 allele and non-responders to anti-TNF therapy [T/G odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.93, p=0.01]. Stratification by disease type indicated an association between the TNFRSF1B rs1061622 allele and non-responders to TNF antagonist in RA (T/G OR 0.69, 95% CI 0.48-0.99, p<0.05) and psoriasis (T/G OR 0.39, 95% CI 0.23-0.67, p<0.001), but not in CD (T/G OR 1.14, 95% CI 0.57-0.93, p=0.57). And there was no association between TNFRSF1A rs767455 genotype and non-responders to the anti-TNF therapy (A/G OR 0.93, 95% CI 0.70-1.23, p=0.59). This meta-analysis demonstrates that TNFRSF1B T allele carriers show a better response to anti-TNF therapy, and individuals carrying TNFRSF1A A allele have no relationship with the response to anti-TNF therapy for autoimmune diseases. The genotyping of this polymorphism could help to optimize the treatment by identifying patients with a likely poor response to biological drugs. PMID:26071216

  13. Target effector role of vascular endothelium in the inflammatory response: insights from the clinical trial of anti-TNF alpha antibody in rheumatoid arthritis.

    PubMed Central

    Paleolog, E

    1997-01-01

    Rheumatoid arthritis (RA) is characterised by chronic joint inflammation and infiltration by cells from the blood, especially activated T cells and macrophages, together with formation of new blood vessels. The overgrowth of the synovial lesion results eventually in destruction of cartilage and bone. Cytokines play a major role in RA, both in systemic inflammatory processes, such as induction of acute phase protein synthesis, and in the stimulation of new blood vessel development and recruitment of leucocytes to developing lesions. The focus for the interplay of many cytokines is the endothelium, the lining layer of the vasculature. This is the primary target for circulating mediators, and it controls the traffic of cells and molecules from the bloodstream into underlying tissues. Targeting the action of individual cytokines--for example, using antibody against tumour necrosis factor alpha (TNF alpha), has been shown to be very effective in the treatment of RA. Blockade of TNF alpha activity results in deactivation of the endothelium, manifested as reduced expression of adhesion molecules and chemoattractant cytokines, leading to diminished trafficking of inflammatory cells to synovial joints. In addition anti-TNF alpha decreases circulating levels of the potent angiogenic cytokine VEGF, suggesting that new blood vessel formation, and hence the supply of nutrients to the growing synovial lesion, is also affected. These observations lend further support to the hypothesis that interruption of a component of the cytokine network in RA may modulate disease progression, and point the way towards the development of new therapeutic strategies for the treatment of chronic inflammatory disease states. PMID:9497911

  14. NIR and MR imaging supported hydrogel based delivery system for anti-TNF alpha probiotic therapy of IBD

    NASA Astrophysics Data System (ADS)

    Janjic, Jelena M.; Berlec, Ales; Bagia, Christina; Liu, Lu S.; Jeric, Irenej; Gach, Michael; Janjic, Bratislav M.; Strukelj, Borut

    2016-03-01

    Current treatment of inflammatory bowel disease (IBD) is largely symptomatic and consists of anti-inflammatory agents, immune-suppressives or antibiotics, whereby local luminal action is preferred to minimize systemic side-effects. Recently, anti-TNFα therapy has shown considerable success and is now being routinely used. Here we present a novel approach of using perfluorocarbon (PFC) nanoemulsion containing hydrogels (nanoemulgels) as imaging supported delivery systems for anti-TNF alpha probiotic delivery in IBD. To further facilitate image-guided therapy a food-grade lactic acid bacterium Lactococcus lactis capable of TNFα-binding was engineered to incorporate infrared fluorescent protein (IRFP). This modified bacteria was then incorporated into novel PFC nanoemulgels. The nanoemulgels presented here are designed to deliver locally anti-TNFα probiotic in the lower colon and rectum and provide dual imaging signature of gel delivery (MRI) across the rectum and lower colon and bacteria release (NIR). NIR imaging data in vitro demonstrates high IRFP expressing and TNFα-binding bacteria loading in the hydrogel and complete release in 3 hours. Stability tests indicate that gels remain stable for at least 14 days showing no significant change in droplet size, zeta potential and pH. Flow cytometry analyses demonstrate the NIRF expressing bacteria L. lactis binds TNFα in vitro upon release from the gels. Magnetic resonance and near-infrared imaging in vitro demonstrates homogeneity of hydrogels and the imaging capacity of the overall formulation.

  15. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis.

    PubMed

    Nguyen, Dao Xuan; Ehrenstein, Michael R

    2016-06-27

    The interplay between inflammatory and regulatory pathways orchestrates an effective immune response that provides protection from pathogens while limiting injury to host tissue. Tumor necrosis factor (TNF) is a pivotal inflammatory cytokine, but there is conflicting evidence as to whether it boosts or inhibits regulatory T cells (T reg cells). In this study, we show that the therapeutic anti-TNF antibody adalimumab, but not the soluble TNF receptor etanercept, paradoxically promoted the interaction between monocytes and T reg cells isolated from patients with rheumatoid arthritis (RA). Adalimumab bound to monocyte membrane TNF from RA patients and unexpectedly enhanced its expression and its binding to TNF-RII expressed on T reg cells. As a consequence, adalimumab expanded functional Foxp3(+) T reg cells equipped to suppress Th17 cells through an IL-2/STAT5-dependent mechanism. Our data not only highlight the beneficial effect of membrane TNF on T reg cell numbers during chronic inflammation, but in addition reveal how a therapeutic antibody that is thought to act by simply blocking its target can enhance the regulatory properties of this proinflammatory cytokine. PMID:27270893

  16. Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-α therapy.

    PubMed

    McGeough, Cathy M; Berrar, Daniel; Wright, Gary; Mathews, Clare; Gilmore, Paula; Cunningham, Rodat T; Bjourson, Anthony J

    2012-06-01

    The identification of patients who will respond to anti-tumor necrosis factor alpha (anti-TNF-α) therapy will improve the efficacy, safety, and economic impact of these agents. We investigated whether killer cell immunoglobulin-like receptor (KIR) genes are related to response to anti-TNF-α therapy in patients with rheumatoid arthritis (RA). Sixty-four RA patients and 100 healthy controls were genotyped for 16 KIR genes and human leukocyte antigen-C (HLA-C) group 1/2 using polymerase chain reaction sequence-specific oligonucleotide probes (PCR-SSOP). Each patient received anti-TNF-α therapy (adalimumab, etanercept, or infliximab), and clinical responses were evaluated after 3 months using the disease activity score in 28 joints (DAS28). We investigated the correlations between the carriership of KIR genes, HLA-C group 1/2 genes, and clinical data with response to therapy. Patients responding to therapy showed a significantly higher frequency of KIR2DS2/KIR2DL2 (67.7% R vs. 33.3% NR; P = 0.012). A positive clinical outcome was associated with an activating KIR-HLA genotype; KIR2DS2 (+) HLA-C group 1/2 homozygous. Inversely, non-response was associated with the relatively inhibitory KIR2DS2 (-) HLA-C group 1/2 heterozygous genotype. The KIR and HLA-C genotype of an RA patient may provide predictive information for response to anti-TNF-α therapy. PMID:21373785

  17. The Effects of Infliximab on Laminin, NFκB, and Anti-TNF Expression through Its Effect on Ischemic Liver Tissue.

    PubMed

    Akdogan, Remzi Adnan; Kalkan, Yildiray; Tümkaya, Levent; Rakici, Halil; Akdogan, Elif

    2016-01-01

    The aim of this study was to investigate the possible protective effects of infliximab on expression of laminin, anti-TNF, and NFκB in the rat hepatic cells after ischemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into three groups: Control (C), sham I/R (ISC), and I/R+ infliximab (ISC inf); each group comprised 10 animals. C group animals underwent laparotomy without I/R injury. In ISC groups after undergoing laparotomy, 1 hour of superior mesenteric artery ligation was done, which was followed by 1 hour of reperfusion. In the ISC inf group, 3 days before I/R, infliximab (3 mg/kg) was administered intravenously. All animals were killed at the end of reperfusion and hepatic tissue samples were obtained for histopathological and histochemical investigations in all groups. Laminin, anti-TNF, and NFκB immunoreactivity were performed for all groups. ISC caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, hemorrhage, and villous congestion. Infliximab treatment significantly attenuated the severity of intestinal I/R injury and it is shown by laminin, anti-TNF, and NFκB immunoreactivity. Because of its anti-inflammatory and antioxidant effects, infliximab pretreatment may have protective effects on hepatic cells in the experimental intestinal I/R model of rats. PMID:27143962

  18. Cost savings of anti-TNF therapy using a test-based strategy versus an empirical dose escalation in Crohn's disease patients who lose response to infliximab

    PubMed Central

    Roblin, Xavier; Attar, Alain; Lamure, Michel; Savarieau, Bernard; Brunel, Pierre; Duru, Gérard; Peyrin-Biroulet, Laurent

    2015-01-01

    Background The use of pharmacokinetics is associated with cost savings in anti-tumor necrosis factor (anti-TNF) therapy, but the long-term cost savings in a large cohort of Crohn's disease (CD) patients are unknown. Aim The goal of this study was to compare the cost of anti-TNF therapy in two cohorts of CD patients losing response to infliximab, one using a test-based strategy and one an empirical dose escalation. Methods We used a selected mathematical model to describe the trajectories of CD patients based on a discrete event system. This design allowed us to track over a given period a double cohort of patients who moved randomly and asynchronously from one state to another, while keeping all the information on their entire trajectory. Both cohorts were modeled using state diagram parameters where transition probabilities from one state to another are derived from literature data. Costs were estimated based on the French health care system. Results Cost savings among the 10,000 CD patients using a test-based strategy were €131,300,293 at 5 years. At 5 years the mean cost saving was €13,130 per patient. The direct cost of the test had no impact on the results until the cost per test reached €2,000. Conclusions A test-based strategy leads to major cost savings related to anti-TNF therapy in CD. PMID:27123185

  19. Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-α treatment

    NASA Astrophysics Data System (ADS)

    Checa, Antonio; Xu, Ning; Sar, Daniel G.; Haeggström, Jesper Z.; Ståhle, Mona; Wheelock, Craig E.

    2015-07-01

    Sphingolipids are bioactive molecules with a putative role in inflammation. Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin. Herein, we quantified the circulating sphingolipid profile in individuals with mild or severe psoriasis as well as healthy controls. In addition, the effects of anti-TNF-α treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P < 0.001 n = 32), but not in mild (n = 32), psoriasis relative to healthy controls (n = 32). These alterations were not reversed in severe patients (n = 16) after anti-TNF-α treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-α treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis.

  20. The Effects of Infliximab on Laminin, NFκB, and Anti-TNF Expression through Its Effect on Ischemic Liver Tissue

    PubMed Central

    Akdogan, Remzi Adnan; Kalkan, Yildiray; Tümkaya, Levent; Rakici, Halil; Akdogan, Elif

    2016-01-01

    The aim of this study was to investigate the possible protective effects of infliximab on expression of laminin, anti-TNF, and NFκB in the rat hepatic cells after ischemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into three groups: Control (C), sham I/R (ISC), and I/R+ infliximab (ISC inf); each group comprised 10 animals. C group animals underwent laparotomy without I/R injury. In ISC groups after undergoing laparotomy, 1 hour of superior mesenteric artery ligation was done, which was followed by 1 hour of reperfusion. In the ISC inf group, 3 days before I/R, infliximab (3 mg/kg) was administered intravenously. All animals were killed at the end of reperfusion and hepatic tissue samples were obtained for histopathological and histochemical investigations in all groups. Laminin, anti-TNF, and NFκB immunoreactivity were performed for all groups. ISC caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, hemorrhage, and villous congestion. Infliximab treatment significantly attenuated the severity of intestinal I/R injury and it is shown by laminin, anti-TNF, and NFκB immunoreactivity. Because of its anti-inflammatory and antioxidant effects, infliximab pretreatment may have protective effects on hepatic cells in the experimental intestinal I/R model of rats. PMID:27143962

  1. Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-α treatment

    PubMed Central

    Checa, Antonio; Xu, Ning; Sar, Daniel G.; Haeggström, Jesper Z.; Ståhle, Mona; Wheelock, Craig E.

    2015-01-01

    Sphingolipids are bioactive molecules with a putative role in inflammation. Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin. Herein, we quantified the circulating sphingolipid profile in individuals with mild or severe psoriasis as well as healthy controls. In addition, the effects of anti-TNF-α treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P < 0.001; n = 32), but not in mild (n = 32), psoriasis relative to healthy controls (n = 32). These alterations were not reversed in severe patients (n = 16) after anti-TNF-α treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-α treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis. PMID:26174087

  2. Convergent Random Forest predictor: methodology for predicting drug response from genome-scale data applied to anti-TNF response.

    PubMed

    Bienkowska, Jadwiga R; Dalgin, Gul S; Batliwalla, Franak; Allaire, Normand; Roubenoff, Ronenn; Gregersen, Peter K; Carulli, John P

    2009-12-01

    Biomarker development for prediction of patient response to therapy is one of the goals of molecular profiling of human tissues. Due to the large number of transcripts, relatively limited number of samples, and high variability of data, identification of predictive biomarkers is a challenge for data analysis. Furthermore, many genes may be responsible for drug response differences, but often only a few are sufficient for accurate prediction. Here we present an analysis approach, the Convergent Random Forest (CRF) method, for the identification of highly predictive biomarkers. The aim is to select from genome-wide expression data a small number of non-redundant biomarkers that could be developed into a simple and robust diagnostic tool. Our method combines the Random Forest classifier and gene expression clustering to rank and select a small number of predictive genes. We evaluated the CRF approach by analyzing four different data sets. The first set contains transcript profiles of whole blood from rheumatoid arthritis patients, collected before anti-TNF treatment, and their subsequent response to the therapy. In this set, CRF identified 8 transcripts predicting response to therapy with 89% accuracy. We also applied the CRF to the analysis of three previously published expression data sets. For all sets, we have compared the CRF and recursive support vector machines (RSVM) approaches to feature selection and classification. In all cases the CRF selects much smaller number of features, five to eight genes, while achieving similar or better performance on both training and independent testing sets of data. For both methods performance estimates using cross-validation is similar to performance on independent samples. The method has been implemented in R and is available from the authors upon request: Jadwiga.Bienkowska@biogenidec.com. PMID:19699293

  3. Similar Clinical and Surgical Outcomes Achieved with Early Compared to Late Anti-TNF Induction in Mild-to-Moderate Ulcerative Colitis: A Retrospective Cohort Study

    PubMed Central

    Fedorak, Darryl K.; Dieleman, Levinus A.; Halloran, Brendan P.

    2016-01-01

    Background. Biologic agents targeting tumor necrosis factor alpha are effective in the management of ulcerative colitis (UC), but their use is often postponed until after failure of other treatment modalities. Objectives. We aim to determine if earlier treatment with infliximab or adalimumab alters clinical and surgical outcomes in UC patients. Methods. A retrospective cohort study was conducted evaluating UC outpatients treated with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first anti-TNF exposure; early initiation was defined as starting treatment within three years of diagnosis. Primary outcomes were colectomy, UC-related hospitalization, and clinical secondary loss of response. Kaplan-Meier analysis was used to assess time to the primary outcomes. Results. 115 patients were included (78 infliximab, 37 adalimumab). Median follow-up was 175.6 weeks (IQR 72.4–228.4 weeks). Fifty-seven (49.6%) patients received early anti-TNF therapy; median time to treatment in this group was 38.1 (23.3–91.0) weeks compared to 414.0 (254.0–561.3) weeks in the late initiator cohort (p < 0.0001). Patients treated with early anti-TNF therapy had more severe endoscopic disease at induction (mean Mayo endoscopy subscore 2.46 (SD ± 0.66) versus 1.86 (±0.67), p < 0.001) and trended towards increased risk of colectomy (17.5% versus 8.6%, p = 0.16) and UC-related hospitalization (43.9% versus 27.6%, p = 0.07). In multivariate regression analysis, early anti-TNF induction was not associated with colectomy (HR 2.02 [95% CI: 0.57–7.20]), hospitalization (HR 1.66 [0.84–3.30]), or secondary loss of response (HR 0.86 [0.52–1.42]). Conclusions. Anti-TNF therapy is initiated earlier in patients with severe UC but earlier treatment does not prevent hospitalization, colectomy, or secondary loss of response. PMID:27478817

  4. Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity.

    PubMed

    Bales, Kelly R; O'Neill, Sharon M; Pozdnyakov, Nikolay; Pan, Feng; Caouette, David; Pi, YeQing; Wood, Kathleen M; Volfson, Dmitri; Cirrito, John R; Han, Byung-Hee; Johnson, Andrew W; Zipfel, Gregory J; Samad, Tarek A

    2016-02-01

    Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function. PMID:26493635

  5. NOVEL IMMUNOTHERAPIES

    PubMed Central

    Yi, Qing

    2010-01-01

    Multiple myeloma is still a fatal disease. Despite advances in high-dose chemotherapy, stem cell transplantation, and the development of novel therapeutics, relapse of the underlying disease remains the primary cause of treatment failure. Strategies for post-transplantation immunomodulation are desirable for eradication of remaining tumor cells. To this end, immunotherapy aimed at inducing myeloma-specific immunity in patients has been explored. Idiotype protein, secreted by myeloma cells, has been the primary target for immunotherapy as it is the best defined tumor-specific antigen. This chapter focuses on novel immunotherapies that are being developed to treat patients with myeloma. I will discuss potential myeloma antigens, antigen-specific T cells and their function on myeloma tumor cells, and T-cell-based and antibody-based immunotherapies for myeloma. Furthermore, clinical studies of T-cell-based immunotherapy in the form of vaccination, allogeneic stem cell transplantation and donor lymphocyte infusions, with or without donor vaccination using patient-derived idiotype, and future application of donor-derived or patient-derived, antigen-specific T-cell infusion in this disease are also discussed. Based on the specificity of the immune effector molecules and cells, immunotherapies with specific T cells or therapeutic antibodies may represent novel strategies for the treatment of multiple myeloma in the near future. PMID:20010170

  6. Lack of replication of genetic predictors for the rheumatoid arthritis response to anti-TNF treatments: a prospective case-only study

    PubMed Central

    2010-01-01

    Introduction We aimed to replicate the strong associations that a recent genome wide association study (GWAS) has found between 16 single nucleotide polymorphisms (SNPs) and response to anti-tumour necrosis factor (TNF) treatment in 89 patients with rheumatoid arthritis (RA). This study is very important because, according to published simulations, associations as strong as the reported ones will mean that these SNPs could be used as predictors of response at the individual level. Methods Disease activity score (DAS28) was evaluated in 151 anti-TNF treated patients with RA of Spanish ancestry at baseline and every 3 months thereafter. Genotypes of the 16 putative predictor SNPs were obtained by single-base extension. Association between the relative change in DAS28 and SNP genotypes was tested by linear regression. In addition, logistic regression was applied to compare genotypes in non-responders (n = 34) versus good-responders (n = 61) following the EULAR response criteria. Results None of the analyses showed any significant association between the 16 SNPs and response to anti-TNF treatments at 3 or 6 months. Results were also negative when only patients treated with infliximab (66.9% of the total) were separately analyzed. These negative results were obtained in spite of a very good statistical power to replicate the reported strong associations. Conclusions We still do not have any sound evidence of genetic variants associated with RA response to anti-TNF treatments. In addition, the possibility we had envisaged of using the results of a recent GWAS for prediction in individual patients should be dismissed. PMID:20423481

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

    PubMed Central

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

    2014-01-01

    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-α therapy was associated with high drug persistence rates. As in rheumatoid arthritis, switching to another anti-TNF-α 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

  8. The anti-TNF-α antibody infliximab inhibits the expression of fat-transporter-protein FAT/CD36 in a selective hepatic-radiation mouse model.

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  10. Allergen Immunotherapy.

    PubMed

    Rael, Efren

    2016-09-01

    Allergies affect a large proportion of the population. Allergies can adversely affect productivity, sleep, and quality of life and can lead to life-threatening reactions. Allergies can spread to affect multiple organ systems. Allergen immunotherapy is the only therapy that can change the natural history of allergic disease. PMID:27545737

  11. Effects of Environmental Factors on Soluble Expression of a Humanized Anti-TNF-α scFv Antibody in Escherichia coli

    PubMed Central

    Sina, Mohammad; Farajzadeh, Davoud; Dastmalchi, Siavoush

    2015-01-01

    Purpose: The bacterial cultivation conditions for obtaining anti-TNF-α single chain variable fragment (scFv) antibody as the soluble product in E. coli was investigated. Methods: To avoid the production of inclusion bodies, the effects of lactose, IPTG, incubation time, temperature, shaking protocol, medium additives (Mg+2, sucrose), pH, osmotic and heat shocks were examined. Samples from bacterial growth conditions with promising results of soluble expression of GST-hD2 scFv were affinity purified and quantified by SDS-PAGE and image processing for further evaluation. Results: The results showed that cultivation in LB medium under induction by low concentrations of lactose and incubation at 10 °C led to partial solubilization of the expressed anti-TNF-α scFv (GST-hD2). Other variables which showed promising increase in soluble expression of GST-hD2 were osmotic shock and addition of magnesium chloride. Furthermore, addition of sucrose to medium suppressed the expression of scFv completely. The other finding was that the addition of sorbitol decreased the growth rate of bacteria. Conclusion: It can be concluded that low cultivation temperature in the presence of low amount of inducer under a long incubation time or addition of magnesium chloride are the most effective environmental factors studied for obtaining the maximum solubilization of GST-hD2 recombinant protein. PMID:26819916

  12. Peanut immunotherapy

    PubMed Central

    2014-01-01

    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

  13. Immunotherapy in all aspects.

    PubMed

    Hanci, Deniz; Şahin, Ethem; Muluk, Nuray Bayar; Cingi, Cemal

    2016-06-01

    Allergen immunotherapy is a form of long-term treatment that decreases symptoms for many people with allergic rhinitis, allergic asthma, conjunctivitis (eye allergy) or stinging insect allergy. In this review, we presented the important topics in immunotherapy. The important aspects of immunotherapy are considered to be "Immunologıcal responses to immunotherapy"; "The principal types of immunotherapy"; "Effectiveness"; "Indications"; "Contraindications"; "Allergen immunotherapy in children"; "Safety"; and "Anaphylactic reactions after immunotherapy". The principal types of immunotherapy are subcutaneous immunotherapy (SCIT) and sublingual immunotherapy. Both of them can be used in indicated cases. When using SCIT, physicians must be more careful because of reported rare fatal cases. The risks and benefits of continuing allergen immunotherapy in patients who have experienced severe systemic reactions should be carefully considered. PMID:25673026

  14. Increased Prevalence of Human Polyomavirus JC Viruria in Chronic Inflammatory Rheumatic Diseases Patients in Treatment with Anti-TNF α: A 18 Month Follow-Up Study.

    PubMed

    Rodio, Donatella Maria; Anzivino, Elena; Mischitelli, Monica; Bellizzi, Anna; Scrivo, Rossana; Scribano, Daniela; Conte, Gianlorenzo; Prezioso, Carla; Trancassini, Maria; Valesini, Guido; Palamara, Anna Teresa; Pietropaolo, Valeria

    2016-01-01

    Chronic inflammatory rheumatic diseases (CIRDs) are immune-mediated pathologies involving joints. To date, TNFα-blocking agents administration is the most promising therapy, although these treatments are associated with an increased Polyomavirus JC (JCPyV) reactivation, the etiological agent of the Progressive Multifocal Leukoencephalopathy (PML). The aim of this study was the recruitment and the analysis of a CIRDs cohort in order to investigate a possible correlation between JCPyV presence and the influence of anti-TNF-α agents on viral loads. Blood and urine samples were collected from 34 CIRDs subjects prior the first anti-TNF-α infusion (T0) and after 3 (T3), 6 (T6), 12 (T12), and 18 (T18) months. Results showed persistent JC viruria significantly higher than JC viremia throughout the 18 month follow-up study (p = 0.002). In JCPyV positive samples, the non-coding control region (NCCR) was analyzed. Results evidenced archetypal structures (type II-S) in all isolates with the exception of a sequence isolated from a plasma sample, that corresponds to the type II-R found in PML subjects. Finally, the viral protein 1 (VP1) genotyping was performed and results showed the prevalence of the European genotypes 1A, 1B, and 4. Since only few studies have been carried out to understand whether there is a PML risk in CIRDs population infected by JCPyV, this study contributes to enrich literature insight on JCPyV biology in this cluster. Further investigations are necessary in order to recognize the real impact of biologics on JCPyV life cycle and to identify possible and specific viral variants related to increased virulence in CIRDs patients. PMID:27242700

  15. Increased Prevalence of Human Polyomavirus JC Viruria in Chronic Inflammatory Rheumatic Diseases Patients in Treatment with Anti-TNF α: A 18 Month Follow-Up Study

    PubMed Central

    Rodio, Donatella Maria; Anzivino, Elena; Mischitelli, Monica; Bellizzi, Anna; Scrivo, Rossana; Scribano, Daniela; Conte, Gianlorenzo; Prezioso, Carla; Trancassini, Maria; Valesini, Guido; Palamara, Anna Teresa; Pietropaolo, Valeria

    2016-01-01

    Chronic inflammatory rheumatic diseases (CIRDs) are immune-mediated pathologies involving joints. To date, TNFα-blocking agents administration is the most promising therapy, although these treatments are associated with an increased Polyomavirus JC (JCPyV) reactivation, the etiological agent of the Progressive Multifocal Leukoencephalopathy (PML). The aim of this study was the recruitment and the analysis of a CIRDs cohort in order to investigate a possible correlation between JCPyV presence and the influence of anti-TNF-α agents on viral loads. Blood and urine samples were collected from 34 CIRDs subjects prior the first anti-TNF-α infusion (T0) and after 3 (T3), 6 (T6), 12 (T12), and 18 (T18) months. Results showed persistent JC viruria significantly higher than JC viremia throughout the 18 month follow-up study (p = 0.002). In JCPyV positive samples, the non-coding control region (NCCR) was analyzed. Results evidenced archetypal structures (type II-S) in all isolates with the exception of a sequence isolated from a plasma sample, that corresponds to the type II-R found in PML subjects. Finally, the viral protein 1 (VP1) genotyping was performed and results showed the prevalence of the European genotypes 1A, 1B, and 4. Since only few studies have been carried out to understand whether there is a PML risk in CIRDs population infected by JCPyV, this study contributes to enrich literature insight on JCPyV biology in this cluster. Further investigations are necessary in order to recognize the real impact of biologics on JCPyV life cycle and to identify possible and specific viral variants related to increased virulence in CIRDs patients. PMID:27242700

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

    PubMed Central

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

    2016-01-01

    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<0.001). Among the forms of IL-17, only IL-17F was decreased after therapy in the MTX cohort (p=0.006), abatacept cohort (p<0.001), and 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

  17. Parasites and immunotherapy: with or against?

    PubMed

    Yousofi Darani, Hossein; Yousefi, Morteza; Safari, Marzieh; Jafari, Rasool

    2016-06-01

    Immunotherapy is a sort of therapy in which antibody or antigen administrates to the patient in order to treat or reduce the severity of complications of disease. This kind of treatment practiced in a wide variety of diseases including infectious diseases, autoimmune disorders, cancers and allergy. Successful and unsuccessful immunotherapeutic strategies have been practiced in variety of parasitic infections. On the other hand parasites or parasite antigens have also been considered for immunotherapy against other diseases such as cancer, asthma and multiple sclerosis. In this paper immunotherapy against common parasitic infections, and also immunotherapy of cancer, asthma and multiple sclerosis with parasites or parasite antigens have been reviewed. PMID:27413282

  18. Gold Nanoparticle Mediated Cancer Immunotherapy

    PubMed Central

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

    2013-01-01

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

  19. Recovery of active anti TNF-α ScFv through matrix-assisted refolding of bacterial inclusion bodies using CIM monolithic support.

    PubMed

    Sushma, Krishnan; Bilgimol, Chuvappumkal Joseph; Vijayalakshmi, Mookambeswaran A; Satheeshkumar, Padikara Kutty

    2012-04-01

    Anti TNF-α molecules are important as therapeutic agents for many of the autoimmune diseases in chronic stage. Here we report the expression and purification of a recombinant single chain variable fragment (ScFv) specific to TNF-α from inclusion bodies. In contrast to the conventional on column refolding using the soft gel supports, an efficient methodology using monolithic matrix has been employed. Nickel (II) coupled to convective interaction media (CIM) support was utilized for this purpose with 6M guanidine hydrochloride (GuHCl) as the chaotropic agent. The protein purified after solubilization and refolding proved to be biologically active with an IC₅₀ value of 15 μg. To the best of our knowledge, this is the first report showing the application of methacrylate based chromatographic supports for matrix-assisted refolding and purification of Escherichia coli inclusion bodies. The results are promising to elaborate the methodology further to exploit the potential positive features of monoliths in protein refolding science. PMID:22386363

  20. EFFECT OF THERAPY WITH ANTI-TNF α DRUGS AND DMARD ON DISEASE ACTIVITY AND HEALTH RELATED QUALITY OF LIFE AMONG WOMEN WITH RHEUMATOID ARTHRITIS.

    PubMed

    Kopciuch, Dorota; Paczkowska, Anna; Leszczynsk, Piotr; Michalak, Michal; Nowakowskai, Elzbieta

    2016-01-01

    The aim of this pilot study was to evaluate the response to 16 and 52 weeks of treatment with adalimumab and etanercept and its effect on disease activity and quality of life in patients with rheumatoid arthritis (RA). Patients were selected from 2155 medical cards of patients of Connective Tissue Health Centre (Poznań, Poland) who were refractory to conventional treatment with disease modifying anti-rheumatic drugs. To assess the disease activity, Disease Activity Score (DAS28) was used and the measurement of quality of life was evaluated with the Polish version of the WHOQoL-Bref questionnaire. To assess the disability, we have used Health Assessment Questionnaire Disability Index (HAQ-DI) and to assess the patients' pain caused by RA, Visual Analogue Scale (VAS) was used. The results of the study show a significant decrease in inflammatory activity of the disease and, consequently, an improvement in quality of life after anti-TNF α treatment. Results obtained with TNF-blockers after 52 weeks of treatment in RA objectively show the efficacy of these drugs and also the patients' perception of the effect on their quality of life. Study results also indicate changes in disability caused by RA and patients' pain due to disease between 16 and 52 weeks of treatment. PMID:27180448

  1. Redo Ileal pouch-anal anastomosis combined with anti-TNF-α maintenance therapy for Crohn's disease with pelvic fistula: report of two cases.

    PubMed

    Araki, Toshimitsu; Okita, Yoshiki; Fujikawa, Hiroyuki; Ohi, Masaki; Tanaka, Koji; Inoue, Yasuhiro; Uchida, Keiichi; Mohri, Yasuhiko; Kusunoki, Masato

    2014-10-01

    Pouch failure has been reported to occur after ileal pouch-anal anastomosis for Crohn's disease. We report two cases of patients with Crohn's disease, who underwent redo ileal pouch-anal anastomosis (redo-IPAA) combined with anti-TNF-α maintenance therapy, with good functional results. The first patient, a man with presumed ulcerative colitis, suffered pelvic fistula recurrence and anastomotic dehiscence. He underwent redo-IPAA, at which time longitudinal ulcers were found. Infliximab was started 4 days postoperatively and continued. The second patient, a woman treated for ulcerative colitis, underwent laparoscopic IPAA 8 years later. After the development of a pelvic fistula, twisted mesentery of the ileal pouch was found intraoperatively and Crohn's disease was diagnosed. Adalimumab therapy resulted in fistula closure. Redo-IPAA was performed to normalize the twisted mesentery of the ileal pouch. No complications have been observed in either patient, both of whom have experienced good functional results after closure of the covering stomas. PMID:24442570

  2. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models.

    PubMed

    Games, Dora; Valera, Elvira; Spencer, Brian; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Patrick, Christina; Ubhi, Kiren; Nuber, Silke; Sacayon, Patricia; Zago, Wagner; Seubert, Peter; Barbour, Robin; Schenk, Dale; Masliah, Eliezer

    2014-07-01

    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 α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-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 α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-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-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-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

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

    PubMed Central

    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

    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 α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-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 α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-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-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118–126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-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

  4. The single-chain anti-TNF-α antibody DLX105 induces clinical and biomarker responses upon local administration in patients with chronic plaque-type psoriasis.

    PubMed

    Tsianakas, Athanasios; Brunner, Patrick M; Ghoreschi, Kamran; Berger, Claudia; Loser, Karin; Röcken, Martin; Stingl, Georg; Luger, Thomas; Jung, Thomas

    2016-06-01

    It is not clear whether TNF-α antagonists used in the treatment of psoriasis need to act systemically, or whether local inhibition of skin-produced TNF-α would be sufficient to silence skin inflammation. To answer this question, we conducted two multicentre, double-blinded, randomized, placebo-controlled clinical trials with the novel single-chain anti-TNF-α-PENTRA(®) -antibody DLX105. Upon intra-dermal injection, DLX105 induced a mean local PASI decrease of 33% over baseline after 2 weeks of treatment, while the placebo response was only 12% (P = 0.001). The clinical response was accompanied by changes in biomarkers such as reductions in K16, Ki67 and epidermal thickness as well as decreased mRNA levels of IL-17, TNF-α, IL-23p19, IL-12p40 and IFN-γ. Next, we applied the drug topically twice daily in a 0.5% hydrogel formulation. While the local PASI did not change, topical DLX105 mediated significant reductions of mRNA levels of key proinflammatory cytokines when compared to placebo, and this effect was further enhanced after weekly tape stripping of plaques to increase drug penetration. These results suggest that longer treatment periods and/or increased local drug concentrations might result in better therapeutic efficacy of topically applied DLX105. In sum, we can show for the first time that local inhibition of TNF-α is sufficient to mediate a biological response in psoriasis that translates into clinical efficacy. PMID:26738450

  5. Role of the protein annexin A1 on the efficacy of anti-TNF treatment in a murine model of acute colitis.

    PubMed

    de Paula-Silva, Marina; Barrios, Bibiana Elisabeth; Macció-Maretto, Lisa; Sena, Angela Aparecida; Farsky, Sandra Helena Poliselli; Correa, Silvia Graciela; Oliani, Sonia Maria

    2016-09-01

    TNF-α is involved in the mechanisms that initiate inflammatory bowel diseases (IBDs). Anti-TNF-α drugs, such as infliximab (IFX), cause non-responsiveness and side effects, indicating the need to investigate alternative therapies for these diseases. The anti-inflammatory protein, annexin A1 (AnxA1), has been associated with the protection of the gastrointestinal mucosa. To further address the role of endogenous AnxA1 on the TNF-α blockade efficacy in a murine model, we assessed colitis induced by Dextran Sulfate Sodium (DSS) in wild-type (WT) and AnxA1(-/-) Balb/c mice treated with IFX. We consistently observed endogenous AnxA1 prevented clinical and physiological manifestations of experimental colitis treated with IFX, additionally the manifestation of the disease was observed earlier in AnxA1(-)(/-) mice. Rectal bleeding, diarrhea, histological score, epithelial damages and collagen degradation caused by DSS were prevented following IFX treatment only in WT mice. IL-6 increased during colitis in WT and AnxA1(-)(/-) mice, decreasing under IFX treatment in WT. The influx of neutrophils and TNF-α secretion were largely elevated in AnxA1(-)(/-) mice when compared to WT mice. In the group WT/DSS+IFX, phagocytes were more susceptible to apoptosis following treatment with IFX. Endogenous expression of AnxA1 increased after DSS and decreased with IFX treatment, demonstrating an attenuated inflammatory response. The data indicate that AnxA1 contributes to the establishment of intestinal homeostasis after blocking of TNF-α was used as a treatment of IBD, constituting a key molecule in the mechanism of action and a potential biomarker of therapeutic efficacy. PMID:27343762

  6. Immunotherapy for lung cancer.

    PubMed

    Steven, Antonius; Fisher, Scott A; Robinson, Bruce W

    2016-07-01

    Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there is now growing worldwide enthusiasm in cancer immunotherapy. We summarize why immune checkpoint blockade therapies have generated efficacious and durable responses in clinical trials and why this has reignited interest in this field. Cancer vaccines have also been explored in the past with marginal success. Identification of optimal candidate neoantigens may improve cancer vaccine efficacy and may pave the way to personalized immunotherapy, alone or in combination with other immunotherapy such as immune checkpoint blockade. Understanding the steps in immune recognition and eradication of cancer cells is vital to understanding why previous immunotherapies failed and how current therapies can be used optimally. We hold an optimistic view for the future prospect in lung cancer immunotherapy. PMID:27101251

  7. Recent progress in allergen immunotherapy.

    PubMed

    Nouri-Aria, Kayhan T

    2008-03-01

    The efficacy of allergen immunotherapy for the treatment of allergic rhinoconjunctivitis with or without seasonal bronchial asthma and anaphylaxis caused by the sting of the hymenoptera class of insects has been clearly demonstrated in numerous well-designed, placebo-controlled trials. Immunotherapy whether by subcutaneous injection of allergen extract or by oral/sublingual routes modifies peripheral and mucosal TH2 responses in favour of TH1 responses and augments IL-10 synthesis by TRegs both locally and by peripheral T cells. Recent researches into the cellular and molecular basis of allergic reactions have advanced our understanding of the mechanisms involved in allergic diseases. They have also helped the development of innovative approaches that are likely to further improve the control of allergic responses in the future. Novel approaches to immunotherapy that are currently being explored include the use of peptide-based allergen preparations, which do not bind IgE and therefore do not activate mast cells, but reduce both Th1 and Th2-cytokine synthesis, while increasing levels of IL-10. Alternative strategies include the use of adjuvants, such as nucleotide immunostimulatory sequences derived from bacteria CpG or monophosphoryl lipid A that potentiate Th1 responses. Blocking the effects of IgE using anti-IgE such as omalizumab, a recombinant humanized monoclonal antibody that selectively binds to IgE, has been shown to be a useful strategy in the treatment of allergic asthma and rhinitis. The combination of anti-IgE-monoclonal antibody omalizumab with allergen immunotherapy has proved beneficial for the treatment of allergic diseases, offering improved efficacy, limited adverse effects, and potential immune-modifying effects. This combination may also accelerate the rapidity by which immunotherapy induces TReg cells. If allergic diseases are due to a lack of allergen-specific TReg cells, then effective therapies should target the induction and the

  8. Immunotherapy for bladder cancer

    PubMed Central

    Fuge, Oliver; Vasdev, Nikhil; Allchorne, Paula; Green, James SA

    2015-01-01

    It is nearly 40 years since Bacillus Calmette–Guérin (BCG) was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest benefit in metastatic disease, although the role in superficial bladder cancer remains unclear. PMID:26000263

  9. Immunotherapy for bladder cancer.

    PubMed

    Fuge, Oliver; Vasdev, Nikhil; Allchorne, Paula; Green, James Sa

    2015-01-01

    It is nearly 40 years since Bacillus Calmette-Guérin (BCG) was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest benefit in metastatic disease, although the role in superficial bladder cancer remains unclear. PMID:26000263

  10. Multifunctional nanoparticles for cancer immunotherapy.

    PubMed

    Saleh, Tayebeh; Shojaosadati, Seyed Abbas

    2016-07-01

    During the last decades significant progress has been made in the field of cancer immunotherapy. However, cancer vaccines have not been successful in clinical trials due to poor immunogenicity of antigen, limitations of safety associated with traditional systemic delivery as well as the complex regulation of the immune system in tumor microenvironment. In recent years, nanotechnology-based delivery systems have attracted great interest in the field of immunotherapy since they provide new opportunities to fight the cancer. In particular, for delivery of cancer vaccines, multifunctional nanoparticles present many advantages such as targeted delivery to immune cells, co-delivery of therapeutic agents, reduced adverse outcomes, blocked immune checkpoint molecules, and amplify immune activation via the use of stimuli-responsive or immunostimulatory materials. In this review article, we highlight recent progress and future promise of multifunctional nanoparticles that have been applied to enhance the efficiency of cancer vaccines. PMID:26901287

  11. Recombinant allergens for specific immunotherapy.

    PubMed

    Cromwell, Oliver; Häfner, Dietrich; Nandy, Andreas

    2011-04-01

    Recombinant DNA technology provides the means for producing allergens that are equivalent to their natural counterparts and also genetically engineered variants with reduced IgE-binding activity. The proteins are produced as chemically defined molecules with consistent structural and immunologic properties. Several hundred allergens have been cloned and expressed as recombinant proteins, and these provide the means for making a very detailed diagnosis of a patient's sensitization profile. Clinical development programs are now in progress to assess the suitability of recombinant allergens for both subcutaneous and sublingual immunotherapy. Recombinant hypoallergenic variants, which are developed with the aim of increasing the doses that can be administered while at the same time reducing the risks for therapy-associated side effects, are also in clinical trials for subcutaneous immunotherapy. Grass and birch pollen preparations have been shown to be clinically effective, and studies with various other allergens are in progress. Personalized or patient-tailored immunotherapy is still a very distant prospect, but the first recombinant products based on single allergens or defined mixtures could reach the market within the next 5 years. PMID:21377719

  12. Decreased levels of metalloproteinase-9 and angiogenic factors in skin lesions of patients with psoriatic arthritis after therapy with anti-TNF

    PubMed Central

    Cordiali-Fei, Paola; Trento, Elisabetta; D'Agosto, Giovanna; Bordignon, Valentina; Mussi, Anna; Ardigò, Marco; Mastroianni, Antonio; Vento, Antonella; Solivetti, Francesco; Berardesca, Enzo; Ensoli, Fabrizio

    2006-01-01

    Background Inflammation represents an early and key event in the development of both the cutaneous psoriasis and psoriatic arthritis. Compelling evidences indicate that the production of TNF-α plays a central role in psoriasis by sustaining the inflammatory process in the skin as well as in the joints. Among the multiple effects produced by TNF-α on keratinocytes, the induction of matrix metalloproteinase-9 (MMP-9), a collagenase implicated in joint inflammatory arthritis which acts as an angiogenesis promoting factor, might represent a key mechanism in the pathogenesis of the disease. Aims of the present study were to investigate a) the role of MMP-9 in the development of psoriasis by assessing the presence of MMP-9 in lesional skin and in sera of psoriatic patients; b) the association of MMP-9 with the activity of the disease; c) the relationship between MMP-9 and TNF-α production. Methods Eleven psoriatic patients, clinically presenting joint symptoms associated to the cutaneous disease, were included in a therapeutic protocol based on the administration of anti-TNF-α monoclonal antibody (Infliximab). Sera and skin biopsies were collected before treatment and after 6 weeks of therapy. Tissues were kept in short term cultures and production soluble mediators such as TNF-α, MMP-9, MMP-2, VEGF and E-Selectin, which include angiogenic molecules associated to the development of plaque psoriasis, were measured in the culture supernatants by immunoenzymatic assays (ng/ml or pg/ml per mg of tissue). MMP-9 concentrations were also measured in the sera. The cutaneous activity of disease was evaluated by the Psoriasis Area and Severity Index (PASI). Results Clinical and laboratory assessment indicated that all but one patients had a significant improvement of the PASI score after three months of therapy. The clinical amelioration was associated to a significant decrease of MMP-9 (P = 0.017), TNF-α (P = 0.005) and E-selectin (P = 0.018) levels, spontaneously released

  13. Immunotherapy for Cervical Cancer

    Cancer.gov

    In an early phase NCI clinical trial, two patients with metastatic cervical cancer had a complete disappearance of their tumors after receiving treatment with a form of immunotherapy called adoptive cell transfer.

  14. Trends in Cancer Immunotherapy

    PubMed Central

    Murphy, Joseph F.

    2010-01-01

    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

  15. Cancer immunotherapy in children

    Cancer.gov

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

  16. IMMUNOTHERAPY IN ACUTE LEUKEMIA

    PubMed Central

    Leung, Wing

    2010-01-01

    Recent advances in immunotherapy of cancer may represent a successful example in translational research, in which progress in knowledge and technology in immunology has lead to new strategies of immunotherapy, and even past failure in many clinical trials have led to a better understanding of basic cancer immunobiology. This article reviews the latest concepts in antitumor immunology and its application in the treatment of cancer, with particular focus on acute leukemia. PMID:19100371

  17. Immunotherapy in lung cancer.

    PubMed Central

    Al-Moundhri, M.; O'Brien, M.; Souberbielle, B. E.

    1998-01-01

    More research and new treatment options are needed in all stages of lung cancer. To this end immunotherapy needs a revival in view of recent improved technologies and greater understanding of the underlying biology. In this review we discuss mechanisms of tumour immunotherapy, non-specific, specific and adoptive, with particular reference to a direct therapeutic action on all subtypes of lung cancer. PMID:9703271

  18. Immunotherapy to Treat Cancer.

    PubMed

    McCune, J S

    2016-09-01

    This issue of Clinical Pharmacology & Therapeutics focuses on immunotherapy as an approach to treat cancer by generating or augmenting an immune response against it. The enthusiasm for immunotherapy has waxed and waned over the past century. Enthusiasm for immunotherapy has risen over the past decade due, in part, to data showing that cancer immunotherapy consistently improves overall survival in select patients with advanced-stage cancer. Antitumor immunotherapy has broad potential and could be used to treat many different types of advanced-stage cancer due to the durable and robust response that it elicits across a diverse spectrum of cancers. This issue covers various aspects of relevant therapeutic topics ranging from discovery of chimeric antigen receptor (CAR) T cells, development of novel immunotherapies using novel pharmacokinetic/dynamic modeling tools, to the utilization of immune checkpoint therapy. Regarding utilization, this issue addresses biomarker selection strategies for personalized treatment of non-small cell lung cancer (NSCLC) with immune checkpoint therapy and also the management of the unique immune response adverse events (irAEs). PMID:27513619

  19. Immunotherapy in gastric cancer

    PubMed Central

    Matsueda, Satoko; Graham, David Y

    2014-01-01

    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

  20. Synthetic biology in cellular immunotherapy

    PubMed Central

    Chakravarti, Deboki; Wong, Wilson W.

    2015-01-01

    The adoptive transfer of genetically engineered T cells with cancer-targeting receptors has shown tremendous promise for eradicating tumors in clinical trials. This form of cellular immunotherapy presents a unique opportunity to incorporate advanced systems and synthetic biology approaches to create cancer therapeutics with novel functions. Here, we first review the development of synthetic receptors, switches, and circuits to control the location, duration, and strength of T cell activity against tumors. In addition, we discuss the cellular engineering and genome editing of host cells (or the chassis) to improve the efficacy of cell-based cancer therapeutics, and to reduce the time and cost of manufacturing. PMID:26088008

  1. What Is Recent in Pancreatic Cancer Immunotherapy?

    PubMed Central

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

    2013-01-01

    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

  2. Immunotherapy: first do no harm.

    PubMed

    Moss, Mark H

    2005-05-01

    Immunotherapy continues to be a treatment modality that is used most exclusively by allergists. The acceptance of immunotherapy for treating children with allergic rhinitis or asthma has been limited by the lack of adequate numbers of pediatric double-blind, placebo-controlled trials of specific allergen immunotherapy; use of venom immunotherapy is more clearly supported by current data. Children represent a unique group of patients where allergic disease may not only be treated using immunotherapy resulting in reduction of symptoms, signs, and complications of disease, but may also hold the best potential for the evasive goal of prevention of the development of future allergic disease. PMID:15878464

  3. Active Immunotherapy of Cancer.

    PubMed

    Chodon, Thinle; Koya, Richard C; Odunsi, Kunle

    2015-01-01

    Clinical progress in the field of cancer immunotherapy has been slow for many years but within the last 5 years, breakthrough successes have brought immunotherapy to the forefront in cancer therapy. Promising results have been observed in a variety of cancers including solid tumors and hematological malignancies with adoptive cell therapy using natural host tumor infiltrating lymphocytes, host cells that have been genetically engineered with antitumor T-cell receptors or chimeric antigen receptors, immune checkpoint inhibitors like anti-CTLA-4, anti-PD-1 or PD-L1 monoclonal antibodies and oncolytic virus-based immunotherapy. However, most treatment modalities have shown limited efficacy with single therapy. The complex nature of cancer with intra- and inter-tumor antigen and genomic heterogeneity coupled with the immune suppressive microenvironment emphasizes the prospect of personalized targeted immunotherapy to manipulate the patient's own immune system against cancer. For successful, robust and long-lasting cure of cancer, a multi-modal approach is essential, combining anti-tumor cell therapy with manipulation of multiple pathways in the tumor microenvironment to ameliorate tumor-induced immunosuppression. PMID:26575466

  4. Oral immunotherapy for food allergy.

    PubMed

    Tang, Mimi L K

    2009-01-01

    Current management of food allergy involves strict avoidance, education on recognizing and managing allergic reactions, and carrying an adrenaline autoinjector. This approach is burdensome and associated with reduced quality of life. Patients with food allergy would benefit greatly from a treatment that could achieve desensitization or long-term tolerance. Recent studies have shown that oral immunotherapy (OIT) can induce desensitization and modulate allergen-specific immune responses; however, it remains uncertain whether OIT can induce long-term tolerance. Nevertheless, successful desensitization provides a major advance in management by reducing the risk of reaction to low amounts of allergen. Allergic reactions during OIT are common, although severe reactions are less common. Therefore, OIT should be performed in specialist centers under close medical supervision and would ideally be conducted as part of ongoing research studies. OIT holds promise as a novel approach to managing food allergy. PMID:19063824

  5. Update on Allergy Immunotherapy

    PubMed Central

    2005-01-01

    This article summarizes and provides commentary regarding guidelines on the administration of immunotherapy (IT) for allergic airway disease. Recent investigations have provided important insights into the immunologic mechanism of IT and the prominent role of interleukin-10-producing regulatory T lymphocytes. The most important aspect of successful IT is the administration of an appropriate dose of an extract containing a sufficient concentration of the relevant allergen. This is largely possible now only with standardized extracts. When the major allergen content of successful IT extracts was quantified, efficacy was demonstrated across a surprisingly narrow concentration range (approximately 5-24 μg per injection), irrespective of the extract. This presumably reflects the concentration of an antigen that drives an immune response toward tolerance. It may be predicted that as major allergen content is quantified in currently nonstandardized extracts, effective IT will also be achieved by administering a dose in this range, in contrast to current practices involving fairly arbitrary dosing decisions. With the availability of nonsedating antihistamines, intranasal corticosteroids, and the leukotriene modifiers, inadequate pharmacologic response or intolerable side effects are less commonly the major indications for starting IT for allergic rhinitis (AR). However, with the recognition that a relatively short course (3-5 years) of IT can provide long-term immunomodulation and clinical benefit, a desire to avoid long-term pharmacotherapy and the associated high costs may be the primary indication for IT in AR cases. While evidence overwhelmingly supports the beneficial influences of IT in asthma cases, the positioning of IT for this disorder is not established. The observed prevention of asthma in children who have AR is intriguing, but further studies are required to assess the extent to which the prevalence and severity of chronic asthma will be reduced when these

  6. Immunotherapy in Peripheral Neuropathies.

    PubMed

    Léger, Jean-Marc; Guimarães-Costa, Raquel; Muntean, Cristina

    2016-01-01

    Immunotherapy has been investigated in a small subset of peripheral neuropathies, including an acute one, Guillain-Barré syndrome, and 3 chronic forms: chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and neuropathy associated with IgM anti-myelin-associated glycoprotein. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis. Either cell-mediated mechanisms or antibody responses to Schwann cell, compact myelin, or nodal antigens are considered to act together in an aberrant immune response to cause damage to peripheral nerves. Immunomodulatory treatments used in these neuropathies aim to act at various steps of this pathogenic process. However, there are many phenotypic variants and, consequently, there is a significant difference in the response to immunotherapy between these neuropathies, as well as a need to improve our knowledge and long-term management of chronic forms. PMID:26602549

  7. Immunotherapy in prostate cancer.

    PubMed

    Sobol, Ilya; Thompson, R H; Dong, Haidong; Krco, Christopher; Kwon, Eugene D

    2015-06-01

    Immunotherapy for the treatment of malignant neoplasms has made significant progress over the last 20 years. Multiple molecular targets and clinical agents have been developed recently, particularly in the field of metastatic adenocarcinoma of the prostate. Sipuleucel-T is currently the only FDA approved immunotherapy for prostate cancer. PSA-TRICOM (Prostvac) currently has a phase III randomized trial underway after a phase II trial showed an improvement in overall survival. Interestingly, both these agents showed improvement in overall survival with no measurable change in disease state, leading to significant controversy as the utility of these agents in prostate cancer. Ipilimumab revealed a benefit for a sub-cohort of men in a post-docetaxel group and is currently undergoing investigation in a pre-docetaxel group. There are a number of other targets such as PD-1 which have shown effectiveness in other neoplasms that will likely be investigated in the future for use in prostate cancer. PMID:25894495

  8. Immunotherapy of Melanoma.

    PubMed

    Snyder, Alexandra; Zamarin, Dmitriy; Wolchok, Jedd D

    2015-01-01

    The history of immunotherapy is rooted in the treatment of melanoma and therapy with immune checkpoint-blocking agents is now a cornerstone for the treatment of metastatic melanoma. The first effective immunotherapies approved by the US Food and Drug Administration in melanoma included interleukin-2 for metastatic disease and interferon alpha in the adjuvant setting. These were followed by a group of new therapies, including checkpoint-blocking antibodies targeting cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1. Therapies intended to 'reeducate' T cells, such as tumor-infiltrating lymphocyte therapy, oncolytic viruses and tumor vaccines, have yielded promising results and are under development. Finally, the integration of the above therapies as well as development of new coinhibitory and costimulatory agents, though in early stages, appear very promising and likely represent the next phase in drug development for the treatment of metastatic melanoma. PMID:26376963

  9. Bladder cancer immunotherapy.

    PubMed

    Lamm, D L; Thor, D E; Stogdill, V D; Radwin, H M

    1982-11-01

    A randomized controlled prospective evaluation of intravesical and percutaneous bacillus Calmette-Guerin immunotherapy was done in 57 patients with transitional cell carcinoma of the bladder. In addition, 9 patients at high risk for tumor recurrence were treated with bacillus Calmette-Guerin produced a self-limited cystitis and 1 complication (hydronephrosis) of immunotherapy was observed. Of the 57 randomized patients 54 were followed for 3 to 30 months. Tumor recurrence was documented in 13 of 26 controls (50 per cent) and only 6 of 28 patients (21 per cent) treated with bacillus Calmette-Guerin (p equals 0.027, chi-square). The interval free of disease was prolonged significantly with bacillus Calmette-Guerin treatment (p equals 0.014, generalized Wilcoxon test). Importantly, a simple purified protein derivative skin test distinguished those patients who responded to bacillus Calmette-Guerin immunotherapy from those who did not. Only 1 of 17 treated patients (6 per cent) whose purified protein derivative test converted from negative to positive had tumor recurrence compared to 5 recurrences (38 per cent) among the 13 patients whose test remained negative or had been positive before treatment (p equals 0.022, chi-square). Bacillus Calmette-Guerin was given to 10 patients with stage B transitional cell carcinoma who were not candidates for cystectomy and 7 are free of disease. Of 5 patients with carcinoma in situ 3 remain free of tumor after bacillus Calmette-Guerin treatment and 5 of 6 who had multiple recurrences after intravesical chemotherapy responded favorably to bacillus Calmette-Guerin immunotherapy. PMID:6757467

  10. Immunotherapy of Fungal Infections.

    PubMed

    Datta, Kausik; Hamad, Mawieh

    2015-11-01

    Fungal organisms are ubiquitous in the environment. Pathogenic fungi, although relatively few in the whole gamut of microbial pathogens, are able to cause disease with varying degrees of severity in individuals with normal or impaired immunity. The disease state is an outcome of the fungal pathogen's interactions with the host immunity, and therefore, it stands to reason that deep/invasive fungal diseases be amenable to immunotherapy. Therefore, antifungal immunotherapy continues to be attractive as an adjunct to the currently available antifungal chemotherapy options for a number of reasons, including the fact that existing antifungal drugs, albeit largely effective, are not without limitations, and that morbidity and mortality associated with invasive mycoses are still unacceptably high. For several decades, intense basic research efforts have been directed at development of fungal immunotherapies. Nevertheless, this approach suffers from a severe bench-bedside disconnect owing to several reasons: the chemical and biological peculiarities of the fungal antigens, the complexities of host-pathogen interactions, an under-appreciation of the fungal disease landscape, the requirement of considerable financial investment to bring these therapies to clinical use, as well as practical problems associated with immunizations. In this general, non-exhaustive review, we summarize the features of ongoing research efforts directed towards devising safe and effective immunotherapeutic options for mycotic diseases, encompassing work on antifungal vaccines, adoptive cell transfers, cytokines, antimicrobial peptides (AMPs), monoclonal antibodies (mAbs), and other agents. PMID:26575463

  11. Discovery of Novel Orally Active Tetrahydro-Naphthyl-N-Acylhydrazones with In Vivo Anti-TNF-α Effect and Remarkable Anti-Inflammatory Properties

    PubMed Central

    Cordeiro, Natália M.; Freitas, Rosana H. C. N.; Fraga, Carlos A. M.

    2016-01-01

    LASSBio-1524 was designed as inhibitor of the IKK-β (kappa β kinase inhibitor) enzyme, which participates in the activation of the nuclear factor κB (NF-κB) canonical pathway, and its three N-acylhydrazone new analogues, LASSBio-1760, LASSBio-1763 and LASSBio-1764 are now being tested on their anti-inflammatory potential. The activity of these compounds was evaluated with the subcutaneous air pouch induced by carrageenan and by subsequent measurement of tumor necrosis factor-α (TNF-α), nitric oxide (NO) and reactive oxygen species (ROS). In the acute inflammation model, the oral pretreatment with doses from 0.3 to 30 mg/kg of N-acylhydrazone derivatives was able to significantly reduce leukocyte migration to the cavity. Pretreatment with LASSBio-1524 and its analogues also decreased NO, TNF-α and ROS biosynthesis an events closely involved with NF-kB pathway. The tetrahydronaphthyl-N-acylhydrazone derivative LASSBio-1764 was the most promising compound from this series, surpassing even LASSBio-1524. Additionally, none of the compounds demonstrated myelotoxicity or cytotoxicity. Cell viability was assayed and these compounds demonstrated to be safe at different concentrations. Western blot analysis demonstrated that LASSBio-1524 and LASSBio-1760 inhibited NF-κB expression in RAW 264.7 cell lineage. Our data indicate that the tested compounds have anti-inflammatory activity, which may be related to inhibition of leukocyte migration, reducing the production of NO, TNF-α and ROS. LASSBio-1524 and LASSBio-1760, in addition to these features, also reduced p65 nuclear expression assessed by western blot in RAW 264.7 murine cells. PMID:27227468

  12. [Aβ immunotherapy for Alzheimer's disease].

    PubMed

    Sakai, Kenji; Yamada, Masahito

    2013-04-01

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

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

    PubMed

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

    2012-01-01

    Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a

  14. Immunotherapies in rheumatologic disorders.

    PubMed

    Miller, Anne V; Ranatunga, Sriya K M

    2012-05-01

    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

  15. [Immunotherapy for Alzheimer's disease].

    PubMed

    Falkentoft, Alexander Christian; Hasselbalch, Steen Gregers

    2016-01-18

    Passive anti-beta-amyloid (Aß) immunotherapy has been shown to clear brain Aß deposits. Results from phase III clinical trials in mild-to-moderate Alzheimer's disease (AD) patients with two monoclonal antibodies bapineuzumab and solanezumab and intravenous immunoglobulin have been disappointing. Subsequent analysis of pooled data from both phase III trials with solanezumab showed a reduction in cognitive decline in patients with mild AD. Solanezumab and new monoclonal antibodies are being tested in patients with prodromal and preclinical AD in search for a disease-modifying treatment. PMID:26815584

  16. Prospects for immunotherapy and vaccines against Cryptosporidium

    PubMed Central

    Mead, Jan R

    2014-01-01

    Cryptosporidium spp is a ubiquitous parasite that has long been recognized as a frequent cause of protozoal diarrhea in humans. While infections in immunocompetent hosts are usually self-limiting, immunocompromised individuals can develop severe, chronic, and life-threatening illness. Vaccine development or immunotherapy that prevents disease or reduces the severity of infection is a relevant option since efficacious drug treatments are lacking. In particular, children in developing countries might benefit the most from a vaccine since cryptosporidiosis in early childhood has been reported to be associated with subsequent impairment in growth, physical fitness, and intellectual capacity. In this review, immunotherapies that have been used clinically are described as well as experimental vaccines and their evaluation in vivo. PMID:24638018

  17. Active immunotherapy options for Alzheimer’s disease

    PubMed Central

    2014-01-01

    Alzheimer’s disease (AD) is the most common cause of dementia and a major contributor to disability and dependency among older people. AD pathogenesis is associated with the accumulation of amyloid-beta protein (Aβ) and/or hyperphosphorylated tau protein in the brain. At present, current therapies provide temporary symptomatic benefit, but do not treat the underlying disease. Recent research has thus focused on investigating the molecular and cellular pathways and processes involved in AD pathogenesis to support the development of effective disease-modifying agents. In accordance with the existing Aβ-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in Aβ-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce Aβ accumulation and prevent downstream pathology in preclinical models. Following AN1792, second-generation active immunotherapies have shown promising results in terms of antibody response and safety. Comparatively, tau immunotherapy is not as advanced, but preclinical data support its development into clinical trials. Results from active amyloid-based immunotherapy studies in preclinical models indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. This strategy, combined with improving our understanding of the complex AD pathogenesis, is imperative to the successful development of these disease-modifying agents. This paper will review the active immunotherapies currently in development, including the benefits and challenges associated with this approach. PMID:24476230

  18. Current status of immunotherapy.

    PubMed

    Suzuki, Susumu; Ishida, Takashi; Yoshikawa, Kazuhiro; Ueda, Ryuzo

    2016-03-01

    The successful use of immune checkpoint inhibitors has been big breakthrough in the development of cancer immunotherapy. Anti-CTLA-4 monoclonal antibody, ipilimumab, is the first-approved immune checkpoint inhibitor and has shown durable objective responses for advanced melanoma beyond the effect of dacarbazine. Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, are other immune checkpoint inhibitors that have demonstrated more effective results than conventional drugs in clinical trials for a variety of advanced solid tumors including melanoma, non-small cell lung carcinoma and renal carcinoma. These studies have indicated that the enhancement of anti-cancer immunity by controlling the immune suppressive environment in cancer tissues is an important issue for the development of cancer immune-therapy. Accordingly, in recent years, the enthusiasm for research of cancer immunology has shifted to studies regarding the formation of the immune suppressive environment, immune suppression mechanisms in cancer tissues and the molecules and cells involved in these pathways. Novel findings from these studies might lead to the development of cancer immunotherapy based on control of the immune suppressive environment. PMID:26819277

  19. Adherence to Sublingual Immunotherapy.

    PubMed

    Incorvaia, Cristoforo; Mauro, Marina; Leo, Gualtiero; Ridolo, Erminia

    2016-02-01

    Adherence is a major issue in any medical treatment. Allergen immunotherapy (AIT) is particularly affected by a poor adherence because a flawed application prevents the immunological effects that underlie the clinical outcome of the treatment. Sublingual immunotherapy (SLIT) was introduced in the 1990s, and the early studies suggested that adherence and compliance to such a route of administration was better than the traditional subcutaneous route. However, the recent data from manufacturers revealed that only 13% of patients treated with SLIT reach the recommended 3-year duration. Therefore, improved adherence to SLIT is an unmet need that may be achieved by various approaches. The utility of patient education and accurate monitoring during the treatment was demonstrated by specific studies, while the success of technology-based tools, including online platforms, social media, e-mail, and a short message service by phone, is currently considered to improve the adherence. This goal is of pivotal importance to fulfill the object of SLIT that is to modify the natural history of allergy, ensuring a long-lasting clinical benefit, and a consequent pharmaco-economic advantage, when patients complete at least a 3-year course of treatment. PMID:26758865

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

    PubMed

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

    2013-10-24

    The added benefit of combining valacyclovir (VACV), an antiviral agent, with etanercept (ETA), an anti-tumor necrosis factor alpha (TNF-α) antibody, for the treatment of herpes simplex virus type 1 (HSV-1) encephalitis (HSE) was evaluated in a mouse model. BALB/c mice were infected intranasally with 1.85x10(4) plaque forming units of HSV-1. Groups of mice received a single intraperitoneal injection of vehicle or ETA (400 μg/mouse) on day 3 post-infection combined or not with VACV (1 mg/ml of drinking water) from days 3 to 21 post-infection. On day 5 post-infection, groups of mice were sacrificed for determination of viral DNA load, detection of ETA in brain homogenates and for in situ hybridization. The survival rate of mice was significantly increased when VACV was administered in combination with ETA (38.5% for VACV vs 78.6% for combined treatment; P=0.04) although VACV or ETA alone had no significant effect compared to the vehicle. The benefit of combined therapy was still present when treatment was delayed until day 4 post-infection. The viral DNA load was significantly reduced in mice treated with VACV alone (P<0.01) or combined with ETA (P<0.05) compared to the uninfected group whereas ETA alone had no effect. These results reinforce the notion that both virus-induced and immune-related mechanisms participate in the pathogenesis of HSE and suggest that potent antiviral agent could be combined with immune-based therapy, such as a TNF-α inhibitor, to improve prognosis of HSE. PMID:24513309

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

    PubMed

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

    2013-12-01

    The added benefit of combining valacyclovir (VACV), an antiviral agent, with etanercept (ETA), an anti-tumor necrosis factor alpha (TNF-α) antibody, for the treatment of herpes simplex virus type 1 (HSV-1) encephalitis (HSE) was evaluated in a mouse model. BALB/c mice were infected intranasally with 1.85 × 104 plaque forming units of HSV-1. Groups of mice received a single intraperitoneal injection of vehicle or ETA (400 μg/mouse) on day 3 post-infection combined or not with VACV (1 mg/ml of drinking water) from days 3 to 21 post-infection. On day 5 post-infection, groups of mice were sacrificed for determination of viral DNA load, detection of ETA in brain homogenates and for in situ hybridization. The survival rate of mice was significantly increased when VACV was administered in combination with ETA (38.5% for VACV vs 78.6% for combined treatment; P = 0.04) although VACV or ETA alone had no significant effect compared to the vehicle. The benefit of combined therapy was still present when treatment was delayed until day 4 post-infection. The viral DNA load was significantly reduced in mice treated with VACV alone (P < 0.01) or combined with ETA (P < 0.05) compared to the uninfected group whereas ETA alone had no effect. These results reinforce the notion that both virus-induced and immune-related mechanisms participate in the pathogenesis of HSE and suggest that potent antiviral agent could be combined with immune-based therapy, such as a TNF-α inhibitor, to improve prognosis of HSE. PMID:24416771

  2. Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells

    PubMed Central

    Prattichizzo, Francesco; Giuliani, Angelica; Recchioni, Rina; Bonafè, Massimiliano; Marcheselli, Fiorella; De Carolis, Sabrina; Campanati, Anna; Giuliodori, Katia; Rippo, Maria Rita; Brugè, Francesca; Tiano, Luca; Micucci, Carla; Ceriello, Antonio; Offidani, Annamaria; Procopio, Antonio Domenico; Olivieri, Fabiola

    2016-01-01

    Endothelial cell senescence is characterized by acquisition of senescence-associated secretory phenotype (SASP), able to promote inflammaging and cancer progression. Emerging evidence suggest that preventing SASP development could help to slow the rate of aging and the progression of age-related diseases, including cancer. Aim of this study was to evaluate whether and how adalimumab, a monoclonal antibody directed against tumor necrosis factor-α (TNF-α), a major SASP component, can prevent the SASP. A three-pronged approach has been adopted to assess the if adalimumab is able to: i) modulate a panel of classic and novel senescence- and SASP-associated markers (interleukin [IL]-6, senescence associated-β-galactosidase, p16/Ink4a, plasminogen activator inhibitor 1, endothelial nitric oxide synthase, miR-146a-5p/Irak1 and miR-126-3p/Spred1) in human umbilical vein endothelial cells (HUVECs); ii) reduce the paracrine effects of senescent HUVECs' secretome on MCF-7 breast cancer cells, through wound healing and mammosphere assay; and iii) exert significant decrease of miR-146a-5p and increase of miR-126-3p in circulating angiogenic cells (CACs) from psoriasis patients receiving adalimumab in monotherapy. TNF-α blockade associated with adalimumab induced significant reduction in released IL-6 and significant increase in eNOS and miR-126-3p expression levels in long-term HUVEC cultures. A significant reduction in miR-146a-5p expression levels both in long-term HUVEC cultures and in CACs isolated from psoriasis patients was also evident. Interestingly, conditioned medium from senescent HUVECs treated with adalimumab was less consistent than medium from untreated cells in inducing migration- and mammosphere- promoting effects on MCF-7 cells. Our findings suggest that adalimumab can induce epigenetic modifications in cells undergoing senescence, thus contributing to the attenuation of SASP tumor-promoting effects. PMID:26943583

  3. Immunotherapy for metastatic prostate cancer

    PubMed Central

    Drake, Charles G.

    2016-01-01

    Chemotherapy with docetaxel is the standard treatment for men with metastatic prostate cancer, and results in statistically significant improvements in survival, as well as in quality of life. However, the response rate to single-agent docetaxel is approximately 40% to 45%, emphasizing a need for alternative approaches. More significantly, with the onset of early, PSA-based detection of prostate cancer and closer follow-up, many men present with metastatic disease that remains asymptomatic. For such patients, the side effects of chemotherapy would compromise their current performance status and, thus, a nontoxic, early treatment option that could improve overall survival would be highly desirable. Immunotherapy represents one such approach; a number of clinical trials have suggested a survival benefit for immunotherapy in metastatic prostate cancer and confirmed that these agents are generally well-tolerated. As is the case for chemotherapy, it is doubtful that maximal survival benefit will be achieved with single-agent immunotherapy; experimental treatments in which mechanistically distinct immunotherapy approaches are combined, as well as approaches in which immunotherapy is combined with chemotherapy or hormonal therapy are currently under investigation. This review will discuss the mechanisms of action of several immunotherapy approaches for metastatic prostate cancer, focusing on active immunotherapy as opposed to administration of anti-tumor antibodies. The relative advantages and disadvantages of current approaches will be noted, and ongoing clinical trials will be highlighted. PMID:18593624

  4. Modified immunotherapy for alopecia areata.

    PubMed

    Yoshimasu, Takashi; Furukawa, Fukumi

    2016-07-01

    Squaric acid dibutylester (SADBE) is a commonly used contact sensitizer in immunotherapy for alopecia areata (AA). Severe contact dermatitis is induced by the currently high recommended sensitization dose of 1%-2% SADBE, often decreasing patient compliance. We assessed a modified immunotherapy for AA using SADBE at a starting concentration of 0.01% without sensitization. After one or two weeks of initial 0.01% SADBE application, the concentration of SADBE was increased gradually to 0.025%, 0.05%, 0.1%, 0.25%, 0.5%, 1% and 2% until the patients felt itching or erythema at the AA lesion site. The modified immunotherapy showed a response rate of 69.4% (25/36), equivalent to conventional immunotherapy using SADBE starting at 1%-2% sensitization. Furthermore, we investigated the combination therapy of SADBE and multiple courses of steroid pulses for AA. The response rate for combination therapy was 73.7% (28/38); however, the group receiving combination therapy showed a significant prevalence of severe AA compared with the group receiving modified immunotherapy only. We reviewed the efficacy and safety of modified immunotherapy without initial sensitization and combination therapy with immunotherapy and multiple courses of pulses for AA. PMID:26932732

  5. Mouse Models of Tumor Immunotherapy.

    PubMed

    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients. PMID:26922998

  6. Chapter 3: Allergen immunotherapy: definition, indication, and reactions.

    PubMed

    Georgy, Mary S; Saltoun, Carol A

    2012-01-01

    Specific allergen immunotherapy is the administration of increasing amounts of specific allergens to which the patient has type I immediate hypersensitivity. It is a disease modifying therapy, indicated for the treatment of allergic rhinitis, allergic asthma, and hymenoptera hypersensitivity. Specific IgE antibodies for appropriate allergens for immunotherapy must be documented. Indications for allergen immunotherapy include (1) inadequate symptom control despite pharmacotherapy and avoidance measures, (2) a desire to reduce the morbidity from allergic rhinitis and/or asthma or reduce the risk of anaphylaxis from a future insect sting, (3) when the patient experiences undesirable side effects from pharmacotherapy, and (4) when avoidance is not possible. Furthermore, patients may seek to benefit from economic savings of allergen immunotherapy compared with pharmacotherapy over time. Several studies have reported that immunotherapy in children with allergic rhinitis appears to prevent the development of new allergic sensitizations and/or new-onset asthma. Humoral, cellular, and tissue level changes occur with allergen immunotherapy including large increases in antiallergen IgG(4) antibodies, a decrease in the postseasonal rise of antiallergen IgE antibodies, reduced numbers of nasal mucosal mast cells and eosinophils, induction of Treg cells, and suppression of Th2 more than Th1 lymphocytes. There is a corresponding increase in IL-10 and transforming growth factor beta. In the United States, allergen immunotherapy is administered by the subcutaneous route in the physician's office, whereas primarily in some countries in Europe, it is administered for allergic rhinitis and asthma by the sublingual route by the patient at home. PMID:22794676

  7. Conference Scene: novelties in immunotherapy.

    PubMed

    Mitsias, Dimitris I; Kalogiros, Lampros A; Papadopoulos, Nikolaos G

    2013-10-01

    The only method aiming to permanently cure allergic disorders is allergen immunotherapy. Over the last 20 years there has been great progress in understanding the mechanisms that govern allergen immunotherapy in order to meet three basic prerequisites: safety, effectiveness and compliance. In the present summary report from the European Academy of Allergology and Clinical Immunology-World Allergy Organization Congress held last June in Milan, we review key points concerning the main axes as diagnosis, novel modalities, routes and protocols, as well as two important immunotherapy fields: food and insect venom allergy. PMID:24088073

  8. Immunotherapy for nasopharyngeal cancer-a review.

    PubMed

    Jain, Amit; Chia, Whay Kuang; Toh, Han Chong

    2016-04-01

    Nasopharyngeal carcinoma (NPC) is associated with the Epstein-Barr virus (EBV) and characterized by peritumoral immune infiltrate. Advanced NPC has high lethality. Immunotherapy directed against EBV antigen targets has been previously explored in clinical trials, and is likely to be validated as an important target in NPC as randomized data emerges in the future. Cancer vaccines and adoptive T cell therapy have been explored in the clinic, with the latter showing the greatest success. Recent advances in gene sequencing technology now allow personalized tumor epitope mapping, whilst the advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis offers the opportunity to activate adaptive T cell response in vivo. Anti-PD1 antibodies have shown promising activity in early phase clinical trials, and randomized studies against chemotherapy are underway. As immunotherapy is incorporated into standard treatment paradigms, issues of optimal combinations with targeting agents, immune adjuvants, and sequence with chemotherapy and radiation therapy will need to be addressed. Effective strategies to increase tumor antigenicity, improve immunological memory and reduce immune escape, will need to be developed to improve treatment outcomes. Here we present a brief history of the evolution of immunotherapy in NPC, and highlight key concepts relevant to its further development in the clinic. PMID:27121882

  9. Laser immunotherapy of canine and feline neoplasia

    NASA Astrophysics Data System (ADS)

    Woods, J. P.; Bartels, Kenneth E.; Davidson, Ellen B.; Ritchey, Jerry W.; Lehenbauer, Terry W.; Nordquist, Robert E.; Chen, Wei R.

    1998-07-01

    The major cause of treatment failure in human and veterinary cancer patients is tumor invasion and metastasis. The inability of local therapy (surgery, radiation, photodynamic therapy) to eradicate a metastatic cancer presents a challenge in the therapy of residual or micrometastatic disease. Because of its local therapy limitations, chromophore-enhanced selective photothermal laser treatment has been augmented with a superimposed laser-induced systemic photobiological reaction, laser immunotherapy. Laser immunotherapy is a novel cancer treatment consisting of: (1) a laser in the infrared wavelength range (i.e. 805 nm solid state laser); (2) a photosensitizer of the corresponding absorption peak [i.e. indocyanine green (ICG)]; and (3) an immunoadjuvant [i.e. glycated chitosan gel (GCG)]. The intratumor injection of the photosensitizer (ICG) and immunoadjuvant (GCG) solution is followed by noninvasive laser irradiation. The laser energy causes tumor cell destruction by photothermal interaction to reduce the tumor burden and at the same time exposes tumor antigens. The immunoadjuvant concomitantly stimulates the host to mount a systemic anti-tumor immune response against the remaining cells of the tumor and to induce a long-term, tumor-specific immunity. This study investigates the feasibility of utilizing laser immunotherapy as an adjunctive therapy for the control of feline fibrosarcoma in future.

  10. Allogeneic stem-cell transplantation with reduced conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell leukemia/lymphoma.

    PubMed

    Okamura, Jun; Utsunomiya, Atae; Tanosaki, Ryuji; Uike, Naokuni; Sonoda, Shunro; Kannagi, Mari; Tomonaga, Masao; Harada, Mine; Kimura, Nobuhiro; Masuda, Masato; Kawano, Fumio; Yufu, Yuji; Hattori, Hiroyoshi; Kikuchi, Hiroshi; Saburi, Yoshio

    2005-05-15

    Sixteen patients with adult T-cell leukemia/lymphoma (ATL) who were all over 50 years of age underwent allogeneic stem cell transplantation with reduced-conditioning intensity (RIST) from HLA-matched sibling donors after a conditioning regimen consisting of fludarabine (180 mg/m2), busulfan (8 mg/kg), and rabbit antithymocyte globulin (5 mg/kg). The observed regimen-related toxicities and nonhematologic toxicities were all found to be acceptable. Disease relapse was the main cause of treatment failure. Three patients who had a relapse subsequently responded to a rapid discontinuation of the immunosuppressive agent and thereafter achieved another remission. After RIST, the human T-cell leukemia virus type 1 (HTLV-1) proviral load became undetectable in 8 patients. RIST is thus considered to be a feasible treatment for ATL. Our data also suggest the presence of a possible graft-versus-ATL effect; an anti-HTLV-1 activity was also found to be associated with this procedure. PMID:15665110

  11. Cytokines in Cancer Immunotherapy

    PubMed Central

    Lee, Sylvia; Margolin, Kim

    2011-01-01

    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

  12. Imaging Biomarkers in Immunotherapy

    PubMed Central

    Juergens, Rosalyn A.; Zukotynski, Katherine A.; Singnurkar, Amit; Snider, Denis P.; Valliant, John F.; Gulenchyn, Karen Y.

    2016-01-01

    Immune-based therapies have been in use for decades but recent work with immune checkpoint inhibitors has now changed the landscape of cancer treatment as a whole. While these advances are encouraging, clinicians still do not have a consistent biomarker they can rely on that can accurately select patients or monitor response. Molecular imaging technology provides a noninvasive mechanism to evaluate tumors and may be an ideal candidate for these purposes. This review provides an overview of the mechanism of action of varied immunotherapies and the current strategies for monitoring patients with imaging. We then describe some of the key researches in the preclinical and clinical literature on the current uses of molecular imaging of the immune system and cancer. PMID:26949344

  13. Immunotherapy for Pediatric Leukemia

    PubMed Central

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

    2013-01-01

    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

  14. Genomic determinants of cancer immunotherapy.

    PubMed

    Miao, Diana; Van Allen, Eliezer M

    2016-08-01

    Cancer immunotherapies - including therapeutic vaccines, adoptive cell transfer, oncolytic viruses, and immune checkpoint blockade - yield durable responses in many cancer types, but understanding of predictors of response is incomplete. Genomic characterization of human cancers has already contributed to the success of targeted therapies; in cancer immunotherapy, identification of tumor-specific antigens through whole-exome sequencing may be key to designing individualized, highly immunogenic therapeutic vaccines. Additionally, pre-treatment tumor mutational and gene expression signatures can predict which patients are most likely to benefit from cancer immunotherapy. Continued work in harnessing genomic, transcriptomic, and immunological data from clinical cohorts of immunotherapy-treated patients will bring the promises of precision medicine to immuno-oncology. PMID:27254251

  15. New routes for allergen immunotherapy.

    PubMed

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

    2012-10-01

    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

  16. Challenges in Clinical Design of Immunotherapy Trials for Malignant Glioma

    PubMed Central

    Rolle, Cleo E.; Sengupta, Sadhak; Lesniak, Maciej S.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common and lethal primary malignant brain tumor. The traditional treatments for GBM, including surgery, radiation, and chemotherapy, only modestly improve patient survival. Therefore, immunotherapy has emerged as a novel therapeutic modality. Immunotherapeutic strategies exploit the immune system's ability to recognize and mount a specific response against tumor cells, but not normal cells. Current immunotherapeutic approaches for glioma can be divided into three categories: immune priming (active immunotherapy), immunomodulation (passive immunotherapy), and adoptive immunotherapy. Immune priming sensitizes the patient's immune cells to tumor antigens using various vaccination protocols. In the case of immunomodulation, strategies are aimed at reducing suppressive cytokines in the tumor microenvironment or using immune molecules to specifically target tumor cells. Adoptive immunotherapy involves harvesting the patient's immune cells, followed by ex vivo activation and expansion prior to re-infusion. This review will provide an overview of the interactions between the central nervous system and the immune system and discuss the challenges facing current immunotherapeutic strategies. PMID:19944979

  17. Immunotherapy for Drug Abuse

    PubMed Central

    Shen, Xiaoyun; Kosten, Thomas R.

    2013-01-01

    Substance use disorders continue to be major medical and social problems worldwide. Current medications for substance use disorders have many limitations such as cost, availability, medication compliance, dependence, diversion of some to illicit use and relapse to addiction after discontinuing their use. Immunotherapies using either passive monoclonal antibodies or active vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They have great potential to help the patient achieve and sustain abstinence and have fewer of the above limitations. This review covers the cocaine vaccine development in detail and provides an overview of directions for developing anti-addiction vaccines against the abuse of other substances. The notable success of the first placebo-controlled clinical trial of a cocaine vaccine, TA-CD, has led to an ongoing multi-site, Phase IIb clinical trial in 300 subjects. The results from these trials are encouarging further development of the cocaine vacine as one of the first anti-addiction vaccines to go forward to the U.S. Food and Drug Administration for review and approval for human use. PMID:22229313

  18. Immunotherapy for drug abuse.

    PubMed

    Shen, Xiaoyun; Kosten, Thomas R

    2011-12-01

    Substance use disorders continue to be major medical and social problems worldwide. Current medications for substance use disorders have many limitations such as cost, availability, medication compliance, dependence, diversion of some to illicit use and relapse to addiction after discontinuing their use. Immunotherapies using either passive monoclonal antibodies or active vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They have great potential to help the patient achieve and sustain abstinence and have fewer of the above limitations. This review covers the cocaine vaccine development in detail and provides an overview of directions for developing anti-addiction vaccines against the abuse of other substances. The notable success of the first placebo-controlled clinical trial of a cocaine vaccine, TA-CD, has led to an ongoing multi-site, Phase IIb clinical trial in 300 subjects. The results from these trials are encouarging further development of the cocaine vacine as one of the first anti-addiction vaccines to go forward to the U.S. Food and Drug Administration for review and approval for human use. PMID:22229313

  19. Immunotherapy of Brain Cancer.

    PubMed

    Roth, Patrick; Preusser, Matthias; Weller, Michael

    2016-01-01

    The brain has long been considered an immune-privileged site precluding potent immune responses. Nevertheless, because of the failure of conventional anti-cancer treatments to achieve sustained control of intracranial neoplasms, immunotherapy has been considered as a promising strategy for decades. However, several efforts aimed at exploiting the immune system as a therapeutic weapon were largely unsuccessful. The situation only changed with the introduction of the checkpoint inhibitors, which target immune cell receptors that interfere with the activation of immune effector cells. Following the observation of striking effects of drugs that target CTLA-4 or PD-1 against melanoma and other tumor entities, it was recognized that these drugs may also be active against metastatic tumor lesions in the brain. Their therapeutic activity against primary brain tumors is currently being investigated within clinical trials. In parallel, other immunotherapeutics such as peptide vaccines are at an advanced stage of clinical development. Further immunotherapeutic strategies currently under investigation comprise adoptive immune cell transfer as well as inhibitors of metabolic pathways involved in the local immunosuppression frequently found in brain tumors. Thus, the ongoing implementation of immunotherapeutic concepts into clinical routine may represent a powerful addition to the therapeutic arsenal against various brain tumors. PMID:27260656

  20. Lymphoma Immunotherapy: Current Status

    PubMed Central

    Zappasodi, Roberta; de Braud, Filippo; Di Nicola, Massimo

    2015-01-01

    The rationale to treat lymphomas with immunotherapy comes from long-standing evidence on their distinctive immune responsiveness. Indolent B-cell non-Hodgkin lymphomas, in particular, establish key interactions with the immune microenvironment to ensure prosurvival signals and prevent antitumor immune activation. However, reports of spontaneous regressions indicate that, under certain circumstances, patients develop therapeutic antitumor immunity. Several immunotherapeutic approaches have been thus developed to boost these effects in all patients. To date, targeting CD20 on malignant B cells with the antibody rituximab has been the most clinically effective strategy. However, relapse and resistance prevent to cure approximately half of B-NHL patients, underscoring the need of more effective therapies. The recognition of B-cell receptor variable regions as B-NHL unique antigens promoted the development of specific vaccines to immunize patients against their own tumor. Despite initial promising results, this strategy has not yet demonstrated a sufficient clinical benefit to reach the regulatory approval. Several novel agents are now available to stimulate immune effector functions or counteract immunosuppressive mechanisms, such as engineered antitumor T cells, co-stimulatory receptor agonist, and immune checkpoint-blocking antibodies. Thus, multiple elements can now be exploited in more effective combinations to break the barriers for the induction of anti-lymphoma immunity. PMID:26388871

  1. Immunotherapy in Breast Cancer.

    PubMed

    Marmé, Frederik

    2016-01-01

    The importance of the tumor microenvironment including immune cell infiltrates in breast cancer has long been recognized. Tumor-infiltrating lymphocytes are prognostic and predictive; however, their prevalence as well as their prognostic and predictive power are subtype-dependent and appear most prominent in aggressive subtypes like triple-negative and HER2-positive disease. The immune responses observed in many cancers are attracted by tumor-associated antigens and, as suggested by recent research, by neoantigens - immunogenic antigens encoded for by non-synonymous mutations. The appealing promise of cancer vaccines has been pursued in breast cancer for over 2 decades; however, despite much effort having been put into vaccine trials, their clinical benefit, with the exception of some encouraging preliminary results, remains disappointing. The main hurdles compromising the efficacy of these vaccination strategies are the difficulties to generate broad and robust immune responses as well as to overcome immune escape mechanisms. The remarkable efficacy of immune checkpoint inhibitors in melanoma and lung cancer has set the ground for a race in the clinical development of numerous agents targeting these immune escape mechanisms in many tumor entities. Early clinical data in metastatic breast cancer suggests at least some clinical activity. This review discusses the current status and future perspectives of immunotherapy in breast cancer. PMID:27260697

  2. IgE immunotherapy

    PubMed Central

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

    2014-01-01

    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

  3. Immunotherapy for malignant glioma

    PubMed Central

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

    2015-01-01

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

  4. The efficiency of peptide immunotherapy for respiratory allergy.

    PubMed

    Incorvaia, Cristoforo; Montagni, Marcello; Ridolo, Erminia

    2016-06-01

    Allergen immunotherapy (AIT) was introduced more than a century ago and is yet the only disease-modifying treatment for allergy. AIT is currently conducted with whole allergen extracts and several studies clearly support its efficacy in the treatment of respiratory allergies, however the need for a long treatment - that affects costs and patients compliance - and possible IgE-mediated adverse events are still unresolved issues. Peptide immunotherapy is based on the use of short synthetic peptides which represent major T-cell epitopes of the allergen with markedly reduced ability to cross-link IgE and activate mast cells and basophils. Data from clinical trials confirmed the efficacy and tolerability of peptide immunotherapy in patients with cat allergy, with a sustained clinical effect after a short course treatment. Peptide therapy is a promising safe and effective new specific treatment for allergy to be developed for the most important allergens causing rhinitis or asthma. PMID:26901667

  5. Acquired resistance to immunotherapy and future challenges.

    PubMed

    Restifo, Nicholas P; Smyth, Mark J; Snyder, Alexandra

    2016-02-01

    Advances in immunotherapy have resulted in remarkable clinical responses in some patients. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Given that many patients have now received various types of immunotherapy, we asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. PMID:26822578

  6. Immunotherapy for tuberculosis: future prospects

    PubMed Central

    Abate, Getahun; Hoft, Daniel F

    2016-01-01

    Tuberculosis (TB) is still a major global health problem. A third of the world’s population is infected with Mycobacterium tuberculosis. Only ~10% of infected individuals develop TB but there are 9 million TB cases with 1.5 million deaths annually. The standard prophylactic treatment regimens for latent TB infection take 3–9 months, and new cases of TB require at least 6 months of treatment with multiple drugs. The management of latent TB infection and TB has become more challenging because of the spread of multidrug-resistant and extremely drug-resistant TB. Intensified efforts to find new TB drugs and immunotherapies are needed. Immunotherapies could modulate the immune system in patients with latent TB infection or active disease, enabling better control of M. tuberculosis replication. This review describes several types of potential immunotherapies with a focus on those which have been tested in humans. PMID:27529060

  7. Immunotherapy of Childhood Sarcomas.

    PubMed

    Roberts, Stephen S; Chou, Alexander J; Cheung, Nai-Kong V

    2015-01-01

    Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing's family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed. PMID:26301204

  8. Immunotherapy of Childhood Sarcomas

    PubMed Central

    Roberts, Stephen S.; Chou, Alexander J.; Cheung, Nai-Kong V.

    2015-01-01

    Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing’s family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed. PMID:26301204

  9. Cancer testis antigen and immunotherapy

    PubMed Central

    Krishnadas, Deepa Kolaseri; Bai, Fanqi; Lucas, Kenneth G

    2013-01-01

    The identification of cancer testis (CT) antigens has been an important advance in determining potential targets for cancer immunotherapy. Multiple previous studies have shown that CT antigen vaccines, using both peptides and dendritic cell vaccines, can elicit clinical and immunologic responses in several different tumors. This review details the expression of melanoma antigen family A, 1 (MAGE-A1), melanoma antigen family A, 3 (MAGE-A3), and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) in various malignancies, and presents our current understanding of CT antigen based immunotherapy.

  10. Hypoallergenic molecules for subcutaneous immunotherapy.

    PubMed

    Jongejan, Laurian; van Ree, Ronald; Poulsen, Lars K

    2016-01-01

    Although a large part of the population suffers from allergies, a cure is not yet available. Allergen-specific immunotherapy (AIT) offers promise for these patients. AIT has proven successful in insect and venom allergies; however, for food allergy this is still unclear. In this editorial we focus on the recent advances in a proof of concept study in food allergy, FAST (Food allergy specific immunotherapy), which may increase interest within the biomolecular and pharmaceutical industry to embark on similar projects of immunology driven precision medicine within the allergy field. PMID:26558320

  11. Future perspectives in cancer immunotherapy

    PubMed Central

    Mountzios, Giannis; Curigliano, Giuseppe

    2016-01-01

    The advent of immunotherapy has transformed the treatment paradigm of several solid tumors and is expected to influence the therapeutic algorithm even more in the future following the results of numerous ongoing clinical trials in a wide range of malignancies. Exploiting the anti-cancer effect of the immune system with the use of vaccines, viral vectors, and more lately with immune check-point inhibitors and chimeric antigen receptor modification, has been proven a successful therapeutic strategy in a broad spectrum of tumors. In particular, immune check-point inhibition in melanoma, non-small-cell lung cancer and renal cancer, peptide vaccination in prostate cancer and glioblastoma, and oncolytic immunotherapy in melanoma are well-established therapeutic modalities that have obtained approval by regulatory authorities and are already in clinical use. A large number of ongoing clinical trials involving thousands of patients are currently seeking to define the appropriate tumor type, therapeutic setting, treatment combination and patient populations in order to maximize clinical benefit from immunotherapeutic agents. In this context, identification of the patients whose tumors are most likely to respond to immunotherapy by the use of appropriate biomarkers will be crucial for the optimal implementation of immunotherapy into the therapeutic armamentarium. PMID:27563660

  12. Immunotherapy Approaches in Cancer Treatment.

    PubMed

    Klener, Pavel; Otáhal, Pavel; Lateckova, Lucie; Klener, Pavel

    2015-01-01

    Tumor immune surveillance paradigm presumes that most pre-malignant cells or early malignant lesions can be eliminated (or at least controlled) by cells of the immune system. A critical feature that distinguishes advanced tumors from early neoplastic lesions is their capability to evade immune control. As a consequence, vast majority of clinically evident (advanced) tumors are poorly immunogenic. The principle goal of immunotherapy is thus a resurrection of the patient's inefficient or suppressed immune system so that it would once again become capable of launching sustained cytolytic attacks against tumor cells, which would ideally result in total and permanent eradication of cancer. Such activation of patient's anticancer immunity, however, can be achieved by strikingly different ways. This current review discusses diverse innovative immunotherapy approaches, which in the last 20 years achieved miraculous successes in the ever-lasting battle against cancer, including cytokine-based immunotherapy approaches, therapeutic monoclonal antibodies and their derivatives, cancer vaccines, and cell-based immunotherapy approaches. PMID:26087990

  13. Engineering opportunities in cancer immunotherapy

    PubMed Central

    Jeanbart, Laura; Swartz, Melody A.

    2015-01-01

    Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges. PMID:26598681

  14. Immunotherapy toxic in obese mice.

    PubMed

    2015-01-01

    New research shows immunotherapy can cause lethal inflammation in both young and aged mice that are obese. Restricting calories in aged mice protected them from toxicity, and giving young obese mice a drug for autoimmune disease prevented the fatal reactions. PMID:25583780

  15. Classification of current anticancer immunotherapies.

    PubMed

    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; Fučíková, Jitka; Gabrilovich, Dmitry I; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M; Klein, Eva; Knuth, Alexander; Lewis, Claire E; Liblau, Roland; Lotze, Michael T; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J; Mittendorf, Elizabeth A; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E; Pienta, Kenneth J; Porgador, Angel; Prendergast, George C; Rabinovich, Gabriel A; Restifo, Nicholas P; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J; Speiser, Daniel E; Spisek, Radek; Srivastava, Pramod K; Talmadge, James E; Tartour, Eric; Van Der Burg, Sjoerd H; Van Den Eynde, Benoît J; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S; Whiteside, Theresa L; Wolchok, Jedd D; Zitvogel, Laurence; Zou, Weiping; Kroemer, Guido

    2014-12-30

    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

  16. Classification of current anticancer immunotherapies

    PubMed Central

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

    2014-01-01

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

  17. A Phase I Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33(+) Acute Myeloid Leukemia.

    PubMed

    Zahler, Stacey; Bhatia, Monica; Ricci, Angela; Roy, Sumith; Morris, Erin; Harrison, Lauren; van de Ven, Carmella; Fabricatore, Sandra; Wolownik, Karen; Cooney-Qualter, Erin; Baxter-Lowe, Lee Ann; Luisi, Paul; Militano, Olga; Kletzel, Morris; Cairo, Mitchell S

    2016-04-01

    Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33(+) relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33(+) AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m(2) × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m(2)). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m(2) per dose), 5 at dose level 2 (6 mg/m(2) per dose), 3 at dose level 3 (7.5 mg/m(2) per dose), and 3 at dose level 4 (9 mg/m(2) per dose). Three of 14 patients received only 1 dose of GO after

  18. [Cancer immunotherapy by immuno-checkpoint blockade].

    PubMed

    Kawakami, Yutaka

    2015-10-01

    As cancer immunotherapies utilizing anti-tumor T-cell responses, immuno-checkpoint blockade and adoptive T-cell immunotherapy have recently achieved durable responses even in advanced cancer patients with metastases. Administration of antibodies on the T-cell surface, CTLA-4 and PD-1 (or PD-1 ligand PD-L1), resulted in tumor regression of not only melanoma and renal cell cancer which were known to be relatively sensitive to immunotherapy, but also various malignancies including lung, bladder, ovarian, gastric, and head and neck cancers, as well as hematological malignancies such as Hodgkin and B-cell malignant lymphomas. These findings have changed the status of immunotherapy in the development of cancer treatments. Currently, development of combinations employing cancer immunotherapy with immuno-checkpoint blockade, as well as personalized cancer immunotherapy based on the evaluation of pretreatment immune status, are in progress. PMID:26458459

  19. Emerging immunotherapy in pediatric lymphoma.

    PubMed

    Erker, Craig; Harker-Murray, Paul; Burke, Michael J

    2016-01-01

    Hodgkin and non-Hodgkin lymphoma collectively are the third most common cancer diagnosed in children each year. For children who relapse or have refractory disease, outcomes remain poor. Immunotherapy has recently emerged as a novel approach to treat hematologic malignancies. The field has been rapidly expanding over the past few years broadening its armamentarium which now includes monoclonal antibodies, antibody-drug conjugates and cellular therapies including bispecific T-cell engagers and chimeric antigen receptor-engineered T cells. Many of these agents are in their infancy stages and only beginning to make their mark on lymphoma treatment while others have begun to show promising efficacy in relapsed disease. In this review, the authors provide an overview of current and emerging immunotherapies in the field of pediatric lymphoma. PMID:26616565

  20. Allergen immunotherapy in polysensitized patient.

    PubMed

    Hrubiško, M; Špičák, V

    2016-05-01

    Specific allergen immunotherapy (AIT) is the only therapeutic method with positive impact on natural course of allergic disease - affecting clinical development (including the progression of rhinitis to asthma) and new sensitisations. The actual problem is the increasing number of patients manifesting poly-sensitivity in allergy skin tests and / or in specific IgE tests. Usually, AIT is not recommended in such individuals. The objective we are facing is that in many patients tested as poly-reactive, we have to distinguish in which cases it is a true polysensitization, and when it is due to cross-reactivity of specific IgE antibodies induced by panallergens. This may really determine when AIT may be an appropriate course of action. The article focuses on this problem in more detail, applying the long time Czech and Slovak experience with allergy testing and allergen immunotherapy. PMID:27152601

  1. Lentiviral vectors in cancer immunotherapy.

    PubMed

    Oldham, Robyn Aa; Berinstein, Elliot M; Medin, Jeffrey A

    2015-01-01

    Basic science advances in cancer immunotherapy have resulted in various treatments that have recently shown success in the clinic. Many of these therapies require the insertion of genes into cells to directly kill them or to redirect the host's cells to induce potent immune responses. Other analogous therapies work by modifying effector cells for improved targeting and enhanced killing of tumor cells. Initial studies done using γ-retroviruses were promising, but safety concerns centered on the potential for insertional mutagenesis have highlighted the desire to develop other options for gene delivery. Lentiviral vectors (LVs) have been identified as potentially more effective and safer alternative delivery vehicles. LVs are now in use in clinical trials for many different types of inherited and acquired disorders, including cancer. This review will discuss current knowledge of LVs and the applications of this viral vector-based delivery vehicle to cancer immunotherapy. PMID:25804479

  2. Immunotherapy as a disease modifier.

    PubMed

    Martin, James G; Shalaby, Karim; Michoud, Marie-Claire

    2006-01-01

    Immunotherapy was formerly the treatment of allergic disease by repeated exposure to allergen. Other approaches to immune modulation have emerged using new knowledge of T cell function. The so-called hygiene hypothesis argues that alterations in our environment have resulted in a failure of the immune system to develop normally, such that excessive Th2 type responses to antigen exposures occur. These observations have prompted therapies designed to promote a shift from Th-2 to Th-1 responses. These therapies include bacterial vaccines and stimulation of the immune system with Toll like receptor ligands or bacterial nucleotide immunostimulatory sequences (CpG motifs). Traditional desensitization immunotherapy is being re-examined and anti-IgE therapy is also enjoying a measure of success. PMID:16798526

  3. Current status of mold immunotherapy.

    PubMed

    Dhillon, M

    1991-05-01

    There is evidence to suggest that molds can cause IgE-mediated upper respiratory tract disorders and immunotherapy is efficacious in a select group. The environmental sampling studies show a remarkably small numbers of molds accounting for a majority of the mold load in various diverse locations. These are Cladosporium, Basidiospores, Aspergillus, and Alternaria-Penicillin families. Basidiospores have been underreported in the older studies because of difficulties in their identification. Whether the absolute mold level is the most important factor leading to IgE formation and induction of upper respiratory tract symptoms is uncertain. Certainly, the majority of the studies are based on the assumption that the absolute level of mold in the environment is the most important factor leading to the development of symptoms, but this is not based on strong evidence. A major problem in the majority of the studies is a lack of standardization of extracts which may lead to false negatives on skin testing and thus produce variable data in population evaluations comparing the prevalence of mold to its ability to induce IgE production and symptoms. The best current trials to document the efficacy of mold immunotherapy have been with the standardized Cladosporium extract. Unfortunately, these results cannot be extrapolated to the commercially available mold extracts available in the United States either for immunotherapy or for skin testing. These extracts are highly variable in their potency, prone to high false negative rates, and at best serve as poor skin testing reagents and possibly even worse immunotherapy reagents. Adequately standardized mold reagents are urgently needed to determine whether the Cladosporium data can be extrapolated to them in any meaningful way. PMID:2035901

  4. New strategies for allergen immunotherapy.

    PubMed

    Carnés, Jerónimo; Robinson, Douglas S

    2008-06-01

    Specific allergen immunotherapy, consisting in the administration of increasing amounts of offending allergens into sensitive patients was first used nearly one hundred years ago and remains in use worldwide for treatment of allergic rhinitis and asthma. It has been recognised as the only effective treatment for type I allergic diseases when the appropriate quantities of allergens are used. The immunological mechanisms by which specific immunotherapy is effective include the modulation of T cells and the response of B-cells and is accompanied by significant decreases of specific IgE and increases in allergen specific IgG antibodies, mainly IgG4. While specific allergen injection immunotherapy is highly effective and the most common way of administration other routes such as oral or intranasal ways have been considered as and alternative to subcutaneous injections. During the last century, allergenic vaccines have been prepared using individual allergens adsorbed to different adjuvant substances. These vaccines have demonstrated efficacy and good results in different clinical trials. However, many novel approaches to allergen immunotherapy have been developed in the last years in order to increase the safety and efficacy of allergenic vaccines. In that way, different and modern vaccines have been prepared including more purified products such as depigmented allergen extracts; allergoids, consisting on big molecules of thousands of kDa, which contain all the individual allergens and show a significant decrease in severe adverse reactions; peptides or small aminoacid sequences; recombinant allergens; hypoallergenic vaccines where the IgE binding sites have been modified; or allergen-CpG fusion molecules. New presentations are under study and new treatments will be developed in the near future with the objective that the prevention of allergic disease may become a reality. The review article also discuss recent patent related to the field. PMID:19075996

  5. House dust allergy and immunotherapy

    PubMed Central

    Thomas, Wayne R.

    2012-01-01

    HDM allergy is associated with asthma, allergic rhinitis and atopic dermatitis. In many countries childhood asthma is predominantly found in HDM-allergic children with their probability of developing disease being proportional to their IgE antibody titers and the early development of Th2 responses. While the pathogenesis is complex and increasingly linked to infection the immunologically-based allergen immunotherapy and anti-IgE antibody therapy are highly beneficial. Immunotherapy could be a short-term treatment providing lifelong relief but the current regimens depend on repeated administration of allergen over years. Immunological investigations point to a contribution of responses outside the Th2 pathway and multiple potential but unproven control mechanisms. Over half of the IgE antibodies are directed to the group 1 and 2 allergens with most of remainder to the group 4, 5, 7 and 21 allergens. This hierarchy found in high and low responders provides a platform for introducing defined allergens into immunotherapy and defined reagents for investigation. PMID:22894952

  6. Novel immunotherapies in lymphoid malignancies.

    PubMed

    Batlevi, Connie Lee; Matsuki, Eri; Brentjens, Renier J; Younes, Anas

    2016-01-01

    The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted 'breakthrough' designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE(®)) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID:26525683

  7. The future of sublingual immunotherapy.

    PubMed

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

    2009-01-01

    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

  8. Viral vectors for cancer immunotherapy.

    PubMed

    Harrop, Richard; Carroll, Miles W

    2006-01-01

    Over the last decade, immunotherapy approaches for the treatment of cancer have been investigated with renewed vigour, perhaps catalyzed by the clinical successes seen with monoclonal antibody and cytokine based therapies. The identification of tumor-associated antigens (TAAs) in multiple cancer types has enabled the development of targeted immunotherapies and allayed some of the safety concerns associated with the induction of deleterious autoimmune reactions. In addition to the TAA or therapeutic gene, the antigen delivery system is equally as important for the development of a successful cancer vaccine. One approach to induce a potent and targeted antitumor response is to use viruses to deliver the TAA to cells of the immune system. A diverse array of oncolytic viruses and recombinant viral vectors encoding numerous therapeutic genes or TAAs have been tested in pre-clinical studies and produced results which, in some cases, justify their clinical development as potential cancer immunotherapies. Within the last 5-10 years, many such recombinant vectors have made the transition from pre-clinical research to clinical development and it is these, which are given most weight in this review. PMID:16146772

  9. Novel immunotherapies in lymphoid malignancies

    PubMed Central

    Batlevi, Connie Lee; Matsuki, Eri; Brentjens, Renier J.; Younes, Anas

    2016-01-01

    The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted ‘breakthrough’ designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE®) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID:26525683

  10. Immunotherapy Targets in Pediatric Cancer

    PubMed Central

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

    2011-01-01

    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

  11. Local and systemic immunotherapy in nasal allergy.

    PubMed

    Palma-Carlos, A G; Palma-Carlos, M L; Spínola Santos, A; Santos, C; Pedro, E; Pregal, A

    1999-10-01

    Two assays have been done to evaluate the effect of immunotherapy in nasal allergy. First, a trial of nasal immunotherapy and second, the study of mediator release after vaccines. Local immunotherapy, applied directly, triggers different response mechanisms. Specific nasal immunotherapy started before seasonal or perennial symptoms peak, has been done by increasing the doses of allergen three times a week during a 3-month period and a manutention period of a weekly nasal puff of the same allergen. Symptom scores and drug consumption have been registered. The results have been compared with the scores obtained in the same patients over the same period of the same year before immunotherapy. In perennial rhinitis blockage, rhinorrea, sneezing and itching scores all decreased. In seasonal rhinitis, a similar score decrease was obtained for blockage, rhinorrea, sneezing and itching. Pharmacological scores also decreased. These data point to a short-term effect of nasal immunotherapy. Tryptase release has been evaluated in nasal washings after nasal challenge with a Parietaria (Pellitory wall) extract before and after specific systemic immunotherapy, in order to evaluate changes in mast cells reactivity. Eight patients were studied, all allergic to Parietaria. Nasal provocation tests have been done before the season with increasing doses of 10, 100 and 1000 PNU and tryptase assayed in nasal washings at 10, 20 and 30 min after provocation. Immunotherapy decreased tryptase release after nasal challenge. The data point to the effect of systemic specific immunotherapy on mast cell reactivity. PMID:10577807

  12. Honeybee venom immunotherapy: certainties and pitfalls.

    PubMed

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

    2012-11-01

    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

  13. Inhibition of lung metastasis by adoptive immunotherapy using Iscador.

    PubMed

    Antony, S; Kuttan, R; Kuttan, G

    1999-01-01

    Adoptive immunotherapy using spleen cells activated with Iscador was found to inhibit tumour growth significantly (P<0.001). Metastatic B16F10 tumour bearing animals treated with a single dose of spleen cells activated with Iscador (in vitro) showed 100% inhibition of tumour nodule formation on 21st day. Single injection of splenocytes isolated from mice treated with Iscador inhibited the tumour nodule formation by 93.8%. Animals treated with in vivo and in vitro activated spleen cells along with Iscador had an increase in life span of 119% and 81% respectively. Treatment of animals with low dose of Iscador after adoptive immunotherapy further augmented the life span. Animals which underwent adoptive immunotherapy showed significantly reduced lung collagen hydroxyproline (9.8 microg/mg protein) and serum sialic acid (24.61 micro/ml serum) levels compared to control tumour bearing animals with increased levels of lung hydroxyproline (26.95 microg/mg protein) and serum sialic acid levels (151.3 microg/ml serum). Serum gamma -glutamyl transpeptidase levels were found to be significantly reduced in the group of animals treated with Iscador and Iscador activated splenocytes (16.6+/-2.3 nmol P-nitroaniline released /ml serum) Group of animals treated with Iscador activated splenocytes alone also showed significantly reduced serum gamma - glutamyl transpeptidase levels (17.3+/-10 nmol P-nitroaniline released /ml serum) compared to control tumour bearing animals (91+/-12 nmol P-nitroaniline released /ml serum). PMID:10073677

  14. Neoantigen-based cancer immunotherapy

    PubMed Central

    Bobisse, Sara; Coukos, George; Harari, Alexandre

    2016-01-01

    Emerging clinical evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy in all cancer types. Recent clinical data clearly demonstrated that human tumor cells express antigenic peptides (epitopes) that can be recognized by autologous tumor-specific T cells and that enhancement of such immune reactivity can potentially lead to cancer control and cancer regression in patients with advanced disease. However, in most cases, it is unclear which tumor antigens (Ags) mediated cancer regression. Mounting evidence indicates that numerous endogenous mutated cancer proteins, a hallmark of tumor cells, can be processed into peptides and presented on the surface of tumor cells, leading to their immune recognition in vivo as “non-self” or foreign. Massively parallel sequencing has now overcome the challenge of rapidly identifying the comprehensive mutational spectrum of individual tumors (i.e., the “mutanome”) and current technologies, as well as computational tools, have emerged that allow the identification of private epitopes derived from their mutanome and called neoantigens (neoAgs). On this basis, both CD4+ and CD8+ neoantigen-specific T cells have been identified in multiple human cancers and shown to be associated with a favorable clinical outcome. Notably, emerging data also indicate that neoantigen recognition represents a major factor in the activity of clinical immunotherapies. In the post-genome era, the mutanome holds promise as a long-awaited ‘gold mine’ for the discovery of unique cancer cell targets, which are exclusively tumor-specific and unlikely to drive immune tolerance, hence offering the chance for highly promising clinical programs of cancer immunotherapy. PMID:27563649

  15. Neoantigen-based cancer immunotherapy.

    PubMed

    Bobisse, Sara; Foukas, Periklis G; Coukos, George; Harari, Alexandre

    2016-07-01

    Emerging clinical evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy in all cancer types. Recent clinical data clearly demonstrated that human tumor cells express antigenic peptides (epitopes) that can be recognized by autologous tumor-specific T cells and that enhancement of such immune reactivity can potentially lead to cancer control and cancer regression in patients with advanced disease. However, in most cases, it is unclear which tumor antigens (Ags) mediated cancer regression. Mounting evidence indicates that numerous endogenous mutated cancer proteins, a hallmark of tumor cells, can be processed into peptides and presented on the surface of tumor cells, leading to their immune recognition in vivo as "non-self" or foreign. Massively parallel sequencing has now overcome the challenge of rapidly identifying the comprehensive mutational spectrum of individual tumors (i.e., the "mutanome") and current technologies, as well as computational tools, have emerged that allow the identification of private epitopes derived from their mutanome and called neoantigens (neoAgs). On this basis, both CD4(+) and CD8(+) neoantigen-specific T cells have been identified in multiple human cancers and shown to be associated with a favorable clinical outcome. Notably, emerging data also indicate that neoantigen recognition represents a major factor in the activity of clinical immunotherapies. In the post-genome era, the mutanome holds promise as a long-awaited 'gold mine' for the discovery of unique cancer cell targets, which are exclusively tumor-specific and unlikely to drive immune tolerance, hence offering the chance for highly promising clinical programs of cancer immunotherapy. PMID:27563649

  16. Mechanisms of immunotherapy to aeroallergens.

    PubMed

    Shamji, M H; Durham, S R

    2011-09-01

    Allergen immunotherapy is allergen-specific, allergen dose- and time-dependent and is associated with long-term clinical and immunological tolerance that persists for years after discontinuation. Successful immunotherapy is accompanied by the suppression of numbers of T-helper 2 (Th2) effector cells, eosinophils, basophils, c-kit+mast cells and neutrophils infiltration in target organs, induction of IL-10 and/or TGF-β+Treg cells and increases in 'protective' non-inflammatory blocking antibodies, particularly IgG4 and IgA2 subclasses with inhibitory activity. These events are accompanied by a reduction and/or a redirection of underlying antigen-specific Th2-type T cell-driven hypersensitivity to the allergen(s) used for therapy. This suppression occurs within weeks or months as a consequence of the appearance of a population of regulatory T cells that exert their effects by mechanisms involving cell-cell contact, but also by the release of cytokines such as IL-10 (increases IgG4) and TGF-β (increases specific IgA). The more delayed-in-time appearance of antigen-specific T-helper 1 responses and alternative mechanisms such as Th2 cell anergy and/or apoptosis may also be involved. The mechanisms of sublingual immunotherapy are similar to those following a subcutaneous administration of allergen, whereas it is likely that additional events following antigen presentation in the sublingual mucosa and regional lymph nodes are involved. These insights have resulted in novel approaches and portend future biomarkers that may be surrogate or predictive of the clinical response to treatment. PMID:21762223

  17. Oral Immunotherapy for Food Allergy.

    PubMed

    Burbank, Allison J; Sood, Puja; Vickery, Brian P; Wood, Robert A

    2016-02-01

    Food allergy is a potentially life-threatening condition with no approved therapies, apart from avoidance and injectable epinephrine for acute allergic reactions. Oral immunotherapy (OIT) is an experimental treatment in which food-allergic patients consume gradually increasing quantities of the food to increase their threshold for allergic reaction. This therapy carries significant risk of allergic reactions. The ability of OIT to desensitize patients to particular foods is well-documented, although the ability to induce tolerance has not been established. This review focuses on recent studies for the treatment of food allergies such as cow's milk, hen's egg, and peanut. PMID:26617227

  18. Lipid A and immunotherapy.

    PubMed

    Ribi, E; Cantrell, J L; Takayama, K; Qureshi, N; Peterson, J; Ribi, H O

    1984-01-01

    Endotoxin isolated from Re mutants of Salmonella typhimurium or Salmonella minnesota and consisting only of 3-deoxy-D-mannooctulosonic acid (KDO) and lipid A synergistically enhances the ability of mycobacterial cell wall skeleton (CWS) to regress transplantable, line-10 tumor (hepatocellular carcinoma) in syngeneic guinea pigs. Tumor regression is rapid, and systemic tumor immunity concomitantly develops when as little as 50 micrograms of each of these two components is combined and injected intralesionally. Selective removal of KDO from endotoxin yields diphosphoryl lipid A, which retains its toxic properties. Subsequent selective removal of the phosphate moiety at the reducing end of the diphosphoryl lipid A molecule yields nontoxic, monophosphoryl lipid A (determined by lethality for chick embryos). Like the parent endotoxin or toxic diphosphoryl lipid A, monophosphoryl lipid A retains the ability to synergistically enhance the antitumor activity of mycobacterial CWS adjuvant. Both di- and monophosphoryl lipid A contain mixtures of a series of structural analogs. They can be separated chromatographically into single components that differ in number, type, and position of ester-linked fatty acids. Comparison of chromatographic fractions reveals that components of toxic and nontoxic lipid A can be paired according to structure. Each component of the pair has the same molecular structure, with the exception of an additional phosphate group in the toxic component. The toxicity of "lipid A's" liberated from endotoxin by acid hydrolysis appears to be determined by the proportion of di- and monophosphoryl lipid A in the hydrolysis mixture. Structural analogs of monophosphoryl lipid A, which differ in degree of O-acylation and type and distribution of fatty acids, have comparable antitumor activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6382555

  19. Novel approaches in cancer immunotherapy.

    PubMed

    Subramaniam, Deepa S; Liu, Stephen V; Giaccone, Giuseppe

    2016-04-01

    Our understanding of tumor immunology has exploded in the past 3 decades. The complex relationships between tumor cells, the tumor microenvironment and the immune system cells, especially the cytotoxic and helper T cells and the regulatory T cells are beginning to be elucidated. In this review, we will attempt to provide a brief primer of tumor immunology. Cytokine therapy has historically been the mainstay of immunotherapy in cancers such as melanoma and kidney cancer. We will review some of the advances made with cancer vaccines, with a focus on peptide vaccines, tumor cell vaccines and immune cell vaccines. The pros and cons of nucleic acid-based vaccines including DNA and RNA vaccines will be discussed. Adoptive cell therapy has made significant progress utilizing chimeric antigen-receptor transduced T cells, especially in hematologic malignancies. We will also consider the key targets in checkpoint inhibition, and summarize some of the preclinical and clinical data with respect to checkpoint inhibition. Progress made in the novel immunotherapeutic approach of oncolytic viral therapy will be analyzed. PDL-1 expression by tumor cells and tumor infiltrating lymphocytes has been looked at as a biomarker in clinical trials. Limitations to such an approach and potential candidates for future predictive biomarkers of response to immunotherapy and biomarkers of autoimmunity and adverse reactions will be considered. PMID:27232512

  20. Novel immunotherapies for hematological malignancies

    PubMed Central

    Nelson, Michelle H.; Paulos, Chrystal M.

    2014-01-01

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

  1. Sublingual immunotherapy: a comprehensive review.

    PubMed

    Cox, Linda S; Larenas Linnemann, Désirée; Nolte, Hendrik; Weldon, David; Finegold, Ira; Nelson, Harold S

    2006-05-01

    Sublingual immunotherapy (SLIT) has been used with increasing frequency in Europe and is viewed with increasing interest by allergists in the United States. To address this interest, a Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology's Immunotherapy and Allergy Diagnostic Committees reviewed the available literature on SLIT and prepared this report. The task force concluded that despite clear evidence that SLIT is an effective treatment, many questions remained unanswered, including effective dose, treatment schedules, and overall duration of treatment. Until these have been determined, an assessment of the cost/benefit ratio of the treatment cannot be made. SLIT does appear to be associated with few serious side effects, but it has not been administered in high-risk asthmatic patients, nor in the studies reviewed has it been administered as a mixture of non-cross-reacting allergens. Furthermore, there is currently no allergy extract approved for this use in the United States, nor is there a Current Procedural Terminology code for billing purposes. All of these factors should be given careful consideration by anyone contemplating initiating SLIT treatment for their allergic patients. PMID:16675328

  2. [Dendritic cells in cancer immunotherapy].

    PubMed

    Gato, M; Liechtenstein, T; Blanco-Luquín, I; Zudaire, M I; Kochan, G; Escors, D

    2015-01-01

    Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities. PMID:26486534

  3. Adoptive immunotherapy against ovarian cancer.

    PubMed

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

    2016-01-01

    The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC.Recently, several preclinical and clinical studies investigated feasibility and activity of adoptive immunotherapy in EOC. Our aim is to highlight prospective of adoptive immunotherapy in EOC, focusing on HLA-restricted Tumor Infiltrating Lymphocytes (TILs), and MHC-independent immune effectors such as natural killer (NK), and cytokine-induced killer (CIK). Adoptive cell therapy (ACT) has shown activity in several pre-clinical models. Available preclinical and clinical data suggest that adoptive cell therapy may provide the best benefit in settings of low tumor burden, minimal residual disease, or maintenance therapy. Further studies are needed to better define the optimal clinical setting. PMID:27188274

  4. Potentiality of immunotherapy against hepatocellular carcinoma

    PubMed Central

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

    2015-01-01

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

  5. Immunotherapy of Metastases Enhances Subsequent Chemotherapy

    NASA Astrophysics Data System (ADS)

    Hanna, Michael G.; Key, Marc E.

    1982-07-01

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

  6. DNA-inorganic hybrid nanovaccine for cancer immunotherapy

    NASA Astrophysics Data System (ADS)

    Zhu, Guizhi; Liu, Yijing; Yang, Xiangyu; Kim, Young-Hwa; Zhang, Huimin; Jia, Rui; Liao, Hsien-Shun; Jin, Albert; Lin, Jing; Aronova, Maria; Leapman, Richard; Nie, Zhihong; Niu, Gang; Chen, Xiaoyuan

    2016-03-01

    Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit

  7. Immunotherapy

    MedlinePlus

    ... Information Specialist Financial Support Online Chats Support Groups Peer-to-Peer Support LLS Community Blogs Caregiver Support Other Helpful ... Information Specialist Financial Support Online Chats Support Groups Peer-to-Peer Support LLS Community Blogs Caregiver Support ...

  8. Targeting neoantigens for cancer immunotherapy.

    PubMed

    Lu, Yong-Chen; Robbins, Paul F

    2016-07-01

    Studies first carried out in the 1980s have demonstrated murine T cells can recognize mutated gene products, known as neoantigens, and that these T cells are capable of mediating tumor rejection. The first human tumor antigens isolated in the early 1990s were the products of non-mutated genes expressed in a tissue-specific manner; subsequent studies have indicated that tumor-infiltrating lymphocytes that are cultured in vitro frequently recognize mutated gene products. In addition, correlative studies indicate that clinical responses to therapies involving the use of antibodies directed against checkpoint inhibitors such as CTLA-4 and PD-1 may be associated with mutational burden, providing indirect evidence that these responses may primarily be mediated by neoantigen-reactive T cells. The importance of neoantigen-reactive T cells may be elucidated by the results of ongoing and future studies aimed at leveraging information gained from mutational profiling to enhance the potency of immunotherapies. PMID:27208041

  9. [Current immunotherapy of multiple sclerosis].

    PubMed

    Paul, F; Ruprecht, K

    2015-08-01

    Following the introduction of interferon beta 1b as the first immunomodulatory therapy for multiple sclerosis (MS) in 1993, there are currently nine substances or substance classes approved for the treatment of MS (i.e. alemtuzumab, azathioprine, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab and teriflunomide). Major developments during the last 5 years include the approval of orally administered medications (i.e. fingolimod, teriflunomide and dimethyl fumarate), a monoclonal antibody (alemtuzumab), as well as glatiramer acetate with an administration frequency three times a week and a pegylated formulation of interferon beta 1a. The broadened therapeutic options enable a more differentiated and individualized therapy of MS; however, evidence-based data for therapeutic decision-making relevant in clinical practice are not always available. Rare but potentially severe and even life-threatening side effects of immunotherapies for MS require continuous pharmacovigilance and adherence to risk management plans. PMID:26253589

  10. Topical Immunotherapy in Alopecia Areata

    PubMed Central

    Singh, Gurcharan; Lavanya, MS

    2010-01-01

    Alopecia Areata (AA) is a common non-scarring alopecia directed against the anagenic hair follicle. Various treatment modalities have been used for the treatment of severe AA. Topical immunotherapy is the best documented treatment so far for severe and refractory AA. Dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphencyprone (DPCP) are the contact allergens used for this purpose. DNCB has been found to be mutagenic by the Ames test and is largely replaced by DPCP and SADBE. DPCP and SADBE are both known to be non-mutagenic compounds and have comparable efficacy results and relapse rates. SADBE requires special solvents and additives to maintain its potency and is more expensive than the rest. DPCP has a response rate varying from 60% in severe Alopecia Areata to 17% in patients with alopecia totalis or universalis, and shows about 88 to 100% high response rate in patients with patchy Alopecia Areata. PMID:21188022

  11. Oral Immunotherapy for Food Allergies.

    PubMed

    Feuille, Elizabeth; Nowak-Węgrzyn, Anna

    2016-01-01

    Oral immunotherapy (OIT) is a promising investigational therapy for food allergy. Clinical trials in peanut, milk, egg, and wheat allergy provide evidence that OIT can effectively desensitize a majority of individuals to a food allergen. While a portion of subjects demonstrate sustained unresponsiveness, the majority regain sensitivity with allergen avoidance. The safety and tolerability of OIT continue to limit its use in some patients. Virtually all studies report adverse reactions that are more frequent during dose escalation but may also occur during maintenance therapy. Recent studies have identified adjunctive therapies (such as omalizumab) which may mitigate adverse effects. There is a paucity of data on the long-term safety and efficacy of OIT. Further study is required before OIT is ready for routine clinical practice. This review is intended to provide the reader with an up-to-date understanding of OIT, including its mechanisms, efficacy, safety profile, and potential utility in clinical practice. PMID:27355816

  12. Immune checkpoints and immunotherapy for colorectal cancer

    PubMed Central

    Singh, Preet Paul; Sharma, Piyush K.; Krishnan, Gayathri; Lockhart, A. Craig

    2015-01-01

    Colorectal cancer (CRC) remains one of the major causes of death worldwide, despite steady improvement in early detection and overall survival over the past decade. Current treatment paradigms, with chemotherapy and biologics, appear to have reached their maximum benefit. Immunotherapy, especially with checkpoint inhibitors, has shown considerable clinical benefit in various cancers, including mismatch-repair-deficient CRC. This has led to the planning and initiation of several clinical trials evaluating novel immunotherapy agents—as single agents, combinations and in conjunction with chemotherapy—in patients with CRC. This article reviews biological and preclinical data for checkpoint inhibitors and discusses various immunotherapy trials in CRC, as well as current efforts in CRC immunotherapy. PMID:26510455

  13. Immunotherapy: Disrupting the Cancer Treatment World

    MedlinePlus

    ... ACS » + - Text Size Immunotherapy: Disrupting the Cancer Treatment World By Elizabeth Mendes June 16, 2014 This story ... of cancer research in depth. The cancer research world is dedicating increasing energy to a rapidly evolving ...

  14. Grass pollen immunotherapy: where are we now.

    PubMed

    Würtzen, Peter A; Gupta, Shashank; Brand, Stephanie; Andersen, Peter S

    2016-04-01

    During allergen immunotherapy (AIT), the allergic patient is exposed to the disease-inducing antigens (allergens) in order to induce clinical and immunological tolerance and obtain disease modification. Large trials of grass AIT with highly standardized subcutaneous and sublingual tablet vaccines have been conducted to document the clinical effect. Induction of blocking antibodies as well as changes in the balance between T-cell phenotypes, including induction of regulatory T-cell subtypes, have been demonstrated for both treatment types. These observations increase the understanding of the immunological mechanism behind the clinical effect and may make it possible to use the immunological changes as biomarkers of clinical effect. The current review describes the recent mechanistic findings for subcutaneous immunotherapy and sublingual immunotherapy/tablet treatment and discusses how the observed immunological changes translate into a scientific foundation for the observed clinical effects of grass pollen immunotherapy and lead to new treatment strategies for grass AIT. PMID:26973122

  15. Who Will Benefit from Cancer Immunotherapy?

    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.

  16. De-Risking Immunotherapy: Report of a Consensus Workshop of the Cancer Immunotherapy Consortium of the Cancer Research Institute.

    PubMed

    Mellman, Ira; Hubbard-Lucey, Vanessa M; Tontonoz, Matthew J; Kalos, Michael D; Chen, Daniel S; Allison, James P; Drake, Charles G; Levitsky, Hy; Lonberg, Nils; van der Burg, Sjoerd H; Fearon, Douglas T; Wherry, E John; Lowy, Israel; Vonderheide, Robert H; Hwu, Patrick

    2016-04-01

    With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies. Several recommendations were made, including making better use of clinical data to inform preclinical research, obtaining adequate tissues for biomarker studies, and choosing appropriate clinical trial endpoints to identify promising drug candidates and combinations in nonrandomized early-phase trials. PMID:27036972

  17. Cancer Immunotherapy: A Treatment for the Masses

    NASA Astrophysics Data System (ADS)

    Blattman, Joseph N.; Greenberg, Philip D.

    2004-07-01

    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.

  18. Defining the critical hurdles in cancer immunotherapy

    PubMed Central

    2011-01-01

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

  19. Oncolytic Immunotherapy for Treatment of Cancer.

    PubMed

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

    2016-01-01

    Immunotherapy entails the treatment of disease by modulation of the immune system. As detailed in the previous chapters, the different modes of achieving immune modulation are many, including the use of small/large molecules, cellular therapy, and radiation. Oncolytic viruses that can specifically attack, replicate within, and destroy tumors represent one of the most promising classes of agents for cancer immunotherapy (recently termed as oncolytic immunotherapy). The notion of oncolytic immunotherapy is considered as the way in which virus-induced tumor cell death (known as immunogenic cancer cell death (ICD)) allows the immune system to recognize tumor cells and provide long-lasting antitumor immunity. Both immune responses toward the virus and ICD together contribute toward successful antitumor efficacy. What is now becoming increasingly clear is that monotherapies, through any of the modalities detailed in this book, are neither sufficient in eradicating tumors nor in providing long-lasting antitumor immune responses and that combination therapies may deliver enhanced efficacy. After the rise of the genetic engineering era, it has been possible to engineer viruses to harbor combination-like characteristics to enhance their potency in cancer immunotherapy. This chapter provides a historical background on oncolytic virotherapy and its future application in cancer immunotherapy, especially as a combination therapy with other treatment modalities. PMID:27240460

  20. Developments in immunotherapy for gastrointestinal cancer.

    PubMed

    Diaz, J L; Wanta, S M; Fishbein, T M; Kroemer, A

    2015-08-01

    Gastrointestinal (GI) cancers are the most commonly occurring cancer worldwide. Colorectal cancer (CRC) is the second and third most commonly diagnosed cancer in women and men, respectively. Despite the advent of screening and the declining incidence of CRC overall, most patients are not diagnosed at an early, localized stage. Due to resistance to chemotherapy, recurrence, and metastatic disease, those diagnosed with advanced disease have only a 12% 5-year survival rate. Given the overwhelming global impact of CRC, the need for advanced therapy is crucial. Targeted immunotherapy in addition to surgical resection, traditional chemotherapy, and radiation therapy is on the rise. For the purpose of this review, we focused on the advances of immunotherapy, particularly in CRC, with mention of research pertaining to particular advances in immunotherapy for other aspects of the GI system. We review basic immunology and the microenvironment surrounding colorectal tumors that lead to immune system evasion and poor responses to chemotherapy. We also examined the way these obstacles are proving to be the targets of tumor specific immunotherapy. We will present current FDA approved immunotherapies such as monoclonal antibodies (mAb) targeting tumor specific antigens, as well as vaccines, adoptive cell therapy, cytokines, and check-point inhibitors. A summation of prior research, current clinical trials, and prospective therapies in murine models help delineate our current status and future strategies on CRC immunotherapy. PMID:25916195

  1. Aptamers: A Feasible Technology in Cancer Immunotherapy

    PubMed Central

    Villanueva, H.; Pastor, F.

    2016-01-01

    Aptamers are single-chained RNA or DNA oligonucleotides (ODNs) with three-dimensional folding structures which allow them to bind to their targets with high specificity. Aptamers normally show affinities comparable to or higher than that of antibodies. They are chemically synthesized and therefore less expensive to manufacture and produce. A variety of aptamers described to date have been shown to be reliable in modulating immune responses against cancer by either blocking or activating immune receptors. Some of them have been conjugated to other molecules to target the immune system and reduce off-target side effects. Despite the success of first-line treatments against cancer, the elevated number of relapsing cases and the tremendous side effects shown by the commonly used agents hinder conventional treatments against cancer. The advantages provided by aptamers could enhance the therapeutic index of a given strategy and therefore enhance the antitumor effect. Here we recapitulate the provided benefits of aptamers with immunomodulatory activity described to date in cancer therapy and the benefits that aptamer-based immunotherapy could provide either alone or combined with first-line treatments in cancer therapy. PMID:27413756

  2. Clinical and Immunological Changes of Immunotherapy in Patients with Atopic Dermatitis: Randomized Controlled Trial

    PubMed Central

    Sánchez Caraballo, Jorge Mario; Cardona Villa, Ricardo

    2012-01-01

    Background. Immunotherapy has proven to be an useful tool in the management of allergic respiratory diseases; however, little has been studied in atopic dermatitis. Objective. To evaluate the clinical and immunological impact of immunotherapy with mites allergen extracts in atopic dermatitis. Methods. Patients with atopic dermatitis were assigned with computer-generated randomization to either of the following groups: (a) controls received only topical treatment with steroids and/or tacrolimus and (b) actively treated patients received topical treatment plus immunotherapy. Levels of serum total IgE, mites-specific IgE and IgG4 were assessed at study start and after one year of immunotherapy. Results. 31 patients in the active group and 29 in the control group completed the study. Symptoms and medication scores were significantly reduced in the active group after six months. Three patients in the control group showed new sensitizations to mites, while 3 patients in the active group showed neosensitization to shrimp with negative oral food challenge. We observed significant increase of mites-specific IgG4 levels in active group. Conclusion. Specific allergen immunotherapy induced a tolerogenic IgG4 response to mite allergens associated with favorable clinical effects in atopic dermatitis patients. PMID:23724240

  3. Immunotherapy using algal-produced Ara h 1 core domain suppresses peanut allergy in mice.

    PubMed

    Gregory, James A; Shepley-McTaggart, Ariel; Umpierrez, Michelle; Hurlburt, Barry K; Maleki, Soheila J; Sampson, Hugh A; Mayfield, Stephen P; Berin, M Cecilia

    2016-07-01

    Peanut allergy is an IgE-mediated adverse reaction to a subset of proteins found in peanuts. Immunotherapy aims to desensitize allergic patients through repeated and escalating exposures for several months to years using extracts or flours. The complex mix of proteins and variability between preparations complicates immunotherapy studies. Moreover, peanut immunotherapy is associated with frequent negative side effects and patients are often at risk of allergic reactions once immunotherapy is discontinued. Allergen-specific approaches using recombinant proteins are an attractive alternative because they allow more precise dosing and the opportunity to engineer proteins with improved safety profiles. We tested whether Ara h 1 and Ara h 2, two major peanut allergens, could be produced using chloroplast of the unicellular eukaryotic alga, Chlamydomonas reinhardtii. C. reinhardtii is novel host for producing allergens that is genetically tractable, inexpensive and easy to grow, and is able to produce more complex proteins than bacterial hosts. Compared to the native proteins, algal-produced Ara h 1 core domain and Ara h 2 have a reduced affinity for IgE from peanut-allergic patients. We further found that immunotherapy using algal-produced Ara h 1 core domain confers protection from peanut-induced anaphylaxis in a murine model of peanut allergy. PMID:26801740

  4. Peptide-based allergen specific immunotherapy for the treatment of allergic disorders.

    PubMed

    El-Qutob, David; Reche, Pedro; Subiza, José L; Fernández-Caldas, Enrique

    2015-01-01

    Allergen specific immunotherapy (ASIT) and environmental control are the only etiologic treatments of allergic rhino-conjunctivitis, asthma and atopic dermatitis. The clinical benefit of ASIT relies on the selection of the patients and the identification and administration of the allergen, or allergens. Different routes of administration have been investigated, including subcutaneous, intradermal, epicutaneous, sublingual, inhaled, or intra-lymphatic. While subcutaneous and sublingual allergen specific immunotherapy may require from 3 to 5 years of treatment, clinical efficacy with intra-lymphatic treatment can be achieved after 3 injections. The most severe side effect of ASIT is anaphylaxis. Novel approaches are being investigated to reduce the allergenicity of immunotherapy vaccines, maintaining immunogenicity. Peptide immunotherapy has been directed mostly against autoimmune diseases, but the use of synthetic peptides for ASIT is a promising field in basic science, applied immunology and in clinical development. Short synthetic peptides bear allergen-specific CD4 T-cell epitopes which induce tolerance by stimulating regulatory (Treg) and Th1 cells. In the present patent review, we describe new trends in allergen immunotherapy using peptides, which, from a clinical point of view, are promising. PMID:25760734

  5. Immunotherapy for acute myeloid leukemia.

    PubMed

    Jurcic, Joseph G

    2005-09-01

    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

  6. Specific Immunotherapy in Atopic Dermatitis

    PubMed Central

    Lee, Jungsoo; Park, Chang Ook

    2015-01-01

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

  7. Immunotherapy in renal cell carcinoma.

    PubMed

    Bukowski, R M

    1999-06-01

    Patients with metastatic renal cell carcinoma continue to present a therapeutic challenge. Current therapeutic approaches involve surgery and various types of immunotherapy. The rationale for this latter form of therapy include the observations of spontaneous tumor regression, the presence of a T-cell-mediated immune response, and the tumor responses observed in patients receiving cytokine therapy. Analysis of prognostic factors in these patients demonstrates that clinical responses occur most frequently in individuals with good performance status. The cytokines interleukin-2 (IL-2, aldesleukin [Proleukin], interferon-alfa (Intron A, Roferon-A), or the combination produce responses in 15% to 20% of patients. Randomized trials suggest that administration of interferon-alfa may result in a modest improvement in median survival. Investigation of the molecular genetics of renal cell carcinoma and the presence of T-lymphocyte immune dysregulation have suggested new therapeutic strategies. Further preclinical and clinical studies investigating inhibitors of angiogenesis or pharmacologic methods to reverse immune dysregulation are ongoing. Therapeutic results in patients with renal cell carcinoma remain limited, and investigational approaches are warranted. PMID:10378218

  8. Melanoma immunotherapy dominates the field

    PubMed Central

    Diamantopoulos, Panagiotis

    2016-01-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  9. Melanoma immunotherapy dominates the field.

    PubMed

    Diamantopoulos, Panagiotis; Gogas, Helen

    2016-07-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  10. International consensus on allergy immunotherapy.

    PubMed

    Jutel, Marek; Agache, Ioana; Bonini, Sergio; Burks, A Wesley; Calderon, Moises; Canonica, Walter; Cox, Linda; Demoly, Pascal; Frew, Antony J; O'Hehir, Robin; Kleine-Tebbe, Jörg; Muraro, Antonella; Lack, Gideon; Larenas, Désirée; Levin, Michael; Nelson, Harald; Pawankar, Ruby; Pfaar, Oliver; van Ree, Ronald; Sampson, Hugh; Santos, Alexandra F; Du Toit, George; Werfel, Thomas; Gerth van Wijk, Roy; Zhang, Luo; Akdis, Cezmi A

    2015-09-01

    Allergen immunotherapy (AIT) has been used to treat allergic disease since the early 1900s. Despite numerous clinical trials and meta-analyses proving AIT efficacious, it remains underused and is estimated to be used in less than 10% of patients with allergic rhinitis or asthma worldwide. In addition, there are large differences between regions, which are not only due to socioeconomic status. There is practically no controversy about the use of AIT in the treatment of allergic rhinitis and allergic asthma, but for atopic dermatitis or food allergy, the indications for AIT are not well defined. The elaboration of a wider consensus is of utmost importance because AIT is the only treatment that can change the course of allergic disease by preventing the development of asthma and new allergen sensitizations and by inducing allergen-specific immune tolerance. Safer and more effective AIT strategies are being continuously developed both through elaboration of new allergen preparations and adjuvants and alternate routes of administration. A number of guidelines, consensus documents, or both are available on both the international and national levels. The international community of allergy specialists recognizes the need to develop a comprehensive consensus report to harmonize, disseminate, and implement the best AIT practice. Consequently, the International Collaboration in Asthma, Allergy and Immunology, formed by the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the World Allergy Organization, has decided to issue an international consensus on AIT. PMID:26162571

  11. Novel immunotherapies for hematologic malignancies.

    PubMed

    Nelson, Michelle H; Paulos, Chrystal M

    2015-01-01

    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

  12. Immunotherapy in Sarcoma: Future Horizons.

    PubMed

    Burgess, Melissa; Gorantla, Vikram; Weiss, Kurt; Tawbi, Hussein

    2015-11-01

    Immunologic approaches to cancer are over a century old. Over the years, the strategy has been fine-tuned from inciting infections in subjects to inhibiting negative regulatory signals from the innate immune system. Sarcomas are among the first tumors to be considered for immune interventions. From Coley's toxin to cytokine-based therapies to adoptive cell therapy, there have been numerous immunotherapeutic investigations in this patient population. A promising strategy includes adoptive T cell therapy which has been studied in small cohorts of synovial sarcoma, a subtype that is known to widely express the cancer testis antigen, NY-ESO-1. Additionally, recent data in metastatic melanoma and renal cell carcinoma demonstrate the utility and tremendous efficacy of immune checkpoint blockade with increased rates of durable responses compared to standard therapies. Responses in traditionally "non-immunogenic" tumors, such as lung and bladder cancers, provide ample rationale for the study of immune checkpoint inhibitors in sarcoma. While immunotherapy has induced some responses in sarcomas, further research will help clarify optimal patient selection for future clinical trials and new combinatorial immunotherapeutic strategies. PMID:26423769

  13. Mechanisms of subcutaneous allergen immunotherapy.

    PubMed

    Soyer, Ozge U; Akdis, Mubeccel; Akdis, Cezmi A

    2011-05-01

    Allergen-specific immunotherapy (SIT) is the only curative approach in the treatment of allergic diseases defined up-to-date. Peripheral T-cell tolerance to allergens, the goal of successful allergen-SIT, is the primary mechanism in healthy immune responses to allergens. By repeated administration of increased doses of the causative allergen, allergen-SIT induces a state of immune tolerance to allergens through the constitution of T regulatory (Treg) cells, including allergen-specific interleukin (IL)-10-secreting Treg type 1 cells and CD4(+)CD25(+)Treg cells; induction of suppressive cytokines, such as IL-10 and transforming growth factor β; suppression of allergen-specific IgE and induction of IgG4 and IgA; and suppression of mast cells, basophils, eosinophils, and inflammatory dendritic cells. This review summarizes the current knowledge on the mechanisms of allergen-SIT with emphasis on the roles of Treg cells in allergen-SIT. PMID:21530813

  14. Immunologic special forces: anti-pathogen cytotoxic T-lymphocyte immunotherapy following hematopoietic stem cell transplantation

    PubMed Central

    Keller, Michael D; Bollard, Catherine M

    2016-01-01

    Anti-pathogen adoptive T-cell immunotherapy has been proven to be highly effective in preventing or controlling viral infections following hematopoietic stem cell transplantation. Recent advances in manufacturing protocols allow an increased number of targeted pathogens, eliminate the need for viral transduction, broaden the potential donor pool to include pathogen-naïve sources, and reduce the time requirement for production. Early studies suggest that anti-fungal immunotherapy may also have clinical benefit. Future advances include further broadening of the pathogens that can be targeted and development of T-cells with resistance to pharmacologic immunosuppression.

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

    PubMed Central

    Singer, Josef; Jensen-Jarolim, Erika

    2014-01-01

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

  16. Use of new technology to improve utilization and adherence to immunotherapy.

    PubMed

    Joshi, Smita; Dimov, Ves

    2014-01-01

    Technology and social media have dramatically altered the landscape in which we practice medicine. Clinicians have increasingly turned to technology and the internet to enhance patient care. Allergists have used these modalities to improve utilization and adherence to immunotherapy. Electronic medical records (EMRs) are being widely adopted by allergy practices and some offer allergy/immunology specific modules that aid in daily workflow. The development of specialized devices that reduce pain associated with immunotherapy administration may improve compliance with immunotherapy. Social media and other forms of electronic communication such as e-mail, Facebook, Twitter, short message service (SMS), and YouTube give clinicians multiple avenues to disseminate information and reach their patients, possibly improving patient adherence to therapy. Finally, tablet computers, online networks, and electronic surveys provide additional ways to connect patients and physicians. PMID:25709743

  17. Current Studies of Immunotherapy on Glioblastoma.

    PubMed

    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

    2014-04-01

    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

  18. Advances in the understanding of cancer immunotherapy.

    PubMed

    Shore, Neal D

    2015-09-01

    The principal role of the immune system is to prevent and eradicate pathogens and infections. The key characteristics or features of an effective immune response include specificity, trafficking, antigen spread and durability (memory). The immune system is recognised to have a critical role in controlling cancer through a dynamic relationship with tumour cells. Normally, at the early stages of tumour development, the immune system is capable of eliminating tumour cells or keeping tumour growth abated; however, tumour cells may evolve multiple pathways over time to evade immune control. Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumour burden, in whom disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve. Because immunotherapies may have a different mechanism of action from traditional cytotoxic or targeted biological agents, immunotherapy techniques have the potential to combine synergistically with traditional therapies. PMID:24612369

  19. [Specific immunotherapy and relocation in occupational allergic bakers].

    PubMed

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

    2007-01-01

    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

  20. Immunotherapy advances in uro-genital malignancies.

    PubMed

    Ratta, Raffaele; Zappasodi, Roberta; Raggi, Daniele; Grassi, Paolo; Verzoni, Elena; Necchi, Andrea; Di Nicola, Massimo; Salvioni, Roberto; de Braud, Filippo; Procopio, Giuseppe

    2016-09-01

    Immunotherapy for the treatment of cancer has made significant progresses over the last 20 years. Multiple efforts have been attempted to restore immune-mediated tumor elimination, leading to the development of several targeted immunotherapies. Data from recent clinical trials suggest that these agents might improve the prognosis of patients with advanced genito-urinary (GU) malignancies. Nivolumab has been the first immune checkpoint-inhibitor approved for pre-treated patients with metastatic renal cell carcinoma. Pembrolizumab and atezolizumab have shown promising results in both phase I and II trials in urothelial carcinoma. Brentuximab vedotin has demonstrated early signals of clinical activity and immunomodulatory effects in highly pre-treated patients with testicular germ cell tumors. In this review, we have summarized the major clinical achievements of immunotherapy in GU cancers, focusing on immune checkpoint blockade as well as the new immunomodulatory monoclonal antibodies (mAbs) under clinical evaluation for these malignancies. PMID:27372200

  1. Development of Novel Immunotherapies for Multiple Myeloma.

    PubMed

    Al-Hujaily, Ensaf M; Oldham, Robyn A A; Hari, Parameswaran; Medin, Jeffrey A

    2016-01-01

    Multiple myeloma (MM) is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM). It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM. PMID:27618026

  2. Improving cancer immunotherapy with DNA methyltransferase inhibitors.

    PubMed

    Saleh, Mohammad H; Wang, Lei; Goldberg, Michael S

    2016-07-01

    Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity. PMID:26646852

  3. Adoptive Immunotherapy for Cancer or Viruses

    PubMed Central

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

    2015-01-01

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

  4. Hyperthermia as an immunotherapy strategy for cancer

    PubMed Central

    Skitzki, Joseph J.; Repasky, Elizabeth A.; Evans, Sharon S.

    2010-01-01

    The use of hyperthermia as an adjunct to cancer immunotherapy is supported by an increasing number of research data. Both preclinical and clinical data results have demonstrated improved antitumor immune responses with the addition of mild hyperthermia. The molecular mechanisms responsible for the improved immune reactivity observed in the presence of hyperthermia include the generation of Hsps, the activation of antigen presenting cells and changes in lymphocyte trafficking. Understanding these hyperthermia-induced processes can serve as the foundation for analyzing current clinical trials, as well as designing future trials in cancer immunotherapy. PMID:19513944

  5. Human Tumor Antigens and Cancer Immunotherapy

    PubMed Central

    Vigneron, Nathalie

    2015-01-01

    With the recent developments of adoptive T cell therapies and the use of new monoclonal antibodies against the immune checkpoints, immunotherapy is at a turning point. Key players for the success of these therapies are the cytolytic T lymphocytes, which are a subset of T cells able to recognize and kill tumor cells. Here, I review the nature of the antigenic peptides recognized by these T cells and the processes involved in their presentation. I discuss the importance of understanding how each antigenic peptide is processed in the context of immunotherapy and vaccine delivery. PMID:26161423

  6. Stinging insect allergy: current perspectives on venom immunotherapy.

    PubMed

    Ludman, Sian W; Boyle, Robert J

    2015-01-01

    Systemic allergic reactions to insect stings affect up to 5% of the population during their lifetime, and up to 32% of beekeepers. Such reactions can be fatal, albeit very rarely, and fear of a further systemic reaction (SR) can lead to significant anxiety and quality of life impairment. A recent Cochrane systematic review confirmed that venom immunotherapy (VIT) is an effective treatment for people who have had a systemic allergic reaction to an insect sting. VIT reduces risk of a further SR (relative risk 0.10, 95% confidence interval 0.03-0.28), but VIT also reduces risk of a future large local reaction, and significantly improves disease-specific quality of life. However, health economic analysis showed that VIT is generally not cost effective for preventing future SRs; most people are stung infrequently, most SRs resolve without long-term consequences, and a fatal outcome is extremely rare. VIT only becomes cost effective if one is stung frequently (eg, beekeepers) or if quality of life improvement is considered. Thus, for most people with insect sting allergy, anxiety and quality of life impairment should be the overriding consideration when making treatment decisions, highlighting the importance of a patient-centered approach. Areas which need to be explored in future research include efforts to improve the safety and convenience of VIT such as the use of sublingual immunotherapy; quality of life effects of venom allergy in children and adolescents as well as their parents; and the optimal duration of treatment. PMID:26229493

  7. Stinging insect allergy: current perspectives on venom immunotherapy

    PubMed Central

    Ludman, Sian W; Boyle, Robert J

    2015-01-01

    Systemic allergic reactions to insect stings affect up to 5% of the population during their lifetime, and up to 32% of beekeepers. Such reactions can be fatal, albeit very rarely, and fear of a further systemic reaction (SR) can lead to significant anxiety and quality of life impairment. A recent Cochrane systematic review confirmed that venom immunotherapy (VIT) is an effective treatment for people who have had a systemic allergic reaction to an insect sting. VIT reduces risk of a further SR (relative risk 0.10, 95% confidence interval 0.03–0.28), but VIT also reduces risk of a future large local reaction, and significantly improves disease-specific quality of life. However, health economic analysis showed that VIT is generally not cost effective for preventing future SRs; most people are stung infrequently, most SRs resolve without long-term consequences, and a fatal outcome is extremely rare. VIT only becomes cost effective if one is stung frequently (eg, beekeepers) or if quality of life improvement is considered. Thus, for most people with insect sting allergy, anxiety and quality of life impairment should be the overriding consideration when making treatment decisions, highlighting the importance of a patient-centered approach. Areas which need to be explored in future research include efforts to improve the safety and convenience of VIT such as the use of sublingual immunotherapy; quality of life effects of venom allergy in children and adolescents as well as their parents; and the optimal duration of treatment. PMID:26229493

  8. Combined Cancer Immunotherapy Against Aurora Kinase A.

    PubMed

    Kaštánková, Iva; Poláková, Ingrid; Dušková, Martina; Šmahel, Michal

    2016-05-01

    Aurora kinase A (AURKA) is a centrosomal protein that is overexpressed in a number of human malignancies and can contribute to tumor progression. As we used this protein as a target of DNA immunization, we increased its immunogenicity by the addition of the PADRE helper epitope and decreased its potential oncogenicity by mutagenesis of the kinase domain. For in vitro analysis of induced immune responses in mice, we identified the Aurka220-228 nonapeptide representing an H-2K epitope. As DNA vaccination against the Aurka self-antigen by a gene gun did not show any antitumor effect, we combined DNA immunization with anti-CD25 treatment that depletes mainly regulatory T cells. Whereas 1 anti-CD25 dose injected before DNA vaccination did not enhance the activation of Aurka-specific splenocytes, 3 doses administered on days of immunizations augmented about 10-fold immunity against Aurka. However, an opposite effect was found for antitumor immunity-only 1 anti-CD25 dose combined with DNA vaccination reduced tumor growth. Moreover, the administration of 3 doses of anti-CD25 antibody alone accelerated tumor growth. Analysis of tumor-infiltrating cells showed that 3 anti-CD25 doses not only efficiently depleted regulatory T cells but also activated helper T cells and CD3CD25 cells. Next, we found that blockade of the PD-1 receptor initiated 1 week after the first immunization was necessary for significant inhibition of tumor growth with therapeutic DNA vaccination against Aurka combined with depletion of CD25 cells. Our results suggest that combined cancer immunotherapy should be carefully evaluated to achieve the optimal antitumor effect. PMID:27070447

  9. Novel insights into immunotherapy for hepatitis B patients.

    PubMed

    Akbar, Sheikh Mohammad Fazle; Al-Mahtab, Mamun; Jahan, Munira; Yoshida, Osamu; Hiasa, Yoichi

    2016-01-01

    The possible use of immunotherapy for hepatitis B has emerged for two major reasons: (1) chronic hepatitis B (CHB) is an immune-mediated pathological condition, and (2) commercially available antiviral drugs are of limited efficacy. Although various immunomodulatory agents have been used to treat patients with CHB during the last three decades, there is currently no consensus among physicians and hepatologists regarding the suitability of immunotherapy for patients with CHB. However, new insights into immunotherapy for CHB have emerged; these may facilitate design of effective and tolerable immunotherapy regimens for these patients. This review provides a comprehensive overview of immunotherapy for CHB. PMID:26626120

  10. [Psychological aspects of immunotherapies in the treatment of malignant melanoma].

    PubMed

    Kovács, Péter; Pánczél, Gitta; Melegh, Krisztina; Balatoni, Tímea; Pörneczy, Edit; Lõrincz, Lenke; Czirbesz, Kata; Gorka, Eszter; Liszkay, Gabriella

    2016-03-01

    Psychological problems may arise in connection with oncomedical treatments in three ways: 1. acute and/or 2. chronic ways, as well as 3. co-morbid psychiatric diseases that already exist must also be taken into account. Immunotherapies have the most common and also clinically relevant psychological side effects. Fatigue, anhedonia, social isolation, psychomotor slowness is reported during treatment. Anti-CTLA-4 antibody (ipilimumab) immunotherapy can present one of the most modern opportunities for adequate treatment for patients having distant metastasis or unresectable tumour. In relation to immunotherapies, acute psychological side effects (acute stress) emerging during treatments develop in a way that can mostly be linked to environmental factors, e.g. notification of diagnosis, hospitalisation, progression, deterioration in quality of life, imminent dates of control. Crisis is a temporary and threatening condition that endangers psychological balance. In such conditions, enhanced psychological vulnerability must be taken into account and doctors play a key role in the rapid recognition of the condition. Chronic psychological problems, which may arise from the depressogenic effect of the applied treatment or originated from a pre-melanoma psychiatric condition, may exceed the diagnostic and psychotherapeutic competences of a clinical psychologist. Even in case of a well-defined depressogenic biological mechanism such as the activation of the pro-inflammatory cytokine pathway, positive environmental effects can reduce symptoms and thus increase compliance. Side effects can be treated successfully using psychotherapeutic methods and/or psychiatric medicines. The application of routinely used complex psychosocial screening packages can provide the easiest method to identify worsening psychological condition during immunotherapy and give rapid feedback to the oncologist and the patient. Team work is of particular importance in a situation like this as it requires

  11. Developing Strategies in the Immunotherapy of Leukemias

    PubMed Central

    Brayer, Jason B.; Pinilla-Ibarz, Javier

    2015-01-01

    Background In the current treatment paradigms for leukemias, hematopoietic stem cell transplant (HSCT) is considered the best option with a curative potential although more often than not it simply delays disease progression. Advances are needed, both in current therapies and in the development of new strategies. Partly from studying the nuances of the curative potential of stem cell transplant, we have come to appreciate the relevance of the immune response and the potential of immunotherapy. Methods This review article summarizes the recent advances in the field of immunology and immunotherapy for leukemia. Results In passive immunotherapy, recent progress in chimeric T-cell antigen receptor technology has been encouraging. In active immunotherapy, a cancer vaccine may potentially enhance HSCT. An overview of various clinical studies of peptide vaccination strategies focusing on molecular targets such as the Wilms’ tumor gene 1 (WT1), proteinase 3 (PR3), and receptor for hyaluronan acid-mediated motility (RHAMM) is provided. Cell-based vaccination strategies are also briefly explored. Conclusions The immune system clearly has the capacity to recognize and react to leukemic cells, and recent evidence directs our attention to the importance of mounting inflammatory and CD4 T-cell responses to complement and support the cytotoxic activity elicited by peptide vaccines. PMID:23302907

  12. Role of IL-2 in cancer immunotherapy.

    PubMed

    Jiang, Tao; Zhou, Caicun; Ren, Shengxiang

    2016-06-01

    Interleukin-2 (IL-2) is one of the key cytokines with pleiotropic effects on immune system. It has been approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Recent progress has been made in our understanding of IL-2 in regulating lymphocytes that has led to exciting new directions for cancer immunotherapy. While improved IL-2 formulations might be used as monotherapies, their combination with other anticancer immunotherapies, such as adoptive cell transfer regimens, antigen-specific vaccination, and blockade of immune checkpoint inhibitory molecules, for example cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) mono-antibodies, would held the promise of treating metastatic cancer. Despite the comprehensive studies of IL-2 on immune system have established the application of IL-2 for cancer immunotherapy, a number of poignant obstacles remain for future research. In the present review, we will focus on the key biological features of IL-2, current applications, limitations, and future directions of IL-2 in cancer immunotherapy. PMID:27471638

  13. Biomarkers for glioma immunotherapy: the next generation

    PubMed Central

    Ung, Timothy H.; Neira, Justin A.; Canoll, Peter; Bruce, Jeffrey N.

    2015-01-01

    The term “biomarker” historically refers to a single parameter, such as the expression level of a gene or a radiographic pattern, used to indicate a broader biological state. Molecular indicators have been applied to several aspects of cancer therapy: to describe the genotypic and phenotypic state of neoplastic tissue for prognosis, to predict susceptibility to anti-proliferative agents, to validate the presence of specific drug targets, and to evaluate responsiveness to therapy. For glioblastoma (GBM), immunohistochemical and radiographic biomarkers accessible to the clinical lab have informed traditional regimens, but while immunotherapies have emerged as potentially disruptive weapons against this diffusely infiltrating, heterogeneous tumor, biomarkers with strong predictive power have not been fully established. The cancer immunotherapy field, through the recently accelerated expansion of trials, is currently leveraging this wealth of clinical and biological data to define and revise the use of biomarkers for improving prognostic accuracy, personalization of therapy, and evaluation of responses across the wide variety of tumors. Technological advancements in DNA sequencing, cytometry, and microscopy have facilitated the exploration of more integrated, high-dimensional profiling of the disease system—incorporating both immune and tumor parameters—rather than single metrics, as biomarkers for therapeutic sensitivity. Here we discuss the utility of traditional GBM biomarkers in immunotherapy and how the impending transformation of the biomarker paradigm—from single markers to integrated profiles—may offer the key to bringing predictive, personalized immunotherapy to GBM patients. PMID:25724916

  14. Topical immunotherapy with diphenylcyclopropenone-induced vitiligo.

    PubMed

    Kutlubay, Zekayi; Engin, Burhan; Songur, Abdullah; Serdaroglu, Server; Tuzun, Yalcin

    2016-08-01

    Topical immunotherapy made by diphenylcyclopropenone (DPCP) is an alternative treatment that can be used safely and efficaciously in recalcitrant alopecia areata patients. DPCP-induced vitiligo is a rare, but documented, unwanted side effect. The real mechanism of DPCP-induced vitiligo is not well known. PMID:26963903

  15. Biomarkers for Immunotherapy: Current Developments and Challenges.

    PubMed

    Spencer, Kristen R; Wang, Jianfeng; Silk, Ann W; Ganesan, Shridar; Kaufman, Howard L; Mehnert, Janice M

    2016-01-01

    Immunotherapy has revolutionized cancer therapy and has been named the cancer advance of the year for 2016. Checkpoint inhibitors have demonstrated unprecedented rates of durable responses in some of the most difficult-to-treat cancers; however, many treated patients do not respond, and the potential for serious side effects exists. There is a growing need to identify biomarkers that will improve the selection of patients who will best respond to therapy, further elucidate drug mechanisms of action, and help tailor therapy regimens. Biomarkers are being explored at the soluble, cellular, and genomic levels, and examples in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors in the tumor microenvironment, circulating immune and tumor cells, and host genomic factors. The search for reliable biomarkers is limited by our incomplete understanding of how immunotherapies modify the already complex immune response to cancer, as well as the contribution of immuno-editing to a dynamic and inducible tumor microenvironment and immune milieu. Furthermore, there has been little extension of any candidate assay into large, prospective studies, and the lack of standardization in measurement and interpretation restricts their validity. Both tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment have been recognized as having both prognostic and predictive value for patients treated with immunotherapy. Alternately, a larger panel of gene signatures, chemokines, and other factors that correlate with response has been proposed. In this article, we will explore the status of current biomarker candidates. PMID:27249758

  16. Adapting conventional cancer treatment for immunotherapy.

    PubMed

    Qiao, Jian; Liu, Zhida; Fu, Yang-Xin

    2016-05-01

    The efficacy of directly killing tumors by conventional cancer therapies, such as chemotherapy and radiotherapy, has been for several decades well established. But, a suppressed immune response might become a lethal side effect after repeated cycles of intensive treatment. Recently, achievements in immune checkpoint inhibitors and adoptive T cell-mediated immunotherapies have resulted in changes in frontline management of advanced cancer diseases. However, accumulated evidence indicates that immunotherapeutic and conventional strategies alone are often ineffective to eradicate big tumors or metastasis. To improve the outcomes of treatment for advanced cancer diseases, the combination of conventional cancer treatment with various immunotherapeutic approaches has been attempted and has shown potential synergistic effects. Recent studies have unexpectedly demonstrated that some strategies of conventional cancer treatment can regulate the immune response positively, thus the understanding of how to adapt conventional treatment for immunotherapy is crucial to the design of effective combination therapy of conventional treatment with immunotherapy. Here, we review both experimental and clinical studies on the therapeutic effect and its mechanisms of combining conventional therapy with immunotherapy in treatment of cancer. PMID:26910191

  17. Biomarkers and correlative endpoints for immunotherapy trials.

    PubMed

    Morse, Michael A; Osada, Takuya; Hobeika, Amy; Patel, Sandip; Lyerly, H Kim

    2013-01-01

    Immunotherapies for lung cancer are reaching phase III clinical trial, but the ultimate success likely will depend on developing biomarkers to guide development and choosing patient populations most likely to benefit. Because the immune response to cancer involves multiple cell types and cytokines, some spatially and temporally separated, it is likely that multiple biomarkers will be required to fully characterize efficacy of the vaccine and predict eventual benefit. Peripheral blood markers of response, such as the ELISPOT assay and cytokine flow cytometry analyses of peripheral blood mononuclear cells following immunotherapy, remain the standard approach, but it is increasingly important to obtain tissue to study the immune response at the site of the tumor. Earlier clinical endpoints such as response rate and progression-free survival do not correlate with overall survival demonstrated for some immunotherapies, suggesting the need to develop other intermediary clinical endpoints. Insofar as all these biomarkers and surrogate endpoints are relevant in multiple malignancies, it may be possible to extrapolate findings to immunotherapy of lung cancer. PMID:23714525

  18. Emerging Opportunities and Challenges in Cancer Immunotherapy.

    PubMed

    Whiteside, Theresa L; Demaria, Sandra; Rodriguez-Ruiz, Maria E; Zarour, Hassane M; Melero, Ignacio

    2016-04-15

    Immunotherapy strategies against cancer are emerging as powerful weapons for treatment of this disease. The success of checkpoint inhibitors against metastatic melanoma and adoptive T-cell therapy with chimeric antigen receptor T cells against B-cell-derived leukemias and lymphomas are only two examples of developments that are changing the paradigms of clinical cancer management. These changes are a result of many years of intense research into complex and interrelated cellular and molecular mechanisms controling immune responses. Promising advances come from the discovery of cancer mutation-encoded neoantigens, improvements in vaccine development, progress in delivery of cellular therapies, and impressive achievements in biotechnology. As a result, radical transformation of cancer treatment is taking place in which conventional cancer treatments are being integrated with immunotherapeutic agents. Many clinical trials are in progress testing potential synergistic effects of treatments combining immunotherapy with other therapies. Much remains to be learned about the selection, delivery, and off-target effects of immunotherapy used alone or in combination. The existence of numerous escape mechanisms from the host immune system that human tumors have evolved still is a barrier to success. Efforts to understand the rules of immune cell dysfunction and of cancer-associated local and systemic immune suppression are providing new insights and fuel the enthusiasm for new therapeutic strategies. In the future, it might be possible to tailor immune therapy for each cancer patient. The use of new immune biomarkers and the ability to assess responses to therapy by noninvasive monitoring promise to improve early cancer diagnosis and prognosis. Personalized immunotherapy based on individual genetic, molecular, and immune profiling is a potentially achievable future goal. The current excitement for immunotherapy is justified in view of many existing opportunities for harnessing

  19. Amyloid beta peptide immunotherapy in Alzheimer disease.

    PubMed

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID:25459121

  20. Use of natural killer cells as immunotherapy for leukaemia

    PubMed Central

    Grzywacz, Bartosz; Miller, Jeffrey S.; Verneris, Michael R.

    2008-01-01

    Natural killer (NK) cells potentially play a significant role in eradicating residual disease following allogeneic haematopoietic cell transplantation, and have been explored as tools for adoptive immunotherapy for chemotherapy-refractory patients. NK cell cytotoxicity is modulated by multiple activating and inhibitory receptors that maintain a balance between self-tolerance and providing surveillance against pathogens and malignant transformation. The functional characteristics of NK cells are dictated by the strength of inhibitory receptor signalling. Major histocompatibility complex (MHC)-specific inhibitory receptor acquisition occurs sequentially during NK cell development, and is determined by the nature of immunological reconstitution after allogeneic haematopoietic cell transplantation. Polymorphisms of inhibitory receptors [killer immunoglobulin-like receptors (KIRs)] and their ligands (MHC) contribute to interindividual variability. As a result, the functional NK cell repertoire of individual donors has variable potential for graft-vs-leukaemia reactions. Models predicting NK cell alloreactivity, including KIR ligand mismatch and missing KIR ligand strategies, are discussed as algorithms for optimal NK cell donor selection. Future modifications to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signalling are being explored. PMID:18790450

  1. Workshop on immunotherapy combinations. Society for Immunotherapy of Cancer annual meeting Bethesda, November 3, 2011.

    PubMed

    Martinez Forero, Ivan; Okada, Hideho; Topalian, Suzanne L; Gajewski, Thomas F; Korman, Alan J; Melero, Ignacio

    2012-01-01

    Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and "perceived" business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace. PMID

  2. Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

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

  3. Inmunoterapias para las adicciones a las drogas Immunotherapies for Drug Addictions

    PubMed Central

    Montoya, Iván D.

    2008-01-01

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

  4. Does Immunotherapy of Viral Warts Provide Beneficial Effects When It Is Combined with Conventional Therapy?

    PubMed Central

    Choi, Jae Woo; Cho, Soyun

    2011-01-01

    Background Cryotherapy has been accepted as the mainstay in treating periunugal and palmoplantar warts. The major drawback of cryotherapy is the requirement of several unbearably painful treatment sessions. Objective This study aims to assess the efficacy of immunotherapy in viral wart treatment, as an adjunctive method to cryotherapy. Methods Retrospective chart review was performed on 124 patients visiting the hospital from January to December 2009 for the treatment of periungual and plantar warts. We analyzed the number of cryotherapy sessions necessary for treating warts and assessed the clinical benefits from the addition of other treatment modalities, by adjusting the various confounding factors. Results Of the 124 investigated patients, immunotherapy with diphenylcyclopropenone (DPCP) was performed in 14 patients (11%), together with cryotherapy. After adjusting the factors related to the therapeutic difficulties of wart, the average number of cryotherapy sessions for the immunotherapy-combined group was significantly lower (3.58±1.25) than that for the cryotherapy only group (5.10±0.44) (p=0.026). However, there were no differences in the number of treatment sessions of cryotherapy when topical 5-FU/salicylic acid agents were added to the treatment. Conclusion Immunotherapy may be a successful adjuvant to cryotherapy in reducing the number of agonizing cryotherapy sessions. PMID:21909196

  5. A practical view of immunotherapy for food allergy

    PubMed Central

    2016-01-01

    Food allergy is common and sometimes life threatening for Korean children. The current standard treatment of allergen avoidance and self-injectable epinephrine does not change the natural course of food allergy. Recently, oral, sublingual, and epicutaneous immunotherapies have been studied for their effectiveness against food allergy. While various rates of desensitization (36% to 100%) and tolerance (28% to 75%) have been induced by immunotherapies for food allergy, no single established protocol has been shown to be both effective and safe. In some studies, immunologic changes after immunotherapy for food allergy have been revealed. Adverse reactions to these immunotherapies have usually been localized, but severe systemic reactions have been observed in some cases. Although immunotherapy cannot be recommended for routine practice yet, results from recent studies demonstrate that immunotherapies are promising for the treatment of food allergy. PMID:26958062

  6. Evolving Immunotherapy Strategies in Urothelial Cancer

    PubMed Central

    Brancato, Sam J.; Lewi, Keidren; Agarwal, Piyush K.

    2016-01-01

    The treatment of nonmuscle-invasive urothelial carcinoma with bacillus Calmette-Guérin (BCG) represents the importance of immunotherapy in the treatment of cancer. Despite its clinical efficacy, up to 30% of patients will ultimately experience progression to muscle-invasive disease. This, along with an improved understanding of the biologic pathways involved, has led to efforts to improve, enhance, or alter the immune response in the treatment of urothelial carcinoma. A number of novel therapeutic approaches currently are being pursued, including recombinant BCG to induce T helper type 1 (Th1) immune responses, nonlive Mycobacterium agents, targeted agents toward cancer-associated antigens, immune-modulating vaccines, and adoptive T-cell therapies. Here, we review the current and future immunotherapy treatment options for patients with urothelial cancer. PMID:25993187

  7. RNA-Based Vaccines in Cancer Immunotherapy

    PubMed Central

    McNamara, Megan A.; Nair, Smita K.; Holl, Eda K.

    2015-01-01

    RNA vaccines traditionally consist of messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and template DNA that encodes the antigen(s) of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm and then the resulting antigens are presented to antigen presenting cells to stimulate an immune response. Alternatively, dendritic cells can be loaded with either tumor associated antigen mRNA or total tumor RNA and delivered to the host to elicit a specific immune response. In this review, we will explain why RNA vaccines represent an attractive platform for cancer immunotherapy, discuss modifications to RNA structure that have been developed to optimize mRNA vaccine stability and translational efficiency, and describe strategies for nonviral delivery of mRNA vaccines, highlighting key preclinical and clinical data related to cancer immunotherapy. PMID:26665011

  8. Development of PROSTVAC immunotherapy in prostate cancer.

    PubMed

    Singh, Parminder; Pal, Sumanta K; Alex, Anitha; Agarwal, Neeraj

    2015-01-01

    PROSTVAC immunotherapy is a heterologous prime-boost regimen of two different recombinant pox-virus vectors; vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against prostate-specific antigen. Both vectors contain transgenes for prostate-specific antigen and a triad of T-cell costimulatory molecules (TRICOM). In a placebo-controlled Phase II trial of men with minimally symptomatic, chemotherapy-naive metastatic castration-resistant prostate cancer, PROSTVAC was well tolerated and associated with a 44% reduction in death. With a novel mechanism of action, and excellent tolerability, PROSTVAC has the potential to dramatically alter the treatment landscape of prostate cancer, not only as a monotherapy, but also in combination with other novel agents, such as immune check point inhibitors and novel androgen receptor blockers. A Phase III trial recently completed accrual. PMID:26235179

  9. Immunological landscape and immunotherapy of hepatocellular carcinoma.

    PubMed

    Prieto, Jesús; Melero, Ignacio; Sangro, Bruno

    2015-12-01

    Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy. PMID:26484443

  10. Development of PROSTVAC immunotherapy in prostate cancer

    PubMed Central

    Singh, Parminder; Pal, Sumanta K; Alex, Anitha; Agarwal, Neeraj

    2015-01-01

    PROSTVAC immunotherapy is a heterologous prime-boost regimen of two different recombinant pox-virus vectors; vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against prostate-specific antigen. Both vectors contain transgenes for prostate-specific antigen and a triad of T-cell costimulatory molecules (TRICOM). In a placebo-controlled Phase II trial of men with minimally symptomatic, chemotherapy-naive metastatic castration-resistant prostate cancer, PROSTVAC was well tolerated and associated with a 44% reduction in death. With a novel mechanism of action, and excellent tolerability, PROSTVAC has the potential to dramatically alter the treatment landscape of prostate cancer, not only as a monotherapy, but also in combination with other novel agents, such as immune check point inhibitors and novel androgen receptor blockers. A Phase III trial recently completed accrual. PMID:26235179