Sample records for anti-tnf immunotherapy reduces

  1. Early tissue responses in psoriasis to the anti-TNF-? biologic etanercept suggest reduced IL-17R expression and signalling

    PubMed Central

    Johnston, A.; Guzman, A. M.; Swindell, W. R.; Wang, F.; Kang, S.; Gudjonsson, J. E.

    2014-01-01

    BACKGROUND Anti-TNF-? therapy has made a significant impact on the treatment of psoriasis. Despite being designed to neutralize TNF-? activity, the mechanism of action of these agents in the resolution of psoriasis remains unclear. OJECTIVES To better understand the mechanism of action of etanercept by examining very early changes in the lesional skin of psoriasis patients responding to etanercept. METHODS 20 chronic plaque psoriasis patients were enrolled and received 50mg etanercept twice weekly. Skin biopsies were obtained before treatment and on days 1, 3, 7 and 14 post-treatment. Skin mRNA expression was analysed by QRT-PCR and microarray; cytokine and phosphoprotein levels were assessed using multiplexed bead arrays. RESULTS In etanercept responders, we observed no significant changes in IL-17A, IL-22 and IFN-? mRNA or protein in the first week of treatment; however, there was a 2.5-fold down-regulation of IL17RC mRNA (p<0.05) after day 1, accompanied by decreased ERK1/2 phosphorylation. Transcriptional analysis revealed genes suppressed by etanercept significantly overlapped with IL-17A-induced genes, and a marked overlap was also observed between the genes suppressed by etanercept and by the anti-IL17A therapy ixekizumab. Finally we show that TNF-? enhances the expression of IL-17RC and shRNA inhibition of IL-17R expression abrogates synergistic gene induction by TNF and IL17A. CONCLUSIONS These results suggest that the early responses of psoriasis plaques to etanercept may be due to decreased tissue responsiveness to IL-17A due to suppressed IL17RC expression in keratinocytes, blunting the strong synergy between TNF-? and IL-17, which contributes to the maintenance of psoriasis lesions. PMID:24601997

  2. [Farmacoeconomic impact of anti-TNF-alpha].

    PubMed

    Leardini, G; Bernardi, C; Vaccaro, E

    2004-01-01

    The anti-TNF-alpha are undoubtedly an efficacious cure in the treatment of rheumatoid arthritis, but their costs are so high that a thorough pharmacoeconomical evaluation is needed in order to identify the specific conditions in which their use is to be considered convenient. For this reason there are related the most important experiences that have studied the cost-efficacy and cost-utility relationships of anti-TNF-alpha drugs, which have been made marketable in Italy. The data available, unfortunately, are too various to allow a final settlement of the chart of convenience between the different therapeutic alternatives. Moreover the socio-medical reality in Italy is so much different from the ones in other countries that it is impossible to try and use the foreign experiences. In a country of high social commitment like Italy, a fair judgment can thereafter be made only when the issue is considered related to our society, taking in account the summation of the medical costs endured by the National Health System, the patient's expenses and the ones that are a consequence of the loss of productivity. PMID:15201944

  3. Distinctive histopathologic phenotype in resection specimens from patients with Crohn's disease receiving anti-TNF-? therapy.

    PubMed

    Schaeffer, David F; Walsh, Joanna C; Kirsch, Richard; Waterman, Matti; Silverberg, Mark S; Riddell, Robert H

    2014-09-01

    Anti-tumor necrosis factor ? (anti-TNF-?) therapy can result in endoscopic healing, reduction of symptoms, and reduced need for surgery and hospitalization in many patients with Crohn's disease (CD). Earlier data suggested that anti-TNF-? therapy may be associated with fibrosis and stricturing. We sought to determine whether anti-TNF-? therapy affects histologic inflammation, fibrosis, and granuloma formation. Hematoxylin and eosin sections from 62 patients with CD treated with either infliximab or adalimumab and 80 controls undergoing the same surgery but without prior exposure to anti-TNF-? therapy were compared. All patients with CD had undergone surgery within 6 months of therapy; CD controls were matched for steroid exposure, procedure, and indication for surgery and were subcategorized and case matched. Blinded histologic assessment of all slides was performed using a semiquantitative scoring system to assess inflammatory changes and fibrosis in all bowel layers. Compared with controls, the group treated with anti-TNF-? showed a reduction in mucosal and submucosal inflammation (P < .05), a decrease in granuloma formation (P < .05), and an increase in duplication of the muscularis mucosae (P < .05). A notable feature was a distinct pattern of hyalinizing submucosal fibrosis that was often devoid of inflammatory cells and that started directly below the muscularis mucosae; this pattern was not observed in the control group (P < .05). Resection specimens from patients with CD treated with anti-TNF-? therapy showed (a) reduced mucosal and submucosal inflammation; (b) a decrease in granuloma formation; and (c) a distinct pattern of submucosal hyaline fibrosis, with increased fibrosis in the muscularis mucosae and muscularis propria. PMID:25022570

  4. 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

  5. The use of an interferon-gamma release assay as a biomarker of response to anti-TNF-alpha treatment.

    PubMed

    Cacciapaglia, Fabio; Buzzulini, Francesca; Arcarese, Luisa; Ferraro, Elisabetta; Afeltra, Antonella

    2014-11-01

    Tumor necrosis factor alpha (TNF-?) is a pleiotropic cytokine that plays a central role in the immune system functioning and in the pathogenesis of rheumatoid arthritis (RA). TNF-? inhibition has been demonstrated effective to treat RA; however, response to anti-TNF-? therapies is heterogeneous, with roughly one-third of patients not achieving disease control. Identification of a biological marker to assess the effectiveness of TNF-? inhibition may help to discriminate patients with a reduced response to anti-TNF-? agents. The aim of this study was to assess whether anti-TNF-? treatment was able to modify the cytokine network interfering with interferon gamma (INF?) release after phytohemagglutinin (PHA) stimulation of peripheral blood mononuclear cells (PBMCs) from RA patients, according to disease activity. We found that RA patients with active disease had low release of INF? after PHA stimulation, but anti-TNF-? agents were able to modify INF? production. In anti-TNF-? responders, we observed a higher release of INF?, achieving levels comparable with those seen in healthy subjects. The ability of PBMCs from RA patients to release INF? may serve as a biomarker of disease activity and response to anti-TNF-?. Larger studies are needed to validate these data. PMID:25381977

  6. Anti-TNF treatments in rheumatoid arthritis: economic impact of dosage modification.

    PubMed

    de la Torre, Inmaculada; Valor, Lara; Nieto, Juan Carlos; Hernández-Flórez, Diana; Hernandez, Diana; Martinez, Lina; Gonzalez, Carlos M; Monteagudo, Indalecio; Longo, Javier Lopez; Montoro, Maria; Carreño, Luis

    2013-06-01

    Rheumatoid arthritis (RA) is a chronic systemic disease that leads to increases in health system economic burden through direct and indirect costs, including chronic treatment, reduced productivity and premature mortality. Anti-TNF agents have represented a major advance in the treatment of RA. The most commonly used (adalimumab, etanercept and infliximab) have demonstrated their cost-effectiveness at label doses. However, physicians may need to adapt the treatment by increasing the dose when a drug is not effective enough or by reducing it when there is a sustained effectiveness. In a cross-sectional study conducted in our hospital in which information from RA patients treated with anti-TNF drugs under conventional and modified doses were collected, the authors analyzed the costs of the medication in order to estimate the mean patient-year cost, the annual costs related to clinical efficacy and the cost per responder patient to anti-TNF treatment when dosage modification is undertaken in daily clinical practice. PMID:23763534

  7. Influence of antiTNF-alpha antibody treatment on fracture healing under chronic inflammation

    PubMed Central

    2014-01-01

    Background The overexpression of tumor necrosis factor (TNF)-? leads to systemic as well as local loss of bone and cartilage and is also an important regulator during fracture healing. In this study, we investigate how TNF-? inhibition using a targeted monoclonal antibody affects fracture healing in a TNF-? driven animal model of human rheumatoid arthritis (RA) and elucidate the question whether enduring the anti TNF-? therapy after trauma is beneficial or not. Methods A standardized femur fracture was applied to wild type and human TNF-? transgenic mice (hTNFtg mice), which develop an RA-like chronic polyarthritis. hTNFtg animals were treated with anti-TNF antibody (Infliximab) during the fracture repair. Untreated animals served as controls. Fracture healing was evaluated after 14 and 28 days of treatment by clinical assessment, biomechanical testing and histomorphometry. Results High levels of TNF-? influence fracture healing negatively, lead to reduced cartilage and more soft tissue in the callus as well as decreased biomechanical bone stability. Blocking TNF-? in hTNFtg mice lead to similar biomechanical and histomorphometrical properties as in wild type. Conclusions High levels of TNF-? during chronic inflammation have a negative impact on fracture healing. Our data suggest that TNF-? inhibition by an anti-TNF antibody does not interfere with fracture healing. PMID:24885217

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

    PubMed

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

    2015-05-01

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

  9. Randomised controlled trial examining the effect of exercise in people with rheumatoid arthritis taking anti-TNF? therapy medication

    PubMed Central

    2011-01-01

    Abstract Background Substantial progress has been made in the medical management of rheumatoid arthritis (RA) over the past decade with the introduction of biologic therapies, including anti-tumour necrosis factor alpha (anti-TNF?) therapy medications. However, individuals with RA taking anti-TNF? medication continue to experience physical, psychological and functional consequences, which could potentially benefit from rehabilitation. There is evidence that therapeutic exercise should be included as an intervention for people with RA, but to date there is little evidence of the benefits of therapeutic exercise for people with RA on anti-TNF? therapy medication. A protocol for a multicentre randomised controlled three-armed study which aims to examine the effect of dynamic group exercise therapy on land or in water for people with RA taking anti-TNF? therapy medication is described. Methods/Design Six hundred and eighteen individuals with RA, on anti-TNF? therapy medication, will be randomised into one of 3 groups: a land-based exercise group; a water-based exercise group or a control group. The land and water-based groups will exercise for one hour, twice a week for eight weeks. The control group will receive no intervention and will be asked not to alter their exercise habits for the duration of the study. The primary outcome measure, the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) which measures functional ability, and secondary measures of pain, fatigue and quality of life, will be assessed at baseline, eight and 24 weeks by an independent assessor unaware of group allocation. Changes in outcome from 0 to 8 weeks and 0 to 24 weeks in the 'land-based exercise group versus control group' and the 'water-based exercise group versus control group' will be examined. Analysis will be conducted on an intention to treat basis. Discussion This trial will evaluate the effectiveness of group exercise therapy on land or in water, for people with RA taking anti-TNF? therapy medication. If these exercise groups are found to be beneficial, they could be conducted in local community facilities thus making these forms of exercise more easily accessible for individuals and potentially reduce the burden on health services. Trial Registration This trial is registered with ClinicalTrials.gov (a service of the United States National Institutes of Health) identifier: NCT00855322. PMID:21232112

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

    PubMed

    Marko, Bani?; Prka, Lidija

    2013-04-01

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

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

    PubMed Central

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

    2014-01-01

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

  12. Anti-TNF-alpha therapies in systemic lupus erythematosus.

    PubMed

    Zhu, Lang-Jing; Yang, Xiao; Yu, Xue-Qing

    2010-01-01

    Tumor necrosis factor (TNF)-alpha is not just a proinflammatory cytokine. It has also been proposed to be an immunoregulatory molecule that can alter the balance of T regulatory cells. Anti-TNF-alpha therapies have been provided clinical benefit to many patients and introduced for treating moderate to severe rheumatoid arthritis, Crohn's disease, and other chronic inflammatory disorders. However, their use also is accompanied by new or aggravated forms of autoimmunity, such as formation of autoantibodies, including antinuclear antibodies (ANAs), antidouble-stranded DNA (dsDNA) antibodies, and anticardiolipin antibodies (ACL). Systemic lupus erythematosus (SLE) is a disease with autoimmune disturbance and inflammatory damage. The role of TNF-alpha in human SLE is controversial. Here we review the role of TNF-alpha in the pathophysiological processes of SLE and the likely effects of blocking TNF-alpha in treatment of SLE. PMID:20625488

  13. Successful anti-TNF-? treatment in a girl with LAD-1 disease and autoimmune manifestations.

    PubMed

    Marsili, Manuela; Lougaris, Vassilios; Lucantoni, Marta; Di Marzio, Daniele; Baronio, Manuela; Vitali, Massimiliano; Lombardi, Giuliano; Chiarelli, Francesco; Breda, Luciana

    2014-10-01

    Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive disorder, caused by the absence or reduced expression of the beta-2 integrins on granulocytes, and characterized by the inability of these cells to emigrate from the bloodstream towards the sites of tissue inflammation. A twelve-year-old girl with a diagnosis of LAD-1 syndrome and recurrent skin and mucosal infections since birth, presented with a two week history of fever, abdominal pain, vomiting, weight loss and polyarthralgia. She underwent an exploratory laparotomy with the finding of inflamed terminal ileum and colon and a normal appendix. Colonoscopy and videocapsule endoscopy showed multiple ileal and colonic mucosal ulcerations, which were compatible with inflammatory bowel disease, confirmed on histological examination. Given the lack of response to conventional therapy (prednisone and mesalamine), a monoclonal anti-TNF-? antibody was started at a dosage of 5 mg/kg at weeks 0,2,4,6 and then every 8 weeks. We observed a significant improvement of all clinical and laboratory parameters after the first weeks of therapy. Five months later, we anticipated the drug's administration every 5 weeks because of a precocious recurrence of symptoms. After 30 months of treatment no relapse nor any relevant side effects have been observed, and corticosteroids were withdrawn. Interestingly, our patient presented a small subset of CD18+ T cells, similarly to previously reported LAD-1 patients with mild phenotype, inflammatory bowel disease and CD18+ somatic revertant T cells. To the best of our knowledge, this is the first LAD-1 pediatric patient with inflammatory autoimmune complications who experienced a positive response to anti-TNF-? treatment. PMID:25135596

  14. 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-) ?, interleukin- (IL-) 1?, and IL-6. However, although biological treatment with anti-TNF-? agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-? blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium. PMID:25061259

  15. Biological treatments in Behçet's disease: beyond anti-TNF therapy.

    PubMed

    Caso, Francesco; Costa, Luisa; Rigante, Donato; Lucherini, Orso Maria; Caso, Paolo; Bascherini, Vittoria; Frediani, Bruno; Cimaz, Rolando; Marrani, Edoardo; Nieves-Martín, Laura; Atteno, Mariangela; Raffaele, Carmela G L; Tarantino, Giusyda; Galeazzi, Mauro; Punzi, Leonardo; Cantarini, Luca

    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-) ?, interleukin- (IL-) 1?, and IL-6. However, although biological treatment with anti-TNF-? agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-? blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium. PMID:25061259

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

    Microsoft Academic Search

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

    2002-01-01

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

  17. Adverse Skin Reactions to Anti-TNF-Alpha Monoclonal Antibody Therapy

    Microsoft Academic Search

    S. A. Devos; N. Van Den Bossche; M. De Vos; J. M. Naeyaert

    2003-01-01

    Various adverse cutaneous reactions to anti-TNF-? monoclonal antibody have been reported. In clinical studies with infliximab (Remicade®) adverse drug reactions were most frequently reported in the respiratory system and in the skin and appendages. We describe here 6 patients receiving anti- TNF-? therapy (infliximab) for Crohn’s disease or rheumatoid arthritis who consulted our out-patient department for adverse cutaneous reactions between

  18. Poly(lactide-co-glycolide) nanoparticles, layer by layer engineered for the sustainable delivery of antiTNF-?.

    PubMed

    Romero, Gabriela; Ochoteco, Olaia; Sanz, David J; Estrela-Lopis, Irina; Donath, Edwin; Moya, Sergio E

    2013-07-01

    A strategy of encapsulation of the antiTNF-? antibody on top of poly(lactide-co-glycolide) nanoparticles (PLGA NPs) is presented on the basis of the complexation of antiTNF-? with alginate (Alg) and subsequent assembly layer by layer with poly(L-lysine) (PLL). The assembly of the antiTNF-?/Alg complex with PLL and its stability in PBS and lysozymes are monitored on a planar support using a quartz crystal microbalance with dissipation. The assembly of the antiTNF-?/Alg complex on PLGA NPs is followed by zeta potential measurements. AntiTNF-? release from the PLGA NPs is measured in PBS at 37 and 60 °C and in the HepG2 cell line following NP uptake, using the Q-ADA kit detection kit. The release follows first-order kinetics with an initial burst. Intracellular release of antiTNF-? is confirmed by confocal Raman microscopy. PMID:23696518

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

    PubMed Central

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

    2014-01-01

    CD66b is a member of the carcinoembryonic antigen family, which mediates the adhesion between neutrophils and to endothelial cells. Allergen-specific immunotherapy is widely used to treat allergic diseases, and the molecular mechanisms underlying this therapy are poorly understood. The present work was undertaken to analyze A) the in vitro effect of allergens and immunotherapy on cell-surface CD66b expression of neutrophils from patients with allergic asthma and rhinitis and B) the in vivo effect of immunotherapy on cell-surface CD66b expression of neutrophils from nasal lavage fluid during the spring season. Myeloperoxidase expression and activity was also analyzed in nasal lavage fluid as a general marker of neutrophil activation. Results CD66b cell-surface expression is upregulated in vitro in response to allergens, and significantly reduced by immunotherapy (p<0.001). Myeloperoxidase activity in nasal lavage fluid was also significantly reduced by immunotherapy, as were the neutrophil cell-surface expression of CD66b and myeloperoxidase (p<0.001). Interestingly, CD66b expression was higher in neutrophils from nasal lavage fluid than those from peripheral blood, and immunotherapy reduced the number of CD66+MPO+ cells in nasal lavage fluid. Thus, immunotherapy positive effects might, at least in part, be mediated by the negative regulation of the CD66b and myeloperoxidase activity in human neutrophils. PMID:24740105

  20. Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease

    PubMed Central

    Scott, Frank I.; Lichtenstein, Gary R.

    2014-01-01

    While anti-TNF agents have had a marked impact in the treatment of inflammatory bowel disease, a significant number of patients lose their response to these medications over time. Clinical trials have demonstrated that antibodies against anti-TNF medications may impact treatment response and increase the risk of infusion reaction. Scheduled dosing and concurrent use of immunomodulators may help to mitigate these risks via inhibiting the formation of these antibodies. The recent availability of assays to measure anti-TNF drug levels and antibodies against anti-TNFs offer the opportunity to assess patients who have lost response with infliximab and adalimumab, and potentially determine the most appropriate therapeutic strategy. There is growing evidence that such testing improves patient outcomes and is cost-effective, although heterogeneity in the assays used in clinical and observational trials has resulted in mixed results. PMID:24452768

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

    PubMed Central

    2012-01-01

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

  2. Nearly Fatal Case of Whipple's Disease in a Patient Mistakenly on Anti-TNF Therapy

    PubMed Central

    Klochan, Christen; Anderson, Teresa A.; Rose, Dusten; Dimitrov, Rosen K.

    2013-01-01

    Whipple's disease is a rare cause of chronic diarrhea and abdominal pain that may be confused with inflammatory bowel disease. We report a Whipple's case misdiagnosed as Crohn's disease in which treatment with anti-tumor necrosis factor (anti-TNF) therapy led to nearly fatal progression. Lymph node tissue obtained during laparotomy for suspected bowel necrosis stained dramatically with periodic acid–Schiff (PAS), and electron microscopy showed a bacterium consistent with Trophyrema whipplei. The patient made a remarkable recovery complicated only by cholestatic hepatitis, which was likely a treatment-associated inflammatory response. This case serves as a reminder that all granulomatous infections should be considered prior to initiation of anti-TNF therapies.

  3. 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

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

    PubMed

    Restrepo, Juan Pablo; Molina, María del Pilar

    2014-01-01

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

  5. Anti-TNF-  treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial

    Microsoft Academic Search

    P. R. Koninckx; M. Craessaerts; D. Timmerman; F. Cornillie; S. Kennedy

    2008-01-01

    BACKGROUND: Endometriosis is associated with an inflammatory response. Hence infliximab, an anti-TNF-a monoclonal antibody, might relieve pain. METHODS: A randomized placebo-controlled trial was designed with 21 women with severe pain and a rectovaginal nodule of at least 1 cm. After 1 month of observation, three infusions of infliximab (5 mg\\/kg) or placebo were given. Surgery was performed 3 months later

  6. A novel anti-TNF scFv constructed with human antibody frameworks and antagonistic peptides.

    PubMed

    Geng, Shusheng; Chang, Hong; Qin, Weisong; Lv, Ming; Li, Yan; Feng, Jiannan; Shen, Beifen

    2015-07-01

    The introduction of TNF inhibitors has revolutionized the treatment of some chronic inflammatory diseases, e.g., rheumatoid arthritis and Crohn's disease. However, immunogenicity is one of the important mechanisms behind treatment failure, and generally, switching to another TNF inhibitor will be the first choice for patients and doctors, which results in unmet need for novel anti-TNF agents. Small antibody molecules with less number of epitope may be valuable in less immunogenicity. In this study, with the help of computer-guided molecular design, single-chain variable fragment (scFv) TSA2 was designed using consensus frameworks of human antibody variable region as scaffold to display anti-TNF antagonistic peptides. TSA2 showed evidently improved bioactivity over TSA1 (anti-TNF scFv explored before) and almost similar activity as S-Remicade (the scFv form of Remicade, anti-TNF antibody approved by FDA), especially in inhibiting TNF-induced cytotoxicity and NF-?B activation. Human antibody consensus frameworks with less immunogenicity have been used in the designing of VH domain antibody, scFv TSA1 and TSA2. A serial of TNF-related works convinced us that the novel design strategy was feasible and could be used to design inhibitors targeting more other molecules than TNF-?. More importantly, these designed inhibitors derived from computer modeling may form a virtual antibody library whose size depends on the number of candidate antagonistic peptides. It will be molecular-targeted virtual antibody library because of the specific antagonistic peptides and the potential antibodies could be determined by virtual screening and then confirmed by biologic experiments. PMID:26059602

  7. Effects of hyaluronic acid conjugation on anti-TNF-? inhibition of inflammation in burns

    PubMed Central

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

    2014-01-01

    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 in order 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-TNF-? alone, mixed with hyaluronic acid or conjugated to hyaluronic acid. We found that non-conjugated anti-TNF-? decreased macrophage infiltration to a greater extent than that conjugated to hyaluronic acid; however there was little effect on the degree of progression or IL-1? 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-? to high molecular weight hyaluronic acid provides sustained, local modulation of the post-injury inflammatory responses compared to direct administration of non-conjugated antibodies. PMID:23765644

  8. anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.

    PubMed

    Armuzzi, A; Lionetti, P; Blandizzi, C; Caporali, R; Chimenti, S; Cimino, L; Gionchetti, P; Girolomoni, G; Lapadula, G; Marchesoni, A; Marcellusi, A; Mennini, F S; Salvarani, C; Cimaz, R

    2014-01-01

    The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs. PMID:24774504

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

    PubMed

    Vande Casteele, Niels; Gils, Ann

    2015-03-01

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

  10. Anti-cytokine biologic treatment beyond anti-TNF in Behçet's disease.

    PubMed

    Arida, Aikaterini; Sfikakis, Petros P

    2014-01-01

    Unmet therapeutic needs in Behçet's disease have drawn recent attention to biological agents targeting cytokines other than TNF. The anti-IL-17 antibody secukinumab and the anti-IL-2 receptor antibody daclizumab were not superior to placebo for ocular Behçet's in randomised controlled trials, comprising 118 and 17 patients, respectively. The anti-IL-1 agents anakinra and canakinumab and the anti-IL-6 agent tocilizumab were given to isolated refractory disease patients, who were either anti-TNF naïve (n=9) or experienced (n=18). No new safety signals were reported. Although a potential for bias to report positive effects and underreport negative cases may exist, Anakinra was partially effective, whereas disease remission was noted after canakinumab in some anti-TNF resistant patients. Tocilizumab appeared effective for neuro-Behçet's, but not for mucocutaneous manifestations. Finally, in a pilot study of 7 patients with relapsing posterior uveitis refractory to azathioprine and/or cyclosporine, the anti-IL-1? antibody Gevokizumab was beneficial. Collectively, it seems that IL-1 and IL-6 are promising targets in patients refractory or intolerant to other regimens including anti-TNFs. However, controlled studies are surely needed. PMID:25268669

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

    SciTech Connect

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

    2009-07-01

    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.

  12. Patient experiences, attitudes and expectations towards receiving information about anti-TNF medication – “It could give me two heads and I’d still try it!”

    PubMed Central

    2013-01-01

    Background Anti-tumour necrosis factor (anti-TNF) therapies are an important recent development in the treatment of autoimmune disease. Despite important side effects relating to immune suppression, there is lack of research into patient experiences, attitudes and expectations about the information they receive prior to starting anti-TNF therapy. Methods In May 2011 participants were purposively sampled to form two focus groups varying in age, anti-TNF agent and pre-therapy disease activity. A semi-structured topic guide was used to explore patients’ experiences regarding the information they received prior to commencing anti-TNF therapy. The focus groups were audio-taped and transcribed verbatim. Data were analysed using content analysis. Results Four key themes were identified. Firstly, weighing the risks and benefits of anti-TNF therapy. However, most participants attached limited importance to side effects, saying their strong desire for RA symptom control was overriding. Two reported deliberately concealing illness in order to continue their medication. Secondly, the desire for information. They suggested that counselling should occur at an early stage and not during a severe RA flare-up. Thirdly, the process of starting anti-TNF. Many identified that their biggest worry was whether they would be eligible for the new medication. They remembered little about the investigations they underwent, and none said they would have objected to being tested for blood borne viruses. Finally, the experience of being on anti-TNF. Most were positive, describing effects on quality of life as well as symptoms. Conclusions The use of qualitative methodology in this study has enabled an understanding of patients’ attitudes towards receiving information about anti-TNF therapy. The results may be useful to health professionals in terms of the timing and content of the information given to patients prior to commencing anti-TNF therapy. PMID:23663548

  13. HTLV-1-associated arthropathy treated with anti-TNF-alpha agent.

    PubMed

    Frenzel, Laurent; Moura, Bertrand; Marcais, Ambroise; Chapdelaine, Hugo; Hermine, Olivier

    2014-07-01

    Human T cell leukemia virus type 1 or HTLV-1 infection is a public health problem in endemic regions like Japan, Central America or Africa. Although the majority of HTLV-1 carriers remain asymptomatic throughout their lives, some patients could develop neurological disorder, inflammatory arthropathy also called HTLV-1-associated arthropathy or T-cell malignancy, the adult T-cell leukemia/lymphoma or ATL with a very poor prognosis. Described to be very close to rheumatoid arthritis, HTLV-1-associated arthropathy patients have few or no response to the first line therapy with corticosteroids and disease modifying antirheumatic drugs or DMARDs. The use of anti-TNF-? agents in these patients is an interesting alternative but asks the question of risk of developing an adult T-Cell leukemia/lymphoma. We reported an exceptional case of a smoldering ATL patient with an HTLV-1-associated arthropathy, refractory to corticosteroid, DMARDs and rituximab therapy, treated successfully with etanercept, without progression to aggressive ATL after 5 years. PMID:24289962

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

    PubMed

    Yasui, Kozo

    2014-01-01

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

  15. Effect of late administration of anti-TNF alpha antibodies on a Salmonella infection in the mouse model.

    PubMed

    Mastroeni, P; Villarreal-Ramos, B; Hormaeche, C E

    1993-06-01

    The effect of late administration of anti-TNF alpha antibodies on the course of a Salmonella infection in mice was evaluated. Administration of anti-TNF alpha antiserum as late as day 5 after challenge enhanced a sublethal primary infection with the virulent Salmonella typhimurium C5 in innately resistant (Ityr) A/J mice by preventing the suppression of exponential bacterial growth in the reticuloendothelial system (RES) (plateau phase). When the anti-TNF alpha treatment was started well after the establishment of the plateau (day 7) a prompt relapse of the infection occurred, with the rapid resurgence of bacterial growth in the reticuloendothelial system leading to the death of the animals. In contrast, late administration of the antiserum did not affect the clearance from the tissues of an avirulent temperature-sensitive mutant of S. typhimurium C5 (C5TS). Innately susceptible (Itys) BALB/c mice immunized with the SL3261 aroA live vaccine acquire solid long-lasting protection from oral challenge with the virulent C5 strain, suppressing growth of the challenge in the RES. Administration of anti-TNF alpha antibodies on day 8 of a secondary oral infection with strain C5 abrogated vaccine-induced protection, with a progressive increase of bacterial numbers in the RES leading to the death of the animals. The results indicate that TNF alpha is constantly required for the control of virulent salmonellae in the RES, both in a sublethal primary infection in innately resistant mice and also in a secondary infection in innately susceptible mice immunized with a live vaccine. TNF alpha may not be essential for bacterial clearance of avirulent organisms from the tissues. PMID:8412619

  16. 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

  17. Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability

    PubMed Central

    Fallahi-Sichani, Mohammad; Flynn, JoAnne L.; Linderman, Jennifer J.; Kirschner, Denise E.

    2012-01-01

    Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with tumor necrosis factor-? (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF antibodies (e.g. infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from antibody-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of antibodies and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases. PMID:22379032

  18. p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice.

    PubMed

    Walls, Ken C; Ager, Rahasson R; Vasilevko, Vitaly; Cheng, Dave; Medeiros, Rodrigo; LaFerla, Frank M

    2014-07-11

    Alzheimer's disease (AD) is a proteinopathy characterized by the accumulation of ?-amyloid (A?) and tau. To date, clinical trials indicate that A? immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with A? pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser(202) and Thr(205) sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting A? pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent A? pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with A? immunotherapy. PMID:24887583

  19. Adalimumab in clinical practice. Outcome in 70 rheumatoid arthritis patients, including comparison of patients with and without previous anti-TNF exposure

    Microsoft Academic Search

    A. N. Bennett; P. Peterson; A. Zain; J. Grumley; G. Panayi; B. Kirkham

    2005-01-01

    Objective. To assess the efficacy and safety of the fully human recombinant monoclonal anti-TNF antibody adalimumab in routine clinical practice, including comparison of patients with and without previous anti-TNF exposure. Methods. We prospectively studied the outcome of 70 rheumatoid arthritis patients treated with adalimumab in normal clinical practice. The primary outcome measures were Disease Activity Score 28 (DAS28), EULAR (European

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

    PubMed Central

    Mercer, Louise K; Green, Adele C; Galloway, James B; Davies, Rebecca; Lunt, Mark; Dixon, William G; Watson, Kath D; Symmons, Deborah PM; Hyrich, Kimme L

    2012-01-01

    Objectives To compare the risk of keratinoctye skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) in patients treated for rheumatoid arthritis (RA) compared with the general population, and to determine whether anti-tumour necrosis factor (TNF) therapy exacerbates this risk. Methods Patients with RA enrolled in the British Society for Rheumatology Biologics Register, a prospective national cohort established in 2001 to monitor the safety of anti-TNF, were followed until 2008. 11 881 patients treated with anti-TNF were compared with 3629 patients receiving non-biological disease-modifying antirheumatic drugs (nbDMARD). Standardised incidence ratios (SIR) were calculated for each cohort and rates between cohorts were compared using Cox proportional HR, adjusted using inverse probability of treatment weighting. Results SIR for skin cancer was increased in both cohorts compared with the English population: SIR 1.72 (95% CI 1.43 to 2.04) anti-TNF; 1.83 (95% CI 1.30 to 2.50) nbDMARD only. In patients without previous skin cancer, BCC incidence per 100 000 patient-years was 342 (95% CI 290 to 402) after anti-TNF and 407 (95% CI 288 to 558) after nbDMARD. HR after anti-TNF adjusted for treatment weighting was 0.95 (95% CI 0.53 to 1.71). SCC incidence per 100 000 patient-years: anti-TNF 53 (95% CI 33 to 79); nbDMARD 43 (95% CI 12 to 110); adjusted HR 1.16 (95% CI 0.35 to 3.84). Conclusions Skin cancers were increased among treated patients with RA. No evidence was found that anti-TNF therapy exacerbates the risk of BCC or SCC but this cannot be excluded. Patients with RA should use sun protection and be monitored for skin cancer. PMID:22241900

  1. Chimerical anti-TNF-alpha, infliximab, inhibits neutrophil chemotaxis and production of reactive oxygen species by blocking the priming effect of mononuclear cells on neutrophils.

    PubMed

    Pay, S; Musabak, U; Erdem, H; Simsek, I; Pekel, A; Sengul, A; Dinc, A

    2005-01-01

    Clinical experience with anti-tumor necrosis factor alpha (anti-TNF-alpha) agents implies that these agents can cause a rapid onset amelioration of the symptoms and laboratory parameters in some inflammatory diseases. Precise explanation of this fast antiinflammatory action is not known. The aim of our study is to investigate the direct and indirect effects of anti-TNF agents on the chemotaxis and reactive oxygen species (ROS) production of neutrophils. For this purpose, isolated neutrophil cultures (INCs) and mixed leukocyte cultures were prepared from the venous blood of healthy subjects. Those cultures were separated to different groups according to the presence of anti-TNF or the stimulation of phytohemagglutinin (PHA). In this study, anti-TNF treatment did not change the migration ability of neutrophils in INCs. However, we established that chimerical anti-TNF-alpha, infliximab, inhibits neutrophil chemotaxis and production of ROS by blocking the priming effect of PHA-stimulated circulating mononuclear cells. These results may explain, at least partly, the rapid onset antiinflammatory actions of these agents observed in clinical practice. PMID:16114504

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

    PubMed

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

    2014-03-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

    2014-01-01

    Background Rheumatoid arthritis (RA) is a chronic autoinflammatory joint disease which leads to the destruction of joints and disability of the patients. Anti-tumour necrosis factor (anti-TNF) drugs can halt radiological progression better than conventional DMARDs even in clinical non-responders. Methods The efficacy of anti-TNF plus methotrexate (MTX) treatment versus MTX monotherapy on clinical and radiological outcomes were compared in early rheumatoid arthritis (RA) patients in clinical practice by retrospective analysis of an observational cohort. 49 early RA patients (group A) on first-line MTX monotherapy and 35 early RA patients (group B) on anti-TNF plus MTX treatment were selected from an observational cohort and evaluated retrospectively focusing on their first twelve months of treatment. Data on disease activity (DAS28) and functional status (HAQ-DI) were collected three monthly. One-yearly radiological progression was calculated according to the van der Heijde modified Sharp method (vdHS). Clinical non-responder patients in both groups were selectively investigated from a radiological point of view. Results Disease activity was decreased and functional status was improved significantly in both groups. One-yearly radiological progression was significantly lower in group B than in group A. The percentage of patients showing radiological non-progression or rapid radiological progression demonstrated a significant advantage for group B patients. In addition non-responder patients in group B showed similar radiological results as responders, while a similar phenomenon was not observed in patients in group A. Conclusions Clinical efficacy within our study was similar for tight-controlled MTX monotherapy as well as for combination treatment with anti-TNF and MTX. However MTX monotherapy was accompanied by more rapid radiological progression and less radiological non-progression. Anti-TNF plus MTX decreased radiological progression even in clinical non-responders supporting the advantage of anti-TNF plus MTX combination in dissociating clinical and radiological effects. PMID:25059769

  5. Melanoma immunotherapy

    PubMed Central

    Sanlorenzo, Martina; Vujic, Igor; Posch, Christian; Dajee, Akshay; Yen, Adam; Kim, Sarasa; Ashworth, Michelle; Rosenblum, Michael D; Algazi, Alain; Osella-Abate, Simona; Quaglino, Pietro; Daud, Adil; Ortiz-Urda, Susanna

    2014-01-01

    Immunotherapy is a cornerstone in the treatment of melanoma, and is intended to modulate the host immunity against the tumor. Immunotherapy can be used in an adjuvant setting, after complete surgical excision in patients with a high risk of disease relapse and as a treatment in advanced (unresectable or metastatic) stages. Development of novel therapeutic approaches and the optimization of existing therapies hold a great promise in the field of melanoma therapy research. Different clinical trials are ongoing, and immunotherapy is showing the ability to confirm durable clinical benefits in selected groups of melanoma patients. The aim of this review is to summarize different types of immunotherapy agents, as well as to discuss different strategies, complementary regimens, and possible biomarkers of response to the treatment. PMID:24651672

  6. Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNF? biologics in rheumatic diseases.

    PubMed

    Mok, C C; van der Kleij, D; Wolbink, G J

    2013-10-01

    The objectives of this study are to evaluate the effect of anti-drug antibodies on the clinical efficacy and withdrawal rate of the anti-TNF? biologics in patients with rheumatic diseases. Consecutive patients with rheumatic diseases recently commenced on anti-TNF? biologics were recruited. Serum samples were collected for assay of drug level and antibody titer against the corresponding biologics. Comparison of the clinical efficacy and drug retention rate was performed between patients with and without anti-drug antibodies. Fifty-eight Chinese patients were studied (64 % women; age 47.8 ± 12.9 years; disease duration 6.7 ± 6.4 years). The proportion of patients using infliximab (IFX), adalimumab (ADA), and etanercept (ETN) was 41, 28, and 31 %, respectively. Antibodies against IFX, ADA, and ETN were demonstrated in 12(50 %), 5(31 %) and 0(0 %) patients, respectively. Patients who developed anti-drug antibodies had significantly lower levels of the corresponding drugs (IFX level: 0.004 ± 0.01 vs 3.81 ± 3.49 ?g/ml; p = 0.002; ADA level: 0.0 vs 7.6 ± 8.3 ?g/ml; p = 0.008). Anti-drug antibody-positive patients had a significantly higher cumulative drug withdrawal rate due to inefficacy (64.7 and 71.8 % vs 10.3 and 10.3 % at month 12 and month 24, respectively; p < 0.001). In rheumatoid arthritis and psoriatic arthritis, non-responders was significantly more frequent in antibody-positive patients (54 vs 13 %; p = 0.01). In spondyloarthritis, the improvement in ankylosing spondylitis disease activity score was significant in patients without antibodies (3.89 ± 0.82 to 2.22 ± 0.86; p = 0.01) but not in those with anti-drug antibodies (3.40 ± 1.67 to 3.23 ± 1.40; p = 0.73). We concluded that the presence of neutralizing antibodies is associated with lower serum levels of the anti-TNF? biologics, leading to lower efficacy and higher withdrawal rate. PMID:23887439

  7. 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

  8. Novel immunotherapies.

    PubMed

    Yi, Qing

    2009-01-01

    Multiple myeloma is still a fatal disease. Despite advances in high-dose chemotherapy and stem-cell transplantation and the development of novel therapeutics, relapse of the underlying disease remains the primary cause of treatment failure. Strategies for posttransplantation 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

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

    PubMed

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

    2015-08-01

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

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

    PubMed Central

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

    2015-01-01

    AIM: To evaluate the incidence and risk factors of Korean tuberculosis (TB) infection in patients with inflammatory bowel disease (IBD) undergoing anti-TNF treatment. METHODS: The data of IBD patients treated with anti-TNFs in 13 tertiary referral hospitals located in the southeastern region of Korea were collected retrospectively. They failed to show response or were intolerant to conventional treatments, including steroids or immunomodulators. Screening measures for latent TB infection (LTBI) and the incidence and risk factors of active TB infection after treatment with anti-TNFs were identified. RESULTS: Overall, 376 IBD patients treated with anti-TNF agents were recruited (male 255, mean age of anti-TNF therapy 32.5 ± 13.0 years); 277 had Crohn’s disease, 99 had ulcerative colitis, 294 used infliximab, and 82 used adalimumab. Before anti-TNF treatment, screening tests for LTBI including an interferon gamma release assay or a tuberculin skin test were performed in 82.2% of patients. Thirty patients (8%) had LTBI. Sixteen cases of active TB infection including one TB-related mortality occurred during 801 person-years (PY) follow-up (1997.4 cases per 100000 PY) after anti-TNF treatment. LTBI (OR = 5.76, 95%CI: 1.57-21.20, P = 0.008) and WBC count < 5000 mm3 (OR = 4.5, 95%CI: 1.51-13.44, P = 0.007) during follow-up were identified as independently associated risk factors. CONCLUSION: Anti-TNFs significantly increase the risk of TB infection in Korean patients with IBD. The considerable burden of TB and marked immunosuppression might be attributed to this risk. PMID:25805938

  11. Bone status in adults with early-onset juvenile idiopathic arthritis following 1-year anti-TNF? therapy and discontinuation of glucocorticoids.

    PubMed

    Brabnikova Maresova, Kristyna; Jarosova, Katerina; Pavelka, Karel; Stepan, Jan J

    2013-08-01

    Juvenile idiopathic arthritis (JIA) is an inflammatory disease associated with bone loss and low bone mineral density (BMD). The treatment involves disease-modifying antirheumatic drugs, glucocorticoids (GCs) and biological agents. The aim of this study was to evaluate effects of 12-month therapy with the anti-tumor necrosis factor alpha (anti-TNF?) preparations on bone mineral density (BMD) and biochemical turnover markers (BTM) in adult patients with JIA who were previously either treated or not treated with glucocorticoids (GC) and to assess effects of the discontinuation of GCs on their bone status. Nineteen adult patients (12 women, 7 men) aged 18-33 years with active JIA were prospectively enrolled to receive the anti-TNF? therapy (infliximab, etanercept or adalimumab). BMD and BTMs were determined at baseline and 1-year follow-up. The anti-TNF? therapy resulted in a significant reduction in disease activity score 28 (DAS28) and C-reactive protein (CRP) and a significant increase in BMD at the lumbar spine and total body and in serum N-terminal propeptide of type I procollagen (PINP, marker of bone formation). No significant changes in serum beta C-terminal telopeptide of type I collagen (?CTX, marker of osteoclastic bone resorption) and osteocalcin (marker of bone remodeling) were found. A significant negative correlation was observed between the change in the DAS28, CRP and serum PINP. The change in serum PINP concentrations positively correlated with the change in lumbar spine BMD. A significant increase in serum PINP was observed only in patients discontinuing GCs during the anti-TNF? treatment. After the initiation of the anti-TNF? therapy in young adults with JIA, the increase in new bone formation can be explained by discontinuation of GCs administration as the patients with the largest reduction in DAS28 and CRP probably are the ones most likely to stop GC. PMID:23370856

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

    PubMed

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

    2015-03-01

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

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

    PubMed Central

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

    2015-01-01

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

  14. Immunological mechanisms of allergen-specific immunotherapy

    Microsoft Academic Search

    Cezmi A. Akdis; Rudolf Valenta; Mark Larché

    2006-01-01

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

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

    Microsoft Academic Search

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

    2010-01-01

    In rheumatic patients candidate to anti-TNF-? treatment, there is an increased risk of developing tuberculosis (TB). The tuberculin\\u000a skin test (TST), the standard diagnostic test for latent tuberculosis infection (LTBI), suffers low specificity and sensitivity.\\u000a Here, we compared the performance characteristics of an in-house ELISPOT-IFN-? assay (using a restricted pool of Mycobacterium tuberculosis-specific peptides or MTP) to TST for the

  16. An Open-Label Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Subjects with Prior Loss of Response or Intolerance to Infliximab for Crohn's Disease

    Microsoft Academic Search

    William J. Sandborn; Stephen Hanauer; Edward V. Loftus; William J. Tremaine; Sunanda Kane; Russell Cohen; Karen Hanson; Therese Johnson; Debra Schmitt; Resa Jeche

    2004-01-01

    BACKGROUND:We assessed the tolerability and clinical benefit of adalimumab, a human antibody to tumor necrosis factor (TNF), in patients with Crohn's disease who had previously received and responded to the chimeric anti-TNF antibody infliximab, but who no longer had a sustained response and\\/or tolerance to infliximab.METHODS:A total of 24 patients with Crohn's disease who had lost responsiveness or developed intolerance

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

    PubMed

    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-? treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P?anti-TNF-? 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-? treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis. PMID:26174087

  18. Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-? 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-? treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P?anti-TNF-? 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-? treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis. PMID:26174087

  19. Anti-TNF-? activity of Portulaca oleracea in vascular endothelial cells.

    PubMed

    Lee, An Sook; Kim, Jin Sook; Lee, Yun Jung; Kang, Dae Gill; Lee, Ho Sub

    2012-01-01

    Vascular inflammation plays a key role in the pathogenesis and progression of atherosclerosis, a main complication of diabetes. The present study investigated whether an aqueous extract of Portulaca oleracea (AP) prevents the TNF-?-induced vascular inflammatory process in the human umbilical vein endothelial cell (HUVEC). The stimulation of TNF-? induced overexpression of adhesion molecules affects vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and E-selectin for example. However, AP significantly suppressed TNF-?-induced over-expression of these adhesion molecules in a dose-dependent manner. In addition, pretreatment with AP dose-dependently reduced an increase of the adhesion of HL-60 cells to TNF-?-induced HUVEC. Furthermore, we observed that stimulation of TNF-? significantly increased intracellular reactive oxygen species (ROS) production. However, pretreatment with AP markedly blocked TNF-?-induced ROS production in a dose-dependent manner. The western blot and immunofluorescence analysis showed that AP inhibited the translocation of p65 NF-?B to the nucleus. In addition, AP suppressed the TNF-?-induced degradation of I?B-? and attenuated the TNF-?-induced NF-?B binding. AP also effectively reduced TNF-?-induced mRNA expressions of monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 in a dose-dependent manner. Taken together, AP prevents the vascular inflammatory process through the inhibition of intracellular ROS production and NF-?B activation as well as the reduction of adhesion molecule expression in TNF-?-induced HUVEC. These results suggested that AP might have a potential therapeutic effect by inhibiting the vascular inflammation process in vascular diseases such as atherosclerosis. PMID:22754320

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

    PubMed

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

    2013-09-15

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

  1. Convergent Random Forest Predictor: Methodology for predicting drug response from genome-scale data applied to anti-TNF response

    PubMed Central

    Bienkowska, Jadwiga; Dagin, Gul; Batliwalla, Franak; Allaire, Normand; Roubenoff, Ronenn; Gregersen, Peter; Carulli, John

    2015-01-01

    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

  2. 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

  3. Clinical Significance of Cartilage Biomarkers for Monitoring Structural Joint Damage in Rheumatoid Arthritis Patients Treated with Anti-TNF Therapy

    PubMed Central

    Niki, Yasuo; Takeuchi, Tsutomu; Nakayama, Masanori; Nagasawa, Hayato; Kurasawa, Takahiko; Yamada, Harumoto; Toyama, Yoshiaki; Miyamoto, Takeshi

    2012-01-01

    Purpose With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage. Methods Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated. Results Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ?HA and ?C2C/CPII from baseline to week 54 correlated significantly with not only ?CRP, but also ?DAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ?HA to ?DAS28 disappeared, whereas correlations of ?C2C/CPII to ?DAS28, ?JNS, and ?HAQ remained significant. These results suggest a role of ?C2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation. Conclusion The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ?C2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3. PMID:22629396

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

    Microsoft Academic Search

    Beth A. Pulaski; Virginia K. Clements; Matthew R. Pipeling; Suzanne Ostrand-Rosenberg

    2000-01-01

    Because they are difficult to treat, animal models of widespread, established metastatic cancer are rarely used to test novel\\u000a immunotherapies. Two such mouse models are used in this report to demonstrate the therapeutic efficacy and to probe the mechanisms\\u000a of a novel combination immunotherapy consisting of the cytokine interleukin-12 (IL-12) combined with a previously described\\u000a vaccine based on MHC class

  5. Immunotherapy with IL2-stimulated splenocytes reduces in vitro the level of Leishmania donovani infection in peritoneal macrophages

    Microsoft Academic Search

    Zohreh Eslami; Martin Olivier; Charles E. Tanner

    1995-01-01

    A study was done in vitro to determine if IL-2-stimulated lymphocytes (LAK cells) would activate infected macrophages to reduce their barden of Leishmania donovani. Macrophagedepleted splenocytes from normal or infected C57BL6 (H-2b; LshS) mice, stimulated in vitro by the IL-2-costaining supernatant of the MLA 144 cell line or by rIL-2, significantly reduced the number of syngeneic resting peritoneal macrophages infected

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

    PubMed

    Costa, Luisa; Caso, Francesco; Atteno, Mariangela; Giannitti, Chiara; Spadaro, Antonio; Ramonda, Roberta; Vezzù, Maristella; Del Puente, Antonio; Morisco, Filomena; Fiocco, Ugo; Galeazzi, Mauro; Punzi, Leonardo; Scarpa, Raffaele

    2014-02-01

    Psoriatic arthritis (PsA) is an inflammatory arthropathy associated with skin and/or nail psoriasis. TNF-?, in addition to its pro-inflammatory role, is an essential cytokine for the host's defense, and its depletion by treatment may facilitate the risk of viral infections or their reactivation. The aim of this study was to evaluate the efficacy and safety of TNF-? blockers in PsA patients with concurrent hepatitis C virus (HCV) infection. This is a multicenter study carried out in four Italian centers specialized in the diagnosis and treatment of PsA. At baseline and after 6 (T6) and 12 months (T12) of therapy, data concerning PsA activity and liver tests were registered. A total of 15 PsA patients with concomitant HCV infection were included in the study. At baseline, 13 patients had low viral load, and liver enzyme tests were within the normal range. During the observation period, these values remained stable. On the other hand, at baseline, a high viral load with slightly increased values of AST and ALT was detected in one patient. At T6 and T12, these values decreased. The remaining patient, at baseline, had low viral load, but with slightly increased AST and ALT values that normalized during the observation period. This is the greatest sample size available in the literature on this topic. The data suggests that anti-TNF-? agents are effective and safe in PsA patients with concomitant HCV. We suggest that the use of anti-TNF-? agents, accompanied by close monitoring, could be a therapeutic option. PMID:23975363

  7. LC-MS metabolomics of psoriasis patients reveals disease severity-dependent increases in circulating amino acids that are ameliorated by anti-TNF? treatment.

    PubMed

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

    2015-01-01

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

  8. Immunotherapy with IL-2-stimulated splenocytes reduces in vitro the level of Leishmania donovani infection in peritoneal macrophages.

    PubMed

    Eslami, Z; Olivier, M; Tanner, C E

    1995-08-01

    A study was done in vitro to determine if IL-2-stimulated lymphocytes (LAK cells) would activate infected macrophages to reduce their burden of Leishmania donovani. Macrophage-depleted splenocytes from normal or infected C57BL/6 (H-2b; LshS) mice, stimulated in vitro by the IL-2-containing supernatant of the MLA 144 cell line or by rIL-2, significantly reduced the number of syngeneic resting peritoneal macrophages infected by L. donovani; LAK cells from infected animals were significantly more effective in reducing the numbers of infected cells. Supernatants of MLA 144-stimulated spleen cells and rIL-2-stimulated splenocytes isolated in Millipore chambers also induced a significant reduction of the infection in vitro. Anti-Thy 1.2 eliminated the ability of the supernatant of MLA 144 to induce an activating function in C57BL/6 splenocytes; monoclonal anti-IL-2 abolished the ability of rIL-2 and of the MLA 144 supernatant to stimulate the splenocytes. Infected resting peritoneal macrophages of C57L (H-2b; LshR) mice were more responsive to activation than those of the C57BL/6 animals, irrespective of the phenotype of the stimulating LAK cells. Lymphokine stimulation reverses the immunological anergy induced in T lymphocytes by Leishmania donovani; IL-2-stimulated LAK splenocytes are highly effective in reducing the intensity of experimental visceral leishmaniasis in vitro in peritoneal macrophages. PMID:8550297

  9. 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 ?-synuclein (?-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of ?-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of ?-syn in the mThy1-?-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of ?-syn. CT ?-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated ?-syn (CT-?-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-?-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant ?-syn with 1H7 and 5C1 prevented CT cleavage of ?-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length ?-syn, but not of the CT-?-syn that lacked the 118–126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of ?-syn suggest that antibodies might be blocking the extracellular truncation of ?-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of ?-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease. PMID:25009275

  10. 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

  11. 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

  12. Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis.

    PubMed Central

    Cope, A P; Londei, M; Chu, N R; Cohen, S B; Elliott, M J; Brennan, F M; Maini, R N; Feldmann, M

    1994-01-01

    Experiments were designed to test the hypothesis that chronic exposure to tumor necrosis factor alpha (TNF) alters the function of activated T lymphocytes. Pretreatment of tetanus toxoid-specific T cell clones with TNF for up to 16 d impaired rechallenge proliferative responses to antigen in a dose- and time-dependent fashion. IL-2 and PHA responses were preserved. Prolonged treatment with TNF impaired production of IL-2, IL-10, IFN gamma, TNF, and lymphotoxin (LT) following stimulation with immobilized OKT3, and resulted in suboptimal expression of the IL-2R alpha chain (Tac) but not CD3, CD4, or HLA-DR antigens, when compared to untreated control cells. By contrast, pretreatment of T cells for prolonged periods in vitro with neutralizing anti-TNF monoclonal antibodies (mAb) enhanced proliferative responses, increased lymphokine production, and upregulated Tac expression following stimulation with OKT3. To determine whether TNF exerts immunosuppressive effects on T cells in vivo, we studied cell-mediated immunity in patients with active rheumatoid arthritis (RA), before and after treatment with a chimeric anti-TNF mAb. Treatment with anti-TNF restored the diminished proliferative responses of PBMC to mitogens and recall antigens towards normal in all patients tested. These data demonstrate that persistent expression of TNF in vitro and in vivo impairs cell-mediated immune responses. Images PMID:8040330

  13. Immunotherapy for Ovarian Cancer: What's Next?

    PubMed Central

    Kandalaft, Lana E.; Powell, Daniel J.; Singh, Nathan; Coukos, George

    2011-01-01

    In the past decade, we have witnessed important gains in the treatment of ovarian cancer; however, additional advances are required to reduce mortality. With compelling evidence that ovarian cancers are immunogenic tumors, immunotherapy should be further pursued and optimized. The dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory antibodies, create new opportunities in ovarian cancer therapeutics. Herein, we review current progress and future prospects in vaccine and adoptive T-cell therapy development as well as immunomodulatory therapy tools available for immediate clinical testing. PMID:21079136

  14. Immunotherapies: The Blockade of Inhibitory Signals

    PubMed Central

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

    2012-01-01

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

  15. Discovery of serum proteomic biomarkers for prediction of response to infliximab (a monoclonal anti-TNF antibody) treatment in rheumatoid arthritis: an exploratory analysis.

    PubMed

    Ortea, Ignacio; Roschitzki, Bernd; Ovalles, Juan Gabriel; Longo, Javier López; de la Torre, Inmaculada; González, Isidoro; Gómez-Reino, Juan J; González, Antonio

    2012-12-21

    Biologics such as TNF antagonists are a new class of drugs that have greatly improved Rheumatoid Arthritis (RA) treatment. However, for unknown reasons, individual patients with RA respond to one of these drugs but not to others even those targeting the same molecule. Methods to predict response are sorely needed because these drugs are currently selected by trial and error, what is very inefficient and prejudicial for the patient and the healthcare system. Here, we have explored the discovery of protein biomarkers in serum from patients treated with infliximab, one of the major anti-TNF drugs. The study was based in a quantitative proteomics approach using 8-plex iTRAQ labeling. It combined depletion of the most abundant serum proteins, two-dimensional LC fractionation, protein identification and relative quantification with a hybrid Orbitrap mass spectrometer. This approach allowed the identification of 315 proteins of which 237 were confidently quantified with two or more peptides. The detection range covered up to 6 orders of magnitude including multiple proteins at the ng/mL level. A new set of putative biomarkers was identified comprising 14 proteins significantly more abundant in the non-responder patients. The differential proteins were enriched in apolipoproteins, components of the complement system and acute phase reactants. These results show the feasibility of this approach and provide a set of candidates for validation as biomarkers for the classification of RA patients before the beginning of treatment, so that anticipated non-responders could be treated with an alternative drug. PMID:23000593

  16. Immunotherapy for allergic rhinitis.

    PubMed

    Walker, S M; Durham, S R; Till, S J; Roberts, G; Corrigan, C J; Leech, S C; Krishna, M T; Rajakulasingham, R K; Williams, A; Chantrell, J; Dixon, L; Frew, A J; Nasser, S M

    2011-09-01

    Allergic rhinitis (AR) affects more than 20% of the population in the United Kingdom and western Europe and represents a major cause of morbidity that includes interference with usual daily activities and impairment of sleep quality. This guidance prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) is for the management of AR in patients that have failed to achieve adequate relief of symptoms despite treatment with intranasal corticosteroids and/or antihistamines. The guideline is based on evidence and is for use by both adult physicians and paediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are indications and contraindications for immunotherapy, criteria for patient selection, the evidence for short- and long-term efficacy of subcutaneous and sublingual immunotherapy, and discussion on safety and the different modes of immunotherapy including, pre-seasonal and co-seasonal treatments. There are sections on children, allergen standardization, vaccines used in the United Kingdom, oral allergy syndrome, cost effectiveness of immunotherapy and practical considerations of undertaking immunotherapy including recommendations on who should undertake immunotherapy and dosing schedules. Finally, there is discussion on potential biomarkers of response to immunotherapy, the use of component-resolved diagnostics, novel approaches, alternative routes and potential areas for future research. PMID:21848757

  17. Immunotherapy in gastric cancer.

    PubMed

    Matsueda, Satoko; Graham, David Y

    2014-02-21

    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

  18. 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

  19. Principles of immunotherapy.

    PubMed

    Olszanski, Anthony J

    2015-05-01

    With recent success stories in melanoma, breast cancer, gastric cancer, renal cell carcinoma, prostate cancer, Hodgkin's lymphoma, squamous cell lung cancer, and other malignancies, immunotherapy has emerged as perhaps the most paradigm-changing treatment strategy to occur on the oncologic front in the last 35 years. At the NCCN 20th Annual Conference, Dr. Anthony J. Olszanski offered a primer on immunotherapeutic basics, featuring the complex interplay between the immune system and cancer; a comparative look at innate and adaptive immunity; and the topics of immune surveillance, tumor escape mechanisms, and immune suppression. Several examples of cancer immunotherapies in action are briefly presented. PMID:25995426

  20. Immunotherapies in neurologic disorders.

    PubMed

    Graves, Donna; Vernino, Steven

    2012-05-01

    Therapy for autoimmune demyelinating disorders has evolved rapidly over the past 10 years to include traditional immunosuppressants as well as novel biologicals. Antibody-mediated neuromuscular disorders are treated with therapies that acutely modulate pathogenic antibodies or chronically inhibit the humoral immune response. In other inflammatory autoimmune disorders of the peripheral and central nervous system, corticosteroids, often combined with conventional immunosuppression, and immunomodulatory treatments are used. Because autoimmune neurologic disorders are so diverse, evidence from randomized controlled trials is limited for most of the immunotherapies used in neurology. This review provides an overview of the immunotherapies currently used for neurologic disorders. PMID:22703853

  1. Cancer immunotherapy – revisited

    Microsoft Academic Search

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

    2011-01-01

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

  2. Immunotherapy for food allergies

    Microsoft Academic Search

    Samuel B. Lehrer; Laurianne G. Wild; Kenneth L. Bost; Ricardo U. Sorensen

    1999-01-01

    Conclusion  The future certainly holds promise for the treatment of food allergies. Generally, future treatments can be divided into immunological\\u000a manipulation of the food-allergic subject (mucosal vaccines, new immunotherapies, cytokine level alterations) or manipulation\\u000a of the food through genetic engineering to diminish or abolish its allergenic activity.

  3. The impact of DMARD and anti-TNF therapy on functional characterization of short-term T-cell activation in patients with rheumatoid arthritis--a follow-up study.

    PubMed

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

    2014-01-01

    Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a systemic dysfunction of T-cells. In this study we tested the impact of DMARD and anti-TNF agents on short-term activation characteristics of T-cells. We enrolled 12 patients with newly diagnosed RA (naïve RA) who were treated with methothrexate (MTX) and glucocorticsteroid (GCS) and 22 patients with established RA non responding to conventional DMARD therapy who were treated with different anti-TNF agents. Nine healthy volunteers served as controls. Blood samples were taken at baseline, then at 4th and 8th week of therapy. The characteristics of several intracellular activation processes during short-term activation of T-cells including cytoplasmic Ca(2+) level, mitochondrial Ca(2+) level, reactive oxygen species (ROS) and nitric oxide (NO) generation were determined by a novel flow-cytometry technique. At baseline, the tested processes were comparable to controls in naïve RA. During GCS therapy, cytoplasmic Ca(2+) level and ROS generation decreased. After the addition of MTX to GCS cytoplasmic Ca(2+) level became comparable to controls, while ROS generation decreased further. In DMARD non responders, cytoplasmic Ca(2+) level was higher than controls at baseline. The cytoplasmic Ca(2+) level became comparable to controls and ROS generation decreased during each of the three anti-TNF-? agent therapies. Mitochondrial Ca(2+) level and NO generation were unaltered in all of the patient groups. These results indicate that intracellular machinery is affected in T-cells of RA patients. This may alter the behavior of T-cells during activation. Different therapeutic approaches may modulate the abnormal T-cell functions. PMID:25098248

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

    PubMed Central

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

    2014-01-01

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

  5. Oral immunotherapy for allergic conjunctivitis.

    PubMed

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

    2014-11-01

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

  6. Passive immunotherapies protect WRvFire and IHD-J-Luc vaccinia virus-infected mice from lethality by reducing viral loads in the upper respiratory tract and internal organs.

    PubMed

    Zaitseva, Marina; Kapnick, Senta M; Meseda, Clement A; Shotwell, Elisabeth; King, Lisa R; Manischewitz, Jody; Scott, John; Kodihalli, Shantha; Merchlinsky, Michael; Nielsen, Henriette; Lantto, Johan; Weir, Jerry P; Golding, Hana

    2011-09-01

    Whole-body bioimaging was employed to study the effects of passive immunotherapies on lethality and viral dissemination in BALB/c mice challenged with recombinant vaccinia viruses expressing luciferase. WRvFire and IHD-J-Luc vaccinia viruses induced lethality with similar times to death following intranasal infection, but WRvFire replicated at higher levels than IHD-J-Luc in the upper and lower respiratory tracts. Three types of therapies were tested: licensed human anti-vaccinia virus immunoglobulin intravenous (VIGIV); recombinant anti-vaccinia virus immunoglobulin (rVIG; Symphogen, Denmark), an investigational product containing a mixture of 26 human monoclonal antibodies (HuMAbs) against mature virion (MV) and enveloped virion (EV); and HuMAb compositions targeting subsets of MV or EV proteins. Bioluminescence recorded daily showed that pretreatment with VIGIV (30 mg) or with rVIG (100 ?g) on day -2 protected mice from death but did not prevent viral replication at the site of inoculation and dissemination to internal organs. Compositions containing HuMAbs against MV or EV proteins were protective in both infection models at 100 ?g per animal, but at 30 ?g, only anti-EV antibodies conferred protection. Importantly, the t statistic of the mean total fluxes revealed that viral loads in surviving mice were significantly reduced in at least 3 sites for 3 consecutive days (days 3 to 5) postchallenge, while significant reduction for 1 or 2 days in any individual site did not confer protection. Our data suggest that reduction of viral replication at multiple sites, including respiratory tract, spleen, and liver, as monitored by whole-body bioluminescence can be used to predict the effectiveness of passive immunotherapies in mouse models. PMID:21715493

  7. Passive Immunotherapies Protect WRvFire and IHD-J-Luc Vaccinia Virus-Infected Mice from Lethality by Reducing Viral Loads in the Upper Respiratory Tract and Internal Organs?

    PubMed Central

    Zaitseva, Marina; Kapnick, Senta M.; Meseda, Clement A.; Shotwell, Elisabeth; King, Lisa R.; Manischewitz, Jody; Scott, John; Kodihalli, Shantha; Merchlinsky, Michael; Nielsen, Henriette; Lantto, Johan; Weir, Jerry P.; Golding, Hana

    2011-01-01

    Whole-body bioimaging was employed to study the effects of passive immunotherapies on lethality and viral dissemination in BALB/c mice challenged with recombinant vaccinia viruses expressing luciferase. WRvFire and IHD-J-Luc vaccinia viruses induced lethality with similar times to death following intranasal infection, but WRvFire replicated at higher levels than IHD-J-Luc in the upper and lower respiratory tracts. Three types of therapies were tested: licensed human anti-vaccinia virus immunoglobulin intravenous (VIGIV); recombinant anti-vaccinia virus immunoglobulin (rVIG; Symphogen, Denmark), an investigational product containing a mixture of 26 human monoclonal antibodies (HuMAbs) against mature virion (MV) and enveloped virion (EV); and HuMAb compositions targeting subsets of MV or EV proteins. Bioluminescence recorded daily showed that pretreatment with VIGIV (30 mg) or with rVIG (100 ?g) on day ?2 protected mice from death but did not prevent viral replication at the site of inoculation and dissemination to internal organs. Compositions containing HuMAbs against MV or EV proteins were protective in both infection models at 100 ?g per animal, but at 30 ?g, only anti-EV antibodies conferred protection. Importantly, the t statistic of the mean total fluxes revealed that viral loads in surviving mice were significantly reduced in at least 3 sites for 3 consecutive days (days 3 to 5) postchallenge, while significant reduction for 1 or 2 days in any individual site did not confer protection. Our data suggest that reduction of viral replication at multiple sites, including respiratory tract, spleen, and liver, as monitored by whole-body bioluminescence can be used to predict the effectiveness of passive immunotherapies in mouse models. PMID:21715493

  8. Immunotherapy for tularemia

    PubMed Central

    Skyberg, Jerod A.

    2013-01-01

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

  9. Oral and sublingual immunotherapy

    PubMed Central

    Burks, Wesley

    2014-01-01

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

  10. 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

  11. Safe Re-administration of Tumor Necrosis Factor-alpha (TNF?) Inhibitors in Patients with Rheumatoid Arthritis or Ankylosing Spondylitis Who Developed Active Tuberculosis on Previous Anti-TNF? Therapy

    PubMed Central

    Suh, Young Sun; Kwok, Seung-ki; Ju, Ji Hyeon; Park, Kyung-Su; Park, Sung-Hwan

    2014-01-01

    There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNF?) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNF? inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNF? therapy in patients with TNF?-associated TB. We used data of 1,012 patients with RA or AS treated with TNF? inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-? releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNF? therapy. All patients discontinued TNF? inhibitors with starting the treatment of TB. Eight patients were re-administered TNF? inhibitors due to disease flares and promptly improved without recurrence of TB. TNF? inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS. PMID:24431903

  12. Immunotherapy of melanoma

    PubMed Central

    Haanen, John B.A.G.

    2013-01-01

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

  13. Venoms, antivenoms and immunotherapy

    Microsoft Academic Search

    J.-P. Chippaux; M. Goyffon

    1998-01-01

    A century after the discovery of antivenom and despite real progress undertaken in its manufacture, its use remains largely empirical. Recent studies of pharmacokinetics of envenoming permitted improved understanding of immunotherapy. Improved purification of the antivenom by using immunoglobulin fragments has lead to increased tolerance and efficiency of antivenom. The respective advantages and disadvantages of F(ab?)2 and F(ab) are discussed

  14. [Fundamentals of immunotherapy. (author's transl)].

    PubMed

    Schulte-Wissermann, H; Gardilcic, S

    1981-03-01

    Immunotherapy, which improves the defense mechanisms of the host, is increasingly being used for the treatment of infectious diseases as well as tumours, in addition to other therapeutic tools. In this publication it is shown than an exact knowledge of the immunologic defense mechanisms is necessary for specific immunotherapy. A summary of the immunotherapeutic possibilities is presented. PMID:6164818

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

  16. 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 (A?) 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 A?-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in A?-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce A? 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

  17. Regulatory T Cells as Immunotherapy

    PubMed Central

    Singer, Benjamin D.; King, Landon S.; D’Alessio, Franco R.

    2014-01-01

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

  18. CCL21 Cancer Immunotherapy

    PubMed Central

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

    2014-01-01

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

  19. Recombinant allergens for allergen-specific immunotherapy: 10 years anniversary of immunotherapy with recombinant allergens.

    PubMed

    Valenta, Rudolf; Linhart, B; Swoboda, I; Niederberger, V

    2011-06-01

    The broad applicability of allergen-specific immunotherapy for the treatment and eventually prevention of IgE-mediated allergy is limited by the poor quality and allergenic activity of natural allergen extracts that are used for the production of current allergy vaccines. Today, the genetic code of the most important allergens has been deciphered; recombinant allergens equalling their natural counterparts have been produced for diagnosis and immunotherapy, and a large panel of genetically modified allergens with reduced allergenic activity has been characterized to improve safety of immunotherapy and explore allergen-specific prevention strategies. Successful immunotherapy studies have been performed with recombinant allergens and hypoallergenic allergen derivatives and will lead to the registration of the first recombinant allergen-based vaccines in the near future. There is no doubt that recombinant allergen-based vaccination strategies will be generally applicable to most allergen sources, including respiratory, food and venom allergens and allow to produce safe allergy vaccines for the treatment of the most common forms of IgE-mediated allergies. PMID:21352238

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

    Microsoft Academic Search

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

    2000-01-01

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

  1. Specific immunotherapy in grass pollen allergy

    PubMed Central

    Mailhol, Claire; Didier, Alain

    2012-01-01

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

  2. 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.

  3. Modified recombinant allergens for safer immunotherapy.

    PubMed

    Ferreira, Fátima; Briza, Peter; Inführ, Daniela; Schmidt, Georg; Wallner, Michael; Wopfner, Nicole; Thalhamer, Josef; Achatz, Gernot

    2006-01-01

    Molecular cloning and recombinant production of allergens offered new perspectives for the increasing problem of allergies. A variety of preparations are being developed aiming to increase safety and improve efficacy of specific immunotherapy. Recombinant-based approaches are mostly focused on genetic modification of allergens to produce molecules with reduced allergenic activity and conserved antigenicity, i.e. hypoallergens. Studies dealing with genetic modifications of allergen genes reported the production of site-directed mutants, deletion mutants, allergen fragments and oligomers, and allergen chimeras. An alternative to genetic engineering is the chemical modification of pure recombinant allergens. It has been shown that allergens modified with immunostimulatory DNA sequences (allergen-ISS conjugates), which masks IgE epitopes and adds a desirable Th1-inducing character to the allergen molecule. Other chemical modifications include oligomerization by aldehydes (allergoids) and maleylation, which seems to target allergens to particular antigen presenting cells. Several of these modified allergen preparations have been already evaluated for their safety in clinical provocation studies. So far, clinical trials showed the efficacy and safety of immunotherapy with an Amb a 1-ISS conjugate for ragweed pollen-allergic patients. In addition, a preparation consisting of hypoallergenic fragments of Bet v 1 was evaluated for immunotherapy of birch pollen-allergic patients. In parallel, several animal studies have now demonstrated the potential of genetic immunization for allergy treatment in the future. PMID:16613559

  4. Recombinant allergens for pollen immunotherapy.

    PubMed

    Wallner, Michael; Pichler, Ulrike; Ferreira, Fatima

    2013-12-01

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

  5. New routes for allergen immunotherapy

    PubMed Central

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

    2012-01-01

    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

  6. Immunotherapy for multiple myeloma.

    PubMed

    Rosenblatt, Jacalyn; Bar-Natan, Michal; Munshi, Nikhil C; Avigan, David E

    2014-02-01

    The potential potency of the immune system in targeting malignant plasma cells in multiple myeloma is best demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease, due to the non-specific nature of allo-reactive T cell responses mediated by donor lymphocytes. Immunotherapeutic approaches that more specifically target the malignant plasma cells have the potential to improve outcomes in multiple myeloma. The development of clinically efficacious immunotherapy in multiple myeloma is dependent on achieving a greater understanding of the complex interactions between the immunologic milieu and the growth of the malignant plasma cell clone. A number of antigens have been identified on malignant plasma cells that may be targeted by both humoral and cell mediated immunotherapeutic strategies. Encouraging results have been demonstrated both pre-clinically and in clinical trials. In this review, we summarize the clinical data evaluating immunotherapeutic approaches for the treatment of multiple myeloma. PMID:24417573

  7. Amyloid-? Immunotherapy for Alzheimer's Disease

    PubMed Central

    Fu, H.J.; Liu, B.; Frost, J.L.; Lemere, C.A.

    2010-01-01

    Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients, however, none of them modify disease progression. Amyloid-? (A?) peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to A? as a target for treatment. A? immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active A? vaccine was halted due to the development of meningoencephalitis in ~ 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine A? immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive A? immunotherapy are underway. In this review, we will provide an update of A? immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying A? immunotherapy for AD. PMID:20205640

  8. Concepts of immunotherapy for glioma.

    PubMed

    Patel, Mira A; Pardoll, Drew M

    2015-07-01

    Immunotherapy is coming to the fore as a viable anti-cancer treatment modality, even in poorly immunogenic cancers such as glioblastoma (GBM). Accumulating evidence suggests that the central nervous system may not be impervious to tumor-specific immune cells and could be an adequate substrate for immunologic anti-cancer therapies. Recent advances in antigen-specific cancer vaccines and checkpoint blockade in GBM provide promise for future immunotherapy in glioma. As anti-GBM immunotherapeutics enter clinical trials, it is important to understand the interactions, if any, between immune-based treatment modalities and the current standard of care for GBM involving chemoradiation and steroid therapy. Current data suggests that chemoradiation may not preclude the success of immunotherapeutics, as their effects may be synergistic. The future of therapy for GBM lies in the power of combination modalities, involving immunotherapy and the current standard of care. PMID:26070552

  9. Amyloid-ß-directed immunotherapy for Alzheimer's disease

    PubMed Central

    Lannfelt, L; Relkin, N R; Siemers, E R

    2014-01-01

    Lannfelt L, Relkin NR, Siemers ER (Uppsala University, Uppsala, Sweden; Weill Cornell Medical College, New York, NY; and Eli Lilly and Co., Indianapolis, IN, USA). Amyloid-ß-directed immunotherapy for Alzheimer’s disease. (Key Symposium). J Intern Med 2014; 275: 284–295. Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing Aß-directed immunotherapies that have passed clinical development Phase IIa. PMID:24605809

  10. Melatonin and ?-Endorphin Changes in Children Sensitized to Olive and Grass Pollen after Treatment with Specific Immunotherapy

    Microsoft Academic Search

    F. Girón-Caro; A. Muñoz-Hoyos; C. Ruiz-Cosano; A. Bonillo-Perales; A. Molina-Carballo; G. Escames; M. Macías; D. Acuña-Castroviejo

    2001-01-01

    Background: Specific immunotherapy for respiratory allergy, a seasonal disease, significantly reduces the inflammatory process, attenuating the clinical symptoms. The mechanism for the clinical beneficial effect of immunotherapy has not yet been clarified. Melatonin shows a circadian and seasonal variation and together with the endogenous opioid system plays an immunomodulatory role acting on both specific and nonspecific immunity responses. Thus, the

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

    2014-12-30

    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

  12. The immunotherapy of Alzheimer's disease

    PubMed Central

    Weksler, Marc E

    2004-01-01

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

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

    2014-01-01

    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

  14. Understanding Resistance to Cancer Immunotherapy.

    PubMed

    2015-07-01

    New research shows that spontaneous antitumor immunity, which predicts clinical benefit from immune checkpoint inhibitors, is absent in some patients with melanoma due to tumor-intrinsic Wnt/?-catenin signaling. Active ?-catenin disrupts CD103+ dendritic cell recruitment, preventing T cells from infiltrating tumors and undermining immunotherapy's effectiveness. PMID:26056132

  15. Anti-TNF alpha in the treatment of ulcerative colitis: a valid approach for organ-sparing or an expensive option to delay surgery?

    PubMed

    Rizzo, Gianluca; Pugliese, Daniela; Armuzzi, Alessandro; Coco, Claudio

    2014-05-01

    Ulcerative colitis (UC) is an inflammatory bowel disease affecting large bowel with variable clinical course. The history of disease has been modified by the introduction of biologic therapy, in particular Infliximab (IFX), that has demonstrated efficacy in inducing fast symptoms remission, promoting mucosal healing and maintaining long-term remission. However, surgery is still needed for UC patients: in case of failure of medical therapy and if acute complications or a malignancy occurred. Surgical treatment is associated with a short-term post-operative mortality and morbidity respectively of 0%-4% and 30%. In this study we systematically analyzed: the role of IFX in reducing the colectomy rate, the risk of post-operative morbidity in pre-operatively IFX-treated patients and the cost-effectiveness of IFX therapy. Four of 5 analyzed randomized controlled trials demonstrated that therapy with IFX significantly reduces the colectomy rate. Moreover, pre-operative treatment with IFX doesn't seem to increase post-operative infectious complications. By an economic point of view, the cost-effectiveness of IFX-therapy was demonstrated for UC patients suffering from moderate to severe UC in a study based on a cost estimation of the National Health Service of England and Wales. However, the argument is debated. PMID:24803795

  16. Role of immunotherapy in the treatment of allergic asthma.

    PubMed

    Yukselen, Ayfer; Kendirli, Seval Guneser

    2014-12-16

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

  17. Nanoparticulate adjuvants and delivery systems for allergen immunotherapy.

    PubMed

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

    2012-01-01

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

  18. Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

    Lima, Cleverton K. F.; Silva, Rafael M.; Lacerda, Renata B.; Santos, Bruna L. R.; Silva, Rafaela V.; Amaral, Luciana S.; Quintas, Luís E. M.; Fraga, Carlos A. M.; Barreiro, Eliezer J.; Guimaraes, Marília Z. P.; Miranda, Ana L. P.

    2014-01-01

    LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-? and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-? production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-? release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol.Kg?1 LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol.Kg?1 only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-? production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-? production, two key therapeutic targets of neuropathic pain, 100 µmol.Kg?1 LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7–11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-? inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model of neuropathic pain without presenting hyperthermia. PMID:24941071

  20. Evaluation of six years allergen immunotherapy in allergic rhinitis and allergic asthma.

    PubMed

    Farid, Reza; Ghasemi, Ramin; Baradaran-Rahimi, Mahmood; Jabbari, Farahzad; Ghaffari, Javad; Rafatpanah, Hooshang

    2006-03-01

    Allergen immunotherapy involves the administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions until a dose is reached that is effective in reducing disease severity from natural exposure. In the present study we evaluated a period of six years immunotherapy allergic rhinitis and allergic asthma patients with positive skin prick test of common aeroallergen. The immunotherapy was performed on 156 patients. One hundred twenty of the cases were allergic rhinitis (80%), 29 cases had allergic asthma and 7 cases were mixed (4.5%). 70% in allergic rhinitis group, 75% in allergic asthma group and 42.8% in mixed group completely improved. Immunotherapy, an older therapeutic method, has now been updated, and with appropriate indications, precautions and methods, has been clearly shown to be effective in the treatment of allergic rhinitis and in some cases of asthma and insect hypersensitivity. PMID:17242501

  1. Regulatory T cells in cancer immunotherapy.

    PubMed

    Nishikawa, Hiroyoshi; Sakaguchi, Shimon

    2014-04-01

    FOXP3(+)CD25(+)CD4(+) regulatory T (Treg) cells, crucial for the maintenance of immunological self-tolerance, are abundant in tumors. Most of them are chemo-attracted to tumor tissues, expanding locally and differentiating into a Treg-cell subpopulation that strongly suppresses the activation and expansion of tumor-antigen-specific effector T cells. Several cancer immunotherapies targeting FOXP3(+)CD4(+) Treg cells, including depletion of Treg cells, are currently being tested in the clinic. In addition, clinical benefit of immune-checkpoint blockade, such as anti-CTLA-4 monoclonal antibody therapy, could be attributed at least in part to depletion of FOXP3(+)CD4(+) Treg cells from tumor tissues. Thus, optimal strategies need to be established for reducing Treg cells or attenuating their suppressive activity in tumor tissues, together with activating and expanding tumor-specific effector T cells. PMID:24413387

  2. 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

  3. Anti-TNF-? therapies: the next generation

    Microsoft Academic Search

    Frances Rena Bahjat; Emmanuel A. Theodorakis; Lyle L. Moldawer; Michael A. Palladino

    2003-01-01

    The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Unregulated activities of these mediators can lead to the development of serious inflammatory diseases. In particular, enhanced tumour-necrosis factor-? (TNF-?) synthesis is associated with the development of rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Inhibiting TNF-? activities in these diseases

  4. Anti-TNF-? Therapy for Ankylosing Spondylitis

    PubMed Central

    Cha, Sang-Won

    2010-01-01

    Background This review evaluated the safety and efficacy of etanercept in patients with ankylosing spondylitis (AS). Methods Of 59 patients with AS, this study reviewed 11 patients who were refractory to conventional therapy and treated with etanercept from September 2005 to January 2008. The mean follow-up duration was 13.6 months. The general improvement was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and adverse effects, complications and inflammatory markers were also assessed. Results The mean BASDAI decreased from 7.1 ± 1.6 before treatment to 4.2 ± 1.8 at 3 months after the etanercept treatment (p = 0.001). The mean erythrocyte sedimentation rate and C-reactive protein were decreased significantly by the etanercept treatment. The greatest improvement in symptoms was enthesitis, followed by skin involvement and morning stiffness. There was a significant difference in the improvement in BASDAI along with the follow up duration (p = 0.04). A serious infection was observed as a complication in 1 case. Conclusions These results suggest that etanercept can induce significant improvement in most patients with less damage. A trial of tumor necrosis factor inhibition is indicated in all AS patients who do not achieve adequate disease control with disease-modifying antirheumatic drugs, such as methotrexate, leflunomide etc. The patients treated with etanercept should be educated about the possibility of infection and monitored closely. PMID:20190998

  5. Poxviral vectors for cancer immunotherapy

    PubMed Central

    Kim, Joseph W.; Gulley, James L.

    2012-01-01

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

  6. Immune mechanisms of sublingual immunotherapy.

    PubMed

    Jay, David C; Nadeau, Kari C

    2014-11-01

    Sublingual immunotherapy (SLIT) is a well-established allergen-specific immunotherapy and a safe and effective strategy to reorient inappropriate immune responses in allergic patients. SLIT takes advantage of the tolerogenic environment of the oral mucosa to promote tolerance to the allergen. Several clinical studies have investigated the complex interplay of innate and adaptive immune responses that SLIT exploits. The oral immune system is composed of tolerogenic dendritic cells that, following uptake of allergen during SLIT, support the differentiation of T helper cell type 1 (Th1) and the induction of IL-10-producing regulatory T cells. Following SLIT, allergic disease-promoting T helper cell type 2 (Th2) responses shift to a Th1 inflammatory response, and IL-10 and transforming growth factor (TGF)-? production by regulatory T cells and tolerogenic dendritic cells suppress allergen-specific T cell responses. These immune changes occur both in the sublingual mucosa and in the periphery of a patient following SLIT. SLIT also promotes the synthesis of allergen-specific IgG and IgA antibodies that block allergen-IgE complex formation and binding to inflammatory cells, thus encouraging an anti-inflammatory environment. Several of these revealing findings have also paved the way for the identification of biomarkers of the clinical efficacy of SLIT. This review presents the emerging elucidation of the immune mechanisms mediated by SLIT. PMID:25195100

  7. Improved Endpoints for Cancer Immunotherapy Trials

    PubMed Central

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

    2010-01-01

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

  8. Immunotherapy: Disrupting the Cancer Treatment World

    MedlinePLUS

    ... a combination of a drug currently used in isolation, Brentuximab vedotin, and the anti-CTLA-4 immunotherapy ... the realm of checkpoint blockade drugs as the technology for making and testing them is more widely ...

  9. PROSTVAC® targeted immunotherapy candidate for prostate cancer.

    PubMed

    Shore, Neal D

    2014-01-01

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

  10. Materials Based Tumor Immunotherapy Vaccines

    PubMed Central

    Li, Weiwei Aileen; Mooney, David J.

    2013-01-01

    Immunotherapy is a promising approach for treating cancer. However, there are limitations inherent to current approaches which may be addressed by integrating them with biomaterial-based strategies. Material platforms have been fabricated to interact with immune cells through spatially- and temporally-controlled delivery of immune modulators and to promote immune cell crosstalk. Particle vaccines have been developed to specifically target and deliver agents to organs, cells and subcellular compartments. These strategies have been shown to generate antigen-specific CTL responses and, in some cases, tumor regression. Therefore, collaboration between immunology and materials engineering is likely to result in the creation of strong vaccines to combat cancer in the future. PMID:23337254

  11. Cancer immunotherapy comes of age

    PubMed Central

    Mellman, Ira; Coukos, George; Dranoff, Glenn

    2014-01-01

    Activating the immune system for therapeutic benefit in cancer has long been a dream of some immunologists, and even a few oncologists. After decades of disappointment, the tide has finally changed due to the success of recent proof-of-concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody ipilimumab to achieve significant increases in survival of patients with metastatic melanoma, an indication where conventional therapies have failed. Viewed in the context of advances in understanding of how tolerance, immunity, and immunosuppression regulate anti-tumor immune responses together with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path forward to obtaining durable, long-lasting responses in cancer patients. PMID:22193102

  12. Dendritic cell immunotherapy: clinical outcomes

    PubMed Central

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

    2014-01-01

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

  13. Immunotherapy

    MedlinePLUS

    ... daily chemotherapy that followed his diagnosis with acute lymphoblastic leukemia. Though his treatments continue (3-1/2 years in total), ... Lymphoma Survivor The Woodlands, TX I was diagnosed with ...

  14. 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.

  15. Addition of immunotherapy boosts pediatric cancer survival

    Cancer.gov

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

  16. 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

  17. 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

  18. Cancer immunotherapy out of the gate: the 22nd annual cancer research institute international immunotherapy symposium.

    PubMed

    2015-05-01

    The 22nd annual Cancer Research Institute (CRI) International Immunotherapy Symposium was held from October 5-8, 2014, in New York City. Titled "Cancer Immunotherapy: Out of the Gate," the symposium began with a Cancer Immunotherapy Consortium satellite meeting focused on issues in immunotherapy drug development, followed by five speaker sessions and a poster session devoted to basic and clinical cancer immunology research. The second annual William B. Coley lecture was delivered by Lieping Chen, one of the four recipients of the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology; the other three recipients were Gordon Freeman, Tasuku Honjo, and Arlene Sharpe. Prominent themes of the conference were the use of genomic technologies to identify neoantigens and the emergence of new immune modulatory molecules, beyond CTLA-4 and PD-1/PD-L1, as new therapeutic targets for immunotherapy. Cancer Immunol Res; 3(5); 444-8. ©2015 AACR. PMID:25941356

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

    PubMed Central

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

    2014-01-01

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

  20. 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

  1. Checkpoint Blockade in Cancer Immunotherapy

    PubMed Central

    Korman, Alan J.; Peggs, Karl S.; Allison, James P.

    2007-01-01

    The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade. PMID:16730267

  2. 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

  3. 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

  4. Combining immunotherapy and radiation for prostate cancer.

    PubMed

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

    2015-02-01

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

  5. Toward integrative cancer immunotherapy: targeting the tumor microenvironment.

    PubMed

    Emens, Leisha A; Silverstein, Samuel C; Khleif, Samir; Marincola, Francesco M; Galon, Jérôme

    2012-01-01

    The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8? T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8? effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of integrative cancer immunotherapies that sculpt the tumor microenvironment to promote definitive tumor rejection. PMID:22490302

  6. 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.

  7. Immunotherapy for chronic hepatitis B virus infections

    Microsoft Academic Search

    Xian-Jie Yu; Gui-Qiang Wang

    2007-01-01

    The immune system functions to control and clear virus infections. Viral persistence has been closely associated with dysfunctional specific immunity, especially cellular immunity. Current antiviral therapies have been disappointing. Immunotherapies with strategies to boost or restore the virus-specific immune response of patients with chronic hepatitis B virus infection have been proposed for curing persistent i n f e c t

  8. Immunoengineering: how nanotechnology can enhance cancer immunotherapy.

    PubMed

    Goldberg, Michael S

    2015-04-01

    Although cancer immunotherapy can lead to durable outcomes, the percentage of patients who respond to this disruptive approach remains modest to date. Encouragingly, nanotechnology can enhance the efficacy of immunostimulatory small molecules and biologics by altering their co-localization, biodistribution, and release kinetics. PMID:25860604

  9. The coming of age of tumour immunotherapy

    Microsoft Academic Search

    Gordon Ada

    1999-01-01

    Compared with the earlier incidence of acute infectious diseases, the introduction of vaccines has been one of the major public health success achievements. In contrast, vaccine development to control some persisting infections such as HIV remains a major challenge. There are many similarities with this task and that of controlling tumours by immunotherapy. Generating CTL responses by using pulsed dendritic

  10. Immunotherapy for the treatment of prostate cancer

    Microsoft Academic Search

    Carlo Buonerba; Philip W. Kantoff; Giuseppe Di Lorenzo

    2011-01-01

    Failure of immune surveillance has a prominent role in tumorigenesis. Cancerous cells can evade T-cell responses to tumor-associated antigens by multiple mechanisms. Active immunotherapy aims to stimulate the immune response against cancer cells. Unlike normal prostate tissue, prostate cancer is not ignored by the immune system, as shown by the presence of tumor infiltrating lymphocytes. This characteristic renders prostate cancer

  11. Immunotherapy for head and neck cancer.

    PubMed

    Wu, Annie A; Niparko, Kevin J; Pai, Sara I

    2008-05-01

    Head and neck cancer represents a challenging disease. Despite recent treatment advances, which have improved functional outcomes, the long-term survival of head and neck cancer patients has remained unchanged for the past 25 years. One of the goals of adjuvant cancer therapy is to eradicate local regional microscopic and micrometastatic disease with minimal toxicity to surrounding normal cells. In this respect, antigen-specific immunotherapy is an attractive therapeutic approach. With the advances in molecular genetics and fundamental immunology, antigen-specific immunotherapy is being actively explored using DNA, bacterial vector, viral vector, peptide, protein, dendritic cell, and tumor-cell based vaccines. Early phase clinical trials have demonstrated the safety and feasibility of these novel therapies and the emphasis is now shifting towards the development of strategies, which can increase the potency of these vaccines. As the field of immunotherapy matures and as our understanding of the complex interaction between tumor and host develops, we get closer to realizing the potential of immunotherapy as an adjunctive method to control head and neck cancer and improve long-term survival in this patient population. PMID:18392689

  12. Immunotherapy of bovine ocular squamous cell carcinomas

    Microsoft Academic Search

    PB Spradbrow; BE Wilson; D Hoffmann; WR Kelly; J Francis

    1977-01-01

    Squamous cell carcinomas were collected from the eyes of cattle and saline phenol extracts of the tumours were prepared. The aqueous phase of the extract was used in studies on the immunotherapy of ocular squamous cell carcinomas in cattle. After a single intramuscular injection of the extract, regression and sometimes complete disappearance of eye tumours were observed in 39 of

  13. Awareness and understanding of cancer immunotherapy in Europe.

    PubMed

    Mellstedt, Håkan; Gaudernack, Gustav; Gerritsen, Winald R; Huber, Christoph; Melero, Ignacio; Parmiani, Giorgio; Scholl, Suzy; Thatcher, Nicholas; Wagstaff, John; Zielinski, Christoph

    2014-01-01

    The use of immunotherapy in the management of cancer is growing, and a range of new immunotherapeutic strategies is becoming available. It is important that people involved in the care of cancer understand how cancer immunotherapies differ from conventional chemotherapy and apply this knowledge to their clinical practice. Therefore, from August-September 2011 we undertook a survey of awareness, attitudes, and perceptions of cancer immunotherapy among 426 healthcare professionals (HCPs) in Europe with the aim of identifying and prioritizing educational needs. Nearly all (98%) HCPs were aware of cancer immunotherapy. While 68% of HCPs indicated a high level of interest in cancer immunotherapies, only 24% of the HCPs had direct experience with them. Overall perceptions of cancer immunotherapy among HCPs were largely positive (60%) and rarely negative (3%). The key advantages of cancer immunotherapy were perceived to be good safety and tolerability (75%), a targeted mechanism of action (61%) and good efficacy (48%). The leading barriers to use of immunotherapies were costs of treatment (58%), past clinical trial failures (45%), and access/formulary restrictions (44%). The results indicate that, among the respondents, awareness of cancer immunotherapy was high but that knowledge levels varied and direct experience with their use was limited. There appears to be a need for educational activities on cancer immunotherapy, as well as generation and communication of clinical data on long-term efficacy and safety. PMID:25424789

  14. Awareness and understanding of cancer immunotherapy in Europe

    PubMed Central

    Mellstedt, Håkan; Gaudernack, Gustav; Gerritsen, Winald R; Huber, Christoph; Melero, Ignacio; Parmiani, Giorgio; Scholl, Suzy; Thatcher, Nicholas; Wagstaff, John; Zielinski, Christoph

    2014-01-01

    The use of immunotherapy in the management of cancer is growing, and a range of new immunotherapeutic strategies is becoming available. It is important that people involved in the care of cancer understand how cancer immunotherapies differ from conventional chemotherapy and apply this knowledge to their clinical practice. Therefore, from August–September 2011 we undertook a survey of awareness, attitudes, and perceptions of cancer immunotherapy among 426 healthcare professionals (HCPs) in Europe with the aim of identifying and prioritizing educational needs. Nearly all (98%) HCPs were aware of cancer immunotherapy. While 68% of HCPs indicated a high level of interest in cancer immunotherapies, only 24% of the HCPs had direct experience with them. Overall perceptions of cancer immunotherapy among HCPs were largely positive (60%) and rarely negative (3%). The key advantages of cancer immunotherapy were perceived to be good safety and tolerability (75%), a targeted mechanism of action (61%) and good efficacy (48%). The leading barriers to use of immunotherapies were costs of treatment (58%), past clinical trial failures (45%), and access/formulary restrictions (44%). The results indicate that, among the respondents, awareness of cancer immunotherapy was high but that knowledge levels varied and direct experience with their use was limited. There appears to be a need for educational activities on cancer immunotherapy, as well as generation and communication of clinical data on long-term efficacy and safety. PMID:25424789

  15. Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

    PubMed Central

    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:22640522

  16. [Immunotherapy of solid tumors. Current status and prospects].

    PubMed

    Valente, M G; Tagliaferri, F; Stipa, F; Arklins, K; Cesareo, S; Sirovich, I

    1996-01-01

    Immunotherapy is the most recent therapeutic strategy in the treatment of cancer. It has not yet achieved an elevated curative efficiency and a wide clinical application. Nevertheless the possibilities of improvement seem very promising. The knowledge of the immune response mechanisms and the first clinical trials have determined a more efficient immunotherapy. Here we will critically analyze current immunotherapeutic strategies by reviewing the latest and the most important experimental works. The latest protocols of immunotherapy have been aimed to be more integrated in the physiological immune response schemes. The orientation of the experimental works have been changed from non specific immunotherapy using lymphokines to immunotherapy with specific lymphocytes expanded in vitro and, finally, the active specific immunotherapy in vivo by modificated tumoral vaccines or by variously manipulated tumoral antigens. PMID:8975338

  17. Immunotherapy prospects for acute myeloid leukaemia

    PubMed Central

    Barrett, A J; Le Blanc, K

    2010-01-01

    While chemotherapy is successful at inducing remission of acute myeloid leukaemia (AML), the disease has a high probability of relapse. Strategies to prevent relapse involve consolidation chemotherapy, stem cell transplantation and immunotherapy. Evidence for immunosurveillance of AML and susceptibility of leukaemia cells to both T cell and natural killer (NK) cell attack and justifies the application of immune strategies to control residual AML persisting after remission induction. Immune therapy for AML includes allogeneic stem cell transplantation, adoptive transfer of allogeneic or autologous T cells or NK cells, vaccination with leukaemia cells, dendritic cells, cell lysates, peptides and DNA vaccines and treatment with cytokines, antibodies and immunomodulatory agents. Here we describe what is known about the immunological features of AML at presentation and in remission, the current status of immunotherapy and strategies combining treatment approaches with a view to achieving leukaemia cure. PMID:20529084

  18. Molecular biomarkers for grass pollen immunotherapy

    PubMed Central

    Popescu, Florin-Dan

    2014-01-01

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

  19. [Transcutaneous applications for vaccination and immunotherapy].

    PubMed

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

    2014-10-15

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

  20. Yeast-based vaccine approaches to cancer immunotherapy

    E-print Network

    Howland, Shanshan W

    2008-01-01

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

  1. Engineering Dendritic Cells to Enhance Cancer Immunotherapy

    Microsoft Academic Search

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

    2011-01-01

    Cancer immunotherapy aims to establish immune-mediated control of tumor growth by priming T-cell responses to target tumor-associated antigens. Three signals are required for T-cell activation: (i) presentation of cognate antigen in self MHC molecules; (ii) costimulation by membrane-bound receptor-ligand pairs; and (iii) soluble factors to direct polarization of the ensuing immune response. The ability of dendritic cells (DCs) to provide

  2. Assessing Immunotherapy Through Cellular and Molecular Imaging

    Microsoft Academic Search

    John W. Barrett; Bryan Au; Ryan Buensuceso; Sonali de Chickera; Vasiliki Economopoulos; Paula Foster; Gregory A. Dekaban

    \\u000a Molecular medicine is focusing its attention on developing immunotherapeutic strategies that engage the immune system to combat\\u000a a number of human diseases, including cancer. As a result, great emphasis has been placed on enhancing existing imaging modalities\\u000a and developing new imaging techniques in order to assess the in vivo consequences of a given immunotherapy. Recently, improvements\\u000a in the resolution and

  3. Regulatory T cells, tumour immunity and immunotherapy

    Microsoft Academic Search

    Weiping Zou

    2006-01-01

    Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment

  4. Bioinformatics for cancer immunology and immunotherapy.

    PubMed

    Charoentong, Pornpimol; Angelova, Mihaela; Efremova, Mirjana; Gallasch, Ralf; Hackl, Hubert; Galon, Jerome; Trajanoski, Zlatko

    2012-11-01

    Recent mechanistic insights obtained from preclinical studies and the approval of the first immunotherapies has motivated increasing number of academic investigators and pharmaceutical/biotech companies to further elucidate the role of immunity in tumor pathogenesis and to reconsider the role of immunotherapy. Additionally, technological advances (e.g., next-generation sequencing) are providing unprecedented opportunities to draw a comprehensive picture of the tumor genomics landscape and ultimately enable individualized treatment. However, the increasing complexity of the generated data and the plethora of bioinformatics methods and tools pose considerable challenges to both tumor immunologists and clinical oncologists. In this review, we describe current concepts and future challenges for the management and analysis of data for cancer immunology and immunotherapy. We first highlight publicly available databases with specific focus on cancer immunology including databases for somatic mutations and epitope databases. We then give an overview of the bioinformatics methods for the analysis of next-generation sequencing data (whole-genome and exome sequencing), epitope prediction tools as well as methods for integrative data analysis and network modeling. Mathematical models are powerful tools that can predict and explain important patterns in the genetic and clinical progression of cancer. Therefore, a survey of mathematical models for tumor evolution and tumor-immune cell interaction is included. Finally, we discuss future challenges for individualized immunotherapy and suggest how a combined computational/experimental approaches can lead to new insights into the molecular mechanisms of cancer, improved diagnosis, and prognosis of the disease and pinpoint novel therapeutic targets. PMID:22986455

  5. Heat Shock Protein (HSP)Based Immunotherapies

    Microsoft Academic Search

    Hongying Zheng; Alexzander Asea

    \\u000a Heat Shock Proteins (HSP) are a diverse group of proteins that as molecular chaperons bind to a variety of cell proteins in\\u000a all cells. HSP also play a significant role in helping the immune system recognize diseased cells. During the past three decades,\\u000a HSP are found to be a potent agent for tumor immunotherapy and studies towards anti-tumor vaccine development

  6. [Compliance with and abandonment of immunotherapy].

    PubMed

    Ruiz, F J; Jiménez, A; Cocoletzi, J; Durán, E

    1997-01-01

    The charts of 247 allergic patients (all ages) who were receiving immunotherapy were studied retrospectively. They belong to a private setting at the city of Santa Ana Chiautempan, Tlax (Mexico). We looked at whether they were compliant or noncompliance. Compliance was considered as those who did not stop immunotherapy during a 18-month period, and shorter periods s noncompliance. One hundred and fifty two (62%) were compliant and 95 (38%) were not. Noncompliance causes were: 29 patients felt better soon, 19 claimed high costs, 8 changed to alternative medicine. 6 felt worse because of immunotherapy, 6 moved to other cities, 2 preferred other allergists and 25 did not answer the questionnaire. Forty six per cent stopped during the first 2 to 6 months and 56% within 8 and 14 with a median of 5.4. Eighty per cent from those who were compliant claimed they felt much better and 18% only slightly better. The average length-compliance was 29.7 months. PMID:9296824

  7. Specific immunotherapy in asthma: efficacy and safety.

    PubMed

    Passalacqua, G; Canonica, G W

    2011-09-01

    The use of specific immunotherapy (SIT) to treat asthma has been, and still is, a matter of debate, and there are no clear or unequivocal indications in the official documents. This is partly due to the fact that there are few studies specifically designed to assess asthma, that none of such studies had a formal sample size calculation, and that objective parameters of pulmonary function have been assessed only sporadically. Nonetheless, there are good quality studies for both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) where asthma symptoms were evaluated, and showing positive results. Moreover, several favourable meta-analyses are available, although their validity is limited by the great heterogeneity of the trials included. The disease modifying effect of SIT, that is the capacity of preventing asthma onset should be also taken into account. Concerning the safety, fatalities seem to be an exceptional event and in Europe no fatality has been reported over the last two decades. Uncontrolled asthma is universally recognized as the most important risk factor for severe adverse events. In conclusion both SLIT and SCIT can be used in asthma associated with rhinitis (which is the most common condition), provided that asthma is adequately controlled by pharmacotherapy. In such case, a measurable clinical benefit on asthma symptoms can be expected. On the other hand, SIT cannot be presently recommended as single therapy when asthma is the unique manifestation of respiratory allergy. PMID:21255159

  8. Immunotherapy for Bone and Soft Tissue Sarcomas

    PubMed Central

    Uehara, Takenori; Fujiwara, Tomohiro; Takeda, Ken; Kunisada, Toshiyuki; Ozaki, Toshifumi; Udono, Heiichiro

    2015-01-01

    Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

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

    PubMed Central

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

    2014-01-01

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

  10. Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer's disease mouse model.

    PubMed

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

    2014-12-01

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

  11. Escalating Immunotherapy of Multiple Sclerosis

    Microsoft Academic Search

    P. Rieckmann; K. V. Toyka

    1999-01-01

    The promising results of several multicenter studies during the last few years have improved the immunomodulatory treatment of multiple sclerosis (MS). The different compounds tested were shown to reduce the number of relapses and to modulate the course of disease to various extents. The transition of the results obtained in therapeutic trials into daily clinical practice is often delayed or

  12. Fine-tuning anti-tumor immunotherapies via stochastic simulations

    PubMed Central

    2012-01-01

    Background Anti-tumor therapies aim at reducing to zero the number of tumor cells in a host within their end or, at least, aim at leaving the patient with a sufficiently small number of tumor cells so that the residual tumor can be eradicated by the immune system. Besides severe side-effects, a key problem of such therapies is finding a suitable scheduling of their administration to the patients. In this paper we study the effect of varying therapy-related parameters on the final outcome of the interplay between a tumor and the immune system. Results This work generalizes our previous study on hybrid models of such an interplay where interleukins are modeled as a continuous variable, and the tumor and the immune system as a discrete-state continuous-time stochastic process. The hybrid model we use is obtained by modifying the corresponding deterministic model, originally proposed by Kirschner and Panetta. We consider Adoptive Cellular Immunotherapies and Interleukin-based therapies, as well as their combination. By asymptotic and transitory analyses of the corresponding deterministic model we find conditions guaranteeing tumor eradication, and we tune the parameters of the hybrid model accordingly. We then perform stochastic simulations of the hybrid model under various therapeutic settings: constant, piece-wise constant or impulsive infusion and daily or weekly delivery schedules. Conclusions Results suggest that, in some cases, the delivery schedule may deeply impact on the therapy-induced tumor eradication time. Indeed, our model suggests that Interleukin-based therapies may not be effective for every patient, and that the piece-wise constant is the most effective delivery to stimulate the immune-response. For Adoptive Cellular Immunotherapies a metronomic delivery seems more effective, as it happens for other anti-angiogenesis therapies and chemotherapies, and the impulsive delivery seems more effective than the piece-wise constant. The expected synergistic effects have been observed when the therapies are combined. PMID:22536975

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

    PubMed Central

    2014-01-01

    Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.

  14. Immunotherapy for hepatocellular carcinoma: From basic research to clinical use

    PubMed Central

    Hong, Yu-Peng; Li, Zi-Duo; Prasoon, Pankaj; Zhang, Qi

    2015-01-01

    Hepatocellular carcinoma (HCC) is a common cancer worldwide with a poor prognosis. Few strategies have been proven efficient in HCC treatment, particularly for those patients not indicated for curative resection or transplantation. Immunotherapy has been developed for decades for cancer control and is attaining more attention as a result of encouraging outcomes of new strategies such as chimeric antigen receptor T cells and immune checkpoint blockade. Right at the front of the new era of immunotherapy, we review the immunotherapy in HCC treatment, from basic research to clinical trials, covering anything from immunomodulators, tumor vaccines and adoptive immunotherapy. The mechanisms, efficacy and safety as well as the approach particulars are unveiled to assist readers to gain a concise but extensive understanding of immunotherapy of HCC. PMID:25954480

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

    PubMed

    Leung, Joanne; Suh, Woong-Kyung

    2014-12-01

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

  16. Adoptive Immunotherapy for Hodgkin’s Lymphoma

    Microsoft Academic Search

    Alana A. Kennedy-Nasser; Catherine M. Bollard; Cliona M. Rooney

    2006-01-01

    Adoptive transfer of tumor-specific T-cells is an attractive strategy for the treatment of patients with refractory or relapsed\\u000a Hodgkin’s lymphoma. However, Hodgkin’s lymphomas possess a range of tumor-evasion mechanisms, which must be overcome before\\u000a the full potential of immunotherapies can be achieved. In this article, we discuss the promise of Epstein-Barr virus-specific\\u000a cytotoxic T-lymphocytes, the roles of cytokines, and other

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

    PubMed

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

    2013-05-22

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

  18. Harnessing the Microbiome to Enhance Cancer Immunotherapy

    PubMed Central

    Nelson, Michelle H.; Diven, Marshall A.; Huff, Logan W.; Paulos, Chrystal M.

    2015-01-01

    The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies. PMID:26101781

  19. Tregs and rethinking cancer immunotherapy

    PubMed Central

    Curiel, Tyler J.

    2007-01-01

    Tumors express antigens that should induce immune-mediated rejection, but spontaneous rejection of established tumors is rare. Recent work demonstrates that one reason for the lack of tumor rejection is that tumors actively defeat host immunity. This concept forces us to rethink current approaches to harnessing potent, specific host immunity to battle cancer, most of which are based on the paradigm that inducing more antitumor immune cells alone is therapeutic. However, as I discuss in this Personal Perspective, a newer paradigm predicts that reducing tumor-driven immune suppression will be clinically beneficial. CD4+CD25+ Tregs are one mechanism of tumor-driven immune evasion that provide prototypical targets for testing novel anticancer treatment strategies within the newer paradigm. PMID:17476346

  20. Immunotherapy for Acute Myeloid Leukemia.

    PubMed

    Lichtenegger, Felix S; Krupka, Christina; Köhnke, Thomas; Subklewe, Marion

    2015-07-01

    Despite longstanding efforts in basic research and clinical studies, the prognosis for patients with acute myeloid leukemia (AML) remains poor. About half of the patients are not medically fit for intensive induction therapy to induce a complete remission and are treated with palliative treatment concepts. The patients medically fit for intensive induction therapy have a high complete remission rate but the majority suffers from relapse due to chemo-refractory leukemic cells. Allogeneic stem cell transplantation as post-remission therapy can significantly reduce the likelihood of relapse, but it is associated with a high rate of morbidity and mortality. Novel therapeutic concepts are therefore urgently sought after. During recent years, the focus has shifted towards the development of novel immunotherapeutic strategies. Some of the most promising are drug-conjugated monoclonal antibodies, T-cell engaging antibody constructs, adoptive transfer with chimeric antigen receptor (CAR) T cells, and dendritic cell vaccination. Here, we review recent progress in these four fields and speculate about the optimal time points during the course of AML treatment for their application. PMID:26111468

  1. ?? T Cells and Their Potential for Immunotherapy

    PubMed Central

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

    2014-01-01

    V?9V?2 (also termed V?2V?2) T cells, a major human peripheral blood ?? T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because ??T cells express both natural killer receptors such as NKG2D and ?? T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated ?? T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to ?? T cells. Utilizing these antimicrobial and anti-tumor properties of ?? T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of ?? T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of ?? T cell-based therapies so far performed. Based on the results of the reported trials, ?? T cells appear to be a promising tool for novel immunotherapies against certain types of diseases. PMID:24520210

  2. Immunotherapy for neurodegenerative diseases: focus on ?-synucleinopathies

    PubMed Central

    Valera, Elvira; Masliah, Eliezer

    2013-01-01

    Immunotherapy is currently being intensively explored as much-needed disease-modifying treatment for neurodegenerative diseases. While Alzheimer’s disease (AD) has been the focus of numerous immunotherapeutic studies, less attention has been paid to Parkinson’s disease (PD) and other neurodegenerative disorders. The reason for this difference is that the amyloid beta (A?) protein in AD is a secreted molecule that circulates in blood and is readably recognized by antibodies. In contrast, ?-synuclein (?-syn), tau, huntingtin and other proteins involved in neurodegenerative diseases have been considered to be exclusively of intracellular nature. However, the recent discovery that toxic oligomeric versions of ?-syn and tau accumulate in the membrane and can be excreted to the extracellular environment has provided a rationale for the development of immunotherapeutic approaches for PD, dementia with Lewy bodies, frontotemporal dementia, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins. Active immunization, passive immunization, and T cell-mediated cellular immunotherapeutic approaches have been developed targeting A?, ?-syn and tau. Most advanced studies, including results from phase III clinical trials for passive immunization in AD, have been recently reported. Results suggest that immunotherapy might be a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and propagation of toxic protein aggregates. In this manuscript we provide an overview on immunotherapeutic advances for neurodegenerative disorders, with special emphasis on ?-synucleinopathies. PMID:23384597

  3. Peptide immunotherapy in experimental autoimmune encephalomyelitis.

    PubMed

    Anderton, Stephen M

    2015-01-01

    We now have potent drugs available to treat the inflammatory component of multiple sclerosis (MS). However, not all patients respond, the drugs are not curative, and the associated risks to beneficial immune surveillance are considerable. A more desirable approach is to specifically target those comparatively rare T lymphocytes that are orchestrating the autoimmune attack. Using the autoantigen itself to instill immune tolerance in those cells remains a holy grail of immunotherapy. Peptide immunotherapy (PIT) is highly effective at silencing autoimmune responses in experimental autoimmune encephalomyelitis (EAE), and clinical trials of PIT are underway in MS. This review discusses the current paradigms for PIT-induced tolerance in naïve T cells. It highlights the need for better understanding of the mode of action of PIT upon memory and effector T cells that are responsible for driving/sustaining ongoing autoimmune pathology. Recent studies in EAEsuggest genetic and epigenetic changes in these pathogenic T-cell populations in response to PIT. Finally, future challenges to effective translation of PIT to the clinic are considered. PMID:26068029

  4. An update on immunotherapy for food allergy

    PubMed Central

    Scurlock, Amy M.; Jones, Stacie M.

    2013-01-01

    Purpose of the review Recent investigation has resulted in significant advances toward definitive therapeutic options for food allergy. In this review, we will explore novel immunotherapeutic interventions for the active treatment of food allergy. Recent findings Because the injection route for allergen immunotherapy to foods has been associated with an unacceptable risk of severe anaphylactic reactions, use of mucosally targeted therapeutic strategies is of significant interest for food allergy. Allergen-specific immunotherapeutic approaches such as oral, sublingual, epicutaneous, and peptide immunotherapy have demonstrated efficacy in increasing threshold dose and inducing immunologic changes associated with both desensitization and oral tolerance in animal and human trials. More global immunomodulatory strategies, such as Traditional Chinese Medicine and anti-IgE therapy have been shown to effectively target the allergic response, and clinical trials are ongoing to determine the efficacy and safety in human food allergy. Summary The advent of therapies that target the mucosal immune response to promote oral tolerance have shown great promise in the treatment of food hypersensitivity. However, there is still significant risk of adverse reactions associated with these therapeutic strategies and further study is needed to carefully advance these therapeutic modalities toward general clinical implementation. PMID:20856110

  5. A European perspective on immunotherapy for food allergies.

    PubMed

    Beyer, Kirsten

    2012-05-01

    Food allergies are common, and frequently, the only treatment option is strict avoidance. Unfortunately, many patients accidentally ingest allergenic foods, which can result in severe anaphylactic reactions. Several immunotherapies are being developed for food allergies; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. Oral immunotherapy seems to be the most promising approach based on results from small uncontrolled and controlled studies. However, it is a challenge to compare results among immunotherapy trials because of differences in protocols. Studies conducted thus far have tested the most prevalent food allergens: it is not clear whether their results can be extended to other allergens. Sublingual administration of immunotherapy has shown some efficacy and fewer side effects than oral administration in some trials, yet neither approach can be recommended for routine practice. Controlled studies with larger numbers of subjects are needed to determine short- and long-term efficacy and side effects. In Europe immunotherapy trials for food allergies face many ethical and regulatory issues. Guidelines from the European Medicine Agency on the clinical development of products for specific immunotherapy of allergic diseases do not adequately address immunotherapy for food allergies, especially for therapies that orally administer native food or that include pediatric patients. PMID:22541359

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

    SciTech Connect

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

    2009-04-17

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

  7. Toxoplasmic encephalitis during mycophenolate mofetil immunotherapy of neuromuscular disease

    PubMed Central

    Chahin, Nizar

    2015-01-01

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

  8. Brain Tumor Immunotherapy: What have We Learned so Far?

    PubMed Central

    Van Gool, Stefaan Willy

    2015-01-01

    High grade glioma is a rare brain cancer, incurable in spite of modern neurosurgery, radiotherapy, and chemotherapy. Novel approaches are in research, and immunotherapy emerges as a promising strategy. Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, we developed an immunotherapy schedule and we categorized patients into clinically defined risk profiles. We learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, we developed a mode of care within academic centers to organize cell-based therapies for experimental clinical trials in a large number of patients. PMID:26137448

  9. GD2-targeted immunotherapy and radioimmunotherapy.

    PubMed

    Dobrenkov, Konstantin; Cheung, Nai-Kong V

    2014-10-01

    Ganglioside GD2 is a tumor-associated surface antigen found in a broad spectrum of human cancers and stem cells. They include pediatric embryonal tumors (neuroblastoma, retinoblastoma, brain tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma), as well as adult cancers (small cell lung cancer, melanoma, soft tissue sarcomas). Because of its restricted normal tissue distribution, GD2 has been proven safe for antibody targeting. Anti-GD2 antibody is now incorporated into the standard of care for the treatment of high-risk metastatic neuroblastoma. Building on this experience, novel combinations of antibodies, cytokines, cells, and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In this review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions. PMID:25440605

  10. Aluminium in Allergies and Allergen immunotherapy.

    PubMed

    Jensen-Jarolim, Erika

    2015-01-01

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

  11. The delicate balance of melanoma immunotherapy

    PubMed Central

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

    2013-01-01

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

  12. Cancer immunotherapy: potential involvement of mediators

    PubMed Central

    Ben-Efraim, S.

    1997-01-01

    The description of a cell-free soluble anti-tumour factor by Carswell et al. in 1975 (Proc Natl Acad Sci USA, 72: 3666–3670) was followed by a long series of experimental and clinical investigations into the role of cell-free mediators in cancer immunotherapy. These investigations included research on the effects of macrophage–derived eicosanoids (cycloxygenase and lipoxygenase derivates of arachidonic acid) and of monokines such as tumour necrosis factor-?, interleukin-1 and granulocyte–monocyte–macrophage–colony stimulating factor) and of lymphocyte products: interleukins and interferons. The investigations yielded information on the effects of various factors on macrophage and T-cell activation in vitro, determination of direct anti-tumour properties on animal and human tumour cells in vitro and on therapeutic effectiveness in tumour-bearing individuals either alone or in combination with other therapeutic factors and their production by tumour cells. During recent years much effort has been dedicated towards the use of the tumour cells transfected with cytokine genes in the preparation of cancer vaccines. Cycloxygenase products (prostaglandins) were usually assumed to inhibit expression of anti-tumour activity by macrophages and an increase in their production in cancer patients was considered as a poor prognostic index. Lipoxygenase (leukotrienes) products were assumed to exhibit antitumour activity and to induce production of IL-1 by macrophages. Interleukins 2, 4, 6, 7, 12 and the interferons were extensively tested for their therapeutic effectiveness in experimental tumour models and in cancer clinical trials. The general conclusion on the use of cell-free mediators for cancer immunotherapy is that much still has to be done in order to assure effective and reproducible therapeutic effectiveness for routine use in the treatment of human neoplasia. PMID:18472817

  13. Immunotherapy Approaches for Malignant Glioma From 2007 to 2009

    Microsoft Academic Search

    Laura A. Johnson; John H. Sampson

    2010-01-01

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

  14. Mechanism of synergistic effect of chemotherapy and immunotherapy of cancer

    Microsoft Academic Search

    Rupal Ramakrishnan; Dmitry I. Gabrilovich

    2011-01-01

    In recent years, the combination of cancer immunotherapy with standard therapeutic modality is gaining credibility due to\\u000a a number of clinical trials demonstrating therapeutic success of such combination therapies. However, the mechanism of this\\u000a phenomenon is poorly understood. Here, we will discuss recent findings that suggest novel mechanisms of synergistic effect\\u000a of cancer immunotherapy and chemotherapy.

  15. Do ?-blockers really enhance the risk of anaphylaxis during immunotherapy?

    Microsoft Academic Search

    David M. Lang

    2008-01-01

    Both ?-blockers and allergen immunotherapy are frequently prescribed, and allergy\\/immunology physicians commonly encounter\\u000a patients who are candidates for immunotherapy and are receiving ?-blockers. The evidence in the medical literature indicates\\u000a that although anaphylaxis does not appear to be more frequent, ?-blocker exposure is associated with greater risk for severe\\u000a anaphylaxis, and for anaphylaxis refractory to treatment. Use of ?-blocker suspension

  16. Immunotherapy of Childhood Cancer: From Biologic Understanding to Clinical Application

    PubMed Central

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

    2010-01-01

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

  17. An update on anti-TNF agents in ulcerative colitis.

    PubMed

    Samaan, Mark A; Bagi, Preet; Vande Casteele, Niels; D'Haens, Geert R; Levesque, Barrett G

    2014-09-01

    Anti-tumor necrosis factor-? agents are key therapeutic options for the treatment of ulcerative colitis. Their efficacy and safety have been shown in large randomized controlled trials. The key evidence gained from these trials of infliximab, adalimumab, and golimumab is reviewed along with their effect on mucosal healing and long-term outcomes. Also reviewed are methods for optimizing their effectiveness, including therapeutic drug monitoring and treat-to-target strategies. Finally, remaining unresolved questions regarding their role and effectiveness are considered including how these may be addressed in future clinical trials. PMID:25110254

  18. The relationship between allergen immunotherapy and omalizumab for treating asthma.

    PubMed

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

    2015-04-01

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

  19. Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy.

    PubMed

    Ahmed, Mahiuddin; Cheung, Nai-Kong V

    2014-01-21

    Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and sarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma in children and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas in adults. Since GD2 expression in normal tissues is restricted to the brain, which is inaccessible to circulating antibodies, and in selected peripheral nerves and melanocytes, it was deemed a suitable target for systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested in clinical trials for neuroblastoma for over the past two decades, with proven safety and efficacy. The main limitations have been acute pain toxicity associated with GD2 expression on peripheral nerve fibers and the inability of antibodies to treat bulky tumor. Several strategies have been developed to reduce pain toxicity, including bypassing complement activation, using blocking antibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on peripheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal antibodies and fragments have been engineered into immunocytokines, immunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted nanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen receptors. The challenges of these approaches will be reviewed to build a perspective for next generation anti-GD2 therapeutics in cancer therapy. PMID:24295643

  20. Stereotactic ablative body radiotherapy combined with immunotherapy: present status and future perspectives.

    PubMed

    Rekers, N H; Troost, E G C; Zegers, C M L; Germeraad, W T V; Dubois, L J; Lambin, P

    2014-10-01

    Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy. PMID:25179250

  1. Allergen-specific immunotherapy for allergic rhinitis in the elderly: is it never too late?

    PubMed

    Milani, Massimo

    2013-07-01

    Evaluation of: Bozek A, Ignasiak B, Filipowska B, Jarzab J. House dust mite sublingual immunotherapy: a double-blind, placebo-controlled study in elderly patients with allergic rhinitis. Clin. Exp. Allergy 43(2), 242-248 (2013). There is a well-accepted tenet in allergen-specific immunotherapy (SIT), especially for respiratory allergies such as rhinitis and asthma: this approach should be, in general, reserved for the pediatric population and young adults. This belief is based on the fact that SIT is considered the only therapy able to modify the course of allergic diseases. In the case of allergic rhinitis, for example, SIT could reduce the risk of asthma developing. Therefore, SIT is evaluated with 'the sooner the better' conviction. In elderly people with respiratory allergies, the 'course' of the disease is considered too advanced and therefore the room and therapeutic value of SIT is considered very limited. Bozek et al. evaluated the clinical efficacy of sublingual SIT (SLIT) with house dust mite (HDM) extracts in elderly (age >60 years) patients with a long history of allergic rhinitis due to HDM allergen exposure. In a 3-year double-blind placebo-controlled study, SLIT was able to significantly reduce the nose-related symptoms and the medication score. The conclusions of the authors were that SLIT with HDM allergens resulted in a significant clinical improvement in the active group compared with the placebo group, particularly during the period of the year in which the heating would be on. This therapy was well tolerated. These observations may lead to the more frequent use of SLIT immunotherapy in the elderly. PMID:23829621

  2. Heat shock protein bystander antigens for peptide immunotherapy in autoimmune disease.

    PubMed

    Zonneveld-Huijssoon, E; Albani, S; Prakken, B J; van Wijk, F

    2013-01-01

    Mucosal administration of an antigen eliciting bystander suppression at the site of inflammation results in effective antigen-specific immunotherapy for autoimmune diseases. Heat shock proteins are bystander antigens that are effective in peptide-specific immunotherapy in both experimental and human autoimmune disease. The efficacy of preventive peptide immunotherapy is increased by enhancing peptide-specific immune responses with proinflammatory agents. Combining peptide-specific immunotherapy with general suppression of inflammation may improve its therapeutic effect. PMID:23199319

  3. Heat shock protein bystander antigens for peptide immunotherapy in autoimmune disease

    PubMed Central

    Zonneveld-Huijssoon, E; Albani, S; Prakken, B J; van Wijk, F

    2013-01-01

    Mucosal administration of an antigen eliciting bystander suppression at the site of inflammation results in effective antigen-specific immunotherapy for autoimmune diseases. Heat shock proteins are bystander antigens that are effective in peptide-specific immunotherapy in both experimental and human autoimmune disease. The efficacy of preventive peptide immunotherapy is increased by enhancing peptide-specific immune responses with proinflammatory agents. Combining peptide-specific immunotherapy with general suppression of inflammation may improve its therapeutic effect. PMID:23199319

  4. Recent developments on immunotherapy for brain cancer

    PubMed Central

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

    2012-01-01

    Introduction Brain tumors are a unique class of cancers since they are anatomically shielded from normal immunosurveillance by the blood brain barrier, lack a normal lymphatic drainage system and reside in a potently immunosuppressive environment. Of the primary brain cancers, glioblastoma multiforme (GBM) is the most common and aggressive in adults. Although treatment options include surgery, radiation and chemotherapy, the average lifespan of GBM patients remains at only 14.6 months post-diagnosis. Areas covered A review of key cellular and molecular immune system mediators in the context of brain tumors including TGF-?, cytotoxic T cells, Tregs, CTLA-4, PD-1, and IDO, is discussed. In addition, prognostic factors, currently utilized immunotherapeutic strategies, on-going clinical trials, and a discussion of new or potential immunotherapies for brain tumor patients are considered. Expert opinion Current drugs that improve the quality of life and overall survival in patients with brain tumors, especially for GBM, are poorly effective. This disease requires a re-analysis of currently accepted treatment strategies, as well as newly designed approaches. Here, we review the fundamental aspects of immunosuppression in brain tumors, new and promising immunotherapeutic drugs, as well as combinatorial strategies that focus on the simultaneous inhibition of immunosuppressive hubs, both in immune- and brain tumor-cells, which is critical to consider for achieving future success for the treatment of this devastating disease. PMID:22533851

  5. [Immunotherapies for multiple sclerosis : review and update].

    PubMed

    Havla, J; Kümpfel, T; Hohlfeld, R

    2015-04-01

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

  6. Mechanisms of allergen-specific immunotherapy

    PubMed Central

    2012-01-01

    Allergen-specific immunotherapy (allergen-SIT) is a potentially curative treatment approach in allergic diseases. It has been used for almost 100 years as a desensitizing therapy. The induction of peripheral T cell tolerance and promotion of the formation of regulatory T-cells are key mechanisms in allergen-SIT. Both FOXP3+CD4+CD25+ regulatory T (Treg) cells and inducible IL-10- and TGF-?-producing type 1 Treg (Tr1) cells may prevent the development of allergic diseases and play a role in successful allergen-SIT and healthy immune response via several mechanisms. The mechanisms of suppression of different pro-inflammatory cells, such as eosinophils, mast cells and basophils and the development of allergen tolerance also directly or indirectly involves Treg cells. Furthermore, the formation of non-inflammatory antibodies particularly IgG4 is induced by IL-10. Knowledge of these molecular basis is crucial in the understanding the regulation of immune responses and their possible therapeutic targets in allergic diseases. PMID:22409879

  7. Sarcoma Immunotherapy: Past Approaches and Future Directions

    PubMed Central

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

    2014-01-01

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

  8. Combining radiotherapy and immunotherapy: A revived partnership

    SciTech Connect

    Demaria, Sandra [Department of Pathology, New York University School of Medicine, New York, NY (United States); Bhardwaj, Nina [Department of Medicine, New York University School of Medicine, New York, NY (United States); McBride, William H. [Department of Radiation Oncology, Experimental Division, University of California at Los Angeles School of Medicine, Los Angeles, CA (United States); Formenti, Silvia C. [Department of Radiation Oncology NYU Cancer Institute, New York University School of Medicine, New York, NY (United States)]. E-mail: silvia.formenti@med.nyu.edu

    2005-11-01

    Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. The current rationale for its use is based largely on the ability of RT to kill the cancer cells by a direct cytotoxic effect. Nevertheless, considerable evidence indicates that RT effects extend beyond the mere elimination of the more radiosensitive fraction of cancer cells present within a tumor at the time of radiation exposure. For instance, a large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This might have far-reaching consequences regarding the response of a patient to treatment, especially if radiation-induced tumor cell kill were to translate into the generation of effective antitumor immunity. Although much remains to be learned about how radiation can impact tumor immunogenicity, data from preclinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance antitumor effects. Conversely, RT could be a useful tool to combine with immunotherapy. This article will briefly summarize what is known about the impact of RT on tumor immunity, including tumor-associated antigens, antigen-presenting cells, and effector mechanisms. In addition, the experimental evidence supporting the contention that RT can be used as a tool to induce antitumor immunity is discussed, and a new approach to radioimmunotherapy of cancer is proposed.

  9. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    PubMed Central

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

    2013-01-01

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

  10. Open questions for Alzheimer’s disease immunotherapy

    PubMed Central

    2014-01-01

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

  11. 162?Establishing the Effectiveness, Cost-Effectiveness and Safety of Oral and Sublingual Immunotherapy for Food Allergy: A Systematic Review and Meta-Analysis of Intervention Studies

    PubMed Central

    Nurmatov, Ulugbek; Devereux, Graham; Sheikh, Azizx

    2012-01-01

    Background Oral and sublingual immunotherapy to food allergens aim to enable the safe consumption of the foods containing these allergens. Methods Systematic review of intervention studies, searching 11 international databases and contacting an international panel of experts. Studies were critically appraised using the Cochrane approach and meta-analysed. Results We identified 721 potentially relevant papers, from which we selected 16 reports of 14 eligible trials (12 randomised controlled trials and 2 controlled clinical trials). Eleven of these trials evaluated oral immunotherapy and the remaining 3 investigated sublingual immunotherapy. Meta-analysis revealed that immunotherapy substantially reduced the average risk of persisting food allergy in patients (RR = 0.24; 95% CI, 0.11-0.50). Pooling of the safety data however revealed an increased average risk of systemic adverse reactions in those receiving immunotherapy (RR = 1.13; 95% CI, 1.00-1.27); the average risk of local (minor oropharyngeal/gastro-intestinal) adverse reactions was also increased in those receiving immunotherapy (RR = 1.16; 95% CI, 1.04, 1.30). Meta-analysis of immunological data demonstrated that allergen skin prick test wheal diameter significantly decreased in experimental groups compared to controls (mean difference –2.96 mm; 95% CI, –4.48, –1.45), whilst specific-IgG4 increased by an average of 19.9 ?g/mL (95% CI, 17.1, 22.6); however there was no change in specific IgE: –5.2 kU/L (95% CI, –12.39, 1.99). Conclusions Oral/sublingual immunotherapy substantially reduces the risk of food allergy, this effect being mediated by immunological mechanisms. However, because of the stringent exclusion criteria used in many of the reviewed studies and the increased risk of systemic adverse events, immunotherapy cannot yet be recommended for routine clinical practice. Future research needs to focus on larger randomised controlled trials investigating long-term clinical tolerance induction, impact on quality of life and estimating the cost-effectiveness of treatment. Overall, this appears to be a promising line of potentially disease-modifying treatment for people with a range of IgE-mediated food allergies.

  12. New modalities of cancer treatment for NSCLC: focus on immunotherapy

    PubMed Central

    Davies, Marianne

    2014-01-01

    Recent advances in the understanding of immunology and antitumor immune responses have led to the development of new immunotherapies, including vaccination approaches and monoclonal antibodies that inhibit immune checkpoint pathways. These strategies have shown activity in melanoma and are now being tested in lung cancer. The antibody drugs targeting cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death protein-1 immune checkpoint pathways work by restoring immune responses against cancer cells, and are associated with unconventional response patterns and immune-related adverse events as a result of their mechanism of action. As these new agents enter the clinic, nurses and other health care providers will require an understanding of the unique efficacy and safety profiles with immunotherapy to optimize potential patient benefits. This paper provides a review of the new immunotherapeutic agents in development for lung cancer, and strategies for managing patients on immunotherapy. PMID:24520205

  13. Therapeutic Effects and Biomarkers in Sublingual Immunotherapy: A Review

    PubMed Central

    Fujimura, Takashi; Okamoto, Yoshitaka; Taniguchi, Masaru

    2012-01-01

    Immunotherapy is considered to be the only curative treatment for allergic diseases such as pollinosis, perennial rhinitis, asthma, and food allergy. The sublingual route is widely applied for immunotherapy for allergy, instead of the conventional administration by subcutaneous route. A recent meta-analysis of sublingual immunotherapy (SLIT) has shown that this approach is safe, has positive clinical effects, and provides prolonged therapeutic effects after discontinuation of treatment. However, the mechanism of SLIT and associated biomarkers are not fully understood. Biomarkers that change after or during SLIT have been reported and may be useful for response monitoring or as prognostic indicators for SLIT. In this review, we focus on the safety, therapeutic effects, including prolonged effects after treatment, and new methods of SLIT. We also discuss response monitoring and prognostic biomarkers for SLIT. Finally, we discuss immunological mechanisms of SLIT with a focus on oral dendritic cells and facilitated antigen presentation. PMID:22500184

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

    PubMed

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

    2014-01-01

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

  15. [Significance of immunotherapy in treatment of bronchial asthma].

    PubMed

    Ha?asa, Józef; Ha?asa, Maciej

    2002-02-01

    When first used, immunotherapy was applied to treatment of infectious diseases. Its high effectiveness gave an impulse to introduce this method in the treatment of allergic diseases, including bronchial asthma. In contrast to pharmacological treatment which treats only the symptoms in allergies, immunotherapy is presently considered to be the only causative treatment. Several conditions have to be fulfilled to obtain the effect of such treatment. Appropriate patients selection, use of the etiologically correct vaccine and continuing the treatment throughout several seasons are the conditions for the therapeutic success. In nonatopic intrinsic asthma or in atopic asthma complicated by bacterial infections the use of autologic or polyvalent (standard) bacterial vaccine should be considered. Because immunotherapy brings a risk of serious side effects such as anaphylactic reaction, only allergy specialist should be entitled to decide of the introduction of such treatment and to supervise its course. PMID:11995252

  16. Targeted alpha particle immunotherapy for myeloid leukemia.

    PubMed

    Jurcic, Joseph G; Larson, Steven M; Sgouros, George; McDevitt, Michael R; Finn, Ronald D; Divgi, Chaitanya R; Ballangrud, Ase M; Hamacher, Klaus A; Ma, Dangshe; Humm, John L; Brechbiel, Martin W; Molinet, Roger; Scheinberg, David A

    2002-08-15

    Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans. PMID:12149203

  17. Adoptive immunotherapy of cancer utilizing genetically engineered lymphocytes.

    PubMed

    Ikeda, Hiroaki; Shiku, Hiroshi

    2015-07-01

    It is becoming increasingly clear that adoptive immunotherapy with genetically engineered T cells has the potential to control and even cure cancer in some patients. On the other hand, severe adverse events associated with efficacy have frequently been reported in clinical trials. Current and near-future challenges for the development of adoptive immunotherapy of cancer using genetically engineered T cells include minimization and prediction of adverse events; identification of new and effective targets, including patient-specific mutations; improvement in T cell functionality, persistence, and memory formation capacity; and utilization of allogeneic or cell line-based T cells. PMID:26041411

  18. Immunogenic Targets for Specific Immunotherapy in Multiple Myeloma

    PubMed Central

    Zhang, Lu; Götz, Marlies; Hofmann, Susanne; Greiner, Jochen

    2012-01-01

    Multiple myeloma remains an incurable disease although the prognosis has been improved by novel therapeutics and agents recently. Relapse occurs in the majority of patients and becomes fatal finally. Immunotherapy might be a powerful intervention to maintain a long-lasting control of minimal residual disease or to even eradicate disseminated tumor cells. Several tumor-associated antigens have been identified in patients with multiple myeloma. These antigens are expressed in a tumor-specific or tumor-restricted pattern, are able to elicit immune response, and thus could serve as targets for immunotherapy. This review discusses immunogenic antigens with therapeutic potential for multiple myeloma. PMID:22611422

  19. Beyond the Immune Suppression: The Immunotherapy in Prostate Cancer

    PubMed Central

    Silvestri, Ida; Cattarino, Susanna; Aglianò, Anna Maria; Collalti, Giulia; Sciarra, Alessandro

    2015-01-01

    Prostate cancer (PCa) is the second most common cancer in men. As well in many other human cancers, inflammation and immune suppression have an important role in their development. We briefly describe the host components that interact with the tumor to generate an immune suppressive environment involved in PCa promotion and progression. Different tools provide to overcome the mechanisms of immunosuppression including vaccines and immune checkpoint blockades. With regard to this, we report results of most recent clinical trials investigating immunotherapy in metastatic PCa (Sipuleucel-T, ipilimumab, tasquinimod, Prostvac-VF, and GVAX) and provide possible future perspectives combining the immunotherapy to the traditional therapies.

  20. Review Article Oncolytic Immunotherapy: Where Are We Clinically?

    E-print Network

    Hemminki, Akseli

    the most popular cancer gene therapy approach. Viruses featuring selective replication in tumor cells, also-resistance to the currently available approaches are needed. Due to hypothetical safety concerns, cancer gene therapyReview Article Oncolytic Immunotherapy: Where Are We Clinically? Akseli Hemminki1,2 1 Cancer Gene

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

    PubMed

    Rosewich, Martin; Lee, Denise; Zielen, Stefan

    2013-07-01

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

  2. Defining and managing expectations for early immunotherapy cancer trials.

    PubMed

    Kieber-Emmons, Thomas; Pennisi, Angela; Lane, Anna; Siegel, Eric; Cannon, Martin; Monzavi-Karbassi, Behjatolah; Makhoul, Issam

    2015-01-01

    This review discusses the concept of expectations in assessing direct benefit to participants in phase I immunotherapy studies. With the push toward a faster assessment of clinical benefit or efficacy, limiting phase I studies to safety determination only is now viewed as obsolete and has been replaced by designs that draw attention to therapeutic benefit or efficacy. While this approach is touted as being more flexible in trial conduct, these designs are particularly problematic for immunotherapy studies. Defining and managing expectations is paramount on understanding the key axioms that emerge that include i) understanding bias in models and mechanistic results, ii) that no test is perfect, iii) it is difficult to select a good predictive biomarker in the absence of clinical data, even for targeted therapies, iv) markers predictive for monotherapy may not be predictive for combination therapy, and v) all about improved patient selection. Considering the heterogeneity of cancers and the immune response of the host, we think that immunotherapy should be developed in parallel with the identification of different clinico-pathological models of immune response to cancer. This approach would accomplish two important goals: 1) provide a biological understanding of the complete in vivo environment, thereby giving investigators the opportunity to optimize and maximize the effect of a specific immunotherapy agent and 2) addressing host environment issues simultaneously so that safety data and perceived benefit can be achieved more quickly. PMID:25723736

  3. Sublingual rush immunotherapy with latex extract in children

    Microsoft Academic Search

    Susana Lopes da Silva; Célia Costa; Natália G. Ferreira; Maria Conceição Santos; J. Costa Trindade

    2005-01-01

    Latex allergy prevalence has increased notably in the last two decades. Latex ubiquity and its cross-reactivity with fruits make complete avoidance difficult to attain and studies have questioned long-term avoidance efficacy. Subcutaneous and sublingual routes of specific immunotherapy (SIT) to latex have been tested in double blind placebo controlled studies, with significant improvement in patients' tolerance to latex. We present

  4. From Bench to Bedside: Immunotherapy for Prostate Cancer

    PubMed Central

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

    2014-01-01

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

  5. T regulatory cells, the evolution of targeted immunotherapy.

    PubMed

    Nizar, S; Meyer, B; Galustian, C; Kumar, D; Dalgleish, A

    2010-08-01

    T regulatory cells are able to suppress anti-tumour immunity in pre-clinical models and in patients. This review highlights the important discoveries in Treg immunology critical to the evolution of targeted immunotherapy. We also describe the therapeutic applications that are currently being assessed and their future potential. PMID:20188145

  6. Tumor stroma-associated antigens for anti-cancer immunotherapy

    Microsoft Academic Search

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

    2006-01-01

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

  7. Prostate cancer as a model for tumour immunotherapy

    Microsoft Academic Search

    Charles G. Drake

    2010-01-01

    Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning

  8. Immunotherapy: Using the Immune System to Treat Cancer

    Cancer.gov

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

  9. Evaluation of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy.

    PubMed

    Harmanci, Koray; Razi, Cem H; Toyran, Muge; Kanmaz, Gozde; Cengizlier, Mehmet R

    2010-03-01

    Specific immunotherapy (SIT) is one of the treatment modalities recomended for the management of asthma and allergic rhinitis by international guidelines. A potential benefit of immunotherapy (IT) is to prevent the development of sensitisation to new allergens. There is stil no conclusion on this subject. One hundred twenty-two children 8-18 years old with intermittent asthma, with or without allergic rhinitis, all of whom were monosensitised to house dust mite (HDM) were selected. Sixty two of these children accepted to receive SIT with HDM extract for 4 years and the remaining 60 did not accept SIT and were treated with asthma medications only. This second group of children served as the control group. At the end of the 4-year study period, 36 of the 53 patients (67.9%) in the SIT group showed no new sensitizations, compared to 38 of 52 (73.0%) in the control group (p = 0.141). The most frequent new sensitizations at the end of the study were pollens, grasses and olive polen, followed by animal dander, alternaria and cockroach. In conclusion, SIT may not prevent the onset of new sensitizations in asthmatic children monosensitized to house dust mites. Further investigation is required to clarify the immunologic mechanisms and other factors by which SIT reduces or not the development of new sensitizations in monosensitized children. PMID:20527510

  10. [A case of eosinophilic esophagogastroenteritis which developed after rush oral immunotherapy for egg allergy].

    PubMed

    Okamoto, Yoshihisa; Kurihara, Kazuyuki

    2015-02-01

    Rush oral immunotherapy was provided to a 9 year old boy suffering from egg allergy. The patient reached the goal of one boiled egg daily on day 22 of treatment. He was discharged from the hospital the following day, with the maintenance dose of one whole egg to be taken daily. However, the patient began to experience abdominal pain and vomiting after ingestion of egg approximately one day after discharge. Blood tests revealed a remarkable increase in eosinophils in peripheral blood, and we reduced the patient's intake of egg. The patient's condition did not improve, and he gradually started to lose weight. Maintenance dosing was stopped completely on day 38. An endoscopic biopsy of the mucosa lining from the esophagus to the duodenum was performed on day 45. The results confirmed prominent diffuse eosinophilic infiltration of the entire upper gastrointestinal tract. The patient was finally diagnosed with eosinophil esophagogastroenteritis. While this condition is rare, it should be considered in future cases of persistent gastrointestinal symptoms during food allergy immunotherapy. PMID:25779063

  11. Effects of local nasal immunotherapy in allergic airway inflammation: Using urea denatured Dermatophagoides pteronyssinus.

    PubMed

    Yu, Sheng-Jie; Liao, En-Chih; Tsai, Jaw-Ji

    2015-04-01

    Despite improvements in anti-allergy medication, the prevalence of allergic airway inflammation remains high, affecting up to 40% of the population worldwide. Allergen immunotherapy is effective for inducing tolerance but has the adverse effect of severe allergic reaction. This can be avoided by denaturing with urea. In this study, we demonstrated that the serum level of allergen-specific IgE in mice sensitized with native Dermatophagoides pteronyssinus (Der p) crude extract after receiving local nasal immunotherapy (LNIT) with urea-denatured Der p crude extract (DN-Dp) significantly decreased compared to that in the normal saline (NS) treatment group. Expressions of IL-4 were significantly reduced in lung tissues after treatment. Inflammation around the bronchial epithelium improved and airway hypersensitivity was down-regulated. LNIT with DN-Dp can down-regulate IL-1b, IL-6 and TNF-a expression and then decrease Der p-induced allergic airway inflammation. This therapeutic modality may be used as an alternative treatment for airway allergic diseases. PMID:25933184

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

    PubMed

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

    1996-05-01

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

  13. Generation of hypoallergenic neoglycoconjugates for dendritic cell targeted vaccination: a novel tool for specific immunotherapy.

    PubMed

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

    2013-01-28

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

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

    PubMed Central

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

    2012-01-01

    The apolipoprotein E (APOE) ?4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid ? (A?) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with A? and facilitates A? fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-A? antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1?E9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble A?40 and A?42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around A? plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in A? binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases. PMID:23129750

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

    E-print Network

    Milchberg, Howard

    INFORMED CONSENT FOR ALLERGY IMMUNOTHERAPY Allergy immunotherapy shots contain water extract of pollen mold or dust to which a patient has been shown to be allergic by skin testing Venom allergy shots checked by our allergy nurse Anyone leaving prior to this time does so against medical advice and repeat

  16. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis

    Microsoft Academic Search

    Antonella Tosti; Maria Silvia Guidetti; Frederico Bardazzi; Cosimo Misciali

    1996-01-01

    Background: Topical immunotherapy has been used in the treatment of children with alopecia areata with encouraging results.Objective: Our purpose was to determine the long-term results in 33 children with severe alopecia areata treated with topical immunotherapy.Methods: From 1983 to 1989 we treated 33 children with topical immunotherapy with squaric acid dibutylester.Results: Complete hair regrowth was observed in 10 children (30.3%).

  17. Perspectives on future Alzheimer therapies: amyloid-? protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer’s disease

    PubMed Central

    2014-01-01

    The symptomatic drugs currently on the market for Alzheimer’s disease (AD) have no effect on disease progression, and this creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy: vaccines and, especially, passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be made highly specific for their target and often with few side effects. Data from recent clinical AD trials indicate that a treatment effect by immunotherapy is possible, providing hope for a new generation of drugs. The first anti-amyloid-beta (anti-A?) vaccine developed by Elan, AN1792, was halted in phase 2 because of aseptic meningoencephalitis. However, in a follow-up study, patients with antibody response to the vaccine demonstrated reduced cognitive decline, supporting the hypothesis that A? immunotherapy may have clinically relevant effects. Bapineuzumab (Elan/Pfizer Inc./Johnson & Johnson), a monoclonal antibody targeting fibrillar A?, was stopped because the desired clinical effect was not seen. Solanezumab (Eli Lilly and Company) was developed to target soluble, monomeric A?. In two phase 3 studies, Solanezumab did not meet primary endpoints. When data from the two studies were pooled, a positive pattern emerged, revealing a significant slowing of cognitive decline in the subgroup of mild AD. The Arctic mutation has been shown to specifically increase the formation of soluble A? protofibrils, an A? species shown to be toxic to neurons and likely to be present in all cases of AD. A monoclonal antibody, mAb158, was developed to target A? protofibrils with high selectivity. It has at least a 1,000-fold higher selectivity for protofibrils as compared with monomers of A?, thus targeting the toxic species of the peptide. A humanized version of mAb158, BAN2401, has now entered a clinical phase 2b trial in a collaboration between BioArctic Neuroscience and Eisai without the safety concerns seen in previous phase 1 and 2a trials. Experiences from the field indicate the importance of initiating treatment early in the course of the disease and of enriching the trial population by improving the diagnostic accuracy. BAN2401 is a promising candidate for A? immunotherapy in early AD. Other encouraging efforts in immunotherapy as well as in the small-molecule field offer hope for new innovative therapies for AD in the future. PMID:25031633

  18. Perspectives on future Alzheimer therapies: amyloid-? protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease.

    PubMed

    Lannfelt, Lars; Möller, Christer; Basun, Hans; Osswald, Gunilla; Sehlin, Dag; Satlin, Andrew; Logovinsky, Veronika; Gellerfors, Pär

    2014-01-01

    The symptomatic drugs currently on the market for Alzheimer's disease (AD) have no effect on disease progression, and this creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy: vaccines and, especially, passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be made highly specific for their target and often with few side effects. Data from recent clinical AD trials indicate that a treatment effect by immunotherapy is possible, providing hope for a new generation of drugs. The first anti-amyloid-beta (anti-A?) vaccine developed by Elan, AN1792, was halted in phase 2 because of aseptic meningoencephalitis. However, in a follow-up study, patients with antibody response to the vaccine demonstrated reduced cognitive decline, supporting the hypothesis that A? immunotherapy may have clinically relevant effects. Bapineuzumab (Elan/Pfizer Inc./Johnson & Johnson), a monoclonal antibody targeting fibrillar A?, was stopped because the desired clinical effect was not seen. Solanezumab (Eli Lilly and Company) was developed to target soluble, monomeric A?. In two phase 3 studies, Solanezumab did not meet primary endpoints. When data from the two studies were pooled, a positive pattern emerged, revealing a significant slowing of cognitive decline in the subgroup of mild AD. The Arctic mutation has been shown to specifically increase the formation of soluble A? protofibrils, an A? species shown to be toxic to neurons and likely to be present in all cases of AD. A monoclonal antibody, mAb158, was developed to target A? protofibrils with high selectivity. It has at least a 1,000-fold higher selectivity for protofibrils as compared with monomers of A?, thus targeting the toxic species of the peptide. A humanized version of mAb158, BAN2401, has now entered a clinical phase 2b trial in a collaboration between BioArctic Neuroscience and Eisai without the safety concerns seen in previous phase 1 and 2a trials. Experiences from the field indicate the importance of initiating treatment early in the course of the disease and of enriching the trial population by improving the diagnostic accuracy. BAN2401 is a promising candidate for A? immunotherapy in early AD. Other encouraging efforts in immunotherapy as well as in the small-molecule field offer hope for new innovative therapies for AD in the future. PMID:25031633

  19. Modulation of immune responses by immunotherapy in allergic diseases.

    PubMed

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

    2014-08-01

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

  20. Molecular imaging of cell-based cancer immunotherapy

    PubMed Central

    Liu, Gang; Swierczewska, Magdalena; Zhang, Xiaoming

    2011-01-01

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

  1. Preamble to the 2015 SITC immunotherapy biomarkers taskforce.

    PubMed

    Butterfield, Lisa H; Disis, Mary L; Fox, Bernard A; Khleif, Samir N; Marincola, Francesco M

    2015-01-01

    The Society for Immunotherapy of Cancer (SITC) has regularly hosted workshops and working groups focused on immunologic monitoring and immune biomarkers. Due to advances in cancer immunotherapy, including positive results from clinical trials testing new agents and combinations, emerging new technologies for measuring aspects of immunity, and novel candidate biomarkers from early phase trials, the SITC Immune Biomarkers Taskforce has reconvened to review the state of the art, identify current hurdles to further success and to make recommendations to the field. Topics being addressed by individual working groups include: (1) validation of candidate biomarkers, (2) identification of the most promising technologies, (3) testing of high throughput immune signatures and (4) investigation of the pre-treatment tumor microenvironment. Resultant recommendations will be published in JITC. PMID:25806107

  2. Combinations of Immunotherapy and Radiation in Cancer Therapy

    PubMed Central

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

    2014-01-01

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

  3. Cancer-associated fibroblasts as targets for immunotherapy

    PubMed Central

    Kakarla, Sunitha; Song, Xiao-Tong; Gottschalk, Stephen

    2013-01-01

    Immunotherapy for solid tumors has shown promise in preclinical as well as early clinical studies. However, its efficacy remains limited. The hindrance to achieving objective, long-lasting therapeutic responses in solid tumors is, in part, mediated by the dynamic nature of the tumor and its complex microenvironment. Tumor-directed therapies fail to eliminate components of the microenvironment, which can reinstate a tumorigenic milieu and contribute to recurrence. Cancer-associated fibroblasts (CAFs) form the most preponderant cell type in the solid tumor microenvironment. Given their pervasive role in facilitating tumor growth and metastatic dissemination, CAFs have emerged as attractive therapeutic targets in the tumor microenvironment. In this article, we highlight the cross-talk between CAFs and cancer cells, and discuss how targeting CAFs has the potential to improve current immunotherapy approaches for cancer. PMID:23194363

  4. Immunotherapy for Non-Small Cell Lung Cancer

    PubMed Central

    2014-01-01

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

  5. Mechanistic Basis of Immunotherapies for Type 1 Diabetes Mellitus

    PubMed Central

    CHEN, WENHAO; XIE, AINI; CHAN, LAWRENCE

    2013-01-01

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

  6. Immunotherapy in prostate cancer: review of the current evidence.

    PubMed

    Fernández-García, E M; Vera-Badillo, F E; Perez-Valderrama, B; Matos-Pita, A S; Duran, I

    2015-05-01

    Prostate cancer is the most common male malignancy in the Western world. Once it metastasizes, it is incurable. The current gold standard for metastatic disease is the combined docetaxel/prednisone regimen. Prostate cancer shows several characteristics that make it a suitable candidate for immunotherapy, as recently exemplified by the approval of sipuleucel-T, the first vaccine to treat any malignancy. Here, we review different tumor-associated antigen immunotherapy strategies currently being investigated, from a humanized radiolabeled monoclonal antibody (J-591) that targets radiation into tumor cells, moving on to vaccines and through to immunomodulator agents such as anti-CPLA-4 and anti-PD-1 monoclonal antibodies that activate T-cell responses via immune checkpoint inhibition. We explore different opinions on the best approach to integrate immunotherapy into existing standard therapies, such as androgen-deprivation therapy, radiotherapy or chemotherapy, and review different combination sequences, patient types and time points during the course of the disease to achieve a lasting immune response. We present data from recent phase III clinical trials that call for a change in trial endpoint design with immunotherapy agents, from the traditional tumor progression to overall survival and how such trials should include immune response measurements as secondary or intermediate endpoints to help identify patient clinical benefit in the earlier phases of treatment. Finally, we join in the recent questioning on the validity of RECIST criteria to measure response to immunotherapeutic agents, as initial increases in the size of tumors/lymph nodes, which are part of a normal immune response, could be categorized as disease progression under RECIST. PMID:25480118

  7. The future of antigen-specific immunotherapy of allergy

    Microsoft Academic Search

    Rudolf Valenta

    2002-01-01

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

  8. Ant venom immunotherapy in Australia: the unmet need.

    PubMed

    Mullins, Raymond J; Brown, Simon G A

    2014-07-01

    Jack jumper ant (JJA) venom allergy is an important cause of anaphylaxis in south-eastern Australia. The efficacy and real-world effectiveness of JJA venom immunotherapy (VIT) to prevent anaphylaxis in allergic patients are now well established, with an evidence base that is at least equivalent to that supporting VIT for allergy to other insect species. The tolerability and safety of JJA VIT are comparable with those of honeybee VIT. PMID:24999895

  9. Clinical experience with CD64-directed immunotherapy. An overview

    Microsoft Academic Search

    Randall T. Curnow

    1997-01-01

    The class I IgG receptor (Fc?RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate\\u000a the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells\\u000a such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed\\u000a immunotherapy

  10. Bacillus Calmette–Guerin immunotherapy for urothelial carcinoma of the bladder

    PubMed Central

    Kresowik, Timothy P

    2009-01-01

    Mycobacterium bovis bacille Calmette–Guerin (BCG) is one of the great success stories of immunotherapy as a treatment for superficial urothelial carcinoma of the bladder. Despite clinical effectiveness in over 50% of patients, the high incidence of local side effects and presence of nonresponders has led to efforts to improve the therapy. Recent advances have suggested a role for neutrophils and TNF-related apoptosis-inducing ligand (TRAIL) in the antitumor inflammatory response. Cell wall components of mycobacteria alone, lowered doses of BCG, and combination with cytokines have been studied as ways to improve the immune response associated with BCG and/or reduce toxicity. This review will discuss the clinical use of BCG, its proposed mechanism of action, and directions of future research to improve efficacy and decrease side effects. PMID:20046960

  11. Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges.

    PubMed

    Teng, Feifei; Kong, Li; Meng, Xiangjiao; Yang, Jia; Yu, Jinming

    2015-08-28

    To date, several kinds of immunomodulating monoclonal antibodies (mAbs) have been applied in clinical trials, such as anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) mAb and anti-programmed death-1 (anti-PD-1) mAb. With the recent success of cancer immunotherapy, especially the checkpoint inhibitors, the renewed interest in immunotherapy as a treatment modality has gained extensive attention. The irradiated tumor cell death can enhance antitumor immunity by inducing antigen expression on tumor cells and activating lymphocytes. Radiotherapy (RT) combined with immunotherapy has revealed promising outcomes in various animal models. However, this new paradigm is often considered as a medical spectacle without a unifying model, and its mechanisms have yet to be elucidated. The purpose of this review is to investigate previously published studies of radiotherapy combined with checkpoint blockades by the following aspects: exploring the potential mechanisms; identifying the most beneficial dose, fraction and target site for RT; finding an appropriate time window to combine these two treatments; and discussing the toxicity and suitable treatment evaluating criteria. PMID:25980820

  12. Mechanisms and ?pplications of ?nterleukins in Cancer Immunotherapy

    PubMed Central

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

    2015-01-01

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

  13. Update on antigen-specific immunotherapy of acute myeloid leukemia.

    PubMed

    Buckley, Sarah A; Walter, Roland B

    2015-06-01

    Among the few drugs that have shown a benefit for patients with acute myeloid leukemia (AML) in randomized clinical trials over the last several decades is the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO). Undoubtedly, this experience has highlighted the value of antigen-specific immunotherapy in AML. A wide variety of therapeutics directed against several different antigens on AML cells are currently explored in preclinical and early clinical studies. On the one hand, these include passive strategies such as unconjugated antibodies targeting one or more antigens, antibodies armed with drugs, toxic proteins, or radionuclides, or adoptive immunotherapies, in particular utilizing T cells engineered to express chimeric antigen receptors (CARs) or modified T cell receptor (TCR) genes; on the other hand, these include active strategies such as vaccinations. With the documented benefit for GO and the emerging data with several classes of therapeutics in other leukemias, in particular small bispecific antibodies and CAR T cells, the future is bright. Nevertheless, a number of important questions related to the choice of target antigen(s), patient population, exact treatment modality, and supportive care needs remain open. Addressing such questions in upcoming studies will ultimately be required to optimize the clinical use of antigen-specific immunotherapies in AML and ensure that such treatments become an effective, versatile tool for this disease for which the outcomes have remained unsatisfactory in many patients. PMID:25896530

  14. Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

    PubMed Central

    2013-01-01

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

  15. The Immune Response to Tumors as a Tool toward Immunotherapy

    PubMed Central

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

    2011-01-01

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

  16. Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

    PubMed Central

    Raman, Rachna; Vaena, Daniel

    2015-01-01

    Localized renal cell carcinoma (RCC) is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR) inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer) has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC. PMID:26161397

  17. IgE-based immunotherapy of cancer: challenges and chances

    PubMed Central

    Singer, J; Jensen-Jarolim, E

    2014-01-01

    Passive immunotherapy with monoclonal antibodies is an indispensable cornerstone of clinical oncology. Notably, all FDA-approved antibodies comprise the IgG class, although numerous research articles proposed monoclonal antibodies of the IgM, IgG, IgA and IgE classes directed specifically against tumor-associated antigens. In particular, for the IgE isotype class, several recent studies could demonstrate high tumoricidic efficacy. Therefore, this review specifically highlights the latest developments toward IgE-based immunotherapy of cancer. Possible mechanisms and safety aspects of IgE-mediated tumor cell death are discussed with special focus on the attracted immune cells. An outlook is given on how especially comparative oncology could contribute to further developments. Humans and dogs have a highly comparable IgE biology, suggesting that translational AllergoOncology studies in patients with canine cancer could have predictive value for the potential of IgE-based anticancer immunotherapy in human clinical oncology. PMID:24117861

  18. Tumour immunogenicity, antigen presentation and immunological barriers in cancer immunotherapy

    PubMed Central

    Escors, David

    2014-01-01

    Since the beginning of the 20th century, scientists have tried to stimulate the anti-tumour activities of the immune system to fight against cancer. However, the scientific effort devoted on the development of cancer immunotherapy has not been translated into the expected clinical success. On the contrary, classical anti-neoplastic treatments such as surgery, radiotherapy and chemotherapy are the first line of treatment. Nevertheless, there is compelling evidence on the immunogenicity of cancer cells, and the capacity of the immune system to expand cancer-specific effector cytotoxic T cells. However, the effective activation of anti-cancer T cell responses strongly depends on efficient tumour antigen presentation from professional antigen presenting cells such as dendritic cells (DCs). Several strategies have been used to boost DC antigen presenting functions, but at the end cancer immunotherapy is not as effective as would be expected according to preclinical models. In this review we comment on these discrepancies, focusing our attention on the contribution of regulatory T cells and myeloid-derived suppressor cells to the lack of therapeutic success of DC-based cancer immunotherapy. PMID:24634791

  19. Alternative A? Immunotherapy Approaches for Alzheimer’s Disease

    PubMed Central

    Town, Terrence

    2009-01-01

    In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer’s disease (AD) with amyloid-?1–42 peptide (A?1–42) and adjuvant resulted in striking mitigation of AD-like pathology – giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after A? vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with A?1–42 plus adjuvant (so-called “active” A? immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland). However, the phase IIa trial was halted after 6 % of patients developed aseptic meningoencephalitis. Despite occurrence of this adverse event, many individuals demonstrated high serum antibody titres to A? and histological evidence of clearance of the hallmark AD pathology, ?-amyloid plaques. While raising justifiable safety concerns, these important results nonetheless demonstrated the feasibility of the active A? immunotherapy approach. This review focuses on alternative approaches to active A? vaccination that are currently in various stages of development – from pre-clinical studies in animal models to current clinical trials. Specifically, the focus is on those strategies that target inflammatory and immune aspects of AD, and can therefore be classified as immunotherapeutic in a broad sense. PMID:19355932

  20. Prevention and Immunotherapy of Secondary Murine Alveolar Echinococcosis Employing Recombinant EmP29 Antigen

    PubMed Central

    Boubaker, Ghalia; Hemphill, Andrew; Huber, Cristina Olivia; Spiliotis, Markus; Babba, Hamouda; Gottstein, Bruno

    2015-01-01

    Alveolar echinococcosis (AE) is caused by infection with the larval stage of the tapeworm Echinococcus multilocularis. An increasing understanding of immunological events that account for the metacestode survival in human and murine AE infection prompted us to undertake explorative experiments tackling the potential of novel preventive and/or immunotherapeutic measures. In this study, the immunoprotective and immunotherapeutic ability of recombinant EmP29 antigen (rEmP29) was assessed in mice that were intraperitoneally infected with E. multilocularis metacestodes. For vaccination, three intraperitoneal injections with 20?g rEmP29 emulsified in saponin adjuvants were applied over 6 weeks. 2 weeks after the last boost, mice were infected, and at 90 days post-infection, rEmP29-vaccinated mice exhibited a median parasite weight that was reduced by 75% and 59% when compared to NaCl- or saponin–treated control mice, respectively. For immunotherapeutical application, the rEmP29 (20?g) vaccine was administered to experimentally infected mice, starting at 1 month post-infection, three times with 2 weeks intervals. Mice undergoing rEmP29 immunotherapy exhibited a median parasite load that was reduced by 53% and 49% when compared to NaCl- and saponin–treated control mice, respectively. Upon analysis of spleen cells, both, vaccination and treatment with rEmP29, resulted in low ratios of Th2/Th1 (IL-4/IFN-?) cytokine mRNA and low levels of mRNA coding for IL-10 and IL-2. These results suggest that reduction of the immunosuppressive environment takes place in vaccinated as well as immunotreated mice, and a shift towards a Th1 type of immune response may be responsible for the observed increased restriction of parasite growth. The present study provides the first evidence that active immunotherapy may present a sustainable route for the control of AE. PMID:26053794

  1. Prevention and Immunotherapy of Secondary Murine Alveolar Echinococcosis Employing Recombinant EmP29 Antigen.

    PubMed

    Boubaker, Ghalia; Hemphill, Andrew; Huber, Cristina Olivia; Spiliotis, Markus; Babba, Hamouda; Gottstein, Bruno

    2015-06-01

    Alveolar echinococcosis (AE) is caused by infection with the larval stage of the tapeworm Echinococcus multilocularis. An increasing understanding of immunological events that account for the metacestode survival in human and murine AE infection prompted us to undertake explorative experiments tackling the potential of novel preventive and/or immunotherapeutic measures. In this study, the immunoprotective and immunotherapeutic ability of recombinant EmP29 antigen (rEmP29) was assessed in mice that were intraperitoneally infected with E. multilocularis metacestodes. For vaccination, three intraperitoneal injections with 20?g rEmP29 emulsified in saponin adjuvants were applied over 6 weeks. 2 weeks after the last boost, mice were infected, and at 90 days post-infection, rEmP29-vaccinated mice exhibited a median parasite weight that was reduced by 75% and 59% when compared to NaCl- or saponin-treated control mice, respectively. For immunotherapeutical application, the rEmP29 (20?g) vaccine was administered to experimentally infected mice, starting at 1 month post-infection, three times with 2 weeks intervals. Mice undergoing rEmP29 immunotherapy exhibited a median parasite load that was reduced by 53% and 49% when compared to NaCl- and saponin-treated control mice, respectively. Upon analysis of spleen cells, both, vaccination and treatment with rEmP29, resulted in low ratios of Th2/Th1 (IL-4/IFN-?) cytokine mRNA and low levels of mRNA coding for IL-10 and IL-2. These results suggest that reduction of the immunosuppressive environment takes place in vaccinated as well as immunotreated mice, and a shift towards a Th1 type of immune response may be responsible for the observed increased restriction of parasite growth. The present study provides the first evidence that active immunotherapy may present a sustainable route for the control of AE. PMID:26053794

  2. Do not forget the joint involvement of sarcoidosis.

    PubMed

    Banse, Christopher; Goëb, Vincent

    2015-07-01

    A letter in response to: Crommelin HA, Vorselaars AD, van Moorsel CH, Korenromp IH, Deneer VH, Grutters JC. Anti-TNF therapeutics for the treatment of sarcoidosis. Immunotherapy 6(10), 1127-1143 (2014). PMID:26098193

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

    PubMed Central

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

    2014-01-01

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

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

    E-print Network

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

  5. Equine sarcoid: BCG immunotherapy compared to cryosurgery in a prospective randomised clinical trial

    Microsoft Academic Search

    Wim R. Klein; Goosen E. Bras; Wim Misdorp; Peter A. Steerenberg; Wim H. de Jong; Rudy H. Tiesjema; Adolf W. Kersjes; E. Joost Ruitenberg

    1986-01-01

    A total of 30 horses with single or multiple sarcoid tumors of the skin were randomly divided into three treatment groups: (i) cryosurgical treatment, (ii) intralesional immunotherapy with a live BCG vaccine, (iii) intralesional immunotherapy with a BCG cell wall preparation. Complete tumour regression was obtained in all 10 crysurgically treated horses, in 6 of 10 live BCG treated horses,

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

    PubMed

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

    2015-02-01

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

  7. An Enhanced Heterologous Virus-Like Particle for Human Papillomavirus Type 16 Tumour Immunotherapy

    PubMed Central

    Jemon, Khairunadwa; Young, Vivienne; Wilson, Michelle; McKee, Sara; Ward, Vernon; Baird, Margaret; Young, Sarah; Hibma, Merilyn

    2013-01-01

    Cervical cancer is caused by high-risk, cancer-causing human papillomaviruses (HPV) and is the second highest cause of cancer deaths in women globally. The majority of cervical cancers express well-characterized HPV oncogenes, which are potential targets for immunotherapeutic vaccination. Here we develop a rabbit haemorrhagic disease virus (RHDV) virus-like particle (VLP)-based vaccine designed for immunotherapy against HPV16 positive tumours. An RHDV-VLP, modified to contain the universal helper T cell epitope PADRE and decorated with an MHC I-restricted peptide (aa 48–57) from the HPV16 E6, was tested for its immunotherapeutic efficacy against the TC-1 HPV16 E6 and E7-expressing tumour in mice. The E6-RHDV-VLP-PADRE was administered therapeutically for the treatment of a pre-existing TC-1 tumour and was delivered with antibodies either to deplete regulatory T cells (anti-CD25) or to block T cell suppression mediated through CTLA-4. As a result, the tumour burden was reduced by around 50% and the median survival time of mice to the humane endpoint was almost doubled the compared to controls. The incorporation of PADRE into the RHDV-VLP was necessary for an E6-specific enhancement of the anti-tumour response and the co-administration of the immune modifying antibodies contributed to the overall efficacy of the immunotherapy. The E6-RHDV-VLP-PADRE shows immunotherapeutic efficacy, prolonging survival for HPV tumour-bearing mice. This was enhanced by the systemic administration of immune-modifying antibodies that are commercially available for use in humans. There is potential to further modify these particles for even greater efficacy in the path to development of an immunotherapeutic treatment for HPV precancerous and cancer stages. PMID:23799135

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

    PubMed Central

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

    2014-01-01

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

  9. Porcine sensitized lymph node cells (immunotherapy) and attenuated irradiation for infiltrative transitional cells carcinoma of bladder.

    PubMed

    Cockett, A T; de Sant'agnese, P A; Hamlin, D J; Keys, H M

    1982-06-01

    Thirty-four patients wih infiltrative bladder carcinoma, Stage B2C or higher were treated with immunotherapy and irradiation. Seventeen patients are alive, and 17 have succumbed to their disease. Eight patients underwent cystectomy after immunotherapy and irradiation; 6 of 8 are alive and well at the present time. The technique of immunotherapy is outlined. New methodology for sequential CT scans and scheduled bladder biopsies is mentioned. The 17 patients have survived twelve to sixty-nine months after immunotherapy and irradiation. Downstaging is demonstrated based on sequential CT scans of the bony pelvis and histologic biopsy. The biopsies reveal eosinophilia and multinucleated giant cells, a specific response to immunotherapy. A prospective randomized study will be initiated. PMID:7090105

  10. Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Yi, Keonwoo

    2014-11-01

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

  12. Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking

    NASA Astrophysics Data System (ADS)

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

    2014-11-01

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

  13. Targeted alpha-particle immunotherapy for acute myeloid leukemia.

    PubMed

    Jurcic, Joseph G; Rosenblat, Todd L

    2014-01-01

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

  14. Current and Emerging Immunotherapies for Castration-resistant Prostate Cancer.

    PubMed

    Saad, Fred; Miller, Kurt

    2015-05-01

    Despite advances in castration-resistant prostate cancer (CRPC) treatment, therapies that provide long-term survival are still needed. In 2010, sipuleucel-T was approved for CRPC on the basis of improved overall survival. Recently, new immunotherapeutic approaches have emerged with perhaps the most exciting being immune-checkpoint inhibition. Here, we provide an overview of immunotherapies for CRPC, with a focus on immune-checkpoint inhibition with ipilimumab. We consider how experience with ipilimumab in melanoma might inform future use in CRPC and describe ongoing phase 3 trials. Finally, we discuss the potential for improved antitumor activity when ipilimumab is combined with hormonal or bone-targeted agents. PMID:25709051

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

    PubMed

    Fadel, Tarek R; Fahmy, Tarek M

    2014-04-01

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

  16. Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm

    PubMed Central

    Khattak, Muhammad; Fisher, Rosalie; Turajlic, Samra

    2013-01-01

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

  17. Vaccine against autoimmune disease: antigen-specific immunotherapy?

    PubMed Central

    Anderson, Robert P; Jabri, Bana

    2013-01-01

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

  18. Cell-based Immunotherapy Against Gliomas: From Bench to Bedside

    PubMed Central

    Bovenberg, M Sarah S; Degeling, M Hannah; Tannous, Bakhos A

    2013-01-01

    Glioblastoma (GBM) comprises 51% of all gliomas and is the most malignant form of brain tumors with a median survival of 18–21 months. Standard-of-care treatment includes maximal surgical resection of the tumor mass in combination with radiation and chemotherapy. However, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. Cellular immunotherapy is currently being explored as therapeutic approach to treat malignant brain tumors. In this review, we discuss advances in active, passive, and vaccine-based immunotherapeutic strategies for gliomas both at the bench and in the clinic. PMID:23648695

  19. A phase II study of active specific immunotherapy and5-FU/Leucovorin as adjuvant therapy for stage III colon carcinoma

    PubMed Central

    Baars, A; Claessen, A M E; Wagstaff, J; Giaccone, G; Scheper, R J; Meijer, S; Schakel, M J A G; Gall, H E; Meijer, C J L M; Vermorken, J B; Pinedo, H M; van den Eertwegh, A J M

    2002-01-01

    Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40–50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48?h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3?mm, while after chemotherapy delayed type hypersensitivity size was 18.4?mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity. British Journal of Cancer (2002) 86, 1230–1234. DOI: 10.1038/sj/bjc/6600254 www.bjcancer.com © 2002 Cancer Research UK PMID:11953877

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

    PubMed Central

    2005-01-01

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

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

    PubMed

    Joshi, Jyoti; Malla, Nancy; Kaur, Sukhbir

    2014-08-01

    Visceral leishmaniasis (VL) represents the second most challenging infectious disease worldwide, leading to nearly 500,000 new cases and 60,000 deaths annually. Ninety per cent of VL cases occur in five countries namely Bangladesh, India, Nepal, Sudan and Brazil. No licensed vaccine is available till date against any form of leishmaniasis. High toxicity and increasing resistance to the current chemotherapeutic regimens have further complicated the situation in VL endemic regions of the world. To combat this situation, immunochemotherapy can provide a solution. In the present study, an attempt has been made to assess the in vivo antileishmanial efficacy of chemotherapy, immunotherapy and immunochemotherapy with the use of a first generation antigen Killed Leishmania donovani (KLD) along with a standard drug sodium stibogluconate (SSG) and a newly tested antileishmanial cisplatin. Inbred BALB/c mice were infected with 10(7) promastigotes/0.1 ml of Leishmania donovani. A month after infection, these animals were given specific immunotherapy (KLD/KLD+MPL-A) or chemotherapy (SSG/cisplatin) or immunochemotherapy (SSG+KLD/SSG+KLD+MPL-A/cisplatin+KLD/cisplatin+KLD+MPL-A). Animals were sacrificed on 1, 15 and 30(th) day post treatment. The efficacy of these combinations was assessed in terms of parasite load and by immunological investigations. Infected mice and normal mice served as controls. Results showed that combination of drug and KLD significantly reduced the parasite burden, enhanced the DTH (Delayed Type Hypersensitivity) responses, showed increased levels of IgG2a and decreased levels of IgG1 as compared to mice given chemotherapy or immunotherapy alone. Further maximum protection was provided by SSG+KLD+MPL-A and it was most effective as depicted by 98.5% reduction in parasite load, a potent increase in IFN-? levels and a significant decrease in IL-10 and IL-4 levels thus skewing the immune response towards Th1 type. Hence, immunochemotherapy is more effective in control of VL in comparison to chemotherapy or immunotherapy. PMID:24747611

  2. Gastric cancer and the epoch of immunotherapy approaches

    PubMed Central

    Niccolai, Elena; Taddei, Antonio; Prisco, Domenico; Amedei, Amedeo

    2015-01-01

    The incidence of gastric cancer (GC) fell dramatically over the last 50 years, but according to IARC-Globocan 2008, it is the third most frequent cause of cancer-related deaths with a case fatality GC ratio higher than other common malignancies. Surgical resection is the primary curative treatment for GC though the overall 5-year survival rate remains poor (approximately 20%-25%). To improve the outcome of resectable gastric cancer, different treatment strategies have been evaluated such as adjuvant or perioperative chemotherapy. In resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit. Moreover, in metastatic patients, chemotherapy is the mainstay of palliative therapy with a median overall survival of 8-10 mo and objective response rates of merely 20%-40%. Therefore, the potential for making key beneficial progress is to investigate the GC molecular biology to realize innovative therapeutic strategies, such as specific immunotherapy. In this review, we provide a panoramic view of the different immune-based strategies used for gastric cancer treatment and the results obtained in the most significant clinical trials. In detail, firstly we describe the therapeutic approaches that utilize the monoclonal antibodies while in the second part we analyze the cell-based immunotherapies. PMID:26019442

  3. Lm-LLO-Based Immunotherapies and HPV-Associated Disease

    PubMed Central

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

    2012-01-01

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

  4. Pilot Trial of FANG Immunotherapy in Ewing's Sarcoma.

    PubMed

    Ghisoli, Maurizio; Barve, Minal; Schneider, Reva; Mennel, Robert; Lenarsky, Carl; Wallraven, Gladice; Pappen, Beena O; LaNoue, John; Kumar, Padmasini; Nemunaitis, Derek; Roth, Alyssa; Nemunaitis, James; Whiting, Sam; Senzer, Neil; Fletcher, Frederick A; Nemunaitis, John

    2015-06-01

    We report on 12 consecutive patients with advanced/metastatic Ewing's sarcoma who were treated as a separate cohort of a phase 1 trial of FANG autologous immunotherapy (1?×?10(6)-2.5?×?10(7) cells/intradermal injection each month for minimum 4 months). Safety and clinical response were monitored. Patient immune response to unmodified autologous tumor cells was assessed by gamma interferon-enzyme-linked immunospot (?IFN-ELISPOT) assay using peripheral blood mononuclear cells from baseline (pretreatment) and multiple postvaccination time points. None of the 12 patients (47 vaccinations) developed grade 2/3/4 drug-related toxicity. Median product release granulocyte-macrophage colony-stimulating factor expression was 1,941 pg/10(6) cells, and TGF?1and TGF?2 knockdown were 99 and 100%, respectively. Eight patients were assessed for ELISPOT response to autologous tumor cells at baseline and all (100%) were negative. In contrast, follow-up ELISPOT response at month 1 or month 4 (one patient) after FANG was positive in all eight patients. One patient achieved a partial tumor response (38% tumor reduction, RECIST 1.1). The Kaplan-Meier estimated survival of these 12 patients at 1 year was 75%. In this phase 1 study in patients with Ewing's sarcoma, FANG immunotherapy was well tolerated, elicited a tumor-specific systemic immune response in all patients, and was associated with favorable 1-year survival. Further clinical testing is indicated. PMID:25917459

  5. Skin as a novel route for allergen-specific immunotherapy.

    PubMed

    Li, Wei; Zhang, Zhuo; Tian, Rong; Zhang, Ke

    2014-01-01

    Subcutaneous allergen specific immunotherapy is an effective treatment of IgE-mediated allergies, but it requires repeated allergen injections with a risk of systemic allergic reactions. Other routes of immunization had been explored to improve patient compliance and safety. Skin is not only a physical barrier between the body and outside world, but also an important immune organ eliciting innate and adaptive immune function. Skin has been used as an ideal site for vaccination of infectious diseases. Food allergen topically applied onto disrupted skin can induce sensitization and food allergy would develop subsequently. However, immune tolerance would be induced if the skin barrier is kept intact. Several mice and human studies on epicutaneous immunotherapy showed successful treatment on IgE-induced allergy models or allergic diseases. Migratory Langerhans cells might play a decisive role in the induction of different immune responses. Further research on the underlying mechanism of the crosstalk between skin and gut or airway is helpful for the understanding of many protective or sensitizing immune responses induced via skin, and also is helpful for the development of new strategy for the treatment of allergic disease. PMID:23701565

  6. [Immune-checkpoints: the new anti-cancer immunotherapies].

    PubMed

    Ileana, Ecaterina; Champiat, Stéphane; Soria, Jean-Charles

    2013-06-01

    The immune system plays a dual role against cancer: it prevents tumor cell outgrowth and also sculpts the immunogenicity of the tumor cells. Cancer cells are able to escape from the immune system by inhibiting T lymphocytes activation. New immunotherapies have been developped to target these T lymphocytes activation modulators: the immune checkpoints. These novel therapies are showing promising results with durable objective responses in some patients. Ipilimumab (anti-CTLA4) was the first of these new therapeutics to be approved by the FDA in March 2011 for advanced melanoma and other immunomodulators trials are ongoing in other cancers with similar encouraging results like with the anti PD-1/PD-L1. These drugs are already challenging our future practice like for evaluation of tumor response or for management of immune related toxicities. Many immune checkpoints have been identified and could potentially be targeted. Future studies will help to identify predictive factors but also to coordinate these new immunotherapies with our classic treatment strategies. PMID:23735730

  7. Adherence issues related to sublingual immunotherapy as perceived by allergists

    PubMed Central

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

    2010-01-01

    Objectives: Sublingual immunotherapy (SLIT) is a viable alternative to subcutaneous immunotherapy to treat allergic rhinitis and asthma, and is widely used in clinical practice in many European countries. The clinical efficacy of SLIT has been established in a number of clinical trials and meta-analyses. However, because SLIT is self-administered by patients without medical supervision, the degree of patient adherence with treatment is still a concern. The objective of this study was to evaluate the perception by allergists of issues related to SLIT adherence. Methods: We performed a questionnaire-based survey of 296 Italian allergists, based on the adherence issues known from previous studies. The perception of importance of each item was assessed by a VAS scale ranging from 0 to 10. Results: Patient perception of clinical efficacy was considered the most important factor (ranked 1 by 54% of allergists), followed by the possibility of reimbursement (ranked 1 by 34%), and by the absence of side effects (ranked 1 by 21%). Patient education, regular follow-up, and ease of use of SLIT were ranked first by less than 20% of allergists. Conclusion: These findings indicate that clinical efficacy, cost, and side effects are perceived as the major issues influencing patient adherence to SLIT, and that further improvement of adherence is likely to be achieved by improving the patient information provided by prescribers. PMID:20622914

  8. Current clinical trials testing combinations of immunotherapy and radiation.

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2011-01-01

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

  10. Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression

    PubMed Central

    Campbell, John D.; Buckland, Karen F.; McMillan, Sarah J.; Kearley, Jennifer; Oldfield, William L.G.; Stern, Lawrence J.; Grönlund, Hans; van Hage, Marianne; Reynolds, Catherine J.; Boyton, Rosemary J.; Cobbold, Stephen P.; Kay, A. Barry; Altmann, Daniel M.; Larché, Mark

    2009-01-01

    Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans. PMID:19528258

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

    PubMed

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

    1997-01-01

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

  12. Monitoring of various types of immunotherapy with gramineal pollens. I. Variation of clinical and biochemical parameters.

    PubMed

    Miguel Lozano, R; Guerra Pasadas, F; Arenas Vacas, A; Daza Muñoz, J C; Torres Murillo, P; Sánchez Guijo, P

    1992-01-01

    We assessed the clinical effectiveness and adverse effect of various types of immunotherapy on 42 pollinotic patients by monitoring their evolution on administration of Perennial lolium specific extract standardized in protein nitrogen units to 14 of them, the same extract but standardized in biological units (BUs) to another 13, and an extract containing four different pollens standardized in BUs to the remaining 15. For this purpose we measured clinical and medicinal scores, liver and kidney biochemical parameters, skin reactions and circulating immunocomplexes (CICs), both before immunotherapy was started (basal levels) and after 3, 6 and 12 month's treatment. We found no significant differences in clinical effectiveness or the occurrence of any adverse effects on administration of the different immunotherapies after one year's monitoring. We did found gradually decreased reactions to the skin tests, which thus provide a reliable means of monitoring allergen-specific immunotherapy. PMID:1296464

  13. Recent advance in antigen-specific immunotherapy for acute myeloid leukemia.

    PubMed

    Kadowaki, Norimitsu; Kitawaki, Toshio

    2011-01-01

    Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML). Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML. PMID:22028726

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

    E-print Network

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

    2008-01-01

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

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

    PubMed

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

    2015-01-01

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

  16. Use of allogeneic NK cells for cancer immunotherapy

    PubMed Central

    Geller, Melissa A; Miller, Jeffrey S

    2012-01-01

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

  17. Evaluation of Current Cancer Immunotherapy: Haemato-Oncology

    PubMed Central

    Hourigan, Christopher; Levitsky, Hyam I.

    2011-01-01

    Hematological malignancies were the first diseases in clinical oncology for which the potential of harnessing the immune system as targeted therapy was unequivocally demonstrated. Unfortunately the use of this highly efficacious modality has been limited to only a subset of patients and diseases due to immune-mediated toxicities resulting from incomplete specificity, and disease-specific determinants of sensitivity versus resistance to immune effector mechanisms. Recent studies however, have begun to elucidate the molecular basis of the observed clinical effects allowing the rational development of next generation of immunotherapeutic combinations. We discuss here cancer antigen targets in hematological malignancies and the specific approaches to induce immunity being pursued, the importance of modulating the host immunoregulatory environment, and the special features of immunological monitoring in clinical investigation. The hematological malignancies represent an ideal setting for the development of immunotherapy due to logistical, clinical monitoring and disease biology factors and may represent an exemplar for immune based treatment in other cancer types. PMID:21952281

  18. Can immunotherapy specifically target acute myeloid leukemic stem cells?

    PubMed Central

    Snauwaert, Sylvia; Vandekerckhove, Bart; Kerre, Tessa

    2013-01-01

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

  19. Checkpoint immunotherapy for cancer: superior survival, unaccustomed toxicities.

    PubMed

    Gedye, C; van der Westhuizen, A; John, T

    2015-07-01

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

  20. Plasmacytoid dendritic cells and immunotherapy in multiple sclerosis.

    PubMed

    von Glehn, Felipe; Santos, Leonilda M; Balashov, Konstantin E

    2012-10-01

    Plasmacytoid dendritic cells (pDCs) are specialized APCs implicated in the pathogenesis of many human diseases. Compared with other peripheral blood mononuclear cells, pDCs express a high level of TLR9, which recognizes viral DNA at the initial phase of viral infection. Upon stimulation, these cells produce large amounts of type I interferon and other proinflammatory cytokines and are able to prime T lymphocytes. Thus, pDCs regulate innate and adaptive immune responses. This article reviews select aspects of pDC biology relevant to the disease pathogenesis and immunotherapy in multiple sclerosis. Many unresolved questions remain in this area, promising important future discoveries in pDC research. PMID:23148757

  1. Plasmacytoid dendritic cells and immunotherapy in multiple sclerosis

    PubMed Central

    von Glehn, Felipe; Santos, Leonilda M; Balashov, Konstantin E

    2013-01-01

    Plasmacytoid dendritic cells (pDCs) are specialized APCs implicated in the pathogenesis of many human diseases. Compared with other peripheral blood mononuclear cells, pDCs express a high level of TLR9, which recognizes viral DNA at the initial phase of viral infection. Upon stimulation, these cells produce large amounts of type I interferon and other proinflammatory cytokines and are able to prime T lymphocytes. Thus, pDCs regulate innate and adaptive immune responses. This article reviews select aspects of pDC biology relevant to the disease pathogenesis and immunotherapy in multiple sclerosis. Many unresolved questions remain in this area, promising important future discoveries in pDC research. PMID:23148757

  2. Particle-mediated delivery of cytokines for immunotherapy

    PubMed Central

    Christian, David A; Hunter, Christopher A

    2012-01-01

    The ability of cytokines to direct the immune response to vaccination, infection and tumors has motivated their use in therapy to augment or shape immunity. To avoid toxic side effects associated with systemic cytokine administration, several approaches have been developed using particle-encapsulated cytokines to deliver this cargo to specific cell types and tissues. Initial work used cytokine-loaded particles to deliver proinflammatory cytokines to phagocytes to enhance antimicrobial and antitumor responses. These particles have also been used to create a cytokine depot at a local site to supplement prophylactic or antitumor vaccines or injected directly into solid tumors to activate immune cells to eliminate established tumors. Finally, recent advances have revealed that paracrine delivery of cytokines directly to T cells has the potential to enhance T-cell mediated therapies. The studies reviewed here highlight the progress in the last 30 years that has established the potential of particle-mediated cytokine immunotherapy. PMID:22512636

  3. Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma.

    PubMed

    Caruso, James P; Cohen-Inbar, Or; Bilsky, Mark H; Gerszten, Peter C; Sheehan, Jason P

    2015-03-01

    The management of metastatic spinal melanoma involves maximizing local control, preventing recurrence, and minimizing treatment-associated toxicity and spinal cord damage. Additionally, therapeutic measures should promote mechanical stability, facilitate rehabilitation, and promote quality of life. These objectives prove difficult to achieve given melanoma's elusive nature, radioresistant and chemoresistant histology, vascular character, and tendency for rapid and early metastasis. Different therapeutic modalities exist for metastatic spinal melanoma treatment, including resection (definitive, debulking, or stabilization procedures), stereotactic radiosurgery, and immunotherapeutic techniques, but no single treatment modality has proven fully effective. The authors present a conceptual overview and critique of these techniques, assessing their effectiveness, separately and combined, in the treatment of metastatic spinal melanoma. They provide an up-to-date guide for multidisciplinary treatment strategies. Protocols that incorporate specific, goal-defined surgery, immunotherapy, and stereotactic radiosurgery would be beneficial in efforts to maximize local control and minimize toxicity. PMID:25727228

  4. Myeloid-derived cells are key targets of tumor immunotherapy

    PubMed Central

    Medina-Echeverz, José; Aranda, Fernando; Berraondo, Pedro

    2014-01-01

    Tumors are composed of heterogeneous cell populations recruited by cancer cells to promote growth and metastasis. Among cells comprising the tumor stroma, myeloid-derived cells play pleiotropic roles in supporting tumorigenesis at distinct stages of tumor development. The tumor-infiltrating myeloid cell contingent is composed of mast cells, neutrophils, dendritic cells, macrophages, and myeloid-derived suppressor cells. Such cells are capable of evading the hostile tumor environment typically prone to immune cell destruction and can even promote angiogenesis, chronic inflammation, and invasion. This paper briefly summarizes the different myeloid-derived subsets that promote tumor development and the strategies that have been used to counteract the protumorigenic activity of these cells. These strategies include myeloid cell depletion, reduction of recruitment, and inactivation or remodeling of cell phenotype. Combining drugs designed to target tumor myeloid cells with immunotherapies that effectively trigger antitumor adaptive immune responses holds great promise in the development of novel cancer treatments. PMID:25050208

  5. Epidermal growth factor receptor and variant III targeted immunotherapy.

    PubMed

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

    2014-10-01

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

  6. Clinical bystander effect exerted by allergen immunotherapy: a hypothesis.

    PubMed

    Ciprandi, G

    2015-03-01

    Allergen Immunotherapy (AIT) is able to restore a physiological Th1 response and Tregs function. This effect is allergen-specific, even though it has been reported that it may also be non-specific, such as also extended to allergens not used in AIT. This immunological phenomenon may also be of clinical nature. This case report shows that a poly-allergic patient, successfully treated with Parietaria extract, also achieved a clinical tolerance towards other causal allergens, such as mites and cat. Of course, this was an anecdote, but it is reasonable to prospect the hypothesis that a bystander clinical effect may be observed during AIT in poly-allergic patients. PMID:25781197

  7. Oncolytic Viruses and Their Application to Cancer Immunotherapy

    PubMed Central

    Chiocca, EA; Rabkin, SD

    2015-01-01

    Oncolytic viruses (OVs) selectively replicate in and kill cancer cells, and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer-selective or can be genetically-engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines, and can be armed with immune modulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy; they include: (i) innate immune responses and the degree of inflammation induced, (ii) types of virus-induced cell death, (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture, and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers (MHC, co-stimulatory, NK receptors), and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing GM-CSF, have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between anti-virus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs. PMID:24764576

  8. Cancer-associated CD43 glycoforms as target of immunotherapy

    PubMed Central

    Tuccillo, Franca Maria; Palmieri, Camillo; Fiume, Giuseppe; de Laurentiis, Annamaria; Schiavone, Marco; Falcone, Cristina; Iaccino, Enrico; Galandrini, Ricciarda; Capuano, Cristina; Santoni, Angela; D'Armiento, Francesco Paolo; Arra, Claudio; Barbieri, Antonio; Piaz, Fabrizio Dal; Venzon, David; Bonelli, Patrizia; Buonaguro, Franco Maria; Scala, Iris; Mallardo, Massimo; Quinto, Ileana; Scala, Giuseppe

    2014-01-01

    CD43 is a sialoglycosylated membrane protein that is involved in cell proliferation and differentiation. CD43 glycoforms that are recognized by the UN1 monoclonal antibody (mAb) were expressed in lymphoblastoid T-cell lines and solid tumors, such as breast, colon, gastric, and squamous cell lung carcinomas, while unexpressed in the normal counterparts. The cancer–association of UN1/CD43 epitope suggested the possibility to use the UN1 mAb for tumor diagnosis and therapy. In this study, we show that the UN1 mAb was endowed with anti-tumor activity in vivo since its passive transfer inhibited the growth of UN1-positive HPB-ALL lymphoblastoid T-cells in mice. Further, we demonstrate that tumor inhibition was due to UN1 mAb-dependent NK-mediated cytotoxicity. By screening a phage displayed random peptide library we identified the phagotope 2/165 as a mimotope of the UN1 antigen, as it harboured a peptide sequence that was specifically recognized by the UN1 mAb and inhibited the binding of the UN1 mAb to UN1-positive tumour cells. Based on sequence homology with the extracellular region of CD43 (amino acids 64 to 83), the 2/165 peptide sequence was likely mimicking the protein core of the UN1/CD43 epitope. When used as vaccine in mice, the 2/165 phagotope raised antibodies against the UN1/CD43 antigen, indicating that the 2/165 phagotope mimicked the UN1 antigen structure, and could represent a novel immunogen for cancer immunotherapy. These findings support the feasibility to use monoclonal antibodies to identify cancer-associated mimotopes for immunotherapy. PMID:24356816

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

    PubMed Central

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

    2015-01-01

    Ovarian cancer is the second most important pelvic gynaecologic malignancy and nowadays still kills 80% of patients. New treatment options are mandatory. Although it has been shown that ovarian cancer is an immunogenic tumor, the possibility of developing immunotherapy has been neglected for a long time. This article focuses on the importance of the immune system in the development and progression of cancer and the possibilities and problems of dendritic cell-based immunotherapy to influence the immune system. PMID:25897374

  10. Immunotherapy for B-Cell Lymphoma: Current Status and Prospective Advances

    PubMed Central

    Hollander, Nurit

    2011-01-01

    Therapy for non-Hodgkin’s lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of rituximab catalyzed the development of new passive immunotherapy strategies that are currently undergoing clinical evaluation. These include improvement of rituximab efficacy, newer generation anti-CD20 antibodies, drug-conjugated and radio labeled anti-CD20 antibodies, monoclonal antibodies targeting non-CD20 lymphoma antigens, and bispecific antibodies. Active immunotherapy aims at inducing long-lasting antitumor immunity, thereby limiting the likelihood of relapse. Current clinical studies of active immunotherapy for lymphoma consist largely of vaccination and immune checkpoint blockade. A variety of protein- and cell-based vaccines are being tested in ongoing clinical studies. Recently completed phase III clinical trials of an idiotype protein vaccine suggest that the vaccine may have clinical activity in a subset of patients. Efforts to enhance the efficacy of active immunotherapy are ongoing with an emphasis on optimization of antigen delivery and presentation of vaccines and modulation of the immune system toward counteracting immunosuppression, using antibodies against immune regulatory checkpoints. This article discusses results of the various immunotherapy approaches applied to date for B-cell lymphoma and the ongoing trials to improve their effect. PMID:22566889

  11. [Intolerance of specific immunotherapy with Hymenoptera venom: jumping the hurdle with omalizumab].

    PubMed

    Wieczorek, D; Kapp, A; Wedi, B

    2014-09-01

    Specific immunotherapy is a very effective and well-tolerated therapeutic option in patients with Hymenoptera venom allergy. Many patients can be successfully treated, and severe side-effects are rarely seen. In most cases local swelling of the injection site is noticed, whereas systemic reactions are uncommon. No reliable biomarkers to prove the positive response to the specific immunotherapy have been validated. But on the other hand the failure of the venom immunotherapy can be verified by performing a sting challenge test; in this case the maintenance dose of the venom immunotherapy has to be increased and the sting challenge test has to be repeated. This approach works well most of the patients. In rare cases severe anaphylactic reactions occur during the initiation of the venom immunotherapy due to individual risk factors. While in the past this necessitated discontinuation of the specific immunotherapy, the current situation has remarkably changed. Since the IgE-antibody omalizumab has been licensed for different indications, a new therapeutic option is available. We have employed this approach since 2005. We share our own practical experience as well as recent data, presenting a management approach for Hymenoptera venom allergy in high-risk patients. PMID:25234627

  12. Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer.

    PubMed

    Smith, Sean G; Koppolu, Bhanu Prasanth; Ravindranathan, Sruthi; Kurtz, Samantha L; Yang, Lirong; Katz, Matthew D; Zaharoff, David A

    2015-06-01

    Bladder cancer is a highly recurrent disease in need of novel, durable treatment strategies. This study assessed the ability of an intravesical immunotherapy composed of a coformulation of the biopolymer chitosan with interleukin-12 (CS/IL-12) to induce systemic adaptive tumor-specific immunity. Intravesical CS/IL-12 immunotherapy was used to treat established orthotopic MB49 and MBT-2 bladder tumors. All mice receiving intravesical CS/IL-12 immunotherapy experienced high cure rates of orthotopic disease. To investigate the durability and extent of the resultant adaptive immune response, cured mice were rechallenged both locally (intravesically) and distally. Cured mice rejected 100 % of intravesical tumor rechallenges and 50-100 % of distant subcutaneous rechallenges in a tumor-specific manner. The ability of splenocytes from cured mice to lyse targets in a tumor-specific manner was assessed in vitro, revealing that lytic activity of splenocytes from cured mice was robust and tumor specific. Protective immunity was durable, lasting for at least 18 months after immunotherapy. In an advanced bladder cancer model, intravesical CS/IL-12 immunotherapy controlled simultaneous orthotopic and subcutaneous tumors in 70 % of treated mice. Intravesical CS/IL-12 immunotherapy creates a robust and durable tumor-specific adaptive immune response against bladder cancer. The specificity, durability, and potential of this therapy to treat both superficial and advanced disease are deserving of consideration for clinical translation. PMID:25754122

  13. Adjuvant, specific, active immunotherapy for resectable squamous cell lung carcinoma: a 5-year survival analysis.

    PubMed

    Takita, H; Hollinshead, A C; Adler, R H; Bhayana, J; Ramundo, M; Moskowitz, R; Rao, U N; Raman, S

    1991-01-01

    In 1976 Stewart et al. (Annals of the New York Academy of Sciences 277:436-466) reported the effectiveness of adjuvant specific active immunotherapy of lung carcinoma in improving the postoperative survival of stage I lung carcinoma patients in a phase II study using lung carcinoma-associated antigen (TAA) and complete Freund's adjuvant (CFA). A phase III study was then designed by the authors to see the effects of specific active immunotherapy compared to the conventional management (no treatment) and to nonspecific immunotherapy. From 1976 to 1981, 85 patients with resectable (stages I and II) squamous cell lung carcinoma were entered into a randomized study: 1) control group; 2) specific immunotherapy group--three monthly doses of 500 micrograms of TAA emulsified with CFA; 3) nonspecific immunotherapy group--three monthly doses of CFA emulsified in saline. All the patients in the study received skin tests with 100 micrograms of the same TAA used for the immunotherapy. Recently, a 5-year follow-up of all the patients became available: The life table 5-year survival of group 1 was 34%, of group 2 was 75%, and of group 3 was 53%. The median survivals for the three groups were group 1, 38 months; group 2, 106 months; and group 3, 71 months. The difference was significant at P = .007 (Cox-Mantel test). PMID:1986150

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

    PubMed

    Moreth, Jens; Mavoungou, Chrystelle; Schindowski, Katharina

    2013-01-01

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

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

    PubMed

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

    2014-09-29

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

  16. Paradoxical increase of IgE binding components during allergen-specific immunotherapy in pollinosis patients.

    PubMed

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

    2014-07-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  19. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice.

    PubMed

    Mirsoian, Annie; Bouchlaka, Myriam N; Sckisel, Gail D; Chen, Mingyi; Pai, Chien-Chun Steven; Maverakis, Emanuel; Spencer, Richard G; Fishbein, Kenneth W; Siddiqui, Sana; Monjazeb, Arta M; Martin, Bronwen; Maudsley, Stuart; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L; Blazar, Bruce R; Wiltrout, Robert H; Taub, Dennis D; Murphy, William J

    2014-11-17

    Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF(+) macrophages in response to ?CD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with ?CD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon ?CD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT. PMID:25366964

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

    PubMed

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

    2015-07-01

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

  1. Feasibility Analysis of p62 (SQSTM1)—Encoding DNA Vaccine as a Novel Cancer Immunotherapy

    PubMed Central

    Shifrin, Victor I.

    2014-01-01

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

  2. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma.

    PubMed

    Rainusso, N; Brawley, V S; Ghazi, A; Hicks, M J; Gottschalk, S; Rosen, J M; Ahmed, N

    2012-03-01

    Despite radical surgery and multi-agent chemotherapy, less than one third of patients with recurrent or metastatic osteosarcoma (OS) survive. The limited efficacy of current therapeutic approaches to target tumor-initiating cells (TICs) may explain this dismal outcome. The purpose of this study was to assess the impact of modified T cells expressing a human epidermal growth factor receptor (HER2)-specific chimeric antigen receptor in the OS TIC compartment of human established cell lines. Using the sarcosphere formation assay, we found that OS TICs were resistant to increasing methotrexate concentrations. In contrast, HER2-specific T cells decreased markedly sarcosphere formation capacity and the ability to generate bone tumors in immunodeficient mice after orthotopic transplantation. In vivo, administration of HER2-specific T cells significantly reduced TICs in bulky tumors as judged by decreased sarcosphere forming efficiency in OS cells isolated from explanted tumors. We demonstrate that HER2-specific T cells target drug resistant TICs in established OS cell lines, suggesting that incorporating immunotherapy into current treatment strategies for OS has the potential to improve outcomes. PMID:22173710

  3. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice

    PubMed Central

    Mirsoian, Annie; Bouchlaka, Myriam N.; Sckisel, Gail D.; Chen, Mingyi; Pai, Chien-Chun Steven; Maverakis, Emanuel; Spencer, Richard G.; Fishbein, Kenneth W.; Siddiqui, Sana; Monjazeb, Arta M.; Martin, Bronwen; Maudsley, Stuart; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L.; Blazar, Bruce R.; Wiltrout, Robert H.; Taub, Dennis D.

    2014-01-01

    Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF+ macrophages in response to ?CD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with ?CD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon ?CD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT. PMID:25366964

  4. Anti-amyloid beta to tau - based immunization: Developments in immunotherapy for Alzheimer disease

    PubMed Central

    Lambracht-Washington, Doris; Rosenberg, Roger N

    2014-01-01

    Immunotherapy might provide an effective treatment for Alzheimer disease (AD). A unique feature of AD immunotherapies is that an immune response against a self antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focussed on two possible targets in this regard: One is the inhibition of accumulation and deposition of Amyloid beta 1-42 (A?42), which is one of the major peptides found in senile plaques and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting A?42 as well as tau with the respective anti-A? or anti-tau antibodies can provide significant improvements in these mice. While anti-A? immunotherapy (active and passive immunizations) is already in several stages of clinical trials, tau based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phoshorylated tau was found, high interest has again focussed on further development of tau based therapies. While A? immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. And last but not least, targeting A? and tau simultaneously with immunotherapy might provide additional therapeutic effects as these two pathologies are likely synergistic; an approach which has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about A?42 and tau biology, present on overview on halted, ongoing and upcoming clinical trials together with ongoing preclinical studies targeting tau or A?42. PMID:24926455

  5. Efficacy analysis of three-year subcutaneous SQ-standardized specific immunotherapy in house dust mite-allergic children with asthma

    PubMed Central

    HUI, YU; LI, LING; QIAN, JUN; GUO, YUN; ZHANG, XILIAN; ZHANG, XIAOJUAN

    2014-01-01

    The present study aimed to evaluate the efficacy of three-year subcutaneous SQ-standardized specific immunotherapy (SCIT) in house dust mite (HDM)-allergic children with asthma. Ninety children with allergic asthma to HDMs, with or without allergic rhinitis, were randomly divided into two groups, the treatment group and the control group. The treatment group received SCIT combined with standardized glucocorticoid management and the control group received standardized glucocorticoid management alone for a period of three years. The mean daily dose of inhaled corticosteroids (ICSs), a four-week diary recording the symptom scores of asthma, peak expiratory flow (PEF) measurements, skin prick test results and serum immunoglobulin E (IgE) levels were assessed prior to treatment and following one, two and three years of treatment. The median dose of ICS was reduced in the treatment group after two and three years of treatment compared with that of the control group. After three years of treatment, the discontinuation percentage of ICS in the treatment group was higher than that in the control group. The treatment group demonstrated significantly reduced daytime and night-time asthmatic symptom scores, increased PEF values and reduced serum IgE levels after two and three years of treatment compared with those in the control group (P<0.05). In conclusion, three-year SCIT treatment combined with ICS is an effective immunotherapy for children with allergic asthma and resulted in a reduction of the required ICS dose. PMID:24520258

  6. Novel Antibody-Based Proteins for Cancer Immunotherapy

    PubMed Central

    Fuenmayor, Jaheli; Montaño, Ramon F.

    2011-01-01

    The relative success of monoclonal antibodies in cancer immunotherapy and the vast manipulation potential of recombinant antibody technology have encouraged the development of novel antibody-based antitumor proteins. Many insightful reagents have been produced, mainly guided by studies on the mechanisms of action associated with complete and durable remissions, results from experimental animal models, and our current knowledge of the human immune system. Strikingly, only a small percent of these new reagents has demonstrated clinical value. Tumor burden, immune evasion, physiological resemblance, and cell plasticity are among the challenges that cancer therapy faces, and a number of antibody-based proteins are already available to deal with many of them. Some of these novel reagents have been shown to specifically increase apoptosis/cell death of tumor cells, recruit and activate immune effectors, and reveal synergistic effects not previously envisioned. In this review, we look into different approaches that have been followed during the past few years to produce these biologics and analyze their relative success, mainly in terms of their clinical performance. The use of antibody-based antitumor proteins, in combination with standard or novel therapies, is showing significant improvements in objective responses, suggesting that these reagents will become important components of the antineoplastic protocols of the future. PMID:24212958

  7. Active immunotherapy induces antibody responses that target tumor angiogenesis.

    PubMed

    Schoenfeld, Jonathan; Jinushi, Masahisa; Nakazaki, Yukoh; Wiener, Daniel; Park, Joosang; Soiffer, Robert; Neuberg, Donna; Mihm, Martin; Hodi, F Stephen; Dranoff, Glenn

    2010-12-15

    The inhibition of VEGF signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that antiangiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune-mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF-secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and angiopoietin-2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy-induced host response that broadly targets the angiogenic network in the tumor microenvironment. PMID:21159637

  8. A new take on comparative immunology; Relevance to immunotherapy

    PubMed Central

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

    2012-01-01

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

  9. [Study of indirect active immunotherapy of Ehrlich carcinoma].

    PubMed

    De Santana, C F; Da Silva, I N

    1974-12-01

    Preliminary results of active immunotherapy ,both in vitro and in vivo, about ascitical Ehrlich carcinoma transplanted in albinic swiss mice are presented. In the in vitro experiment, tumor cells were marked with the immunoglobulin, anti-tumor-associated antigens (TAA) and were coupled to a dinitrophenyl radical (Ig DNP anti-TAA). These cells were meaningfully hindered from migration in presence of swiss albinic mice's splenic cells. These mice were sensibilized to the tumor cells marked with Ig-DNP. The injection of a Ig-DNP anti-TAA 0,3 ml, every third days, intraperitoneal way, in a span of 21 days, in albinical swiss mice with a transplant of 3 X 10(5) Ehrlich carcinoma cells (group A) 24 hours before, constituted the in vivo test. The growth ought to be compared to an Ig-DNP tolerant group (group B), which received equal quantities of tumor cells and followed the same plan of treatment, as well as to another control group transplanted under the same conditions, but with no treatment (group C). Eight days from the experiment, there was a clear difference between group A and groups B and C. The last two groups died from 13th to the 26th day after the transplant. On the contrary, the whore group A continued alive and with no sign of ascitical tumor. Nevertheless, an animal of group A died after the 28th day, due to a solid tumor in the abdominal wall. PMID:4471334

  10. Molecular Alterations in Pediatric Sarcomas: Potential Targets for Immunotherapy

    PubMed Central

    Goletz, Theresa J.; Mackall, Crystal L.; Berzofsky, Jay A.

    1998-01-01

    Purpose/results/discussion. Recurrent chromosomal translocations are common features of many human malignancies. While such translocations often serve as diagnostic markers, molecular analysis of these breakpoint regions and the characterization of the affected genes is leading to a greater understanding of the causal role such translocations play in malignant transformation. A common theme that is emerging from the study of tumor-associated translocations is the generation of chimeric genes that, when expressed, frequently retain many of the functional properties of the wild-type genes from which they originated. Sarcomas, in particular, harbor chimeric genes that are often derived from transcription factors, suggesting that the resulting chimeric transcription factors contribute to tumorigenesis. The tumor-specific expression of the fusion proteins make them likely candidates for tumor-associated antigens (TAA) and are thus of interest in the development of new therapies. The focus of this review will be on the translocation events associated with Ewing's sarcomas/PNETs (ES), alveolar rhabdomyosarcoma (ARMS), malignant melanoma of soft parts (MMSP) (clear cell sarcoma), desmoplastic small round cell tumor (DSRCT), synovial sarcoma (SS), and liposarcoma (LS), and the potential for targeting the resulting chimeric proteins in novel immunotherapies. PMID:18521238

  11. Immunotherapy for Alzheimer’s disease: hoops and hurdles

    PubMed Central

    2013-01-01

    Alzheimer’s disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease. Extracellular plaques, containing various forms of amyloid-? protein (A?), and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated tau protein, are two major pathological hallmarks of the AD brain. Aggregation, deposition, and N-terminal modification of A? protein and tau phosphorylation and aggregation are thought to precede the onset of cognitive decline, which is better correlated with tangle formation and neuron loss. Active and passive vaccines against various forms of A? have shown promise in pre-clinical animal models. However, translating these results safely and effectively into humans has been challenging. Recent clinical trials showed little or no cognitive efficacy, possibly due to the fact that the aforementioned neurodegenerative processes most likely pre-existed in the patients well before the start of immunotherapy. Efforts are now underway to treat individuals at risk for AD prior to or in the earliest stages of cognitive decline with the hope of preventing or delaying the onset of the disease. In addition, efforts to immunize against tau and other AD-related targets are underway. PMID:24148220

  12. Active DNA A?42 vaccination as immunotherapy for Alzheimer disease

    PubMed Central

    Lambracht-Washington, Doris; Rosenberg, Roger N.

    2013-01-01

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

  13. Mast cells as targets for immunotherapy of solid tumors.

    PubMed

    Oldford, Sharon A; Marshall, Jean S

    2015-01-01

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

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

    PubMed Central

    Spencer, Brian; Masliah, Eliezer

    2014-01-01

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

  15. Seed-based oral vaccines as allergen-specific immunotherapies.

    PubMed

    Takaiwa, Fumio

    2011-03-01

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

  16. The Future of Sublingual Immunotherapy in the United States.

    PubMed

    Pleskovic, Nicole; Bartholow, Ashton; Gentile, Deborah A; Skoner, David P

    2015-08-01

    Sublingual immunotherapy (SLIT) is a safe and effective treatment for allergic rhinitis (AR) and allergic rhinoconjunctivitis (ARC). The Food and Drug Administration (FDA) in the USA has approved three SLIT tablets for the treatment of AR and ARC in relation to pollen. Specifically, Grastek® and Oralair® are two formulations approved to treat patients suffering with AR/ARC to grass pollen, and Ragwitek™ is a formulation approved to treat patients suffering with AR/ARC to ragweed pollen. Although these approvals provide support for physicians to prescribe SLIT, barriers to prescribing SLIT still remain such as FDA approval for additional formulations, a standard dose and dosing schedule, and cost/insurance coverage. In order to further support the use of SLIT, research is currently being conducted to expand the indication for SLIT to other common comorbidities to AR/ARC. For example, allergic asthma, food allergies, and atopic dermatitis are other diseases which are being explored. The future of SLIT in the USA is unknown; however, education will be necessary for both providers and patients. PMID:26149585

  17. Immunocompetent murine models for the study of glioblastoma immunotherapy

    PubMed Central

    2014-01-01

    Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor-induced immunosuppressive mechanisms that promote immune escape and immuno-resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches. PMID:24779345

  18. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy.

    PubMed

    Leconet, W; Larbouret, C; Chardès, T; Thomas, G; Neiveyans, M; Busson, M; Jarlier, M; Radosevic-Robin, N; Pugnière, M; Bernex, F; Penault-Llorca, F; Pasquet, J-M; Pèlegrin, A; Robert, B

    2014-11-20

    AXL receptor tyrosine kinase (RTK) is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated antihuman AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting growth arrest-specific factor 6 (GAS6) binding, induced downexpression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy. PMID:24240689

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

    PubMed Central

    2013-01-01

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

  20. Combined hyperthermia and immunotherapy treatment of multiple pulmonary metastases in mice.

    PubMed

    Strauch, E D; Fabian, D F; Turner, J; Lefor, A T

    1994-02-01

    The combination of immunotherapy and hyperthermia results in a greater reduction in tumour growth compared to either therapy used alone in a murine subcutaneous tumour model. To evaluate this combination further we tested it in a murine pulmonary metastasis model. Mice were given 5 x 10(5) MCA-105 sarcoma cells on day 0 intravenously resulting in the formation of pulmonary metastases. Mice were treated with local hyperthermia to the left hemithorax with a transcutaneous microwave applicator or with whole-body hyperthermia to 41 degrees C for 30 min on days 3 and 6. Immunotherapy included 5 x 10(7) syngeneic LAK cells administered on days 3 and 6 and interleukin-2 given intraperitoneally three times daily on days 3-7. Animals were killed on day 12 and pulmonary nodules enumerated. While the addition of whole-body hyperthermia to immunotherapy had no significant effect on tumour growth, the combination of local hyperthermia and immunotherapy significantly decreased the number of pulmonary nodules by 94% compared to controls in combined experiments. The mechanism of this beneficial effect may be related to increased trafficking of immune active cells to the tumour-bearing site, an increase in the sensitivity of tumour cells to lysis, or perhaps a local release of cytokines induced by hyperthermia. This study established the efficacy of combined immunotherapy and hyperthermia for the treatment of visceral metastases and provides impetus for the initiation of clinical trials. PMID:8186870

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

    Microsoft Academic Search

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

    1998-01-01

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

  2. Impact of T cell selection methods in the success of clinical adoptive immunotherapy.

    PubMed

    Ramírez, Natalia; Beloki, Lorea; Ciaúrriz, Miriam; Rodríguez-Calvillo, Mercedes; Escors, David; Mansilla, Cristina; Bandrés, Eva; Olavarría, Eduardo

    2014-04-01

    Chemotherapy and/or radiotherapy regular regimens used for conditioning of recipients of hematopoietic stem cell transplantation (SCT) induce a period of transient profound immunosuppression. The onset of a competent immunological response, such as the appearance of viral-specific T cells, is associated with a lower incidence of viral infections after haematopoietic transplantation. The rapid development of immunodominant peptide virus screening together with advances in the design of genetic and non-genetic viral- and tumoural-specific cellular selection strategies have opened new strategies for cellular immunotherapy in oncologic recipients who are highly sensitive to viral infections. However, the rapid development of cellular immunotherapy in SCT has disclosed the role of the T cell selection method in the modulation of functional cell activity and of in vivo secondary effects triggered following immunotherapy. PMID:24077876

  3. Immunotherapy for urothelial cancer: from BCG to checkpoint inhibitors and beyond.

    PubMed

    Wu, Yin; Enting, Deborah; Rudman, Sarah; Chowdhury, Simon

    2015-05-01

    Since its introduction almost 40 years ago, intravesical BCG for non-muscle invasive bladder cancer remains one of the most successful cancer immunotherapies. However, up to 40% of patients will progress after BCG therapy and develop invasive bladder cancer. Despite its extensive clinical use, we are only beginning to understand how BCG works. Here we review preclinical and clinical data that implicate BCG-induced Th1 and cytotoxic cellular immune responses in cancer regression. We propose that future immunotherapies should aim to augment Th1 and/or cellular responses in those that fail BCG therapy. We review clinical trials of immunotherapy in bladder cancer with a focus on the promising role of checkpoint blockade inhibitors that target the programmed cell death 1/programmed death-ligand 1 (PD-L1) axis and/or cytotoxic T lymphocyte antigen 4. PMID:25882710

  4. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges

    PubMed Central

    2013-01-01

    Recent years have witnessed much progress in both basic research and clinical trials regarding cancer immunotherapy with chimeric antigen receptor (CAR)-engineered T cells. The unique structure of CAR endows T cell tumor specific cytotoxicity and resistance to immunosuppressive microenvironment in cancers, which helps patients to better tackle the issue of immunological tolerance. Adoptive immunotherapy (AIT) using this supernatural T cell have gained momentum after decades of intense debates because of the promising results obtained from preclinical models and clinical trials. However, it is very important for us to evaluate thoroughly the challenges/obstacles before widespread clinical application, which clearly warrants more studies to improve our understanding of the mechanism underlying AIT. In this review, we focus on the critical issues related to the clinical outcomes of CAR-based adoptive immunotherapy and discuss the rationales to refine this new cancer therapeutic modality. PMID:23829929

  5. Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration

    PubMed Central

    Martínez-Fernández de la Cámara, Cristina; Hernández-Pinto, Alberto M.; Olivares-González, Lorena; Cuevas-Martín, Carmen; Sánchez-Aragó, María; Hervás, David; Salom, David; Cuezva, José M.; de la Rosa, Enrique J.; Millán, José M; Rodrigo, Regina

    2015-01-01

    Growing evidence suggests that inflammation is involved in the progression of retinitis pigmentosa (RP) both in patients and in animal models. The aim of this study was to investigate the effect of Adalimumab, a monoclonal anti-TNF? antibody, on retinal degeneration in a murine model of human autosomal recessive RP, the rd10 mice at postnatal day (P) 18. In our housing conditions, rd10 retinas were seriously damaged at P18. Adalimumab reduced photoreceptor cell death, as determined by scoring the number of TUNEL-positive cells. In addition, nuclear poly (ADP) ribose (PAR) content, an indirect measure of PAR polymerase (PARP) activity, was also reduced after treatment. The blockade of TNF? ameliorated reactive gliosis, as visualized by decreased GFAP and IBA1 immunolabelling (Müller cell and microglial markers, respectively) and decreased up-regulation of TNF? gene expression. Adalimumab also improved antioxidant response by restoring total antioxidant capacity and superoxide dismutase activity. Finally, we observed that Adalimumab normalized energetic and metabolic pattern in rd10 mouse retinas. Our study suggests that the TNF? blockade could be a successful therapeutic approach to increase photoreceptor survival during the progression of RP. Further studies are needed to characterize its effect along the progression of the disease. PMID:26170250

  6. Allergen specific immunotherapy has no influence on standard chemistry and hematology laboratory parameters in clinical studies

    PubMed Central

    2014-01-01

    Background A set of standard clinical chemistry and hematology parameters are usually measured during clinical studies. The major outcome of these standard tests is to control that the drug investigated does not lead to pathophysiological changes in respective organs or blood. In some cases based on scientific rationale such tests may not be needed. In this paper we report on a standard set of clinical chemistry and hematology laboratory parameters measured before and after treatment in three different immunotherapy studies, representing different routes of administration and different formulations. Methods Thirteen hematological laboratory parameters and eight clinical chemistry parameters were evaluated from three double-blind, placebo-controlled, randomized, multi-centre, phase III studies. The three studies include one with sublingual immunotherapy (n?=?185), one subcutaneous immunotherapy trial with an aluminium hydroxide-adsorbed recombinant hypoallergenic Bet v1-FV (n?=?211) and one with pre-seasonal subcutaneous immunotherapy with a 6-grass pollen allergoid (n?=?154). Results Allergen specific immunotherapy with both administration forms and formulations respectively did not show any influence on any of the 21 laboratory parameters analyzed. Few patients had a change in laboratory parameters from within normal range at baseline to either below or above at end-of-treatment. No differences between active and placebo were seen with respect to number of patients with such a change. Conclusions This study with different preparations and routes of application indicates that the value of repeated measurements of standard clinical chemistry and hematology parameters during allergen immunotherapy should be discussed further. PMID:24955235

  7. ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy

    PubMed Central

    Li, Chunyang; Li, Weiyun; Xiao, Jun; Jiao, Shaozhuo; Teng, Fei; Xue, Shengjie; Zhang, Chi; Sheng, Chun; Leng, Qibin; Rudd, Christopher E; Wei, Bin; Wang, Hongyan

    2015-01-01

    PD-1 negatively regulates CD8+ cytotoxic T lymphocytes (CTL) cytotoxicity and anti-tumor immunity. However, it is not fully understood how PD-1 expression on CD8+ CTL is regulated during anti-tumor immunotherapy. In this study, we have identified that the ADAP-SKAP55 signaling module reduced CD8+ CTL cytotoxicity and enhanced PD-1 expression in a Fyn-, Ca2+-, and NFATc1-dependent manner. In DC vaccine-based tumor prevention and therapeutic models, knockout of SKAP55 or ADAP showed a heightened protection from tumor formation or metastases in mice and reduced PD-1 expression in CD8+ effector cells. Interestingly, CTLA-4 levels and the percentages of tumor infiltrating CD4+Foxp3+ Tregs remained unchanged. Furthermore, adoptive transfer of SKAP55-deficient or ADAP-deficient CD8+ CTLs significantly blocked tumor growth and increased anti-tumor immunity. Pretreatment of wild-type CD8+ CTLs with the NFATc1 inhibitor CsA could also downregulate PD-1 expression and enhance anti-tumor therapeutic efficacy. Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy. PMID:25851535

  8. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice.

    PubMed

    Jeanbart, Laura; Kourtis, Iraklis C; van der Vlies, André J; Swartz, Melody A; Hubbell, Jeffrey A

    2015-08-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress effector T cell responses and can reduce the efficacy of cancer immunotherapies. We previously showed that ultra-small polymer nanoparticles efficiently drain to the lymphatics after intradermal injection and target antigen-presenting cells, including Ly6c(hi) Ly6g(-) monocytic MDSCs (Mo-MDSCs), in skin-draining lymph nodes (LNs) and spleen. Here, we developed ultra-small polymer micelles loaded with 6-thioguanine (MC-TG), a cytotoxic drug used in the treatment of myelogenous leukemia, with the aim of killing Mo-MDSCs in tumor-bearing mice and thus enhancing T cell-mediated anti-tumor responses. We found that 2 days post-injection in tumor-bearing mice (B16-F10 melanoma or E.G7-OVA thymoma), MC-TG depleted Mo-MDSCs in the spleen, Ly6c(lo) Ly6g(+) granulocytic MDSCs (G-MDSCs) in the draining LNs, and Gr1(int) Mo-MDSCs in the tumor. In both tumor models, MC-TG decreased the numbers of circulating Mo- and G-MDSCs, as well as of Ly6c(hi) macrophages, for up to 7 days following a single administration. MDSC depletion was dose dependent and more effective with MC-TG than with equal doses of free TG. Finally, we tested whether this MDSC-depleting strategy might enhance cancer immunotherapies in the B16-F10 melanoma model. We found that MC-TG significantly improved the efficacy of adoptively transferred, OVA-specific CD8(+) T cells in melanoma cells expressing OVA. These findings highlight the capacity of MC-TG in depleting MDSCs in the tumor microenvironment and show promise in promoting anti-tumor immunity when used in combination with T cell immunotherapies. PMID:25982370

  9. Enhanced dendritic cell-based immunotherapy using low-dose cyclophosphamide and CD25-targeted antibody for transplanted Lewis lung carcinoma cells.

    PubMed

    Son, Cheol-Hun; Bae, Jae-Ho; Lee, Hong-Rae; Shin, Dong-Yeok; Yang, Kwangmo; Park, You-Soo

    2015-04-01

    Regulatory T cells (Tregs) is one of the main obstacles to the success of cancer immunotherapy. The effect of dendritic cell (DC)-based immunotherapy can be attenuated by immune suppressive functions of Tregs. We used a CD25-targeted antibody and low-dose cyclophosphamide (CTX) as immunomodulators to increase the antitumor effect of intratumoral injection of immature DCs into the irradiated tumor cells (IR/iDC). CTX or CD25-targeted antibody alone showed a significant reduction in the number of Tregs within the tumor microenvironment. When they are combined with IR/iDC, the number of Tregs was further reduced. Although IR/IDC showed strong antitumor effects such as reduction in tumor growth, increase in Th1 immune response, and improvement of survival, the therapeutic effect was further improved by combining treatments with immunomodulators. CTX and CD25-targeted antibody showed no significant difference in tumor growth when combined with IR/iDC, but CTX further increased the number of interferon (IFN)-?-secreting T cells, cytotoxicity, and survival rate. Although irradiation induced depletion of T lymphocytes, administration of DCs recovered this depletion. Particularly, the lymphocytes were more significantly increased when CTX and IR/iDC were combined. Low-dose CTX has already been used as an immunomodulator in clinical trials, and it offers several advantages, including convenience, low-cost, and familiarity to clinicians. However, CD25-targeted antibody cannot only deplete Tregs, but also may affect IL-2-dependent effector T lymphocytes. Therefore, CTX is an effective means to inhibit Tregs, and an effective immunomodulatory agent for multimodality therapy such as combination treatment of conventional cancer therapy and immunotherapy. PMID:25751500

  10. Specific immunotherapy in Albanian patients with anaphylaxis to hymenoptera venoms

    PubMed Central

    Mingomataj, Ervin; Priftanji, Alfred; Qirko, Etleva; Dinh, Q Thai; Fischer, Axel; Peiser, Christian; Groneberg, David A

    2002-01-01

    Background Severe allergic reactions during rush-specific immunotherapy (Rush-SIT) may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during Rush-SIT in a cohort of patients with allergy towards hymenoptera venom in the mediterranean population of Albania. Methods A retrospective study was performed using the clinical reports of 37 patients with venom of bee (apinae), wasp (vespidae, subfamily vespinae) or paperwasp (vespidae, subfamily polistinae) allergy treated with Rush-SIT between 1987 and 1996. After hymenoptera sting allergy diagnosis according to anamnesis and intracutaneous tests the patient were treated with Rush-SIT. The protocol lasted 3 – 4 d with an increase in the concentration from 0.01 ?g/ml to 100 ?g/ml. Anaphylactic reactions were classified according to the Mueller-classification. Results The frequency of reactions during Rush-SIT for bee-venom was 4.7% and for wasp-venom was 1.5% (p < 0.01). The mean frequency of reactions of Mueller grade II for the bee-venom Rush-SIT patients during the first 4 d (= 26 injections) was 0.73 and for the wasp-venom Rush-SIT patients 0.15. No patient experienced a third-degree reaction. 94.6% of the patient supported an end dose of 100 ?g. Conclusions Rush-SIT is a reliable method for the treatment of anaphylactic reactions to hymenoptera venom even in less developed countries. Bee-venom Rush-SIT was found to cause higher numbers allergic reactions than wasp or paperwasp Rush-SIT. PMID:12201901

  11. Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice

    PubMed Central

    Horikawa, Mayuka; Minard-Colin, Veronique; Matsushita, Takashi; Tedder, Thomas F.

    2011-01-01

    Current therapies for non-Hodgkin lymphoma commonly include CD20 mAb to deplete tumor cells. However, the response is not durable in a substantial proportion of patients. Herein, we report our studies in mice testing the hypothesis that heterogeneity in endogenous tissue CD20+ B cell depletion influences in vivo lymphoma therapy. Using highly effective CD20 mAbs that efficiently deplete endogenous mature B cells and homologous CD20+ primary lymphoma cells through monocyte- and antibody-dependent mechanisms, we found that lymphoma depletion and survival were reduced when endogenous host B cells were not depleted, particularly a rare IL-10–producing B cell subset (B10 cells) known to regulate inflammation and autoimmunity. Even small numbers of adoptively transferred B10 cells dramatically suppressed CD20 mAb–mediated lymphoma depletion by inhibiting mAb-mediated monocyte activation and effector function through IL-10–dependent mechanisms. However, the activation of innate effector cells using a TLR3 agonist that did not activate B10 cells overcame the negative regulatory effects of endogenous B10 cells and enhanced lymphoma depletion during CD20 immunotherapy in vivo. Thus, we conclude that endogenous B10 cells are potent negative regulators of innate immunity, with even small numbers of residual B10 cells able to inhibit lymphoma depletion by CD20 mAbs. Consequently, B10 cell removal could provide a way to optimize CD20 mAb–mediated clearance of malignant B cells in patients with non-Hodgkin lymphoma. PMID:22019587

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

    NASA Astrophysics Data System (ADS)

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

    2003-03-01

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

  13. Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy

    PubMed Central

    Maazi, H; Shirinbak, S; den Boef, L E; Fallarino, F; Volpi, C; Nawijn, M C; van Oosterhout, A J M

    2013-01-01

    Allergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic T lymphocyte antigen 4–immunoglobulin (CTLA-4–Ig) has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co-stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA-4–Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA-4–Ig acts as an adjuvant for experimental SIT. We evaluated the adjuvant effects of CTLA-4–Ig on SIT in a mouse model of ovalbumin-driven asthma. We used both wild-type and IDO-deficient mice to assess the role of IDO in the adjuvant effects of CTLA-4–Ig. Co-administration of CTLA-4–Ig strongly increased SIT-induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA-4–Ig, as an adjuvant for SIT, is equally effective in IDO-deficient and wild-type mice, demonstrating that the effect of CTLA-4–Ig is independent of IDO expression. We show that CTLA-4–Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA-4–Ig is independent of IDO, we conclude that it acts by blocking CD28-mediated T cell co-stimulation. PMID:23480191

  14. Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy

    PubMed Central

    Pender, Michael P; Burrows, Scott R

    2014-01-01

    Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein–Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV-specific CD8+ T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8+ T cells, activation of innate immunity by EBV-encoded small RNA molecules in the CNS, expression of ?B-crystallin in EBV-infected B cells leading to a CD4+ T-cell response against oligodendrocyte-derived ?B-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8+ T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production. PMID:25505955

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

    Microsoft Academic Search

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

    2006-01-01

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

  16. Sublingual Immunotherapy Efficacy of Dermatophagoides farinae Vaccine in a Murine Asthma Model

    Microsoft Academic Search

    Hai-qiong Yu; Xiang-hui Li; Hua Guo; Zhi-gang Liu; Pei-xin Ran; Kun-mei Ji; Jun Wang

    2010-01-01

    Background: Allergen-specific sublingual immunotherapy is a potential treatment for allergic diseases. Its effective dose and underlying mechanism are still to be explored. Here, we investigated the efficacy and mechanism of sublingually administered Dermatophagoides farinae (Der f) vaccine in a murine asthma model. Methods: BALB\\/c mice were sensitized intraperitoneally with Der f extract absorbed to alum, followed by sublingual treatment with

  17. Process Development for Standardized Generation of Monocyte-Derived Dendritic Cells: Applicability in Breast Cancer Immunotherapy

    Microsoft Academic Search

    H. R. BOHNENKAMP; T. Noll

    There is increasing interest in the generation of dendritic cells (DC) for cancer immunotherapy. In order to utilize DC in clinical trials the necessity of standardized, reproducible and easy to use protocols are the matter of interest. We describe here the process development for the generation of DC as the result of investigation of culture conditions as well as consumption

  18. Active Specific Immunotherapy for Melanoma: Phase I Trial of Allogeneic Lysates and a Novel Adjuvant1

    Microsoft Academic Search

    Malcolm S. Mitchell; June Kan-Mitchell; Raymond A. Kempf; Hungyi Shau; Susan Lind

    A Phase I trial of active specific immunotherapy for melanoma was performed to measure the toxicity and immunological effects of the therapy. A mixture of mechanical lysates (homogenates) of two melanoma cell lines was injected together with a novel adjuvant, DETOX, into 22 patients. Several types of cell-mediated and humoral immunity to mela noma-associated antigens were measured serially. In the

  19. SOY IMMUNOTHERAPY FOR PEANUT-ALLERGIC MICE: MODULATION OF THE PEANUT-ALLERGIC RESPONSE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background Allergen-specific immunotherapy (IT) is an effective therapeutic modality to prevent further anaphylactic episodes in patients with insect sting hypersensitivity and is being investigated for peanut allergy. So far, peanut-specific IT has been unsuccessful because of the side effects of ...

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

    SciTech Connect

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

    2013-11-15

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

  1. Experimental investigations on the immunomodulating activity of polybacterial preparation for peroral immunotherapy and immunoprophylaxis of uroinfections

    Microsoft Academic Search

    P. Nenkov; I. Mitov; S. Marinova; R. Markova

    1995-01-01

    The immunomodulating effect of a polybacterial immunostimulator Urostim in experimental animal models was investigated. The preparation was created for immunotherapy and immunoprophylaxis of uroinfections. It consists of killed bacterial cells and their lysates of four microbial species: Escherichia coli expressing type 1 pili, Rc mutant of E. coli, Klebsiella pneumoniae, Proteus mirabilis and Enterococcus faecalis, BALB\\/c mice and guinea-pigs were

  2. Immunotherapy against antibiotic-resistant bacteria: the Russian experience with an antistaphylococcal hyperimmune plasmaand immunoglobulin

    Microsoft Academic Search

    Jeanne Kelly

    2000-01-01

    The Russian experience with the preparation and clinical application of an antitoxic antistaphylococcal hyperimmune plasma and immunoglobulin is described. The immunotherapies were developed in the late 1960s and put into widespread use in the Soviet Union for the prophylaxis and treatment of sepsis, pneumonia, and other conditions caused by an epidemic of antibiotic-resistant Staphylococcus aureus.

  3. Prevention of manifest metastasis with monoclonal antibodies: A novel approach to immunotherapy of solid tumours

    Microsoft Academic Search

    E Schneider-Gädicke; G Riethmüller

    1995-01-01

    Until now, surgery, chemotherapy and radiotherapy have remained the mainstay of current cancer therapy. The major limitation of chemo- and radiotherapy is their narrow therapeutic index between cancer and normal cells. In the search for less toxic and more specific therapies, various modalities of immunotherapy have been tried. It is now increasingly recognised that patients presenting with minimal cancer burden

  4. Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy.

    PubMed

    Burton, Bronwen R; Britton, Graham J; Fang, Hai; Verhagen, Johan; Smithers, Ben; Sabatos-Peyton, Catherine A; Carney, Laura J; Gough, Julian; Strobel, Stephan; Wraith, David C

    2014-01-01

    Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4(+) T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4(+) T cells. Analysis of the CD4(+) T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4(+) T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy. PMID:25182274

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

    Cancer.gov

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

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

    PubMed Central

    2010-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Behrmann, Jason

    2010-01-01

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

  9. Immunotherapy in allergic fungal sinusitis: The controversy continues. A recent review of literature.

    PubMed

    Doellman, Mary S; Dion, Gregory R; Weitzel, Erik Kent; Reyes, Erika Gonzalez

    2013-01-01

    Allergic fungal sinusitis (AFS), also referred to as allergic fungal rhinosinusitis (AFRS), is a noninvasive, eosinophilic form of recurrent chronic allergic hypertrophic rhinosinusitis. AFS has distinct clinical, histopathological, and prognostic findings that differentiate it from other forms of sinusitis. The core pathogenesis and optimum treatment strategies remain debated. Concerns surround the use of immunotherapy for AFS because allergen-specific immunoglobulin G (IgG) induced by immunotherapy could theoretically incite a Gell and Coombs type III (complex mediated) reaction. Type I hypersensitivity is established by high serum levels of allergen-specific IgE to various fungal antigens and positive Bipolaris skin test results. Type III hypersensitivity is established by an IgG-mediated process defined by the presence of allergen-specific IgG that forms complexes with fungal antigen inducing an immunologic inflammatory response. These reveal the multiple immunologic pathways through which AFS can impact host responses. Recent literature establishing benefits of fungal immunotherapy and no evidence of type III-mediated reactions, severe local reactions, or delayed reactions, indicate that application of AFS desensitization is a reasonable therapeutic strategy for this difficult to manage entity. Our review should encourage further clinical acceptance of AFS desensitization because the existing literature on this subject shows benefits of fungal immunotherapy and no evidence of type III-mediated reactions, severe local reactions, or delayed reactions. PMID:23772324

  10. Birch and ragweed pollen immunotherapy in the treatment of pollen-food allergy syndrome

    Microsoft Academic Search

    A. H. Nowak-Wegrzyn; S. Mofidi; S. Ma; L. Bardina; K. Beyer

    2004-01-01

    RationaleFruit\\/vegetable allergy affects up to 50% of pollen-allergic adults. Pollen sensitization is regarded as the primary event with subsequent development of allergy to cross-reactive fruits and vegetables. We sought to determine the effect of pollen immunotherapy on pollen-food allergy syndrome.

  11. Effective anti-tumor adoptive immunotherapy: utilization of exogenous IL2-independent cytotoxic T lymphocyte clones

    Microsoft Academic Search

    Michihiro Iwashiro; Wang Jinyan; Masaaki Toda; Wang Linan; Takuma Kato; Kagemasa Kuribayashi

    2002-01-01

    To attain one of the final goals for cancer immunotherapy, cytotoxic T lymphocyte (CTL) clones were selected on the basis of exogenous IL-2 independence after limiting dilution culture from mixed lymphocyte tumor cell culture cells of FBL-3 tumor-immune spleens. About 10% of the clones could be propagated up to >5 times by weekly passages in the presence of splenic feeder

  12. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: More than one plus one?

    Microsoft Academic Search

    Sharmilan Thanendrarajan; Michael Nowak; Hinrich Abken; Ingo G. H. Schmidt-Wolf

    2011-01-01

    The immune system can be harnessed to fight cancer by active (stimulating the patient's intrinsic immune response to cancer) and by passive (transfer of active humoral or cellular immunity) immunotherapy. While for each strategy proof-of-principle was provided, clinical benefit was limited likely due to malfunction of lymphocytes. Increasing knowledge of both the mechanism of vaccination through dendritic cells (DCs) and

  13. Specific active immunotherapy in advanced renal cell carcinoma: A clinical longterm follow-up study

    Microsoft Academic Search

    T. Tallberg; H. Tykkä

    1986-01-01

    The results of a 15-year follow-up study on 127 patients with renal cell carcinoma treated with immunotheapy are presented. All patients were suffering from advanced renal cell carcinoma and were treated by palliative nephrectomy and specific active immunotherapy using polymerized autologous tumour tissue with adjuvant and supportive dietary measures. The longest survival time was 164 months. Of the patients nephrectomized

  14. Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors.

    PubMed

    Wang, Enxiu; Wang, Liang-Chuan; Tsai, Ching-Yi; Bhoj, Vijay; Gershenson, Zack; Moon, Edmund; Newick, Kheng; Sun, Jing; Lo, Albert; Baradet, Timothy; Feldman, Michael D; Barrett, David; Puré, Ellen; Albelda, Steven; Milone, Michael C

    2015-07-01

    Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3? and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity toward B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR). We show that this simple, KIR-based CAR (KIR-CAR) triggers robust antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunotyrosine-based activation motifs-containing adaptor. T cells modified to express a KIR-CAR and DAP12 exhibit superior antitumor activity compared with standard first- and second-generation CD3?-based CARs in a xenograft model of mesothelioma highly resistant to immunotherapy. The enhanced antitumor activity is associated with improved retention of chimeric immunoreceptor expression and improved effector function of isolated tumor-infiltrating lymphocytes. These results support the exploration of KIR-CARs for adoptive T-cell immunotherapy, particularly in immunotherapy-resistant solid tumors. Cancer Immunol Res; 3(7); 815-26. ©2015 AACR. PMID:25941351

  15. Biomarkers in amyloid-? immunotherapy trials in Alzheimer's disease.

    PubMed

    Blennow, Kaj; Hampel, Harald; Zetterberg, Henrik

    2014-01-01

    Drug candidates directed against amyloid-? (A?) are mainstream in Alzheimer's disease (AD) drug development. Active and passive A? immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-A? drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that A? deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-A? drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and A? biomarkers (CSF A?42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain A? pathology. Pharmacodynamic A? and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-A? drug as disease modifying. PMID:23799530

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

    PubMed Central

    Wood, Laurence M.; Paterson, Yvonne

    2014-01-01

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

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

    PubMed Central

    Srivastava, Neeharika; McDermott, David

    2014-01-01

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

  18. Hepatoprotective Effect of Infliximab, an Anti-TNF-? Agent, on Carbon Tetrachloride-Induced Hepatic Fibrosis

    Microsoft Academic Search

    Ibrahim Halil Bahcecioglu; Suleyman Serdar Koca; Orhan Kursat Poyrazoglu; Mehmet Yalniz; Ibrahim Hanifi Ozercan; Bilal Ustundag; Kazim Sahin; Adile Ferda Dagli; Ahmet Isik

    2008-01-01

    To assess the effect of infliximab, an anti-tumor necrosis factor (TNF)-? agent, on the carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats. Rats were randomized into three groups (n?=?9). The control group received only intraperitoneal (i.p.) olive oil. Hepatic fibrosis was induced by repeated i.p. injections\\u000a of 1.5 ml\\/kg CCl4 (1:3 mixture with olive oil) for 5 weeks in the remaining two groups

  19. Monitoring patients treated with anti-TNF-  biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies

    Microsoft Academic Search

    M. Svenson; P. Geborek; T. Saxne; K. Bendtzen

    2007-01-01

    Objectives. Infliximab is an anti-tumour necrosis factor-? (TNF-? ) mouse-human IgG1\\/? antibody used to treat patients with rheumatoid arthritis (RA) and other inflammatory diseases. Unfortunately, response failure and side-effects due to immunogenicity of the drug are not rare. In this study, we have compared different methods of assessing drug levels and anti-infliximab antibodies (Abs) and analysed the character of these

  20. Everyday Cognitive Failure in Sarcoidosis: The Prevalence and the Effect of Anti-TNF-? Treatment

    Microsoft Academic Search

    Marjon D. Elfferich; Patty J. Nelemans; Rudolf W. Ponds; Jolanda De Vries; Petal A. Wijnen; Marjolein Drent

    2010-01-01

    Background: Cognitive symptoms, such as concentration problems, are frequently recorded by sarcoidosis patients. Objectives: The aim of this study was to assess the prevalence of perceived everyday cognitive failure in sarcoidosis patients and healthy controls. Furthermore, the effect of treatment on cognitive functioning was examined. Methods: The study included 343 sarcoidosis patients (44.6% females; age 49.3 ± 11.0 years). They

  1. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms.

    PubMed

    Ordás, Ingrid; Mould, Diane R; Feagan, Brian G; Sandborn, William J

    2012-04-01

    Crohn's disease and ulcerative colitis are chronic inflammatory disorders resulting from immune dysregulation. Patients who fail conventional medical therapy require biological treatment with monoclonal antibodies (mAbs). Although mAbs are highly effective for induction and maintenance of clinical remission, not all patients respond, and a high proportion of patients lose response over time. One factor associated with loss of response is immunogenicity, whereby the production of antidrug antibodies accelerates mAb clearance. However, other factors related to patient and disease characteristics also influence the pharmacokinetics of mAbs. These factors include gender, body size, concomitant use of immunosuppressive agents, disease type, serum albumin concentration, and the degree of systemic inflammation. Because it is important to maintain clinically effective concentrations to provide optimal clinical response and drug exposure is affected by patient factors, a better understanding of the pharmacology of mAbs will ultimately result in better patient care. PMID:22357456

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

    Microsoft Academic Search

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

    2009-01-01

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

  3. Failure of anti-TNF therapy to reactivate previously septic prosthetic joints

    PubMed Central

    Manolios, Nicholas; Burneikis, Anthony; Spencer, David; Howe, Graydon

    2013-01-01

    A patient with long-standing rheumatoid arthritis was admitted with Streptococcus pneumoniae septicaemia and bilateral septic knee joints. He was treated conservatively with intravenous antibiotics and arthroscopic washouts and discharged home on oral antibiotics. Six months posthospital discharge, following re-exacerbation of arthritis, an informed consent was given by the patient to continue antitumour necrosis factor therapy. After 5?years of observation, there has been no recurrence of sepsis and the rheumatoid arthritis remains in remission. PMID:23839609

  4. Do anti-TNF agents have equal efficacy in patients with rheumatoid arthritis?

    Microsoft Academic Search

    Sergio Schwartzman; Roy Fleischmann; G James Morgan Jr

    2004-01-01

    Tumor necrosis factor (TNF) antagonists have dramatically improved the outcomes of rheumatoid arthritis (RA). Three agents currently available in the USA – infliximab, etanercept, and adalimumab – have been designed to modify the biologic effects of TNF. Infliximab and adalimumab are monoclonal antibodies, and etanercept is a soluble protein. The pharmacokinetic and pharmacodynamic properties of each differs significantly from those

  5. A potential therapeutic effect of CYP2C8 overexpression on anti-TNF-? activity

    PubMed Central

    LIU, WANJUN; WANG, BEI; DING, HU; WANG, DAO WEN; ZENG, HESONG

    2014-01-01

    Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid catalysed by cytochrome P450 (CYP) epoxygenases. In addition to regulating vascular tone EETs may alleviate inflammation and ROS. The present study was conducted to determine whether CYP2C8 gene overexpression was able to increase the level of EETs, and subsequently prevent TNF-? induced inflammation and reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) and macrophages. Peroxisome proliferator-activated receptor ? (PPAR?) activation, nuclear factor-?B (NF-?B) activation, endothelial nitric oxide synthase (eNOS) activation, gp-91 activation, and inflammatory cytokine expression were detected by western blot analysis or enzyme-linked immunosorbent assay. Intracellular reactive oxygen species (ROS) was measured by flow cytometry, while the migration of vascular smooth muscle cells (VSMCs) was detected by Transwell assay. pCMV-mediated CYP2C8 overexpression and its metabolites, EETs, markedly suppressed TNF-? induced inflammatory cytokines IL-6 and MCP-1 expression via the activation of NF-?B and degradation of I?B?. Moreover, pretreatment with 11,12-EET significantly blocked TNF-?-induced ROS production. CYP2C8-derived EETs also effectively alleviated the migration of VSMCs and improved the function of endothelial cells through the upregulation of eNOS, which was significantly decreased under the stimulation of TNF-?. Furthermore, these protective effects observed were mediated by PPAR? activation. To the best of our knowledge, the results of the present study demonstrated for the first time that CYP2C8-derived EETs exerted antivascular inflammatory and anti-oxidative effects, at least in part, through the activation of PPAR?. Thus, the CYP2C8 gene may be useful in the prevention and treatment of vascular inflammatory diseases. PMID:25017038

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

    E-print Network

    Raychaudhuri, Soumya

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

  7. Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy.

    PubMed

    Henmar, H; Lund, G; Lund, L; Petersen, A; Würtzen, P A

    2008-09-01

    Different vaccines containing intact allergens or chemically modified allergoids as active ingredients are commercially available for specific immunotherapy. Allergoids are claimed to have decreased allergenicity without loss of immunogenicity and this is stated to allow administration of high allergoid doses. We compared the allergenicity and immunogenicity of four commercially available chemically modified grass pollen allergoid products with three commercially available intact grass pollen allergen vaccines. The allergenicity was investigated with immunoglobulin (Ig)E-inhibition and basophil activation assays. Human T cell proliferation and specific IgG-titres following mouse immunizations were used to address immunogenicity. Furthermore, intact allergen vaccines with different contents of active ingredients were selected to study the influence of the allergen dose. In general, a lower allergenicity for allergen vaccines was clearly linked to a reduced immunogenicity. Compared with the vaccine with the highest amount of intact allergen, the allergoids caused reduced basophil activation as well as diminished immunogenicity demonstrated by reduced T cell activation and/or reduced induction of murine grass-specific IgG antibodies. Interestingly, intact allergen vaccines with lower content of active ingredient exhibited similarly reduced allergenicity, while immunogenicity was still higher or equal to that of allergoids. The low allergenicity observed for some allergoids was inherently linked to a significantly lower immunogenic response questioning the rationale behind the chemical modification into allergoids. In addition, the linkage between allergenicity, immunogenicity and dose found for intact allergen vaccines and the immunogen as well as allergenic immune responses observed for allergoids suggest that the modified allergen vaccines do not contain high doses of immunologically active ingredients. PMID:18647321

  8. Immunotherapy of hepatocellular carcinoma with autologous lymphokine-activated killer cells and\\/or recombinant interleukin-2

    Microsoft Academic Search

    Takashi Ishikawa; Michio Imawari; Takashi Moriyama; Shin Ohnishi; Nobuyuki Matsuhashi; Gen Suzuki; Fumimaro Takaku

    1988-01-01

    Five patients with hepatocellular carcinoma were subjected to immunotherapy: three patients were treated by adoptive immunotherapy with lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2), and two patients by systemic administration of rIL-2 alone. In one patient with diffuse-type hepatocellular carcinoma and portal vein thrombosis who was treated by infusion of LAK cells (a total number of 1.5x1010 cells\\/13 doses)

  9. Long-term Effects of Specific Allergen Immunotherapy Against House Dust Mites in Polysensitized Patients With Allergic Rhinitis

    PubMed Central

    Kim, Sang Hoon; Lee, Kun Hee; Kim, Sung Wan; Cho, Joong Saeng

    2014-01-01

    Purpose Allergen-specific immunotherapy is the only currently available treatment to modify the natural history of allergic rhinitis (AR). If patients are polysensitized, it is difficult to identify the allergen causing the allergic symptoms. We evaluated the effectiveness of immunotherapy against house dust mites (HDMs) in AR patients polysensitized to both HDMs and seasonal allergens. Methods Thirty AR patients polysensitized to both HDMs and seasonal allergens (group A) and 30 patients sensitized to HDMs only (group B) were enrolled in this study. All subjects who received immunotherapy against HDMs for more than 2 years were evaluated by the multiple allergen simultaneous test (MAST) to determine the specific IgE level in luminescence units, total eosinophil counts in peripheral blood, serum total IgE, total nasal symptom scores, and the rhinoconjunctivitis quality of life questionnaire (RQLQ) before and after immunotherapy. Results There were no statistical differences in levels of total and specific IgE, or total eosinophil count between the two groups. The total nasal symptom scores, RQLQ and medication scores significantly decreased after immunotherapy in both groups, however no significant differences were noted between the two groups. Conclusions We determined that the primary causative allergen of AR in Seoul, Korea is perennial allergens, such as HDMs, rather than seasonal allergens. This study provides a reference for the selection of allergens to use in immunotherapy for polysensitized AR patients living in an urban environment. PMID:25374753

  10. Sublingual allergoid immunotherapy: a new 4-day induction phase in patients allergic to house dust mites.

    PubMed

    D'Anneo, R W; Bruno, M E; Falagiani, P

    2010-01-01

    Sublingual immunotherapy with monomeric allergoid (allergoid SLIT), given according to the standard scheme, has proved effective and safe in many clinical trials. However, its build-up phase requires a long time ranging from 16 days to 14 weeks. This study therefore investigated whether, with a four-day up-dosing, the same benefit could be achieved in a shorter time. Thirty rhinitic and/or asthmatic patients (16 M and 14 F, mean age 36+/-8.2 years) allergic to house dust mites (HDM) with or without other sensitizations were randomized to allergoid SLIT or standard drug therapy. The build-up phase lasted four days. The first day the patients took a 300 AU tablet, the second day two 300 AU tablets, the third day three 300 AU tablets and the fourth day four 300 AU tablets. The total amount taken during the up-dosing was 3000 AU. Patients were then treated for 12 months at the dosage of 2000 AU/week (total amount of allergen: 104,000 AU/year). The symptom score and drug consumption were recorded from November to February on monthly diary cards. At baseline and after 12 months a Visual Analogue Scale (VAS) was used to rate the patients? well-being. Skin prick test reactivity was evaluated before and after the 12-month treatment in both groups using 10 mg/mL histamine as reference. VAS scores rose significantly (about 45%) in both groups in comparison to baseline (p=0.001). In addition, there was a significantly greater reduction of the global symptoms score (about 52%) - but not in drug consumption - in the SLIT group in comparison to controls (p=0.0004). The SLIT group showed a highly significant reduction (about 39%) in skin prick test reactivity (p=0.000003) while the control group remained unchanged (p=0.5226). No severe adverse events were observed. Even with this short four-day up-dosing, the allergoid SLIT proves to be safe. In addition, it is already effective in patients allergic to HDM after 12 months, and significantly reduces allergen-specific skin reactivity. PMID:20646350

  11. Allogeneic Cell-Mediated Immunotherapy at the Stage of Minimal Residual Disease following High-Dose Chemotherapy Supported by Autologous Stem Cell Transplantation

    Microsoft Academic Search

    Shimon Slavin

    2005-01-01

    Cumulative clinical experience suggests that immunotherapy may be an effective tool for eradicating tumor cells resistant to maximum tolerated doses of chemotherapy and radiation. Immunotherapy is much more effective when applied at the stage of minimal residual disease, especially against slowly growing tumors because development of graft-versus-leukemia, lymphoma, myeloma, or in a broader sense graft-versus-tumor effects renders immunotherapy more time

  12. Decline of Ves v 5-specific blocking capacity in wasp venom-allergic patients after stopping allergen immunotherapy.

    PubMed

    Möbs, C; Müller, J; Rudzio, A; Pickert, J; Blank, S; Jakob, T; Spillner, E; Pfützner, W

    2015-06-01

    While allergen-specific immunotherapy (AIT) is very efficient in hymenoptera venom (HV)-allergic patients, long-term outcome after finishing AIT is not well investigated, especially regarding mechanisms that are suggested to contribute to allergen-specific tolerance. Here, we analyse the Ves v 5-inhibitory activity of sera from wasp venom-allergic patients using the novel cell-free enzyme-linked immunosorbent facilitated antigen binding (ELIFAB) assay. Compared to pre-AIT, sera from patients undergoing AIT displayed an increased ability to inhibit Ves v 5 binding by IgE antibodies. In contrast, this inhibitory activity was reduced in patients having finished AIT 5-12 years ago. Allergen-blocking capacity correlated with serum concentrations of Ves v 5-specific IgG4 which rose during AIT but almost reached pretreatment levels in patients who had stopped AIT more than 5 years ago. These data raise questions about how long allergen tolerance is maintained in AIT-treated HV-allergic patients and suggest that the ELIFAB assay might be an easy-to-use tool assessing long-term tolerance in patients treated with HV-AIT. PMID:25753563

  13. Locally Advanced Lung Cancer: An Optimal Setting for Vaccines and Other Immunotherapies

    PubMed Central

    Iyengar, Puneeth; Gerber, David E.

    2013-01-01

    Lung cancer has traditionally been considered relatively resistant to immunotherapies. However, recent advances in the understanding of tumor-associated antigens, anti-tumor immune responses, and tumor immunosuppression mechanisms have resulted in a number of promising immunomodulatory therapies such as vaccines and checkpoint inhibitors. Locally advanced non-small cell lung cancer (NSCLC) is an optimal setting for these treatments because standard therapies such as surgery, radiation, and chemotherapy may enhance anti-tumor immune effects by debulking the tumor, increasing tumor antigen presentation, and promoting T-cell response and trafficking. Clinical trials incorporating immunomodulatory agents into combined modality therapy of locally advanced NSCLC have shown promising results. Future challenges include identifying biomarkers to predict those patients most likely to benefit from this approach, radiographic assessment of treatment effects, the timing and dosing of combined modality treatment including immunotherapies, and avoidance of potentially overlapping toxicities. PMID:23708072

  14. Natural and Induced Regulatory T Cells: Targets for Immunotherapy of Autoimmune Disease and Allergy

    PubMed Central

    Nicolson, K.S.; Wraith, D.C.

    2009-01-01

    Recent advances in immunology have greatly increased our understanding of immunological tolerance. In particular, there has been a resurgence of interest in mechanisms of immune regulation. Immune regulation refers to the phenomenon, previously known as immune suppression, by which excessive responses to infectious agents and hypersensitivities to otherwise innocuous antigens such as self antigens and allergens are avoided. We now appreciate that various distinct cell types mediate immune suppression and that some of these may be induced by appropriate administration of antigens, synthetic peptides and drugs of various types. The induction of antigen specific immunotherapy for treatment of autoimmune and allergic diseases remains the ‘holy grail’ for treatment of these diseases. This goal comes ever closer as understanding of the mechanisms of immune suppression and in particular antigen specific immunotherapy increases. Here we review evidence that immune suppression is mediated by various different subsets of CD4 T cells. PMID:16918477

  15. Cancer Immunotherapy Utilized Bubble Liposomes and Ultrasound as Antigen Delivery System

    NASA Astrophysics Data System (ADS)

    Oda, Yusuke; Otake, Shota; Suzuki, Ryo; Otake, Shota; Nishiie, Norihito; Hirata, Keiichi; Taira, Yuichiro; Utoguchi, Naoki; Maruyama, Kazuo

    2010-03-01

    In dendritic cells (DCs)-based cancer immunotherapy, it is important to present the epitope peptide derived from tumor associated antigens (TAAs) on MHC class I in order to induce tumor specific cytotoxic T lymphocytes (CTLs). However, MHC class I molecules generally present the epitope peptides derived from endogenous antigens for DCs but not exogenous ones such as TAAs. Recently, we developed the novel liposomal bubbles (Bubble liposomes) encapsulating perfluoropropane nanobubbles. In this study, we attempted to establish the novel antigen delivery system to induce MHC class I presentation using the combination of ultrasound and Bubble liposomes. Using ovalbumin (OVA) as model antigen, the combination of Bubble liposomes and ultrasound exposure for the DC could induce MHC class I presentation. In addition, the viability of DCs was more than 80%. These results suggest that Bubble liposomes might be a novel ultrasound enhanced antigen delivery tool in DC-based cancer immunotherapy.

  16. Cancer immunotherapy in clinical practice—the past, present, and future

    PubMed Central

    Goel, Gaurav; Sun, Weijing

    2014-01-01

    Considerable progress has been made in the field of cancer immunotherapy in recent years. This has been made possible in large part by the identification of new immune-based cellular targets and the development of novel approaches aimed at stimulating the immune system. The role played by the immunosuppressive microenvironment in the development of tumors has been established. The success of checkpoint-inhibiting antibodies and cancer vaccines has marked the beginning of a new era in cancer treatment. This review highlights the clinically relevant principles of cancer immunology and various immunotherapeutic approaches that have either already entered mainstream oncologic practice or are currently in the process of being evaluated in clinical trials. Furthermore, the current barriers to the development of effective immunotherapies and the potential strategies of overcoming them are also discussed. PMID:25189717

  17. Combination delivery of TGF-? inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

    NASA Astrophysics Data System (ADS)

    Park, Jason; Wrzesinski, Stephen H.; Stern, Eric; Look, Michael; Criscione, Jason; Ragheb, Ragy; Jay, Steven M.; Demento, Stacey L.; Agawu, Atu; Licona Limon, Paula; Ferrandino, Anthony F.; Gonzalez, David; Habermann, Ann; Flavell, Richard A.; Fahmy, Tarek M.

    2012-10-01

    The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-? (TGF-?), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-? inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

  18. Armed Therapeutic Viruses – A Disruptive Therapy on the Horizon of Cancer Immunotherapy

    PubMed Central

    Bauzon, Maxine; Hermiston, Terry

    2014-01-01

    For the past 150?years cancer immunotherapy has been largely a theoretical hope that recently has begun to show potential as a highly impactful treatment for various cancers. In particular, the identification and targeting of immune checkpoints have given rise to exciting data suggesting that this strategy has the potential to activate sustained antitumor immunity. It is likely that this approach, like other anti-cancer strategies before it, will benefit from co-administration with an additional therapeutic and that it is this combination therapy that may generate the greatest clinical outcome for the patient. In this regard, oncolytic viruses are a therapeutic moiety that is well suited to deliver and augment these immune-modulating therapies in a highly targeted and economically advantageous way over current treatment. In this review, we discuss the blockade of immune checkpoints, how oncolytic viruses complement and extend these therapies, and speculate on how this combination will uniquely impact the future of cancer immunotherapy. PMID:24605114

  19. Progress in the development of specific immunotherapies for house dust mite allergies.

    PubMed

    Moingeon, Philippe

    2014-12-01

    Allergen-specific immunotherapy is used to treat patients exposed and co-sensitized to the two common house dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae. Based on seroepidemiological studies and a detailed characterization of mite allergens, an optimal immunotherapeutic product should associate extracts from the two Dermatophagoides species, and include both bodies and fecal particles. Both subcutaneous and sublingual immunotherapies performed with aqueous mite extracts are safe and efficacious in children and adults with mite-induced rhinitis and/or asthma. Double-blind placebo-controlled studies are conducted to further document the efficacy of immunotherapeutic products, with promising results that were obtained already with sublingual tablets. Current developments of second-generation products relying upon recombinant allergens and peptides are reviewed. PMID:25187166

  20. Combination delivery of TGF-? inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy.

    PubMed

    Park, Jason; Wrzesinski, Stephen H; Stern, Eric; Look, Michael; Criscione, Jason; Ragheb, Ragy; Jay, Steven M; Demento, Stacey L; Agawu, Atu; Licona Limon, Paula; Ferrandino, Anthony F; Gonzalez, David; Habermann, Ann; Flavell, Richard A; Fahmy, Tarek M

    2012-10-01

    The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-? (TGF-?), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-? inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8(+) T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses. PMID:22797827

  1. Immunotherapy of Malignant Disease Using Chimeric Antigen Receptor Engrafted T Cells

    PubMed Central

    Maher, John

    2012-01-01

    Chimeric antigen receptor- (CAR-) based immunotherapy has been under development for almost 25 years, over which period it has progressed from a new but cumbersome technology to an emerging therapeutic modality for malignant disease. The approach involves the genetic engineering of fusion receptors (CARs) that couple the HLA-independent binding of cell surface target molecules to the delivery of a tailored activating signal to host immune cells. Engineered CARs are delivered most commonly to peripheral blood T cells using a range of vector systems, most commonly integrating viral vectors. Preclinical refinement of this approach has proceeded over several years to the point that clinical testing is now being undertaken at several centres, using increasingly sophisticated and therapeutically successful genetic payloads. This paper considers several aspects of the pre-clinical and clinical development of CAR-based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies. PMID:23304553

  2. Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants

    PubMed Central

    Nogueira, Lilian; Nishimura, Yoshiaki; Phad, Ganesh; West, Anthony P.; Halper-Stromberg, Ariel; Horwitz, Joshua A.; Gazumyan, Anna; Liu, Cassie; Eisenreich, Thomas R.; Lehmann, Clara; Fätkenheuer, Gerd; Williams, Constance; Shingai, Masashi; Martin, Malcolm A.; Bjorkman, Pamela J.; Seaman, Michael S.; Zolla-Pazner, Susan; Karlsson Hedestam, Gunilla B.; Nussenzweig, Michel C.

    2014-01-01

    Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian–human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants. PMID:25385756

  3. Clinical Implications of Minimal Residual Disease Monitoring for Stem Cell Transplantation after Reduced Intensity and Nonmyeloablative Conditioning

    Microsoft Academic Search

    Avichai Shimoni; Arnon Nagler

    2004-01-01

    Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for a variety of hematological malignancies; however, relapse and treatment-related toxicities are major obstacles to cure. Nonmyeloablative and reduced-intensity conditioning regimens were designed not to eradicate the malignancy completely, but rather to be immunosuppressive enough to allow engraftment, and to serve as a platform for additional cellular immunotherapy. Minimal residual

  4. An Observational Study on Outgrowing Food Allergy during Non-Birch Pollen-Specific, Subcutaneous Immunotherapy

    Microsoft Academic Search

    R. Alonso; E. Enrique; F. Pineda; M. Basagaña; M. M. San Miguel-Moncín; J. Bartra; R. Palacios; A. Cisteró-Bahíma

    2007-01-01

    Background: Birch pollen-specific immunotherapy (SIT) decreases allergy to foods containing birch pollen-homologous allergens. Cross-reactivity was also observed between plane tree pollen and some vegetable foods. Objective: The aim of this study was to evaluate the outgrowing of food allergy by patients suffering from vegetable food allergy associated with plane tree pollinosis (rhinoconjunctivitis and\\/or asthma) during plane tree pollen SIT. Methods:

  5. Impact of Sublingual Immunotherapy on Specific Antibody Levels in Asthmatic Children Allergic to House Dust Mites

    Microsoft Academic Search

    Nerin N. Bahceciler; Cigdem Arikan; Alison Taylor; Mubeccel Akdis; Kurt Blaser; Isil B. Barlan; Cezmi A. Akdis

    2005-01-01

    Objective: To evaluate the clinical outcome and changes in allergen-specific antibodies during sublingual immunotherapy (SLIT) in house dust mite (HDM)-allergic asthma patients and to compare levels of allergen-specific antibodies in HDM-allergic patients before and after treatment with that of healthy controls. Method: Thirty-one asthma patients allergic to HDM were studied. Patients in groups I (n = 17) and II (n

  6. Hypoallergenic Forms of the Ryegrass Pollen Allergen Lol p 5 as Candidates for Immunotherapy

    Microsoft Academic Search

    Ines Swoboda; Nicole de Weerd; Prem L. Bhalla; Verena Niederberger; W. R. Sperr; Peter Valent; Helga Kahlert; Helmut Fiebig; Christof Ebner; Susanne Spitzauer; Rudolf Valenta; Mohan B. Singh

    2001-01-01

    Almost 25% of the world’s population suffer from the symptoms of type I allergy (e.g. allergic rhinoconjunctivitis, asthma, dermatitis, food allergy, and anaphylactic shock). Allergic individuals exhibit an increased tendency to produce IgE antibodies against otherwise harmless environmental antigens (allergens).Whereas the symptoms of allergic diseases can be controlled by pharmacotherapy, allergen-specific immunotherapy is the only approach towards a causative treatment

  7. An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis

    Microsoft Academic Search

    S. H. Wong; M. D. Saunders; A. J. Larner; K. Das; I. K. Hart

    2010-01-01

    BackgroundVoltage-gated potassium channel antibody-positive limbic encephalitis (VGKC+LE) frequently improves with immunotherapy, although the optimum regimen is unknown. The effectiveness of a combination immunomodulatory regimen was tested in consecutive VGKC+LE patients.MethodsThis was an open-label prospective study of nine VGKC+LE patients. All patients had plasma exchange (50 ml\\/kg), intravenous immunoglobulin (2 g\\/kg) and intravenous methylprednisolone (1 g×3), followed by maintenance oral prednisolone

  8. Intralymphatic Injections as a New Administration Route for Allergen-Specific Immunotherapy

    Microsoft Academic Search

    Julia M. Martínez-Gómez; Pål Johansen; Iris Erdmann; Gabriela Senti; Reto Crameri; Thomas M. Kündig

    2009-01-01

    Background: IgE-mediated allergy can be treated by subcutaneous allergen-specific immunotherapy (SIT). However, the percentage of allergic patients undergoing SIT is low, mainly due to the long duration of the therapy and the risk of severe systemic allergic reactions associated with the allergen administration. To improve the safety and attractiveness of SIT for patients, alternative routes of allergen administration are being

  9. Construction and Characterization of an Attenuated Listeria monocytogenes Strain for Clinical Use in Cancer Immunotherapy

    Microsoft Academic Search

    Anu Wallecha; Paulo Cesar Maciag; Sandra Rivera; Yvonne Paterson; Vafa Shahabi

    2009-01-01

    Listeria monocytogenes has been exploited previously as a vaccine vector for the delivery of heterologous proteins such as tumor-specific antigens for active cancer immunotherapy. However, for effective use of live vector in clinics, safety is a major concern. In the present study, we describe an irreversibly attenuated and highly immunogenic L. monocytogenes platform, the L. monocytogenes dal-, dat-, and actA-deleted

  10. Immunology in the clinic review series; focus on cancer: glycolipids as targets for tumour immunotherapy

    PubMed Central

    Durrant, L G; Noble, P; Spendlove, I

    2012-01-01

    Research into aberrant glycosylation and over-expression of glycolipids on the surface of the majority of cancers, coupled with a knowledge of glycolipids as functional molecules involved in a number of cellular physiological pathways, has provided a novel area of targets for cancer immunotherapy. This has resulted in the development of a number of vaccines and monoclonal antibodies that are showing promising results in recent clinical trials. PMID:22235996

  11. Effects of Cancer Immunotherapy with Indomethacin and Interleukin2 on Murine Hemopoietic Stem Cells 1

    Microsoft Academic Search

    Mary Nel Saarloos; Nelson K. S. Khoo; Peeyush K. Lala

    1992-01-01

    We examined: (a) whether in vitro-generated lymphocyte-activated killer (LAK) cells from normal mice and splenic killer cells from tumor- bearing mice subjected to interleukin-2 (IL-2) therapy alone or in com- bination with chronic indomethacin therapy have any detrimental ef- fects on the spleen colony-forming units (CFU-S) of the normal bone marrow (BM); and (b) the effects of these immunotherapy protocols

  12. Non-Fc-Mediated Mechanisms Are Involved in Clearance of Amyloid In Vivo by Immunotherapy

    Microsoft Academic Search

    Brian J. Bacskai; Stephen T. Kajdasz; Megan E. McLellan; Dora Games; Peter Seubert; Dale Schenk; Bradley T. Hyman

    2002-01-01

    Transgenic (Tg) mouse models overexpressing amyloid precur- sor protein (APP) develop senile plaques similar to those found in Alzheimer's disease in an age-dependent manner. Recent reports demonstrated that immunotherapy is effective at pre- venting or removing amyloid- deposits in the mouse models. To characterize the mechanisms involved in clearance, we used antibodies of either IgG1 (10d5) or IgG2b (3d6) applied

  13. Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs

    Microsoft Academic Search

    V A Varney; M Gaga; A J Frew; V R Aber; A B Kay; S R Durham

    1991-01-01

    OBJECTIVE--To evaluate the efficacy and safety of immunotherapy (hyposensitisation) in patients with severe summer hay fever. DESIGN--A randomised, double blind, placebo controlled study of a biologically standardised depot grass pollen extract. SETTING--Allergy clinic, Royal Brompton and National Heart Hospital, London. PATIENTS--40 adults (mean age 35 years) with a history of severe grass pollen allergy uncontrolled by standard antiallergic drugs. Patients

  14. Characterization of PLGA microspheres for the controlled delivery of IL1 ? for tumor immunotherapy

    Microsoft Academic Search

    Limor Chen; Ron N Apte; Smadar Cohen

    1997-01-01

    This paper describes the preparation and characterization of poly(lactic-co-glycolic acid) microspheres for the continuous delivery of a recombinant human interleukin-1? (IL-1?), a cytokine that is investigated for the immunotherapy of tumors. The polymers forming the microspheres were from two different sources, had a comonomer ratio of 50:50 or 75:25 (lactic\\/glycolic acid), and mol. wts. of 5–15 kDa, and were expected

  15. Time-dependent cytotoxic drugs selectively cooperate with IL18 for cancer chemo-immunotherapy

    Microsoft Academic Search

    Ioannis Alagkiozidis; Andrea Facciabene; Marinos Tsiatas; Carmine Carpenito; Fabian Benencia; Sarah Adams; Zdenka Jonak; Carl H June; Daniel J Powell Jr; George Coukos

    2011-01-01

    Background  Time-dependent chemotherapeutic agents can selectively target tumor cells in susceptible phases of the cell cycle however\\u000a a fraction of tumor cells in non-vulnerable cell cycle phases remain drug-resistant. Immunotherapy represents a promising\\u000a approach to overcome the limitation of phase-specific drugs and improve their clinical efficacy. Here, we investigated the\\u000a potential use of anticancer chemotherapeutic drugs in combination with IL-18, a

  16. In Vivo, Multimodal Imaging of B Cell Distribution and Response to Antibody Immunotherapy in Mice

    Microsoft Academic Search

    Daniel L. J. Thorek; Patricia Y. Tsao; Vaishali Arora; Lanlan Zhou; Robert A. Eisenberg; Andrew Tsourkas; Derya Unutmaz

    2010-01-01

    BackgroundB cell depletion immunotherapy has been successfully employed to treat non-Hodgkin's lymphoma. In recent years, increasing attention has been directed towards also using B-cell depletion therapy as a treatment option in autoimmune disorders. However, it appears that the further development of these approaches will depend on a methodology to determine the relation of B-cell depletion to clinical response and how

  17. The finely regulating well-defined functional polymeric nanocarriers for anti-tumor immunotherapy.

    PubMed

    Li, Wei; Zhang, Li; Zhang, Ge; Wei, Huafeng; Zhao, Mengxin; Li, Huafei; Guo, Shangjing; Gao, Jie; Kou, Geng; Li, Bohua; Dai, Jianxin; Wang, Hao; Guo, Yajun

    2013-04-01

    Cancer is the second leading cause of death around the world. Cancer may be induced by viral infection (EBV,HBV and HPV), bacterial infection (Helicobacter pylori), carcinogen, ultraviolet (UV) radiation exposure, and genetic mutation. Tumor can be suppressed by traditional surgery, radiotherapy, and/or chemotherapy with devastating side effects and very poor quality of postoperative life. The therapeutic index has been further promoted by the newly developed nanomedicine. However, the disseminated tumor cells can result in micrometastases. So the cancer can just be supresssed but not cured by these ways. Fortunately, the developments of immunology have successfully improved many disciplines with special effort on oncology. Various immune cells including B cells, T-lymphocytes (TL), natural killer(NK) cells, dendritic cells (DCs), macrophages, and polymorphonuclear leukocytes are recruited to the tumor. These immune cells can recognize, eliminate, and protect the body from viral, bacterial infections, and the transformed cells(pre-cancer cell) extension. The modification of host immune system, and/or the utilization of components of the immune system for cancer treatment are called immunotherapy. The immunotherapy is not only to target and kill tumor cells in aspecific manner, but also to alert the immune system to eradicate the disseminated tumor cells present in the blood circulation and micro-metastases in remote organs. Herein, the development of immunology, cancer immunotherapy,tumor immuno escape was introduced firstly. Then the correlations between host, the tumor and the nano particulates were proposed. And how to improve the cancer immunotherapy by finely nanocarrier's engineering (nanoimmunotherapy) was systematically illustrated with special focus on the unique pathology of tumor microenviroments and properties of immuno cells. PMID:23469780

  18. Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: the way forward.

    PubMed

    Panza, Francesco; Solfrizzi, Vincenzo; Imbimbo, Bruno P; Tortelli, Rosanna; Santamato, Andrea; Logroscino, Giancarlo

    2014-03-01

    Both active and passive anti-?-amyloid (A?) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain A? deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of A?, were disappointing. Also solanezumab, directed at the mid-region of A?, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active A? vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-A? immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-A? immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the A? cascade hypothesis of AD. PMID:24490853

  19. Novel Strategies for Immunotherapy in Multiple Myeloma: Previous Experience and Future Directions

    PubMed Central

    Danylesko, Ivetta; Beider, Katia; Shimoni, Avichai; Nagler, Arnon

    2012-01-01

    Multiple myeloma (MM) is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation is a relatively effective treatment, but residual malignant sites may cause relapse. Allogeneic transplantation may result in durable responses due to antitumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. Cellular immunotherapy using specific antigen-presenting cells (APCs), to overcome aspects of immune incompetence in MM patients, has received great attention, and numerous clinical trials have evaluated the potential for dendritic cell (DC) vaccines as a novel immunotherapeutic approach. This paper will summarize the data investigating aspects of immunity concerning MM, immunotherapy for patients with MM, and strategies, on the way, to target the plasma cell more selectively. We also include the MM antigens and their specific antibodies that are of potential use for MM humoral immunotherapy, because they have demonstrated the most promising preclinical results. PMID:22649466

  20. Immunotherapy for Prostate Cancer: Lessons from Responses to Tumor-Associated Antigens

    PubMed Central

    Westdorp, Harm; Sköld, Annette E.; Snijer, Berit A.; Franik, Sebastian; Mulder, Sasja F.; Major, Pierre P.; Foley, Ronan; Gerritsen, Winald R.; de Vries, I. Jolanda M.

    2014-01-01

    Prostate cancer (PCa) is the most common cancer in men and the second most common cause of cancer-related death in men. In recent years, novel therapeutic options for PCa have been developed and studied extensively in clinical trials. Sipuleucel-T is the first cell-based immunotherapeutic vaccine for treatment of cancer. This vaccine consists of autologous mononuclear cells stimulated and loaded with an immunostimulatory fusion protein containing the prostate tumor antigen prostate acid posphatase. The choice of antigen might be key for the efficiency of cell-based immunotherapy. Depending on the treatment strategy, target antigens should be immunogenic, abundantly expressed by tumor cells, and preferably functionally important for the tumor to prevent loss of antigen expression. Autoimmune responses have been reported against several antigens expressed in the prostate, indicating that PCa is a suitable target for immunotherapy. In this review, we will discuss PCa antigens that exhibit immunogenic features and/or have been targeted in immunotherapeutic settings with promising results, and we highlight the hurdles and opportunities for cancer immunotherapy. PMID:24834066

  1. Histological and morphological studies of immune responses induced by laser immunotherapy

    NASA Astrophysics Data System (ADS)

    Nordquist, Robert E.; Naylor, Mark F.; Liu, Hong; Chen, Yichao; Chen, Wei R.

    2008-02-01

    Laser energy can induce acute photothermal tissue damage, but without systemic effect in the treatment of tumors. However, it could serve as a precursor of immune responses if its photothermal actions could be used effectively as a means of producing tumor-specific antigens and other immunological stimulation elements. When used in a combination with immunoadjuvants, laser photothermal energy had been successfully applied in the treatment of metastatic tumors. Pre-clinical and preliminary clinical studies have demonstrated the systemic and immunological effects of the combination of laser irradiation and immunological stimulation through eradication of primary and secondary tumors, and through molecular and cellular anti-tumor immune activities. This study focuses on the histological and morphological aspects of laser immunotherapy induced immune responses, using glycated chitosan as the adjuvant and an 805-nm laser as the source of photothermal energy source. Cellular activities, such as tumor destruction and lymphocyte infiltration after the laser immunotherapy treatment were observed and analyzed. These cellular activities further support the hypothesis that induced immune activities are crucial outcome of laser immunotherapy.

  2. NOVEL NEOADJUVANT IMMUNOTHERAPY REGIMEN SAFETY AND SURVIVAL IN HEAD AND NECK SQUAMOUS CELL CANCER

    PubMed Central

    Fee, Willard E.; Dolan, Robert W.; Moyer, Jeffrey S.; Kaplan, Michael J.; Spring, Paul M.; Suen, James; Kenady, Daniel E.; Newman, Jason G.; Carroll, William R.; Gillespie, M. Boyd; Freeman, Scott M.; Baltzer, Lorraine; Kirkley, Terry D.; Brandwein, Harvey J.; Hadden, John W.

    2014-01-01

    Background Cellular immune suppression is observed in head and neck squamous cell cancer (HNSCC) and contributes to poor prognosis. Restoration of immune homeostasis may require primary cell-derived cytokines at physiologic doses. An immunotherapy regimen containing a biologic, with multiple-active cytokine components, and administered with cytoxan, zinc, and indomethacin was developed to modulate cellular immunity. Methods Study methods were designed to determine the safety and efficacy of a 21-day neoadjuvant immunotherapy regimen in a phase 2 trial that enrolled 27 therapy-naïve patients with stage II to IVa HNSCC. Methods included safety, clinical and radiologic tumor response, disease-free survival (DFS), overall survival (OS), and tumor lymphocytic infiltrate (LI) data collection. Results Acute toxicity was minimal. Patients completed neoadjuvant treatment without surgical delay. By independent radiographic review, 83% had stable disease during treatment. OS was 92%, 73%, and 69% at 12, 24, and 36 months, respectively. Histologic analysis suggested correlation between survival and tumor LI. Conclusion Immunotherapy regimen was tolerated. Survival results are encouraging. PMID:21284052

  3. Immunotherapy for house dust mite sensitivity: where are the knowledge gaps?

    PubMed

    Biagtan, Mark; Viswanathan, Ravi; Bush, Robert K

    2014-12-01

    House dust mites (HDMs) are found in the environments where human habitation exists. Their density is dependent on environmental relative humidity; therefore, higher populations are present in areas of the world with higher humidity levels, e.g., coastal areas and tropics. To date, 24 HDM allergens have been identified. Many of these represent digestive enzymes since HDM feces are the major source of allergen exposure. IgE- medicated sensitization to HDM allergens is an important factor in the pathogenesis of allergic diseases since it is the most common aeroallergen detected by skin testing or in vitro IgE assays. Sensitization to HDM allergens often occurs early in life and appears to play an important role in the progression from allergic rhinitis to asthma (the so-called Allergic March) in children. HDM sensitization is also associated with asthma across all age groups. Efforts to control environmental exposure to HDM allergens have often proven to be unsuccessful. While medications can improve symptoms, only immunotherapy currently provides disease-modifying effects in allergic rhinitis and asthma. Several systemic reviews and meta-analysis indicate that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are effective in the treatment of allergic rhinitis and asthma for HDM sensitivity. In this report, we review recent studies and the evidence for the use of HDM SCIT and SLIT. Fundamental gaps in knowledge are identified which could lead to improved approaches to HDM allergy. PMID:25354663

  4. The High Molecular Weight Stress Proteins: Identification, Cloning, and Utilization in Cancer Immunotherapy*

    PubMed Central

    Wang, Xiang-Yang; Subjeck, John R.

    2013-01-01

    Although the large stress/heat shock proteins (HSPs), i.e., Hsp110 and Grp170, were identified over 30 years ago, these abundant and highly conserved molecules have received much less attention compared to other conventional HSPs. Large stress proteins act as molecular chaperones with exceptional protein-holding capability and prevent the aggregation of proteins induced by thermal stress. The chaperoning properties of Hsp110 and Grp170 are integral to the ability of these molecules to modulate immune functions and are essential for developing large chaperone complex vaccines for cancer immunotherapy. The potent antitumor activity of the Hsp110/Grp170-tumor protein antigen complexes, demonstrated in preclinical studies, has led to a phase I clinical trial through the National Cancer Institute's RAID Program that is presently underway. Here we review aspects of the structure and function of these large stress proteins, their roles as molecular chaperones in the biology of cell stress, and prospects for their use in immune regulation and cancer immunotherapy. Lastly, we will discuss the recently revealed immunosuppressive activity of scavenger receptor A that binds to Hsp110 and Grp170, as well as the feasibility of targeting this receptor to promote T-cell activation and antitumor immunity induced by large HSP vaccines and other immunotherapies. PMID:23829534

  5. T cell-mediated immunotherapy of metastases: state of the art in 2005.

    PubMed

    Schirrmacher, Volker

    2005-08-01

    Advances in cellular and molecular immunology have led to the development of strategies for effective augmentation of antitumour immune responses in cancer patients. This review focuses on the manipulation of T cell immunity either by active specific immunotherapy (ASI) using tumour vaccines, or by adoptive immunotherapy (ADI) with immune T cells. Such therapies offer exquisite specificity of tumour recognition based on the ability of the T cell to distinguish single amino acid differences in any protein from any compartment of the tumour cell. Examples are presented of clinical survival benefits for cancer patients by postoperative ASI with a modified autologous tumour vaccine of high quality. Furthermore, clinical studies employing ADI with T cells activated and expanded ex vivo have demonstrated 'proof of principle' that tumour-specific T cells are capable of mediating anticancer activity in vivo, as measured by regression of metastatic tumours. Translation of these findings into a standardised immunotherapy is, however, not easy and will require coordination and cooperation among academic, private and federal sectors. PMID:16050783

  6. Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity.

    PubMed

    Focke, M; Swoboda, I; Marth, K; Valenta, R

    2010-03-01

    Allergen-specific immunotherapy (SIT) is the only specific and disease-modifying approach for the treatment of allergy but several disadvantages have limited its broad applicability. We argue that the majority of the possible disadvantages of SIT such as unwanted effects, poor efficacy and specificity as well as inconvenient application are related to the poor quality of natural allergen extracts, which are the active ingredients of all currently available allergy vaccines. Because of the progress made in the field of molecular allergen characterization, new allergy vaccines based on recombinant allergens, recombinant hypoallergenic allergen derivatives and allergen-derived T cell peptides have entered clinical testing and hold promise to reduce the side-effects and to increase the specificity as well as the efficacy of SIT. Here, we present a refined immunotherapy concept, which is based on the use of peptides derived from allergen surfaces that exhibit reduced, allergen-specific IgE as well as T cell reactivity. These peptides when fused to non-allergenic carriers give rise to allergen-specific protective IgG responses with T cell help from a non-allergenic carrier molecule. We summarize the experimental data demonstrating that such peptide vaccines can bypass allergen-specific IgE as well as T cell activation and may be administered at high doses without IgE- and T cell-mediated side-effects. Should these peptide vaccines prove efficacious and safe in clinical trials, it may become possible to develop convenient, safe and broadly applicable forms of SIT as true alternatives to symptomatic, drug-based allergy treatment. PMID:20210812

  7. Effectiveness and safety of orally administered immunotherapy for food allergies: a systematic review and meta-analysis.

    PubMed

    Nurmatov, Ulugbek; Devereux, Graham; Worth, Allison; Healy, Laura; Sheikh, Aziz

    2014-01-14

    The aim of using oral and sublingual immunotherapy with food allergies is to enable the safe consumption of foods containing these allergens in patients with food allergies. In the present study, a systematic review of intervention studies was undertaken; this involved the searching of eleven international databases for controlled clinical trials. We identified 1152 potentially relevant papers, from which we selected twenty-two reports of twenty-one eligible trials (i.e. eighteen randomised controlled trials and three controlled clinical trials). The meta-analysis revealed a substantially lower risk of reactions to the relevant food allergen in those receiving orally administered immunotherapy (risk ratios (RR) 0·21, 95 % CI 0·12, 0·38). The meta-analysis of immunological data demonstrated that skin prick test responses to the relevant food allergen significantly decreased with immunotherapy (mean difference - 2·96 mm, 95 % CI - 4·48, - 1·45), while allergen-specific IgG4 levels increased by an average of 19·9 (95 % CI 17·1, 22·6) ?g/ml. Sensitivity analyses excluding studies at the highest risk of bias and subgroup analyses in relation to specific food allergens and treatment approaches generated comparable summary estimates of effectiveness and immunological changes. Pooling of the safety data revealed an increased risk of local (i.e. minor oropharyngeal/gastrointestinal) adverse reactions with immunotherapy (RR 1·47, 95 % CI 1·11, 1·95); there was a non-significant increased average risk of systemic adverse reactions with immunotherapy (RR 1·08, 95 % CI 0·97, 1·19). There is strong evidence that orally administered immunotherapy can induce immunomodulatory changes and thereby promote desensitisation to a range of foods. However, given the paucity of evidence on longer-term safety, effectiveness and cost-effectiveness, orally administered immunotherapy should not be used outside experimental conditions presently. PMID:23945022

  8. Bovine antibody-based oral immunotherapy for reduction of intragastric Helicobacter pylori colonization: A randomized clinical trial

    PubMed Central

    den Hoed, CM; de Vries, AC; Mensink, PBF; Dierikx, CM; Suzuki, H; Capelle, L; van Dekken, H; Ouwendijk, R; Kuipers, EJ

    2011-01-01

    BACKGROUND: Antibiotic-based regimens are frequently used for the treatment of Helicobacter pylori infection. These regimens fail to eradicate H pylori in 15% to 40% of patients, primarily due to antimicrobial resistance and insufficient patient compliance. Effective prevention and eradication of H pylori by passive immunization with orally administered bovine antibodies has been demonstrated in animal studies, and may serve as an alternative therapy in humans. OBJECTIVE: To study the efficacy and safety of orally administered bovine anti-H pylori antibodies for the reduction of intragastric bacterial load and eradication of H pylori in humans. METHODS: Dairy cows were immunized against H pylori. After confirmation of the presence of anti-H pylori antibodies in the milk, the milk was subsequently processed into a whey protein concentrate (WPC). In a prospective, double-blind, placebo-controlled randomized clinical trial, H pylori-infected subjects were randomly assigned to treatment with the WPC preparation or placebo. Study medication was continued for 28 days; subjects were followed-up for 56 days. RESULTS: Of the 30 subjects included, 27 completed the protocol. Of these 27 evaluable subjects, 14 were treated with WPC and 13 with placebo. There was no significant difference in urea breath test decrease between the WPC- and placebo-treated group (P=0.75). H pylori-associated gastritis and density were not significantly reduced in either group after treatment (P>0.05 for all). CONCLUSION: Bovine antibody-based oral immunotherapy appears to be safe, but does not significantly reduce intragastric H pylori density in humans. Further studies are needed to determine whether WPC treatment has additional value to conventional antibiotic treatment for H pylori. PMID:21523262

  9. Efficacy of Mycobacterium indicus pranii Immunotherapy as an Adjunct to Chemotherapy for Tuberculosis and Underlying Immune Responses in the Lung

    PubMed Central

    Gupta, Ankan; Ahmad, Farhan J.; Ahmad, Faiz; Gupta, Umesh D.; Natarajan, Mohan; Katoch, Vishwamohan; Bhaskar, Sangeeta

    2012-01-01

    Background The 9-month-long chemotherapy of tuberculosis often results in poor compliance and emergence of drug-resistant strains. So, improved therapeutic strategy is urgently needed. Immunotherapy could be beneficial for the effective management of the disease. Previously we showed the protective efficacy of Mycobacterium indicus pranii (MIP) when given as prophylactic vaccine in animal models of tuberculosis. Methods We sought to investigate whether MIP can be used as an adjunct to the chemotherapy in guinea pig models of tuberculosis. Efficacy of MIP was evaluated when given subcutaneously or by aerosol. Results MIP-therapy as an adjunct to the chemotherapy was found to be effective in accelerating bacterial killing and improving organ pathology. MIP-immunotherapy resulted in higher numbers of activated antigen-presenting cells and lymphocytes in the infected lungs and also modulated the granulomatous response. Early increase in protective Th1 immune response was observed in the immunotherapy group. Following subsequent doses of MIP, decrease in the inflammatory response and increase in the immunosuppressive response was observed, which resulted in the improvement of lung pathology. Conclusion MIP immunotherapy is a valuable adjunct to chemotherapy for tuberculosis. Aerosol route of immunotherapy can play a crucial role for inducing immediate local immune response in the lung. PMID:22844392

  10. Helper T Lymphocyte Response in the Peripheral Blood of Patients with Intraepithelial Neoplasia Submitted to Immunotherapy with Pegylated Interferon-?

    PubMed Central

    Michelin, Márcia Antoniazi; Montes, Letícia; Nomelini, Rosekeila Simões; Trovó, Marco Aurélio; Murta, Eddie Fernando Candido

    2015-01-01

    Immunotherapy in cancer patients is a very promising treatment and the development of new protocols and the study of the mechanisms of regression is imperative. The objective of this study was to evaluate the production of cytokines in helper T (CD4+) lymphocytes during immunotherapy with pegylated IFN-? in patients with cervical intraepithelial neoplasia (CIN). We conducted a prospective study with 17 patients with CIN II-III using immunotherapy with pegylated IFN-? subcutaneouly weekly, and using flow cytometry we evaluated the peripheric CD4+ T lymphocytes. The results show that in the regression group the patients presented a significant increase in the amount of IFN-? during the entire immunotherapy, compared with the group without a response. The amount of CD4+ T lymphocytes positive for IL-2, IL-4, IL-10 and TGF-? is significantly lower in patients with good clinical response. The results also demonstrate that patients with regression have a higher amount of intracellular TNF-? in CD4+ T lymphocytes before the start of treatment. Analyzing these data sets, it can be concluded that immunotherapy is a viable clinical treatment for patients with high-grade CIN and that the regression is dependent on the change in the immune response to a Th1 pattern. PMID:25764160

  11. Immunotherapy Using Autoclaved L. major Antigens and M. vaccae with Meglumine Antimoniate, for the Treatment of Experimental Canine Visceral Leishmaniasis

    PubMed Central

    Jamshidi, Sh; Avizeh, R; Mohebali, M; Bokaie, S

    2011-01-01

    Background To evaluate immunotherapy against canine visceral leishmaniasis, Leishmania major antigen and heat-killed Mycobacterium vaccae (SRL172) were used as stimulators of immune defense mechanisms and the results were compared with standard chemotherapy meglumine antimoniate. Methods Nineteen mongrel dogs aging 1-3 years old were used in this experiment. Infection was carried out in 15 out of 19 dogs using L. infantum, isolated from a naturally infected poly-symptomatic dog. Results All the cases showed positive serologic results by direct agglutination test during 30-60 days following inoculation. In the first group, which was under chemotherapy (GlucantimeR), one of the members showed recurrence of the disease despite rapid effect of the therapeutic protocol. Immunotherapy using SRL172 caused complete cleaning of the parasite in group 2, but the speed was less than Glucantime. Immunotherapy using L. major antigen combined with M. vaccae in group 3 and combine administration of immunotherapy and chemotherapy in group 4 both were with relapsing of one case in each group. Group 5 and 6 were consisted of positive and negative control dogs, respectively. Conclusion Immunotherapy seems to be an adjuvant in treatment of canine leishmaniasis but it needs more investigation for final confirmation. PMID:22347294

  12. Role of radiation therapy as immune activator in the era of modern immunotherapy for metastatic malignant melanoma.

    PubMed

    Okwan-Duodu, Derick; Pollack, Brian P; Lawson, David; Khan, Mohammad K

    2015-02-01

    Metastatic melanoma is difficult to treat, and often portends a grim prognosis. For patients with cerebral metastases, the prognosis is even more dire. Systemic immunotherapy and targeted agents are emerging as the mainstay of treatment for metastatic melanoma. Although immunotherapy has been shown to prolong relapse-free survival and long-term control of micrometastatic disease, the response rate is suboptimal, prompting the need to optimize and improve therapy. Accumulating evidence suggests that in addition to effective locoregional control, radiation therapy (RT) may induce immune activation and expansion of T lymphocytes recognizing melanocyte-specific antigens including activated cytotoxic T lymphocytes that can potentially kill melanoma cells. In some cases, RT contributes to the clearance of metastatic disease in distant, nonirradiated regions, a bystander phenomenon called the abscopal effect. Here, we evaluate the potential promise of ablative radiation treatment in the era of modern immunotherapy by presenting a patient with metastatic melanoma who remained disease free for over 3 years after an initial diagnosis of advanced metastatic melanoma with brain, subcutaneous tissue, mesenteric, pelvic, and retroperitoneal involvement. The patient failed initial stereotactic radiosurgery, but responded to whole-brain RT in combination with interleukin-2 immunotherapy. Thus, combination RT with immunotherapy may be synergistic by promoting the release and processing of melanoma antigens that can be presented by dendritic cells. This in turn may augment the response to therapies that center on expansion and/or activation of antitumor T cells. PMID:23648438

  13. OxLDL-pulsed dendritic cells: an immunotherapy in atherosclerosis

    Microsoft Academic Search

    Kim Habets; Gijs van Puijvelde; Leonie van Duivenvoorde; Eva van Wanrooij; Paula de Vos; Jan Willem; Cohen Tervaert; Theo van Berkel

    Abstract Background. Modification of lipoproteins plays an important role in the development,of atherosclerosis. Oxidatively modified low-density lipoprotein (oxLDL) has a number of pro-inflammatory effects, whereas immunization,with various forms of oxLDL is able to reduce,atherosclerosis. The uptake of modified LDL by dendritic cells (DCs) and the presentation of epitopes thereof may form an important step in the immunomodulatoryeffects of LDL. In

  14. Therapeutic outcomes of combining cryotherapy, chemotherapy and DC-CIK immunotherapy in the treatment of metastatic non-small cell lung cancer.

    PubMed

    Yuanying, Yuan; Lizhi, Niu; Feng, Mu; Xiaohua, Wang; Jianying, Zeng; Fei, Yao; Feng, Jiang; Lihua, He; Jibing, Chen; Jialiang, Li; Kecheng, Xu

    2013-10-01

    Currently there are no effective therapies for the treatment of metastatic non-small cell lung cancer (NSCLC). Here, we conducted a retrospective study of 161 patients to evaluate the therapeutic effects of combining cryosurgery, chemotherapy and dendritic cell-activated cytokine-induced killer cells (DC-CIK) immunotherapy. The overall survival (OS) after diagnosis of metastatic NSCLC to patient death was assessed during a 5-years follow-up period. OS of patients who received comprehensive cryotherapy was (median OS, 20 months; n = 86) significantly longer than that of patients who did not received cryotherapy (median OS, 10 months; n = 75; P < 0.0001). Five treatment combinations were selected: chemotherapy (n = 44); chemo-immunotherapy (n = 31); cryo-chemotherapy (n = 32); cryo-immunotherapy (n = 21); and cryo-chemo-immunotherapy (n = 33). A combination of cryotherapy with either chemotherapy or immunotherapy lead to significantly longer OS (18 months and 17 months, respectively) compared to chemotherapy and chemo-immunotherapy (8.5 months and 12 months, respectively; P < 0.001); however, the median OS of patients who underwent cryo-chemo-immunotherapy was significantly longer (27 months) compared to the other treatment programs (P < 0.001). In conclusion, a combination of cryotherapy, chemotherapy and DC-CIK immunotherapy proved the best treatment option for metastatic NSCLC in this group of patients. PMID:23948179

  15. Autologous aldrithiol-2-inactivated HIV-1 combined with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose as a vaccine platform for therapeutic dendritic cell immunotherapy.

    PubMed

    Miller, Elizabeth; Spadaccia, Meredith; Sabado, Rachel; Chertova, Elena; Bess, Julian; Trubey, Charles Mac; Holman, Rose Marie; Salazar, Andres; Lifson, Jeffrey; Bhardwaj, Nina

    2015-01-01

    Therapeutic interventions for HIV-1 that successfully augment adaptive immunity to promote killing of infected cells may be a requisite component of strategies to reduce latent cellular reservoirs. Adoptive immunotherapies utilizing autologous monocyte-derived dendritic cells (DCs) that have been activated and antigen loaded ex vivo may serve to circumvent defects in DC function that are present during HIV infection in order to enhance adaptive immune responses. Here we detail the clinical preparation of DCs loaded with autologous aldrithiol-2 (AT-2)-inactivated HIV that have been potently activated with the viral mimic, Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (Poly-ICLC). HIV is first propagated from CD4+ T cells from HIV-infected donors and then rendered non-replicative by chemical inactivation with aldrithiol-2 (AT-2), purified, and quantified. Viral inactivation is confirmed through measurement of Tat-regulated ?-galactosidase reporter gene expression following infection of TZM-bl cells. In-process testing for sterility, mycoplasma, LPS, adventitious agents, and removal of AT-2 is performed on viral preparations. Autologous DCs are generated and pulsed with autologous AT-2-inactivated virus and simultaneously stimulated with Poly-ICLC to constitute the final DC vaccine product. Phenotypic identity, maturation, and induction of HIV-specific adaptive immune responses are confirmed via flow cytometric analysis of DCs and cocultured autologous CD4+ and CD8+ T cells. Lot release criteria for the DC vaccine have been defined in accordance with Good Manufacturing Practice (GMP) guidelines. The demonstrated feasibility of this approach has resulted in approval by the FDA for investigational use in antiretroviral (ART) suppressed individuals. We discuss how this optimized DC formulation may enhance the quality of anti-HIV adaptive responses beyond what has been previously observed during DC immunotherapy trials for HIV infection. PMID:25444812

  16. Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients.

    PubMed

    Gao, Daiqing; Li, Changyou; Xie, Xihe; Zhao, Peng; Wei, Xiaofang; Sun, Weihong; Liu, Hsin-Chen; Alexandrou, Aris T; Jones, Jennifer; Zhao, Ronghua; Li, Jian Jian

    2014-01-01

    Gastric and colorectal cancers (GC and CRC) have poor prognosis and are resistant to chemo- and/or radiotherapy. In the present study, the prophylactic effects of dendritic cell (DC) vaccination are evaluated on disease progression and clinical benefits in a group of 54 GC and CRC patients treated with DC immunotherapy combined with cytokine-induced killer (CIK) cells after surgery with or without chemo-radiotherapy. DCs were prepared from the mononuclear cells isolated from patients using IL-2/GM-CSF and loaded with tumor antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-?, and CD3 antibodies. The DC/CIK therapy started 3 days after low-dose chemotherapy and was repeated 3-5 times in 2 weeks as one cycle with a total of 188.3 ± 79.8 × 10(6) DCs and 58.8 ± 22.3 × 10(8) CIK cells. Cytokine levels in patients' sera before and after treatments were measured and the follow-up was conducted for 98 months to determine disease-free survival (DFS) and overall survival (OS). The results demonstrate that all cytokines tested were elevated with significantly higher levels of IFN-? and IL-12 in both GC and CRC cohorts of DC/CIK treated patients. By Cox regression analysis, DC/CIK therapy reduced the risk of post-operative disease progression (p<0.01) with an increased OS (<0.01). These results demonstrate that in addition to chemo- and/or radiotherapy, DC/CIK immunotherapy is a potential effective approach in the control of tumor growth for post-operative GC and CRC patients. PMID:24699863

  17. Efficacy of Sublingual Immunotherapy with Dermatophagoides farinae Extract in Monosensitized and Polysensitized Patients with Allergic Rhinitis: Clinical Observation and Analysis.

    PubMed

    Xu, Chen-Xia; Zhang, Miao-Lian; Li, Bi-Zhou; He, Ying; Zou, Ze-Hong; Wu, Qiu-Rong; Tao, Ai-Lin; Lai, He; Sun, Jin-Lu

    2015-01-01

    Aim. To investigate differences in the efficacy of sublingual immunotherapy with Dermatophagoides farinae drops in monosensitized and polysensitized allergic rhinitis patients. Methods. The patients enrolled in the study were treated for more than one year by sublingual immunotherapy (SLIT) using Dermatophagoides farinae drops and were divided into a monosensitized group (n = 20) and a polysensitized group (n = 30). Total nasal symptom scores of patients before and after SLIT were analyzed to evaluate the curative effect. The phylogenetic tree of dust mite allergens as well as other allergens that were tested by skin prick test was constructed to help the analysis. Results. There was no significant difference in the efficacy of SLIT between dust mite monosensitized and polysensitized patients. Conclusions. Both dust mite monosensitized and polysensitized patients could be cured by SLIT using Dermatophagoides farinae drops. This study provides a reference for the selection of allergens to be used in immunotherapy for polysensitized AR patients. PMID:26000283

  18. Specific IgE response to different grass pollen allergen components in children undergoing sublingual immunotherapy

    PubMed Central

    2012-01-01

    Background Grass pollen is a major cause of respiratory allergy worldwide and contain a number of allergens, some of theme (Phl p 1, Phl p 2, Phl p 5, and Phl 6 from Phleum pratense, and their homologous in other grasses) are known as major allergens. The administration of grass pollen extracts by immunotherapy generally induces an initial rise in specific immunoglobulin E (sIgE) production followed by a progressive decline during the treatment. Some studies reported that immunotherapy is able to induce a de novo sensitisation to allergen component previously unrecognized. Methods We investigated in 30 children (19 males and 11 females, mean age 11.3 years), 19 treated with sublingual immunotherapy (SLIT) by a 5-grass extract and 11 untreated, the sIgE and sIgG4 response to the different allergen components. Results Significant increases (p?

  19. Immunotherapy of the rat 13762SC mammary adenocarcinoma by vaccinia virus augmentation of tumor immunity.

    PubMed

    Archer, T P; Bretscher, P; Ziola, B

    1990-01-01

    We studied whether vaccinia virus (VV) functioned as an immunogenic carrier in augmenting anti-tumor immunity in rats bearing a syngeneic metastatic tumor. The primary tumor was induced by injecting 10(6) 13762SC mammary adenocarcinoma cells subcutaneously into the right hind footpad of Fischer 344 rats. A concomitant anti-tumor response is induced by the tumor as demonstrated by the inhibited growth of a second tumor challenge given in the contralateral footpad 3-15 days later. Attempts were made to increase the concomitant immunity by injecting tumor-bearing animals intramuscularly with irradiated, VV-infected or uninfected 13762SC cells without adjuvant. Provided the immunotherapy was done within 5 days of the tumor challenge, administration of 10(6)-10(7) irradiated, VV-infected 13762SC cells resulted in significantly slower tumor growth, or led to complete tumor regression, compared to control animals given no treatment. In contrast, tumor growth in animals given only VV or given irradiated, uninfected 13762SC cells, alone or mixed with VV, was the same as that in control animals. Kinetics of early primary tumor growth were predictive of a longer-term anti-tumor effect. Rechallenge of 13762SC tumor-cured animals with either the homologous or with a heterologous syngeneic mammary adenocarcinoma showed the animals to be specifically 13762SC tumor-resistant, since only rats challenged with the heterologous mammary adenocarcinoma developed progressive tumors. We interpret these results to mean that early immunotherapy with irradiated, VV-infected 13762SC cells enhances an on-going anti-tumor immune response sufficiently to cause rejection of the primary tumor and any metastases that have occurred. We also believe that later immunotherapy with irradiated, VV-infected cells has no effect due to tumor-induced immunosuppression becoming paramount. PMID:2225567

  20. GSK's antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development.

    PubMed

    Brichard, Vincent G; Lejeune, Diane

    2007-09-27

    From the first evidence that the immune system could recognize tumors, different types of tumor antigens have been identified and deeply characterized. Several different approaches aimed at targeting these antigens have already been the subject of clinical studies. In this field, the GSK Biologicals' approach relying on recombinant proteins combined with an immunological Adjuvant System in a specific clinical setting, has entertained hopes of developing a new class of well tolerated anti-cancer therapy. This methodology led to promising advances with MAGE-A3 immunotherapy in NSCLC and has the potential to be applied to all tumor types. PMID:17916463

  1. In Vitro Evaluation of Allergen Potencies of Commercial House Dust Mite Sublingual Immunotherapy Reagents

    PubMed Central

    Park, Kyung Hee; Son, Mina; Choi, Soo-Young; Park, Hey Jung; Lee, Jae-Hyun; Jeong, Kyoung Yong; Lee, Joo-Shil

    2015-01-01

    Purpose The clinical efficacy of allergen-immunotherapy is known to be dose dependent. However, optimal maintenance dosage has not yet been determined for sublingual immunotherapy (SLIT). Furthermore, since companies adopt their own units for expression of allergenicity, the allergen concentrations of individual reagents cannot be compared easily. We sought to measure and compare the allergenicities of 3 commercially available house dust mite (HDM) SLIT regents and a subcutaneous immunotherapy reagent. Methods We measured the HDM allergenic potency of the maintenance dosages of three SLIT reagents: Staloral® (300 index of reactivity [IR] /mL, recommended maintenance dosage [MD]: 120 IR), SLITone® (1,000 standard therapeutic unit [STU]/mL, recommended MD: 200 STU), Wolwopharma® (100 µg/mL, recommended MD: 20 µg), and subcutaneous immunotherapy regents of Hollister-Stier (10,000 allergy unit [AU] /mL). The allergenic potency was assessed by measuring the total protein concentrations, mite group 1 and 2 allergens using 2-site ELISA, and an inhibition test against IgE specific to Dermatophagoides farinae and Dermatophagoides pteronyssinus. Results The protein content of the Wolwopharma® reagent was 1.5-261.4 times higher than that of the other 2 SLIT reagents. The concentration of group 1 major allergens in Staloral® (132.03 µg/mL) was 33- to 44.5-fold higher than in SLITone® (4.00 µg/mL) and Wolwopharma® (2.97 µg/mL). The concentration of group 2 major allergen was also 8.9- to 10.5-fold higher in Staloral® (15.7 µg/mL) than in SLITone® (1.8 µg/mL) or Wolwopharma® (1.5 µg/mL). An ELISA inhibition study against HDM-specific IgE showed that the allergen potency of Staloral® reagent is 8.5-fold and 21-fold higher than that of SLITone® or Wolwopharma®, respectively. The differences between the maintenance dosages are further exaggerated by the differences in the recommended volumes of SLIT reagents. Conclusions The allergen potencies of commercially available HDM SLIT reagents are markedly different. Consensus regarding the optimal allergen concentration for SLIT reagents used to treat HDM respiratory allergies is needed. PMID:25729619

  2. Highlights of the society for immunotherapy of cancer (SITC) 27th annual meeting

    PubMed Central

    2013-01-01

    The 27th annual meeting of the Society for Immunotherapy of Cancer (SITC) was held on October 26–28, 2012 in North Bethesda, Maryland and the highlights of the meeting are summarized. The topics covered at this meeting included advances in cancer treatment using adoptive cell therapy (ACT), oncolytic viruses, dendritic cells (DCs), immune check point modulators and combination therapies. Advances in immune editing of cancer, immune modulation by cancer and the tumor microenvironment were also discussed as were advances in single cell analysis and the manufacture and potency testing of tumor infiltrating lymphocytes (TIL).

  3. Update on the use of transgenic rice seeds in oral immunotherapy.

    PubMed

    Takaiwa, Fumio

    2013-03-01

    Rice seed provides an ideal production platform for pharmaceuticals in terms of high productivity and stability, as well as the scalability, safety and economy that are expected in plant production systems. Furthermore, these therapeutic products are bioencapsulated in protein bodies, which are seed-specific storage organelles that provide protection from digestion by gastrointestinal enzymes during delivery to the gut-associated lymphoid tissue. Thus, rice seed provides an ideal delivery system for the mucosal immune system. Oral immunotherapy using unprocessed transgenic rice seed containing therapeutic products has been demonstrated to induce effective mucosal immune tolerance and immune reactions against allergies and pathogens. PMID:23444957

  4. Immunotherapy with injectable hydrogels to treat obstructive nephropathy.

    PubMed

    Soranno, Danielle E; Lu, Hoang D; Weber, Heather M; Rai, Reena; Burdick, Jason A

    2014-07-01

    Hydrogels are gaining attention as injectable vehicles for delivery of therapeutics for a range of applications. We describe self-assembling and injectable Dock-and-Lock hydrogels for local delivery of interleukin-10 (IL-10) to abate the progression of inflammation and fibrosis that leads to chronic kidney disease. As monitored with a fluorescent tag, hydrogels degraded within a few days in vitro and matched IL-10 release profiles; however, hydrogels remained in the kidney for up to 30 days in vivo. A unilateral ureteral obstruction (UUO) mouse model was used to investigate in vivo outcomes after hydrogel injection and IL-10 delivery. Eight groups were investigated (7, 21, 35 days, n?=?4): healthy, sham, healthy injected with mouse serum albumin (MSA), healthy?+?hydrogel, UUO, UUO?+?IL-10, UUO?+?hydrogel, UUO?+?hydrogel/IL-10. 15 ?L of IL-10, hydrogel, or hydrogel/IL-10 was injected under the renal capsule 3 days after the UUO. Immunohistochemistry (IHC) was performed on paraffin sections to identify macrophages and apoptotic cells and trichrome staining was used to evaluate fibrosis. There were no significant differences in inflammatory markers between all control groups. With hydrogel delivery, macrophage infiltration and apoptosis were significantly reduced at days 21 and 35 compared to untreated animals. By day 35, IL-10 delivery via hydrogel reduced macrophage infiltration and apoptosis more than IL-10 injection alone. Fibrosis was decreased by day 35 in all treatment groups. This work supports the use of hydrogel delivery of IL-10 to treat chronic kidney disease. PMID:23913854

  5. CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues

    SciTech Connect

    Fujii, Masakazu, E-mail: masakazu731079@yahoo.co.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Inoguchi, Toyoshi, E-mail: toyoshi@intmed3.med.kyushu-u.ac.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan) [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Batchuluun, Battsetseg, E-mail: battsetseg.batchuluun@gmail.com [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Sugiyama, Naonobu, E-mail: nao1@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Kobayashi, Kunihisa, E-mail: nihisak@fukuoka-u.ac.jp [Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, 1-1-1 Zokumyoin, Chikushino, Fukuoka 818-8502 (Japan)] [Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, 1-1-1 Zokumyoin, Chikushino, Fukuoka 818-8502 (Japan); Sonoda, Noriyuki, E-mail: noriyuki@intmed3.med.kyushu-u.ac.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan) [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Takayanagi, Ryoichi, E-mail: takayana@intmed3.med.kyushu-u.ac.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2013-08-16

    Highlights: •CTLA-4Ig completely alleviates HFD-induced insulin resistance. •CTLA-4Ig reduces epididymal and subcutaneous fat tissue weight and adipocyte size. •CTLA-4Ig alters ATM polarization from inflammatory M1 to anti-inflammatory M2. •CTLA-4Ig may lead to a novel anti-obesity/inflammation/insulin resistance agent. •We identified the mechanism of the novel favorable effects of CTLA-4lg. -- Abstract: It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophage polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein ?, peroxisome proliferator-activated receptor ?, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.

  6. Immunotherapy for Cervical Cancer: Research Status and Clinical Potential

    PubMed Central

    Su, Jun-Han; Wu, Anjui; Scotney, Elizabeth; Ma, Barbara; Monie, Archana; Hung, Chien-Fu; Wu, T.-C.

    2010-01-01

    The high-risk types of human papillomavirus (HPV) have been found to be associated with most cervical cancers and play an essential role in the pathogenesis of the disease. Despite recent advances in preventive HPV vaccine development, such preventive vaccines are unlikely to reduce the prevalence of HPV infections within the next few years, due to their cost and limited availability in developing countries. Furthermore, preventive HPV vaccines may not be capable of treating established HPV infections and HPV-associated lesions, which account for high morbidity and mortality worldwide. Thus, it is important to develop therapeutic HPV vaccines for the control of existing HPV infection and associated malignancies. Therapeutic vaccines are quite different from preventive vaccines in that they require the generation of cell-mediated immunity, particularly T cell-mediated immunity, instead of the generation of neutralizing antibodies. The HPV-encoded early proteins, E6 and E7 oncoproteins, form ideal targets for therapeutic HPV vaccines since they are consistently expressed in HPV-associated cervical cancer and its precursor lesions and thus play crucial roles in the generation and maintenance of HPV-associated disease. Our review will cover the various therapeutic HPV vaccines for cervical cancer, including live vector-based, peptide or protein-based, nucleic acid-based, and cell-based vaccines targeting the HPV E6 and/or E7 antigens. Furthermore, we will review the studies using therapeutic HPV vaccines in combination with other therapeutic modalities and review the latest clinical trials on therapeutic HPV vaccines. PMID:20199126

  7. Cancer testis antigens--their importance in immunotherapy and in the early detection of cancer.

    PubMed

    Suri, Anil

    2006-04-01

    The development of successful immunotherapeutic strategies requires the identification and characterisation of immunogenic cancer antigens that will be recognised by the host immune system, leading to tumour rejection. The concept of immunotherapy is based on the assumption that antigenic structures expressed in tumours can be used for therapeutic approaches employing the autologous immune system or by the application of immunotherapeutic reagents. Based on this concept, there is a great need to gain profound knowledge of the actual protein/antigen expression and its distribution pattern within normal tissues and cancerous tissues. Cancer testis (CT) antigens represent a unique class of tumour antigens, which are expressed in a variety of cancerous tissues and are silent in normal tissues, except for the testis. Owing to their restricted gene expression in the testis and various malignancies, CT antigens represent potential defined targets for antigen-based vaccination and antigen-directed immunotherapy to control cancer growth. Moreover, the analysis of humoral and cellular immune responses to CT antigens has proved useful for identifying novel cancer serum biomarkers with potential implications in early diagnosis of cancer. PMID:16548764

  8. Unlocking the Combination: Potentiation of Radiation-Induced Antitumor Responses with Immunotherapy

    PubMed Central

    Wattenberg, Max M.; Fahim, Ahmed; Ahmed, Mansoor M.; Hodge, James W.

    2014-01-01

    There is increasing evidence of the potential for radiation therapy to generate antitumor immune responses. The mechanisms of this immune-activating potential include actions on tumor cells such as immunogenic cell death and phenotypic change. Radiation modulates tumor cell surface expression of cell death receptors, tumor-associated antigens and adhesion molecules. This process of immunomodulation sensitizes tumor cells to immune-mediated killing. Radiation also affects immune compartments, including antigen-presenting cells, cytotoxic T lymphocytes and humoral immunity, leading to specific antitumor immune responses. Recognizing the importance of immunity as a potentiator of response to radiation leads to rational augmentation of antitumor immunity by combining radiation and immunotherapy. Targeted immunotherapy manipulates the immune system in a way that best synergizes with radiation. This article discusses the ability of radiation monotherapy to induce antitumor immunity, with a focus on the effect of radiation on antigen-presenting cells and cytotoxic T lymphocytes. We define two important responses generated by tumor cells, immunogenic cell death and immunomodulation, both of which are radiation dose-dependent. In conclusion, we describe the translation of several combination therapies from the preclinical to the clinical setting and identify opportunities for further exploration. PMID:24960415

  9. Utilizing Cytokines to Function-Enable Human NK Cells for the Immunotherapy of Cancer

    PubMed Central

    Romee, Rizwan; Leong, Jeffrey W.; Fehniger, Todd A.

    2014-01-01

    Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy. PMID:25054077

  10. Superiority of intravesical immunotherapy with Corynebacterium parvum and Allium sativum in control of murine bladder cancer.

    PubMed

    Marsh, C L; Torrey, R R; Woolley, J L; Barker, G R; Lau, B H

    1987-02-01

    Intravesical immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum (CP), keyhole limpet hemocyanin (KLH), and an extract of Allium sativum (AS) was studied in mice transplanted intravesically with mouse bladder tumor cells (MBT-2). Female C3H/He mice were anesthetized with sodium pentobarbital. Two X 10(5) MBT-2 cells were delivered into the bladder transurethrally using a small catheter, immediately after the posterior wall of the bladder had been electrocauterized. Bladder tumor became palpable or demonstrable microscopically in two weeks. Immunotherapy with BCG (2 X 10(6) CFU), CP (250 micrograms), KLH (50 micrograms), or AS (25 mg) was administered directly into the bladder via urethral catheter on day 1, day 6, or days 1 and 6. On day 21 the bladders and spleens were excised and weighed, and the bladders were examined macroscopically and microscopically for evidence of tumor. The results of the study showed that two treatments given one and six days after tumor transplant yielded the lowest tumor incidence and that CP and AS appeared equally effective or even slightly more effective than BCG in this model. These results suggest that clinical evaluation of CP or AS may be worthwhile. PMID:3806842

  11. The Optimal Partnership of Radiation and Immunotherapy: from Preclinical Studies to Clinical Translation

    PubMed Central

    Demaria, Sandra; Pilones, Karsten A.; Vanpouille-Box, Claire; Golden, Encouse B.; Formenti, Silvia C.

    2014-01-01

    The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed. PMID:24937779

  12. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy

    PubMed Central

    Leone, Robert D.; Lo, Ying-Chun; Powell, Jonathan D.

    2015-01-01

    The last several years have witnessed exciting progress in the development of immunotherapy for the treatment of cancer. This has been due in great part to the development of so-called checkpoint blockade. That is, antibodies that block inhibitory receptors such as CTLA-4 and PD-1 and thus unleash antigen-specific immune responses against tumors. It is clear that tumors evade the immune response by usurping pathways that play a role in negatively regulating normal immune responses. In this regard, adenosine in the immune microenvironment leading to the activation of the A2a receptor has been shown to represent one such negative feedback loop. Indeed, the tumor microenvironment has relatively high concentrations of adenosine. To this end, blocking A2a receptor activation has the potential to markedly enhance anti-tumor immunity in mouse models. This review will present data demonstrating the ability of A2a receptor blockade to enhance tumor vaccines, checkpoint blockade and adoptive T cell therapy. Also, as several recent studies have demonstrated that under certain conditions A2a receptor blockade can enhance tumor progression, we will also explore the complexities of adenosine signaling in the immune response. Despite important nuances to the A2a receptor pathway that require further elucidation, studies to date strongly support the development of A2a receptor antagonists (some of which have already been tested in phase III clinical trials for Parkinson Disease) as novel modalities in the immunotherapy armamentarium. PMID:25941561

  13. Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma.

    PubMed

    Zhao, Xuan; Zhang, Zhen; Li, Hong; Huang, Jianmin; Yang, Shuangning; Xie, Tan; Huang, Lan; Yue, Dongli; Xu, Li; Wang, Liping; Zhang, Weixing; Zhang, Yi

    2015-07-01

    Cytokine induced killer (CIK) cell-based treatments have shown antitumor activity against renal cell carcinoma (RCC) in vitro and in vivo. But the therapeutic options and benefits of various CIK cells were unknown for different stages of RCC. In this random clinical trial, the 3-year disease free survival (DFS) of operable RCC patients treated with autologous tumor lysate-pulsed dendritic cells co-cultured with cytokine induced killer (Ag-DC-CIK) was 96.7% compared with 57.7% in the control group. Ag-DC-CIK immunotherapy decreased the risk of post-operative disease progression and relapse (P?=?0.0418). In inoperable RCC patients treated with CIK, the 3-year overall survival (OS) and progression-free survival (PFS) were significantly longer than the control group (P?=?0.0116 and P?=?0.0212). The CD4(+)/CD8(+) T cell ratio in peripheral blood increased after the last cell infusion in the CIK treatment group, and especially further increased in the Ag-DC-CIK treatment group (P?=?0.002). No severe toxicity was observed after infusion of CIK cells. Therefore, tumor antigen-sensitized Ag-DC-CIK cells might be more efficient and personalized for the patients with tumor resection, and CIK cells could improve the prognosis for those inoperable patients. According to the stages of RCC patients, different CIK cell-based immunotherapies would help to achieve more beneficial effects. PMID:25843292

  14. Dendritic Cells for Active Anti-Cancer Immunotherapy: Targeting Activation Pathways Through Genetic Modification

    PubMed Central

    Breckpot, Karine; Escors, David

    2009-01-01

    Tumour immunotherapy has become a treatment modality for cancer, harnessing the immune system to recognize and eradicate tumour cells specifically. It is based on the expression of tumour associated antigens (TAA) by the tumour cells and aims at the induction of TAA-specific effector T cell responses, whilst overruling various mechanisms that can hamper the anti-tumour immune response, e.g. regulatory T cells (Treg). (Re-) activation of effector T cells requires the completion of a carefully orchestrated series of specific steps. Particularly important is the provision of TAA presentation and strong stimulatory signals, delivered by co-stimulatory surface molecules and cytokines. These can only be delivered by professional antigen-presenting cells, in particular dendritic cells (DC). Therefore, DC need to be loaded with TAA and appropriately activated. It is not surprising that an extensive part of DC research has focused on the delivery of both TAA and activation signals to DC, developing a one step approach to obtain potent stimulatory DC. The simultaneous delivery of TAA and activation signals is therefore the topic of this review, emphasizing the role of DC in mediating T cell activation and how we can manipulate DC for the pill-pose of enhancing tumour immunotherapy. As we gain a better understanding of the molecular and cellular mechanisms that mediate induction of TAA-specific T cells, rational approaches for the activation of T cell responses can be developed for the treatment of cancer. PMID:19857199

  15. Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma.

    PubMed

    Ascierto, Paolo A

    2015-03-01

    Since 2011, the approval of four different classes of novel drugs (the anti-CTLA-4 agent, ipilimumab; BRAF inhibitors [BRAFi]; MEK inhibitors [MEKi]; and the anti-PD-1 drug, pembrolizumab) has revolutionized the care of advanced melanoma, with the disease becoming a model for the development of new treatments for other types of cancer. Further advances in the treatment of melanoma represented some of the key highlights of the European Society of Medical Oncology (ESMO) 2014 congress. The first phase III trial of an anti-PD-1 agent to report the CA209-037 study included 405 patients with metastatic melanoma previously treated with ipilimumab who were randomized 2:1 to receive nivolumab 3 mg/kg every 2 weeks or investigator's choice chemotherapy. Nivolumab was associated with a higher response rate than chemotherapy and was well tolerated, with adverse events mostly low grade and manageable using recommended treatment algorithms. New data on other immunotherapies, namely ipilimumab and pembrolizumab, were also reported. In addition, outside of immunotherapy, combination approaches involving targeted agents were also a major focus of ESMO this year, with two major phase III studies of combined BRAF inhibition and MEK inhibition being reported. Overall, new clinical trial findings reported at ESMO further endorse the view that melanoma, given the continued development of novel, effective compounds, can accurately be described as the most "dynamic" field of oncology at present. PMID:25549844

  16. Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials.

    PubMed

    Reardon, David A; Okada, Hideho

    2015-07-01

    In much of medical oncology, including neuro-oncology, there is great interest to evaluate the therapeutic potential of immune-based therapies including vaccines, adoptive T cell strategies and modulators of immune checkpoint regulators such as cytotoxic T lymphocyte antigen 4 and programmed death 1. Immune-based treatments exert an indirect anti-tumor effect by generating potent, tumor-targeting immune responses. Robust anti-tumor immune responses have been shown to achieve encouraging radiographic responses across the spectrum of applied immunotherapeutics which are felt to be indicative of a bona fide anti-tumor effect. Conversely, worsening of imaging findings, particularly early in the course of immunotherapy administration, can be challenging to interpret with growing evidence demonstrating that at least a subset of such patients ultimately will derive meaningful clinical benefit. The immune related response criteria were generated to provide guidance regarding the interpretation of such complex imaging findings, for general medical oncologists prescribing immunotherapeutics. An analogous effort that addresses challenges associated with imaging assessment and incorporates nuances associated with neuro-oncology patients is underway and is referred to as the immunotherapy response assessment in neuro-oncology criteria. PMID:25707876

  17. [MODERN CONCEPT OF PATHOGENESIS OF ALLERGIC DISEASES AND NEW POTENTIALITIES OF IMMUNOTHERAPY].

    PubMed

    Berezhnaya, N; Sepiashvili, R

    2015-06-01

    Despite the undoubted success of specific immunotherapy of allergic diseases (desensitization), one should confess that its effectiveness is not always satisfactory, and this explains the ongoing search for new approaches to immunotherapy. This conclusion is based on the results of basic research in immunology and allergy which provide new opportunities for therapy. The analysis of relevant work related to the study of allergic processes makes it possible to allocate two items: 1) specific hyposensitization-therapeutic approach that is primarily aimed at the final stage of the allergic reaction development; 2) development of allergic phenotype begins at early stages of B lymphocyte development while its final stage, IgE hyperproduction, depends on multiple of pre- and accompanying factors. Unfortunately, we should say that there are many issues in the development of allergic reaction that are beyond our understanding. Nevertheless, today new mechanisms of pathogenesis are revealed and there is a real opportunity for new approaches to the treatment of this pathology. Some of such various mechanisms will be discussed below. PMID:26087724

  18. Immunoglobulin E-binding epitopes of mite allergens: from characterization to immunotherapy.

    PubMed

    Cui, Yubao

    2014-12-01

    House dust mites and storage mites produce a number of allergens that can induce hypersensitivity reactions in humans and result in allergic diseases like asthma, rhinitis, and dermatitis. Recent advances in identifying and characterizing these allergens--and, in particular, their immunoglobulin E (IgE)-binding epitopes--have produced a wealth of knowledge. Here, methods for identifying IgE-binding epitopes, from immunoassays to in silico approaches, are summarized and placed in context with the identification of epitopes of mite allergens, particularly from the Dermatophagoides spp. major allergen groups 1 and 2. Finally, the transfer of this information to the clinical development and application of new diagnostic and immunotherapeutic approaches is discussed. While progress in recent years has built on the specific immunotherapies established decades ago, much work remains to be done to mitigate mite allergic disease. Future studies should seek to identify epitopes for mite species beyond Dermatophagoides and for minor allergens. Efforts in translational medicine should use the current epitope data to develop modified allergens for immunotherapy. PMID:24218295

  19. A New Hope in Immunotherapy for Malignant Gliomas: Adoptive T Cell Transfer Therapy

    PubMed Central

    Chung, Dong-Sup; Shin, Hye-Jin; Hong, Yong-Kil

    2014-01-01

    Immunotherapy emerged as a promising therapeutic approach to highly incurable malignant gliomas due to tumor-specific cytotoxicity, minimal side effect, and a durable antitumor effect by memory T cells. But, antitumor activities of endogenously activated T cells induced by immunotherapy such as vaccination are not sufficient to control tumors because tumor-specific antigens may be self-antigens and tumors have immune evasion mechanisms to avoid immune surveillance system of host. Although recent clinical results from vaccine strategy for malignant gliomas are encouraging, these trials have some limitations, particularly their failure to expand tumor antigen-specific T cells reproducibly and effectively. An alternative strategy to overcome these limitations is adoptive T cell transfer therapy, in which tumor-specific T cells are expanded ex vivo rapidly and then transferred to patients. Moreover, enhanced biologic functions of T cells generated by genetic engineering and modified immunosuppressive microenvironment of host by homeostatic T cell expansion and/or elimination of immunosuppressive cells and molecules can induce more potent antitumor T cell responses and make this strategy hold promise in promoting a patient response for malignant glioma treatment. Here we will review the past and current progresses and discuss a new hope in adoptive T cell therapy for malignant gliomas. PMID:25009822

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

    PubMed Central

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

    2015-01-01

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

  1. The “Trojan Horse” Approach to Tumor Immunotherapy: Targeting the Tumor Microenvironment

    PubMed Central

    Nelson, Delia; Fisher, Scott; Robinson, Bruce

    2014-01-01

    Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumors may be more effective, particularly those that overcome natural suppressive factors in the tumor microenvironment. The “Trojan Horse” approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more “full frontal” treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient “dangerous” tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients. PMID:24955376

  2. Utilizing the BiTE (bispecific T-cell engager) platform for immunotherapy of cancer.

    PubMed

    Stieglmaier, Julia; Benjamin, Jonathan; Nagorsen, Dirk

    2015-08-01

    Various approaches of T-cell-based cancer immunotherapy are currently under investigation, among these are BiTE® (bispecific T-cell engager) antibody constructs, which have a unique design and mechanism of action. They are constructed by genetically linking onto a single polypeptide chain the minimal binding domains of monoclonal antibodies for tumor-associated surface antigens and for the T-cell receptor-associated molecule CD3. Concurrent engagement of the target cell antigen and CD3 leads to activation of polyclonal cytotoxic T-cells, resulting in target cell lysis. Blinatumomab, a BiTE targeting CD19, is being investigated in a broad range of B-cell malignancies and has recently been approved in the USA by the US FDA for Philadelphia chromosome-negative relapsed/refractory B-acute lymphoblastic leukemia under the trade name BLINCYTO™. The BiTE platform is one of the clinically most advanced T-cell immunotherapy options. PMID:25971805

  3. Allergen-specific immunotherapy in asthmatic children: from the basis to clinical applications.

    PubMed

    Aryan, Zahra; Compalati, Enrico; Comapalati, Enrico; Canonica, Giorgio Walter; Rezaei, Nima

    2013-06-01

    Atopic asthma in childhood with the tendency to persist into adult life is an important issue in pediatrics. Allergen-specific immunotherapy (SIT) is the only curative treatment option for these children, being directed to the causes of the disease. The Th2 phenotype is a predominant immunological pattern in atopic asthma and SIT leads to apoptosis/anergy of T cells and induces immune-regulatory responses and immune deviation towards Th1. Many factors can affect the safety and efficacy of SIT, such as pattern of sensitization, allergy vaccine (allergen extracts, adjuvants and conjugated molecules), route of administration (subcutaneous or sublingual) and different treatment schedules. Overall, asthma symptoms and medication scores usually decrease following a SIT course and the most common observed side effects are restricted to local swelling, erythema and pruritus. Compared with conventional pharmacotherapy, SIT may be more cost effective, providing a benefit after discontinuation and a steroid-sparing effect. In addition, it can prevent new sensitizations in monosensitized asthmatic children. Microbial supplements such as probiotics, immunomodulatory substances like anti-IgE/leukotrienes, antibodies and newer allergen preparations such as recombinant forms have been tested to improve the efficacy and safety of SIT with inconclusive results. In conclusion, SIT provides an appropriate solution for childhood asthma that should be employed more often in clinical practice. Further studies are awaited to improve current knowledge regarding the mechanisms behind SIT and determine the most appropriate materials and schedule of immunotherapy for children with asthma. PMID:23750794

  4. Modulation of Bone Morphogenic Protein Signaling in T-Cells for Cancer Immunotherapy

    PubMed Central

    Kuczma, Michal; Kurczewska, Agnieszka; Kraj, Piotr

    2015-01-01

    Immunotherapy is becoming an increasingly attractive therapeutic alternative for conventional cancer therapy. In recent years Foxp3+ regulatory T-cells (TR) were identified as the major obstacle to effective cancer immunotherapy. The abundance of these cells in peripheral blood is increased in patients with multiple types of cancer and their prevalence among tumor-infiltrating lymphocytes correlated with poor clinical prognosis. In contrast, removal or inactivation of TR cells led to enhanced antitumor immune response and better efficacy of cancer vaccines. We report that Bone Morphogenic Protein Receptor 1? (BMPR1?, Alk-3), is expressed by activated effector CD4+ and TR cells and modulates functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the transforming growth factor (TGF)-? family of cytokines that also include TGF? and activins. BMPs play crucial roles in- embryonic development, tissue differentiation and homeostasis and development of cancer. It was demonstrated that BMPs and activins synergize with TGF? to regulate thymic T-cell development, maintain TR cells and control peripheral tolerance. Inactivation of BMPR1? in T-cells results in impaired thymic and peripheral generation of TR cells. BMPR1? -deficient activated T-cells produced higher level of interferon (IFN)-? than BMPR1?-sufficient T-cells. Moreover, transplanted B16 melanoma tumors grew smaller in mice lacking expression of BMPR1? in T-cells and tumors had few infiltrating TR cells and a higher proportion of CD8+ T-cells than wild-type mice. PMID:24350726

  5. The combination of radiotherapy and immunotherapy using glycated chitosan as an immunological stimulant

    NASA Astrophysics Data System (ADS)

    Chang, Chun-Yuan; Leu, Jyh-Der; Wang, Chung-Yi; Chen, Wei R.; Lee, Yi-Jang

    2015-03-01

    Immunotherapy has been reported to effectively treat various cancers. In addition, scientists are dedicated in finding whether the combination of radiotherapy and immunotherapy can efficiently suppress cancer progression and recurrence. Although radiotherapy has been widely used for breast cancer, better strategies to overcome the latestage breast cancer remains explored. The glycated chitosan (GC), a novel immunological stimulant, was demonstrated to trigger local immune response facilitating the enhancement of radiosensitivity. Our previous study also revealed that the cell mortality and invasive ability were decreased under GC treatment, but the underlying mechanism remains unclear. In this study, we used 4T1-3R-L, a derived murine breast cancer cell line from the spontaneous metastasized liver lesion. We combined ionizing radiation with GC to treat 4T1-3R-L and found the expression of DNA damage-related genes such as gamma-H2AX was more than radiation alone In addition, the cell cycle distribution and colony forming assay showed an increased sub-G1 population and decreased cell survival rate after IR combined GC treatment. Taken together, we sought to elucidate the underlying mechanism by the investigation of DNA damage repair process when IR combined with GC, and to explore another advantage of GC to aid other cancer treatments. Based on our most updated results, the GC treatment is able to effectively increase the radiosensitivity through an immune-responsive signaling transduction, indicating that GC could be a valuable therapeutic strategy for treating against advanced breast cancers.

  6. Genetic Manipulation of NK Cells for Cancer Immunotherapy: Techniques and Clinical Implications

    PubMed Central

    Carlsten, Mattias; Childs, Richard W.

    2015-01-01

    Given their rapid and efficient capacity to recognize and kill tumor cells, natural killer (NK) cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Recent advances in viral transduction and electroporation have now allowed detailed characterization of genetically modified NK cells and provided a better understanding for how these cells can be utilized in the clinic to optimize their capacity to induce tumor regression in?vivo. Improving NK cell persistence in?vivo via autocrine IL-2 and IL-15 stimulation, enhancing tumor targeting by silencing inhibitory NK cell receptors such as NKG2A, and redirecting tumor killing via chimeric antigen receptors, all represent approaches that hold promise in preclinical studies. This review focuses on available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors in?vivo, we foresee genetic engineering as an obligatory pathway required to exploit the full potential of NK-cell based immunotherapy in the clinic. PMID:26113846

  7. SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery

    PubMed Central

    2011-01-01

    Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies. PMID:21929757

  8. Sustained low-level expression of interferon-? promotes tumor development: potential insights in tumor prevention and tumor immunotherapy

    Microsoft Academic Search

    Yu-Fei He; Xiao-Hong Wang; Gui-Mei Zhang; Hong-Tao Chen; Hui Zhang; Zuo-Hua Feng

    2005-01-01

    Although the proinflammatory cytokine interferon-? (IFN-?) has been generally thought to enhance antitumor immune responses and be involved in antitumor mechanisms of many other immunotherapy molecules, it has also been reported that IFN-? could promote tumor immune evasion. In this report, by using an ideal mouse model that expresses IFN-? locally in muscle, we demonstrate that sustained low-level expression of

  9. Antitumor Immunotherapy via Antigen Delivery from a Live Attenuated Genetically Engineered Pseudomonas aeruginosa Type III Secretion System-Based Vector

    Microsoft Academic Search

    Olivier Epaulard; Bertrand Toussaint; Lauriane Quenee; Madiha Derouazi; Nabil Bosco; Christian Villiers; Rozenn Le Berre; Benoit Guery; Didier Filopon; Laurence Crombez; Patrice N. Marche; Benoit Polack

    2006-01-01

    Immunotherapy requiring an efficient T lymphocyte response is initiated by antigen delivery to antigen-presenting cells. Several studies have assessed the efficiency of various antigen loading procedures, including microbial vectors. Here a live strain of Pseudomonas aeruginosa was engineered to translocate a recombinant antigenic protein into mammalian cells via the type III secretion system, a bacterial device translocating effector proteins into

  10. Adverse Events During Immunotherapy Against Grass Pollen-Induced Allergic Rhinitis - Differences Between Subcutaneous and Sublingual Treatment.

    PubMed

    Aasbjerg, Kristian; Dalhoff, Kim Peder; Backer, Vibeke

    2015-08-01

    Allergic rhinitis (AR) triggered by grass pollen is a common disease, affecting millions of people worldwide. Treatment consists of symptom-alleviating drugs, such as topical corticosteroids or antihistamines. Another option is potentially curative immunotherapy, currently available as sublingual and subcutaneous treatment. We investigated the potential differences in the prevalence and severity of adverse events related to subcutaneous and sublingual immunotherapy (SLIT) against grass pollen-induced AR. A thorough literature search was performed with PubMed and EMBASE. The findings were compared with the available summaries of product characteristics (SPC) and with commercial pharmacology databases (Micromedex). The majority of available safety data originate from registered products of standardized allergens. A surprisingly large percentage of drugs, especially those used in the United States, have no systematically collected safety data. No sufficiently powered randomized trials comparing sublingual and subcutaneous immunotherapy (SCIT) were available, but general safety assessments indicate that sublingual tablet treatment is safer than subcutaneous treatment. Not all commonly used immunotherapy drugs are officially registered, and not all have systematically collected safety data. This is especially true for older drugs used in the United States. In contrast, newer drugs that have undergone extensive clinical testing have better documentation, but unified collection of safety data is still lacking. Considering the evidence available, most drugs elicit similar side effects from the same organ systems, and symptoms from the sublingual drug classes are probably less severe. However, a head-to-head comparison of safety and efficacy is lacking. PMID:25968654

  11. Clinical effects of immunotherapy of DC-CIK combined with chemotherapy in treating patients with metastatic breast cancer.

    PubMed

    Mao, Qixin; Li, Lianfang; Zhang, Chongjian; Sun, Yadong; Liu, Shanqing; Cui, Shude

    2015-05-01

    This study aimed to analyze the clinical effects of dendritic cell (DC) and cytokine-induced killer (CIK) immunotherapy combined with chemotherapy on patients with metastatic breast cancer. Twenty patients were included into this study who were diagnosed as metastatic breast cancer (MBC). DC and CIK were augmented by in vitro culture and then rein fused into body through vein.The pain relief rate (RR), toxic and side effects of chemotherapy, immunity functions and living qualityof patients were observed. DC and CIK cells were induced by the autologous peripheral blood mononuclear cells (PBMC). Meanwhile, flow cytometry was used to measure T cell subsets and natural killer T (NKT) cells in patients in the two groups before and after the biological treatment. After DC and CIK were rein fused into the patients body, no severe side-effect was found. It was also found that cellular immunotherapy combined with chemotherapy the immunotherapy of cells improved the immunity, the living qualityof patients and the disease control rate (DCR). In conclusion, cellular immunotherapy produces small side effects; it combined with chemotherapyis able to improve the DCR and living quality of patients and prolong their lives. PMID:26051718

  12. Melanocyte Destruction after Antigen-specific Immunotherapy of Melanoma: Direct Evidence of T Cell-mediated Vitiligo

    Microsoft Academic Search

    Cassian Yee; John A. Thompson; Patrick Roche; David R. Byrd; Peter P. Lee; Michael Piepkorn; Karla Kenyon; Mark M. Davis; Stanley R. Riddell; Philip D. Greenberg

    Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previ- ously in humans. In this study, we describe a patient with

  13. Production of Salivary Immunoglobulin A and Suppression of Dermatophagoides pteronyssinus-Induced Airway Inflammation by Local Nasal Immunotherapy

    Microsoft Academic Search

    Yi-Hsia Liu; Jaw-Ji Tsai

    2005-01-01

    Background: Local nasal immunotherapy (LNIT) is an effective immunotherapeutic modality, especially when targeting a single immunodominant peptide from an allergen. However, the working mechanisms of LNIT are poorly understood. We hypothesized that LNIT with a mixture of group 2 allergens of Dermatophagoides pteronyssinus (Der p 2) protein and fungal immunomodulatory peptide (FIP) would generate suppression of Der p-induced airway inflammation

  14. Adoptive Immunotherapy against Experimental Visceral Leishmaniasis with CD8+ T Cells Requires the Presence of Cognate Antigen

    PubMed Central

    Polley, Rosalind; Stager, Simona; Prickett, Sara; Maroof, Asher; Zubairi, Soombul; Smith, Deborah F.; Kaye, Paul M.

    2006-01-01

    CD8+ T cells have a protective role in experimental visceral leishmaniasis. However, the observation that inflammatory cytokines induce bystander activation of CD8+ T cells questions the need for antigen-dependent effector function. Here, we demonstrate that successful adoptive immunotherapy with CD8+ T cells is strictly dependent upon the presence of cognate antigen. PMID:16369038

  15. Immunotherapy in Cancer: A Combat between Tumors and the Immune System; You Win Some, You Lose Some.

    PubMed

    Madorsky Rowdo, Florencia Paula; Baron, Antonela; Urrutia, Mariela; Mordoh, José

    2015-01-01

    Cancer immunotherapy has emerged as a treatment modality, mainly as the result of discoveries in the immune response regulation, including mechanisms that turn off immune responses. Immunogenic cutaneous melanoma is a canonical model for therapeutic immunotherapy studies. "Passive" immunotherapy with monoclonal antibodies (mAbs) has outpaced "active" immunotherapy with anti-tumor vaccines, and mAbs that antagonize the off responses have been recently introduced in clinical practice. Despite these recent successes, many unresolved practical and theoretical questions remain. Notably unknown are the identity of the lymphocytes that eliminate tumor cells, which white cells enter into tumors, through which endothelium, in what order, and how they perform their task. The parameters of size and location that could be used to determine in which tumors the immune response may be sufficient to eradicate the tumor are yet unknown. Immunotherapy has been so far more efficient to treat solid and hematologic tumors located outside the central nervous system, than primary brain tumors and brain metastases. In contrast to recent advances with mAbs, anti-tumor vaccine development has been lagging behind. The multiplicity of antigens that must be targeted to achieve significant clinical response is partially responsible for this lag, especially in melanoma, one of the most mutated tumors. Further hampering vaccination results is the fact that tumor elimination by the immune system is the result of a race between tumors with different growth rates and the relatively slow development of the adaptive immune response. The enhancement of the native arm of the immune response or the administration of targeted chemotherapy to slow tumor development, are approaches that should be studied. Finally, criteria used to analyze patient response to immunotherapeutic treatments must be perfected, and the patient populations that could benefit the most from this approach must be better defined. PMID:25859247

  16. Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity.

    PubMed

    Rigo, Valentina; Corrias, Maria Valeria; Orengo, Anna Maria; Brizzolara, Antonella; Emionite, Laura; Fenoglio, Daniela; Filaci, Gilberto; Croce, Michela; Ferrini, Silvano

    2014-05-01

    IL-21 is an immune-enhancing cytokine, which showed promising results in cancer immunotherapy. We previously observed that the administration of anti-CD4 cell-depleting antibody strongly enhanced the anti-tumor effects of an IL-21-engineered neuroblastoma (NB) cell vaccine. Here, we studied the therapeutic effects of a combination of recombinant (r) IL-21 and anti-CD4 monoclonal antibodies (mAb) in a syngeneic model of disseminated NB. Subcutaneous rIL-21 therapy at 0.5 or 1 ?g/dose (at days 2, 6, 9, 13 and 15 after NB induction) had a limited effect on NB development. However, coadministration of rIL-21 at the two dose levels and a cell-depleting anti-CD4 mAb cured 28 and 70 % of mice, respectively. Combined immunotherapy was also effective if started 7 days after NB implant, resulting in a 30 % cure rate. Anti-CD4 antibody treatment efficiently depleted CD4(+) CD25(high) Treg cells, but alone had limited impact on NB. Combination immunotherapy by anti-CD4 mAb and rIL-21 induced a CD8(+) cytotoxic T lymphocyte response, which resulted in tumor eradication and long-lasting immunity. CD4(+) T cells, which re-populated mice after combination immunotherapy, were required for immunity to NB antigens as indicated by CD4(+) T cell depletion and re-challenge experiments. In conclusion, these data support a role for regulatory CD4(+) T cells in a syngeneic NB model and suggest that rIL-21 combined with CD4(+) T cell depletion reprograms CD4(+) T cells from immune regulatory to anti-tumor functions. These observations open new perspectives for the use of IL-21-based immunotherapy in conjunction with transient CD4(+) T cell depletion, in human metastatic NB. PMID:24647609

  17. Seasonal asthma in northern California: allergic causes and efficacy of immunotherapy.

    PubMed

    Reid, M J; Moss, R B; Hsu, Y P; Kwasnicki, J M; Commerford, T M; Nelson, B L

    1986-10-01

    Inland areas of northern California have an intense grass pollination in the spring of each year. This is accompanied by a stirking rise in the incidence of asthma. We documented this relationship and designed a trial to test the efficacy of immunotherapy for grass-pollen asthma. Aeroallergen counts were performed on the roof of the allergy clinic of David Grant Medical Center from January 1981 to December 1984 by a gravity collector. These counts were compared to counts done on a Rotorod at a nearby hospital from July 1982 to September 1984. Climatologic factors were also tabulated. Visits for asthma and rhinitis to our emergency room and asthma admissions to our hospital were counted for the 4-year period. A randomized, double-blinded, placebo-controlled trial of immunotherapy with grass-pollen extract was performed from November 1984 to June 1985. Two groups of clinically and immunologically well-matched subjects were started on an accelerated preseasonal trial of immunotherapy. One group received a standardized grass extract, and the other group did not. Both groups received other extracts of aeroallergens to which they were skin test positive that occur locally in the spring and summer. This was done because of our dissatisfaction with a histamine placebo used in a previous pilot study. Symptom medication scores (SMS) and immunologic parameters were followed. For the 4-year period, grass-pollen count (GPC) correlated strongly with asthma emergency room visits (r = 0.90; p less than 0.001) and for rhinitis (r = 0.92; p less than 0.001). Asthma admissions also correlated strongly with GPC (r = 0.72; p less than 0.001). Other aeroallergens either did not correlate significantly or occurred in such small numbers that they could not be seriously considered. Rotorod counts supported these conclusions with the exceptions of some Basidiomycetes. Climatologic factors demonstrated no relationship to the incidence of asthma. Asthma SMS were lower in the grass-treated group, p less than 0.05. Rhinitis SMS were also lower but did not reach significance, p = 0.11. RGGI sIgE did not rise significantly in the grass-treated group but did in the placebo-treated group. RGGI sIgE rose in both groups, although to significantly higher levels in the grass-treated group, p less than 0.001. The asthma SMS were inversely related to increasing RGGI cumulative dose, p less than 0.10. Linear regression analysis of the dose-response scattergram suggests that a cumulative dose of approximately 90 micrograms of RGGI may be desirable.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3771951

  18. A Safe Bacterial Microsyringe for In Vivo Antigen Delivery and Immunotherapy

    PubMed Central

    Le Gouëllec, Audrey; Chauchet, Xavier; Laurin, David; Aspord, Caroline; Verove, Julien; Wang, Yan; Genestet, Charlotte; Trocme, Candice; Ahmadi, Mitra; Martin, Sandrine; Broisat, Alexis; Cretin, François; Ghezzi, Catherine; Polack, Benoit; Plumas, Joël; Toussaint, Bertrand

    2013-01-01

    The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the “killed but metabolically active” (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery. PMID:23531551

  19. A safe bacterial microsyringe for in vivo antigen delivery and immunotherapy.

    PubMed

    Le Gouëllec, Audrey; Chauchet, Xavier; Laurin, David; Aspord, Caroline; Verove, Julien; Wang, Yan; Genestet, Charlotte; Trocme, Candice; Ahmadi, Mitra; Martin, Sandrine; Broisat, Alexis; Cretin, François; Ghezzi, Catherine; Polack, Benoit; Plumas, Joël; Toussaint, Bertrand

    2013-05-01

    The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the "killed but metabolically active" (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery. PMID:23531551

  20. Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model.

    PubMed

    Castillo-Carranza, Diana L; Guerrero-Muñoz, Marcos J; Sengupta, Urmi; Hernandez, Caterina; Barrett, Alan D T; Dineley, Kelly; Kayed, Rakez

    2015-03-25

    In Alzheimer's disease (AD), the pathological accumulation of tau appears to be a downstream effect of amyloid ? protein (A?). However, the relationship between these two proteins and memory loss is unclear. In this study, we evaluated the specific removal of pathological tau oligomers in aged Tg2576 mice by passive immunotherapy using tau oligomer-specific monoclonal antibody. Removal of tau oligomers reversed memory deficits and accelerated plaque deposition in the brain. Surprisingly, A?*56 levels decreased, suggesting a link between tau and A? oligomers in the promotion of cognitive decline. The results suggest that tau oligomerization is not only a consequence of A? pathology but also a critical mediator of the toxic effects observed afterward in AD. Overall, these findings support the potential of tau oligomers as a therapeutic target for AD. PMID:25810517

  1. Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy

    PubMed Central

    2013-01-01

    Summary Adoptive cellular immunotherapy (ACT) is a potentially curative therapy for patients with advanced cancer. Eradication of tumor in mouse models and humans correlates with both a high dose of adoptively transferred cells and cells with a minimally differentiated phenotype that maintain replicative capacity and multipotency. We speculate that response to ACT not only requires transfer of cells with immediate cytolytic effector function to kill the bulk of fast-growing tumor, but also transfer of tumor-specific cells that maintain an ability for self-renewal and the capacity to produce a continual supply of cytolytic effector progeny until all malignant cells are eliminated. Current in vitro methods to expand cells to sufficient numbers and still maintain a minimally differentiated phenotype are hindered by the biological coupling of clonal expansion and effector differentiation. Therefore, a better understanding of the physiologic mechanism that couples cell expansion and differentiation in CD8+ T cells may improve the efficacy of ACT. PMID:24329803

  2. Genetics and immunotherapy: using the genetic landscape of gliomas to inform management strategies.

    PubMed

    Wang, Joanna Y; Bettegowda, Chetan

    2015-07-01

    Recent work in genetics has identified essential driver mutations in gliomas and has profoundly changed our understanding of tumorigenesis. New insights into the molecular basis of glioma has informed the development of therapies demonstrating considerable potential, including immunotherapeutic approaches such as peptide and dendritic cell vaccines against EGFRvIII. However, the selective targeting of one component of a dysregulated pathway may be inadequate for a durable clinical response, given the intratumoral heterogeneity of glioblastoma (GBM) and hypermutated profiles displayed by tumor recurrences. Immune checkpoint blockade with anti-cytotoxic T lymphocyte antigen-4 (CTLA) and anti-programmed cell death 1 (PD-1) have demonstrated encouraging results in clinical trials with other solid tumors, and recent data suggest that this type of therapy may be particularly useful for tumors with high mutational burdens. Although the survival for patients with GBM has remains grim, the use of immunotherapy may finally change patient outcomes. PMID:25697584

  3. Highlights of the First International “Immunotherapy in Pediatric Oncology: Progress and Challenges” Meeting

    PubMed Central

    Capitini, Christian M.; Cooper, Laurence J.N.; Egeler, R. Maarten; Handgretinger, Rupert; Locatelli, Franco; Sondel, Paul M.; Mackall, Crystal L.

    2009-01-01

    The first annual conference on immunotherapy in pediatric oncology was held in Bethesda, MD, USA, from September 9–10, 2008 to discuss the state-of-the-art of immunotherapeutic strategies currently being explored in pediatric oncology. Major topics included targeting cell surface receptors, understanding and improving T cell-based therapies, augmenting innate immune strategies and enhancing graft-versus-leukemia for pediatric malignancies. As can be seen in the summaries of the individual presentations, significant progress has been made in developing preclinical models of pediatric tumors while a variety of novel immunobiologic therapies are approaching, or already in, the clinic. While there is much excitement about the potential utility of these agents, a great deal of challenges lie ahead in improving the efficacy of each of these modalities as well as getting them to patients in a timely fashion. The resulting discussions will hopefully lead to new collaborations and insight for further translational and clinical studies. PMID:19346873

  4. Radiation-inducible Immunotherapy for Cancer: Senescent Tumor Cells as a Cancer Vaccine

    PubMed Central

    Meng, Yuru; Efimova, Elena V; Hamzeh, Khaled W; Darga, Thomas E; Mauceri, Helena J.; Fu, Yang-Xin; Kron, Stephen J; Weichselbaum, Ralph R

    2012-01-01

    Radiotherapy offers an effective treatment for advanced cancer but local and distant failures remain a significant challenge. Here, we treated melanoma and pancreatic carcinoma in syngeneic mice with ionizing radiation (IR) combined with the poly(ADP-ribose) polymerase inhibitor (PARPi) veliparib to inhibit DNA repair and promote accelerated senescence. Based on prior work implicating cytotoxic T lymphocytes (CTLs) as key mediators of radiation effects, we discovered that senescent tumor cells induced by radiation and veliparib express immunostimulatory cytokines to activate CTLs that mediate an effective antitumor response. When these senescent tumor cells were injected into tumor-bearing mice, an antitumor CTL response was induced which potentiated the effects of radiation, resulting in elimination of established tumors. Applied to human cancers, radiation-inducible immunotherapy may enhance radiotherapy responses to prevent local recurrence and distant metastasis. PMID:22334019

  5. HDAC inhibition suppresses primary immune responses, enhances secondary immune responses, and abrogates autoimmunity during tumor immunotherapy.

    PubMed

    Bridle, Byram W; Chen, Lan; Lemay, Chantal G; Diallo, Jean-Simon; Pol, Jonathan; Nguyen, Andrew; Capretta, Alfredo; He, Rongqiao; Bramson, Jonathan L; Bell, John C; Lichty, Brian D; Wan, Yonghong

    2013-04-01

    Histone deacetylase inhibitors (HDACi) can modulate innate antiviral responses and render tumors more susceptible to oncolytic viruses (OVs); however, their effects on adaptive immunity in this context are largely unknown. Our present study reveals an unexpected property of the HDACi MS-275 that enhances viral vector-induced lymphopenia leading to selective depletion of bystander lymphocytes and regulatory T cells while allowing expansion of antigen-specific secondary responses. Coadministration of vaccine plus drug during the boosting phase focuses the immune response on the tumor by suppressing the primary immune response against the vaccine vector and enhancing the secondary response against the tumor antigen. Furthermore, improvement of T cell functionality was evident suggesting that MS-275 can orchestrate a complex array of effects that synergize immunotherapy and viral oncolysis. Surprisingly, while MS-275 dramatically enhanced efficacy, it suppressed autoimmune pathology, profoundly improving the therapeutic index. PMID:23295947

  6. Targeting the Innate Immune System as Immunotherapy for Acute Myeloid Leukemia

    PubMed Central

    Curran, Emily; Corrales, Leticia; Kline, Justin

    2015-01-01

    Because of its disseminated nature and lack of tumor-draining lymph nodes, acute myeloid leukemia (AML) likely employs unique immune evasion strategies as compared to solid malignancies. Targeting these unique mechanisms may result in improved immunotherapeutic approaches. Emerging data suggest that a specific dendritic cell (DC) subset, CD8? DCs, may be responsible for mediating tolerance in AML and thus targeting the innate immune system may be of benefit in this disease. Promising immune targets include the toll-like receptors, calreticulin/CD47, the stimulator of interferon genes pathway, and signal transducer and activator of transcription 3 (STAT3). However, it is becoming clear that compensatory mechanisms may limit the efficacy of these agents alone and thus rationale combinations of immunotherapies are warranted. This review discusses the potential immune evasion strategies in AML, as well as discussion of the promising innate immune targets, both alone and in combination, for this disease. PMID:25914882

  7. Adoptive T cell Transfer for Cancer Immunotherapy in the Era of Synthetic Biology

    PubMed Central

    Kalos, Michael; June, Carl H.

    2013-01-01

    Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Synthetic biology-based engineering of T lymphocytes to express high affinity antigen-receptors can overcome immune tolerance, which has been a major limitation of immunotherapy-based strategies. Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cell expansion have facilitated broader evaluation of this technology, moving adoptive transfer from a “boutique” application to the cusp of a mainstream technology. The major challenge currently facing the field is to increase the specificity of engineered T cells for tumors, since targeting shared antigens has the potential to lead to on-target off-tumor toxicities, as observed in recent trials. As the field of adoptive transfer technology matures, the major engineering challenge is the development of automated cell culture systems, so that the approach can extend beyond specialized academic centers and become widely available. PMID:23890063

  8. Dendritic Cells in Cancer Immunotherapy Clinical Trials: Are We Making Progress?

    PubMed Central

    Butterfield, Lisa H.

    2013-01-01

    Dendritic cells (DC) have been tested in cancer immunotherapy clinical trials for two decades. Over this time, the methods of DC culture (or manufacture) have evolved, the approaches for antigen loading have broadened, the maturation signals have varied and different sites of administration have been tested. The post-vaccination immunologic questions asked have also varied between trials and over time. In this review, I will consider multiple aspects of DC-based vaccines tested in cancer patients, including the cell culture, antigen loading, maturation, and delivery, as well as what we have learned from testing immune responses in vaccinated patients who have benefited clinically, and those who have not measurably benefited. PMID:24379816

  9. Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene.

    PubMed

    Link, C J; Traynor, A; Seregina, T; Burt, R K

    1999-01-01

    The overall goal of adoptive immunotherapy with genetically modified lymphocytes is to decrease the morbidity and mortality associated with allogeneic bone marrow transplantation. The initial data reviewed here suggest that the behavior of the allogeneic HStk transgenic cells can be modified after administration to patients. Further study is needed to identify the response rates and risks associated with this procedure. In particular, larger studies will be needed with appropriate randomization to determine if the response rate to genetically modified cells is equivalent to the response rates with unmodified cells. Wider application of these techniques in the initial setting of allogeneic transplantation will undoubtedly occur and such trials have been initiated at several institutions. Careful attention to vector, suicide gene, selectable marker, efficiency of transduction, and cell dose will be necessary when comparing different trials since these variables will probably affect transgenic cell survival and response rates. [figure: see text] PMID:10800657

  10. Cytokine Immunotherapy

    Microsoft Academic Search

    Megan Nelles; Vincenzo Salerno; Yixin Xu; Christopher J. Paige

    \\u000a The immune system protects the body not only from invasion by foreign infectious agents but also from abnormal self-cells\\u000a with the capacity to cause disease. Several lines of evidence suggest that the immune system can effectively rid the body\\u000a of cells with malignant potential under normal physiologic conditions and tumor development results from a failure of the\\u000a immune system. There

  11. Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model

    PubMed Central

    Williams, Emily L.; Dunn, Stuart N.; James, Sonya; Johnson, Peter W.; Cragg, Mark. S.; Glennie, Martin J.; Gray, Juliet C.

    2013-01-01

    Purpose Neuroblastoma is one of the commonest extra-cranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models. Experimental design Neuroblastoma bearing mice were treated with mAb targeting 4-1BB, CD40 and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy was assessed. Results In the Neuro2a model, treatment of established tumor with either anti-4-1BB, anti-CD40 or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40-60% of mice. This is dependent on NK and CD8+ T cells and is associated with tumor CD8+ lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single agent mAb therapy provides ineffective therapy. However if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination then 60% long term survival is achieved. This is associated with the generation of survivin-specific T cell immunity, which again is only demonstrated in the presence of tumor antigen. Conclusions These data suggest the combination of antigen and co-stimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal-residual disease setting. PMID:23649004

  12. Combination Immunotherapy for High-Risk Resected and Metastatic Melanoma Patients

    PubMed Central

    Riker, Adam I.; Rossi, Gabriela R.; Masih, Prerna; Alsfeld, L. C.; Denham, Fiona; Tennant, Lucinda; Ramsey, W. Jay; Vahanian, Nicholas N.; Link, Charles J.

    2014-01-01

    Background Patients with advanced melanoma have a poor outcome. We hypothesize that combination immunotherapy can synergistically activate host immunity to generate an effective treatment for patients with high-risk, resected stage 3, recurrent, refractory, or stage 4 melanoma. Methods We conducted a phase 2 clinical trial of HyperAcute Melanoma (HAM) vaccine (NLG-12036, NewLink Genetics) combined with pegylated interferon (Sylatron, Merck). Trial design consisted of a 12-week regimen with the initial 4 weekly treatments consisting of HAM alone (intradermally) followed by 8 additional treatments of HAM plus Sylatron (subcutaneously, 6 ?g/kg). Trial endpoint outcomes include clinical response, overall safety, and correlative findings for observed antitumor effect. Results Our cohort consisted of 25 patients with a median age of 60. Twenty-one patients completed the trial and 4 stopped because of progressive disease (PD). According to the Response Evaluation Criteria in Solid Tumors, of the 16 stage 4 patients, 2 had a complete response (CR), 1 had stable disease, and 4 had no evidence of disease (NED) after resection. For stage 2/3 patients, 3 of 9 remained NED, and the 1 stage 2C patient had slow PD with a single site resected and is currently NED. The median overall survival time was 29 months, with 60% of the patients surviving for >1 year. Of the 25 patients, 12 (48%) are still alive. All evaluable patients (21/21) seroconverted, developing autoimmune antibodies. Four of 25 patients developed vitiligo, correlating with 2 CR patients and 2 NED patients. Conclusion Combination immunotherapy with HAM plus Sylatron shows clinical efficacy with tumor regression and concomitant immune activation. Optimization of dosing schedules and therapeutic efficacy should be further explored to enhance the benefit of this promising immunotherapeutic approach. PMID:24940124

  13. Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor

    PubMed Central

    Alme, Angela; Senaldi, Liana; Zarek, Paul E.; Horton, Maureen; Powell, Jonathan D.

    2013-01-01

    The A2A adenosine receptor plays a critical and non-redundant role in suppressing inflammation at sites of hypoxia and tissue damage. The tumor microenvironment has high levels of adenosine as a result of hypoxia and ectopic expression of enzymes responsible for the generation of extracellular adenosine. Thus, we sought to determine the ability of A2A receptor null mice to immunologically reject tumors. We observed that mice lacking the A2A adenosine receptor showed significantly delayed growth of lymphoma cells when compared to WT mice. Furthermore, when immunized with a low dose of tumor or with an irradiated GM-CSF–secreting tumor vaccine, A2A receptor null mice showed significantly enhanced protection from a subsequent high-dose challenge from both immunogenic and poorly immunogenic tumor lines. This increase in protection was accompanied by an increase in the number of tumor-antigen-specific CD8 T cells at the vaccine-site draining lymph node. Finally, we found that A2A receptor null mice displayed more robust anti-tumor responses than WT mice when they were treated with a soluble B7-DC/Fc fusion protein designed to antagonize B7-H1-mediated co-inhibition. This combinatorial immunotherapy strategy could also be recapitulated with pharmacological A2A receptor blockade paired with B7-DC/Fc administration. In light of these data, we believe that blockade of the A2A adenosine receptor is an attractive target for tumor immunotherapy that synergizes with other immunomodulatory approaches currently in clinical trials. PMID:22116345

  14. Can immunotherapy be useful as a “functional cure” for infection with Human Immunodeficiency Virus-1?

    PubMed Central

    2012-01-01

    Immunotherapy aims to assist the natural immune system in achieving control over viral infection. Various immunotherapy formats have been evaluated in either therapy-naive or therapy-experienced HIV-infected patients over the last 20?years. These formats included non-antigen specific strategies such as cytokines that stimulate immunity or suppress the viral replication, as well as antibodies that block negative regulatory pathways. A number of HIV-specific therapeutic vaccinations have also been proposed, using in vivo injection of inactivated virus, plasmid DNA encoding HIV antigens, or recombinant viral vectors containing HIV genes. A specific format of therapeutic vaccines consists of ex vivo loading of autologous dendritic cells with one of the above mentioned antigenic formats or mRNA encoding HIV antigens. This review provides an extensive overview of the background and rationale of these different therapeutic attempts and discusses the results of trials in the SIV macaque model and in patients. To date success has been limited, which could be explained by insufficient quality or strength of the induced immune responses, incomplete coverage of HIV variability and/or inappropriate immune activation, with ensuing increased susceptibility of target cells. Future attempts at therapeutic vaccination should ideally be performed under the protection of highly active antiretroviral drugs in patients with a recovered immune system. Risks for immune escape should be limited by a better coverage of the HIV variability, using either conserved or mosaic sequences. Appropriate molecular adjuvants should be included to enhance the quality and strength of the responses, without inducing inappropriate immune activation. Finally, to achieve a long-lasting effect on viral control (i.e. a “functional cure”) it is likely that these immune interventions should be combined with anti-latency drugs and/or gene therapy. PMID:22958464

  15. Trends in Specific Immunotherapy for Allergic Rhinitis: A Survey of Chinese ENT Specialists

    PubMed Central

    Zhou, Han; Tao, Qi-Lei; Wei, Jun-Min; Xu, Geng

    2014-01-01

    Purpose Specific immunotherapy (SIT) is a suitable but uncommon treatment option for allergic rhinitis (AR) in China. The current understanding and attitude of Chinese ENT (ear, nose, and throat) specialists in regards to SIT is unclear. This study investigates current trends in the awareness and application status of SIT among Chinese ENT specialists. Methods We performed a nationwide, cross-sectional survey with a specially designed questionnaire given to 800 ENT specialists in China. A member of the trained research group conducted face-to-face interviews with each respondent. Results Most of the respondents considered AR (96.0%) and allergic asthma (96.0%) the most suitable indications for SIT. Of all respondents, 77.0% recommended the application of SIT as early as possible; in addition, SIT was considered 'relatively controllable and safe' by most respondents (80.6%). The highest allergen-positive rate in AR was associated with house dust mite (47.7%) and obvious differences existed among geographical regions. Conventional subcutaneous immunotherapy was the most highly recommended treatment option (96.2%). 'The high cost of SIT' (86.6%) and 'lack of patient knowledge of SIT' (85.2%) were probably the main reasons for the lower clinical use of SIT in China. Conclusions Most cases showed that the opinions of Chinese ENT specialists appeared to be in agreement with recent SIT progress and international guidelines; however, many areas still need to enhance the standardization and use of SIT in China. Clinical guidelines for SIT require improvement; in addition, Chinese ENT specialists need continuing medical education on SIT. PMID:24991452

  16. Current status of granulocyte–macrophage colony-stimulating factor in the immunotherapy of melanoma

    PubMed Central

    2014-01-01

    In 2012, it was estimated that 9180 people in the United States would die from melanoma and that more than 76,000 new cases would be diagnosed. Surgical resection is effective for early-stage melanoma, but outcomes are poor for patients with advanced disease. Expression of tumor-associated antigens by melanoma cells makes the disease a promising candidate for immunotherapy. The hematopoietic cytokine granulocyte–macrophage colony-stimulating factor (GM-CSF) has a variety of effects on the immune system including activation of T cells and maturation of dendritic cells, as well as an ability to promote humoral and cell-mediated responses. Given its immunobiology, there has been interest in strategies incorporating GM-CSF in the treatment of melanoma. Preclinical studies with GM-CSF have suggested that it has antitumor activity against melanoma and can enhance the activity of anti-melanoma vaccines. Numerous clinical studies have evaluated recombinant GM-CSF as a monotherapy, as adjuvant with or without cancer vaccines, or in combination with chemotherapy. Although there have been suggestions of clinical benefit in some studies, results have been inconsistent. More recently, novel approaches incorporating GM-CSF in the treatment of melanoma have been evaluated. These have included oncolytic immunotherapy with the GM-CSF–expressing engineered herpes simplex virus talimogene laherparepvec and administration of GM-CSF in combination with ipilimumab, both of which have improved patient outcomes in phase 3 studies. This review describes the diverse body of preclinical and clinical evidence regarding use of GM-CSF in the treatment of melanoma. PMID:24971166

  17. Safety and feasibility of oral immunotherapy to multiple allergens for food allergy

    PubMed Central

    2014-01-01

    Background Thirty percent of children with food allergy are allergic to more than one food. Previous studies on oral immunotherapy (OIT) for food allergy have focused on the administration of a single allergen at the time. This study aimed at evaluating the safety of a modified OIT protocol using multiple foods at one time. Methods Participants underwent double-blind placebo-controlled food challenges (DBPCFC) up to a cumulative dose of 182 mg of food protein to peanut followed by other nuts, sesame, dairy or egg. Those meeting inclusion criteria for peanut only were started on single-allergen OIT while those with additional allergies had up to 5 foods included in their OIT mix. Reactions during dose escalations and home dosing were recorded in a symptom diary. Results Forty participants met inclusion criteria on peanut DBPCFC. Of these, 15 were mono-allergic to peanut and 25 had additional food allergies. Rates of reaction per dose did not differ significantly between the two groups (median of 3.3% and 3.7% in multi and single OIT group, respectively; p?=?.31). In both groups, most reactions were mild but two severe reactions requiring epinephrine occurred in each group. Dose escalations progressed similarly in both groups although, per protocol design, those on multiple food took longer to reach equivalent doses per food (median +4 mo.; p?immunotherapy using multiple food allergens simultaneously to be feasible and relatively safe when performed in a hospital setting with trained personnel. Additional, larger, randomized studies are required to continue to test safety and efficacy of multi-OIT. Trial registration Clinicaltrial.gov NCT01490177 PMID:24428859

  18. Combining immunotherapy with oncogene-targeted therapy: a new road for melanoma treatment.

    PubMed

    Aris, Mariana; Barrio, María Marcela

    2015-01-01

    Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50?years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF-inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field. PMID:25709607

  19. Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy.

    PubMed

    Mehraj, Vikram; Jenabian, Mohammad-Ali; Vyboh, Kishanda; Routy, Jean-Pierre

    2014-01-01

    Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication. PMID:25624956

  20. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy.

    PubMed

    Töpfer, Katrin; Cartellieri, Marc; Michen, Susanne; Wiedemuth, Ralf; Müller, Nadja; Lindemann, Dirk; Bachmann, Michael; Füssel, Monika; Schackert, Gabriele; Temme, Achim

    2015-04-01

    NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell-resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti-PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3? signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-? release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti-PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy. PMID:25740942