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Sample records for anti-tnf immunotherapy reduces

  1. Anti-TNF immunotherapy reduces CD8+ T cellmediated antimicrobial activity against Mycobacterium tuberculosis in humans

    PubMed Central

    Bruns, Heiko; Meinken, Christoph; Schauenberg, Philipp; Hrter, Georg; Kern, Peter; Modlin, Robert L.; Antoni, Christian; Stenger, Steffen

    2009-01-01

    The incidence of tuberculosis is increased during treatment of autoimmune diseases with anti-TNF antibodies. This is a significant clinical complication, but also provides a unique model to study immune mechanisms in human tuberculosis. Given the key role for cell-mediated immunity in host defense against Mycobacterium tuberculosis, we hypothesized that anti-TNF treatment impairs T celldirected antimicrobial activity. Anti-TNF therapy reduced the expression in lymphocytes of perforin and granulysin, 2 components of the T cellmediated antimicrobial response to intracellular pathogens. Specifically, M. tuberculosisreactive CD8+CCR7CD45RA+ effector memory T cells (TEMRA cells) expressed the highest levels of granulysin, lysed M. tuberculosis, and infected macrophages and mediated an antimicrobial activity against intracellular M. tuberculosis. Furthermore, TEMRA cells expressed cell surface TNF and bound the anti-TNF therapeutic infliximab in vitro, making them susceptible to complement-mediated lysis. Immune therapy with anti-TNF was associated with reduced numbers of CD8+ TEMRA cells and decreased antimicrobial activity against M. tuberculosis, which could be rescued by the addition of CD8+ TEMRA cells. These results suggest that anti-TNF therapy triggers a reduction of CD8+ TEMRA cells with antimicrobial activity against M. tuberculosis, providing insight into the mechanism whereby key effector T cell subsets contribute to host defense against tuberculosis. PMID:19381021

  2. Anti-TNF immunotherapy and tuberculosis reactivation: another mechanism revealed

    PubMed Central

    Miller, Elizabeth A.; Ernst, Joel D.

    2009-01-01

    Anti-TNF immunotherapy has revolutionized the treatment of some inflammatory diseases, such as RA. However, a major concern is that patients receiving this therapy have an increased risk of fungal and bacterial infection, particularly of reactivating latent tuberculosis (TB). In this issue of the JCI, in an effort to understand how anti-TNF immunotherapy affects host mechanisms required to control TB, Bruns and colleagues examined the effects of the anti-TNF therapeutic infliximab on Mycobacterium tuberculosisspecific human lymphocytes (see the related article beginning on page 1167). The authors report that a granulysin-expressing CD45RA+ subset of effector memory CD8+ T cells that contributes to the killing of intracellular M. tuberculosis is depleted in vivo by infliximab in patients with RA, and that these cells are susceptible to complement-mediated lysis in the presence of infliximab in vitro. The study provides insight into host defense mechanisms that act to control TB infection and how they are affected during anti-TNF immunotherapy for autoimmune disease. PMID:19422095

  3. Anti-TNF-? therapy reduces endothelial cell activation in non-diabetic ankylosing spondylitis patients.

    PubMed

    Genre, Fernanda; Lpez-Mejas, Raquel; Miranda-Filloy, Jos A; Ubilla, Begoa; Mijares, Vernica; Carnero-Lpez, Beatriz; Gmez-Acebo, Ins; Dierssen-Sotos, Trinidad; Remuzgo-Martnez, Sara; Blanco, Ricardo; Pina, Trinitario; Gonzlez-Juanatey, Carlos; Llorca, Javier; Gonzlez-Gay, Miguel A

    2015-12-01

    Endothelial dysfunction can be detected by the presence of elevated levels of biomarkers of endothelial cell activation. In this study, we aimed to establish whether correlations of these biomarkers with characteristics of patients with ankylosing spondylitis (AS) exist. We also studied the effect of anti-TNF-? therapy on these biomarkers. Serum sE-selectin, MCP-1 and sVCAM-1 levels were measured by ELISA in 30 non-diabetic AS patients undergoing anti-TNF-? therapy, immediately before and after an infusion of infliximab. Correlations of these biomarkers with clinical features, systemic inflammation, metabolic syndrome and other serum and plasma biomarkers of cardiovascular risk were studied. Potential changes in the concentration of these biomarkers following an infliximab infusion were also assessed. sE-selectin showed a positive correlation with CRP (p=0.02) and with other endothelial cell activation biomarkers such as sVCAM-1 (p=0.019) and apelin (p=0.008). sVCAM-1 negatively correlated with BMI (p=0.018), diastolic blood pressure (p=0.008) and serum glucose (p=0.04). sVCAM-1 also showed a positive correlation with VAS spinal pain (p=0.014) and apelin (p<0.001). MCP-1 had a negative correlation with LDL cholesterol (p=0.026) and ESR (p=0.017). Patients with hip involvement and synovitis and/or enthesitis in other peripheral joints showed higher levels of MCP-1 (p=0.004 and 0.02, respectively). A single infliximab infusion led to a significant reduction in sE-selectin (p=0.0015) and sVCAM-1 (p=0.04). Endothelial dysfunction correlates with inflammation and metabolic syndrome features in patients with AS. A beneficial effect of the anti-TNF-? blockade on endothelial dysfunction, manifested by a reduction in levels of biomarkers of endothelial cell activation, was observed. PMID:26143161

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

    PubMed

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

    2016-06-01

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

  5. Optimization of anti-TNF therapy in patients with Inflammatory Bowel Disease.

    PubMed

    Strik, A S; Bots, S J A; D'Haens, G; Lwenberg, M

    2016-03-01

    After the introduction of anti-tumor necrosis factor (anti-TNF) agents, the clinical outcome of patients with Inflammatory Bowel Disease (IBD) has improved significantly. However, use of anti-TNF therapy is complicated by loss of response. In order to maintain remission, adequate serum levels are required. Hence, therapeutic drug monitoring (TDM) is important in order to optimize serum drug levels, especially in patients with loss of response to these agents. Optimization of anti-TNF therapy by applying TDM enables clinicians to regain response to TNF blockers in a significant proportion of patients. It is important to use anti-TNF agents in their most optimal way, since these therapeutic agents are expensive and the medical options after failing anti-TNF therapy are limited. Here, we will discuss how to optimize treatment with anti-TNF agents in IBD patients in order to improve treatment efficacy, prevent anti-drug antibody formation, reduce side effects, discontinue unnecessary treatment and manage costs. PMID:26681400

  6. [Anti-TNF alpha in dermatology].

    PubMed

    Mahe, E; Descamps, V

    2002-12-01

    The discovery of the major role of TNF alpha in the physiopathology of certain inflammatory diseases and notably in rheumatoid arthritis and Crohn's disease has led to the development of anti-TNF alpha drugs. These new therapeutic arms issued from bio-technology have rapidly demonstrated their efficacy in the treatment of these two diseases. The anti-TNF alpha arsenal is currently dominated by etanercept, a fusion protein composed of a soluble TNF alpha receptor, and infliximab, a chimeric monoclonal antibody. However, new molecules will soon enrich this arsenal. TNF alpha is a major cytokine of inflammatory diseases of the skin. Many dermatological diseases will probably benefit from these new treatments. Two studies have already demonstrated their interest in cutaneous and articular psoriasis. Encouraging sporadic results suggest other potential indications (Behcet's disease, bullous dermatitis, neutrophilic dermatitis, toxic epidermal necrolysis, systemic vascularitis,.). These promising new treatments, although expensive, and with yet unknown long term side effects, justify rigorous assessment of their efficacy and tolerance in each indication. Here again the dermatologist has a major role to play in post-marketing pharmacovigilance. PMID:12536174

  7. 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-Muoz, Alberto Daniel; Brambila-Tapia, Aniel Jessica Leticia; Zavala-Cerna, Mara Guadalupe; Vsquez-Jimnez, Jos Clemente; De la Cerda-Trujillo, Liliana Faviola; Vzquez-Del Mercado, Mnica; Rodriguez-Jimenez, Norma Alejandra; Daz-Rizo, Valeria; Daz-Gonzlez, Viviana; Cardona-Muoz, Ernesto German; Dvalos-Rodrguez, 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

  8. Association Between Anti-TNF-? Therapy and Interstitial Lung Disease

    PubMed Central

    Herrinton, Lisa J.; Harrold, Leslie R.; Liu, Liyan; Raebel, Marsha A.; Taharka, Ananse; Winthrop, Kevin L.; Solomon, Daniel H.; Curtis, Jeffrey R.; Lewis, James D.; Saag, Kenneth G.

    2013-01-01

    Background Anti-TNF-? agents have been hypothesized to increase the risk of interstitial lung disease (ILD), including its most severe manifestation, pulmonary fibrosis. Methods We conducted a cohort study among autoimmune disease patients who were members of Kaiser Permanente Northern California, 19982007. We obtained therapies from pharmacy data and diagnoses of ILD from review of X-ray and computed tomography reports. We compared new users of anti-TNF-? agents to new users of non-biologic therapies using Cox proportional hazards analysis to adjust for baseline propensity scores and time-varying use of glucocorticoids. We also made head-to-head comparisons between anti-TNF-? agents. Results Among the 8,417 persons included in the analysis, 38 (0.4%) received a diagnostic code for ILD by the end of follow-up, including 23 of 4,200 (0.5%) who used anti-TNF-? during study follow-up, and 15 of 5,423 (0.3%) who used only non-biologic therapies. The age- and gender-standardized incidence rate of ILD, per 100 person-years, was 0.21 (95% CI 00.43) for rheumatoid arthritis and appreciably lower for other autoimmune diseases. Compared to use of non-biologic therapies, use of anti-TNF-? therapy was not associated with a diagnosis of ILD among RA patients (adjusted hazard ratio, 1.03; 95% CI 0.512.07). Nor did head-to-head comparisons across anti-TNF-? agents suggest important differences in risk, although the number of cases available for analysis was limited. Conclusion The study provides evidence that compared to non-biologic therapies anti-TNF-? therapy does not increase the occurrence of ILD among patients with autoimmune diseases, and informs research design of future safety studies of ILD. PMID:23359391

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

    PubMed

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

    2013-04-01

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

  10. IBD: Indication extrapolation for anti-TNF biosimilars.

    PubMed

    Vande Casteele, Niels; Sandborn, William J

    2015-07-01

    Biosimilar monoclonal antibodies (mAbs) to TNF are being developed that are highly similar, but not identical to the innovator molecules. CT-P13, a biosimilar of infliximab, is the first anti-TNF mAb to get approval in South Korea, Europe and Canada. However, uncertainties remain about indication extrapolation and interchangeability. PMID:26077557

  11. Anti-TNF-Alpha Therapy and Systemic Vasculitis

    PubMed Central

    Kaplanski, Gilles

    2014-01-01

    TNF-α is a pleiotropic cytokine, which plays a major role in the pathogenesis of numerous autoimmune and/or inflammatory systemic diseases. Systemic vasculitis constitutes a group of rare diseases, characterized by inflammation of the arterial or venous vessel wall, causing stenosis and thrombosis. Treatment of the different type of vasculitis mainly relies on steroids and immunosuppressive drugs. In case of refractory or relapsing diseases, however, a second line of treatment may be required. Anti-TNF-α drugs have been used in this setting during the last 15 years with inconsistent results. We reviewed herein the use of anti-TNF-α therapy in different kind of vasculitis and concluded that, except for Behcet's disease, this therapeutic option has not demonstrated significant improvement in the treatment of vasculitis. PMID:24719524

  12. 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

  13. Anti-TNF-? therapy for sight threatening uveitis

    PubMed Central

    Lindstedt, E W; Baarsma, G S; Kuijpers, R W A M; van Hagen, P M

    2005-01-01

    Aim: To describe the effect of additional treatment with anti-TNF-? therapy in a case series of 13 patients with serious sight threatening uveitis. Methods: 13 patients with serious sight threatening uveitis were included, of whom six had Behets disease, five had idiopathic posterior uveitis, one had sarcoidosis, and one birdshot retinochoroiditis. Onset and course of ocular inflammation, inflammatory signs, and visual acuity were assessed. Patients were treated with 200 mg (approximately 3 mg/kg) infliximab infusion. Repeat infusions were given based on clinical response. Results: Infliximab treatment resulted in an effective suppression of ocular inflammation in all patients. In patients with non-Behets disease uveitis visual acuity in six out of eight improved or was stable. In patients with Behets disease visual acuity in five out of six improved or was stable. Conclusion: Anti-TNF-? treatment may be of value in the treatment of uveitis, and in patients with Behets disease, leading to suppression of ocular inflammation, vasculitis, and improvement of vision in the majority. Based on these results a controlled masked study is warranted. PMID:15834077

  14. DADS neuropathy associated with anti-TNF-? therapy.

    PubMed

    McGinty, Ronan Niall; McNamara, Brian; Moore, Helena

    2015-01-01

    A 52-year-old man with idiopathic Parkinson's disease and severe rheumatoid arthritis presented with a 1-year history of progressively worsening limb paraesthesia. Examination showed sensory loss in a glove and stocking distribution, absent reflexes and unsteady tandem gait. Nerve conduction studies suggested an acquired peripheral neuropathy with distal demyelination, which-together with the clinical phenotype-was consistent with a Distal Acquired Demyelinating Symmetric (DADS) neuropathy pattern. This was attributed to therapy with adalimumab, an antitumor necrosis factor (TNF)-? agent, which the patient had been taking for 2?years for rheumatoid arthritis. One month after discontinuing adalimumab, the limb paraesthesia had resolved completely and the patient had a normal tandem gait. Demyelinating disorders may rarely occur as complications of anti-TNF-? agents and therefore have implications for pretreatment counselling and ongoing monitoring. DADS neuropathy is a subtype of chronic inflammatory demyelinating polyradiculoneuropathy, which responds poorly to standard therapy and has not previously been described with anti-TNF-? therapy. PMID:26607186

  15. Biological Treatments in Behet's Disease: Beyond Anti-TNF Therapy

    PubMed Central

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

    2014-01-01

    Behet'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. Anti-TNF therapy: past, present and future

    PubMed Central

    Monaco, Claudia; Nanchahal, Jagdeep; Taylor, Peter

    2015-01-01

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

  17. 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

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

    PubMed Central

    Winthrop, Kevin L.; Baddley, John W.; Chen, Lang; Liu, Liyan; Grijalva, Carlos G.; Delzell, Elizabeth; Beukelman, Timothy; Patkar, Nivedita M.; Xie, Fenglong; Saag, Kenneth G.; Herrinton, Lisa J.; Solomon, Daniel H.; Lewis, James D.; Curtis, Jeffrey R.

    2013-01-01

    Importance Herpes zoster (HZ) reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates HZ risk, and whether monoclonal antibodies carry greater risk than etanercept. Objectives To ascertain whether initiation of anti-TNF therapy compared with non-biologic comparators is associated with increased HZ risk Design, Setting, and Patients We identified new users of anti-TNF therapy among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis-psoriatic arthritis-ankylosing spondylitis (PsO-PsA-AS) patients during 19982007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared HZ incidence between new anti-TNF users and patients initiating non-biologic disease modifying drugs (DMARDs) within each inflammatory disease cohort (last participant follow-up Dec 31, 2007). Within these cohorts, we used Cox regression models to compare propensity-score adjusted HZ incidence between new anti-TNF and non-biologic DMARD users while controlling for baseline corticosteroid use. Main Outcome Measure Incidence of herpes zoster cases occurring after initiation of new anti- TNF or non-biologic DMARD therapy Results Among 32,208 new users of anti-TNF therapy, we identified 310 HZ cases. Crude incidence rates among anti-TNF users for RA, IBD, and PsO-PsA-AS were 12.1/1000 pt-yrs, (95% CI 10.713.6), 11.3/1000 (95% CI 7.716.7), and 4.4/1000 (95% CI 2.87.0) respectively. Baseline use of corticosteroids of > 10mg/day was associated with elevated risk [adjusted HR 2.13 (1.64, 2.75) compared with no baseline use. For RA patients, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators [adjusted HR 1.00 (95% CI 0.771.29) and comparable between all three anti-TNF therapies studied. Conclusions and Relevance Among patients with RA and other select inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk for HZ compared to patients who initiated non-biologic treatment regimens. PMID:23462785

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

    PubMed Central

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

    2013-01-01

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

  20. A guide to preparation of patients with inflammatory bowel diseases for anti-TNF-α therapy

    PubMed Central

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

    2014-01-01

    Current therapy of moderate-to-severe inflammatory bowel disease (IBD) often involves the use of anti-tumor necrosis factor alpha (TNF-α) agents. Although very effective, theses biologics place the patient at increased risk for developing infections and lymphomas, the latter especially when in combination with thiopurines. Appropriate patient selection, counseling, and education are all important features for the successful use of anti-TNF-α therapy. A thorough history to rule-out contraindications of this therapy and emphasis on monitoring guidelines are important steps preceding administration of anti-TNF-α agents. This therapy should only be considered if a recent evaluation has established that the patient has active IBD. In addition, it is important to exclude disease mimickers. Anti-TNF-α agents have been considered to present a globally favorable benefit/risk ratio. However, it is important that in routine practice, initiation of anti-TNF-α therapy be carefully discussed with the patient, extensively explaining the potential benefits and risks of such treatment. Prior to starting anti-TNF-α therapy, the patients need to be screened for latent tuberculosis, hepatitis B virus infection, and (usually) hepatitis C virus and HIV infection. Vaccination schedules of IBD patients should be evaluated and updated prior to the commencement of anti-TNF-α therapy. Ordinarily, immunization in adult patients with IBD should not deviate from recommended guidelines for the general population. With the exception of live vaccines, immunizations can be safely administered in patients with IBD, even those on immunosuppressants or biologics. The purpose of this review is providing an overview of appropriate steps to prepare patients with IBD for anti-TNF-α therapy. PMID:24667275

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

    PubMed Central

    2014-01-01

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

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

    PubMed Central

    Aberer, Werner; Massone, Cesare

    2014-01-01

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

  3. 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

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

    PubMed Central

    Angel, Kristin

    2012-01-01

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

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

    PubMed

    Spiliopoulou, I; Foka, A; Bounas, A; Marangos, M N

    2014-06-01

    We describe a Mycobacterium kansasii cutaneous infection that was diagnosed in a 52-year-old female patient with sarcoidosis receiving anti-TNF agents. The diagnosis was based on the positive culture of the foot ulcerative tissue. The isolation and identification of bacterium was based on phenotypic and molecular methods. Therapy and follow-up of the patient is discussed. PMID:24773076

  6. Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment.

    PubMed

    Nordgaard-Lassen, Inge; Dahlerup, Jens Frederik; Belard, Erika; Gerstoft, Jan; Kjeldsen, Jens; Kragballe, Knud; Ravn, Pernille; Srensen, Inge Juul; Theede, Klaus; Tjellesen, Lone

    2012-07-01

    These national clinical guidelines outlining the screening, prophylaxis and critical information required prior to initiating anti-TNF-alpha treatment have been approved by the Danish Society for Gastroenterology. Anti-TNF-alpha therapy is widely used in gastroenterology (for inflammatory bowel disease), rheumatology (for rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies) and dermatology (for psoriasis). With this background, the Danish Society for Gastroenterology established a group of experts to assess evidence for actions recommended before treatment with anti-TNF-alpha agents. Screening should take place for both active tuberculosis and latent tuberculosis. Screening must evaluate the risk of hepatitis B exposure/infection and that of other viral infections such as human immunodeficiency virus (HIV) and varicella zoster virus (VZV). The assessment should include a history of previous malignancies (cases of malignant disease within 5 years of anti-TNF-alpha treatment should be carefully considered). The physical examination should include lung/heart auscultation and lymph node examination, and the paraclinical investigations should include chest X-rays and laboratory tests, including an interferon gamma release assay, a hepatitis B test, an HIV test and, when prior VZV infection is uncertain, a VZV antibody test. Prophylaxis: Isoniazid should be administered in cases of suspected latent TB infection. Antiviral treatment is recommended in HBsAg-positive patients at the start of anti-TNF-alpha treatment. Before anti-TNF-alpha therapy, vaccination with 23-valent pneumococcal vaccine is recommended, and HBV vaccination may be considered in seronegative patients. Annual vaccination against seasonal influenza is recommended. Human papilloma virus vaccination should be administered in accordance with the guidelines of the National Board of Health of Denmark. In patients without a prior VZV infection, VZV vaccination may be considered. Information for patients: Anti-TNF-alpha treatment results in a generally increased risk of infection and latent tuberculosis flare-up. Women are advised to comply with the national guidelines for screening for cervical cancer, and their HPV immunisation status should be clarified. An increased risk of lymphoma with biological therapy in combination with thiopurines should be mentioned. Patients are advised to seek medical advice in case of herpes zoster infection. PMID:22759856

  7. Autoimmunogenicity during anti-TNF therapy in patients with psoriasis and psoriatic arthritis

    PubMed Central

    Goździalska, Anna; Lipko-Godlewska, Sylwia; Obtułowicz, Aleksander; Sułowicz, Joanna; Podolec, Katarzyna; Wojas-Pelc, Anna

    2015-01-01

    Introduction The tumor necrosis factor (TNF-α) was initially described as lymphotoxin or cachectin. The discovery of therapies blocking the action of TNF-α, in 1988, started a new era in the therapy. One of often reported adverse effects related to the use of TNF-α antagonists is induction of the formation of autologous antibodies and antibodies neutralizing anti-TNF drugs. The development of anti-TNF-induced lupus or classical drug-induced lupus is more rarely reported. Aim To evaluate the presence and the level of anti-nuclear antibodies in patients with psoriasis and psoriatic arthritis and the influence of anti-TNF therapy used on the concentration of antinuclear antibody (ANA). Material and methods A total of 28 subjects were included in the study. 71.4% of subjects were diagnosed with psoriatic arthritis and 28.6% with plaque psoriasis. Results Among the patients with plaque psoriasis, the antinuclear antibodies were found in 25% of subjects and in 80% of patients with psoriatic arthritis. After the treatment an increase in the titer or appearance of antibodies was found in 66.7% in the infliximab group, 18.2% in the etanercept group and 54.7% in the adalimumab group. No subjects developed symptoms of drug-induced systemic lupus. Conclusions Our findings have shown that all anti-TNF therapies induced ANA in psoriatic arthritis and psoriatic patients. Considering a mild course of lupus induced by anti-TNF treatment and, usually intrinsic, resolution of symptoms, the biological therapy still appears as a safe treatment for patients. PMID:26366147

  8. 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

  9. 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 acidSchiff (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. PMID:26157813

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

    PubMed

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

    2012-10-01

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

  11. IgA vasculitis associated with anti-TNF-? inhibitors in a patient with Crohn's disease.

    PubMed

    Nishikawa, Jun; Hosokawa, Ayumu; Akashi, Momoko; Mihara, Hiroshi; Nanjo, Sohachi; Yoshita, Hiroki; Ando, Takayuki; Kajiura, Shinya; Fujinami, Haruka; Sugiyama, Toshiro

    2015-01-01

    Anti-TNF-? inhibitors have been widely used in the treatment of inflammatory bowel disease. Although they have good clinical efficacy and tolerance, they remain a matter of concern because they cause drug-induced autoimmune disorders as side effects. Here, we report a case of a patient with Crohn's disease who developed IgA vasculitis after infliximab and adalimumab treatment. A 17-year-old male with Crohn's disease who had received scheduled infliximab treatment for the preceding 19 months complained of purpura on his lower limbs. He was diagnosed with infliximab-induced IgA vasculitis. Switching infliximab to adalimumab resulted in rapid improvement of the condition. However, 21 months after switching to adalimumab, his purpura recurred. Drug-induced IgA vasculitis is a rare complication caused by infliximab and adalimumab; however, diagnosis in the early phase and appropriate management of patients receiving anti-TNF-? inhibitors is critical to a successful patient outcome. PMID:26440688

  12. Rocky Mountain Spotted Fever in a patient treated with anti-TNF-alpha inhibitors.

    PubMed

    Mays, Rana M; Gordon, Rachel A; Durham, K Celeste; LaPolla, Whitney J; Tyring, Stephen K

    2013-01-01

    Rocky Mountain Spotted Fever (RMSF) is a tick-bourne illness, which can be fatal if unrecognized. We discuss the case of a patient treated with an anti-TNF-alpha inhibitor for rheumatoid arthritis who later developed a generalized erythematous macular eruption accompanied by fever. The clinical findings were suggestive of RMSF, which was later confirmed with serology. Prompt treatment with doxyclycine is recommended for all patients with clinical suspicion of RMSF. PMID:23552004

  13. Effects of hyaluronic acid conjugation on anti-TNF-α 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-α alone, mixed with hyaluronic acid or conjugated to hyaluronic acid. We found that non-conjugated anti-TNF-α 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-1β levels. A simple transport model is proposed to analyze the results, which predicts qualitative and quantitative differences between untreated burn sites and those treated with the conjugates. Our results indicate that conjugation of anti-TNF-α to high molecular weight hyaluronic acid provides sustained, local modulation of the post-injury inflammatory responses compared to direct administration of non-conjugated antibodies. PMID:23765644

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

    PubMed Central

    Bendtzen, Klaus

    2015-01-01

    Specific inhibition of the cytokine, tumor necrosis factor-α (TNF), has revolutionized the treatment of patients with several autoimmune diseases, and genetically engineered anti-TNF antibody constructs now constitute a heavy medicinal expenditure in many countries. Unfortunately, up to 30% of patients do not respond and about 50% of those who do loose response with time. Furthermore, safety may be compromised by immunogenicity with the induction of anti-drug-antibodies (ADA). Assessment of drug pharmacokinetics and ADA is increasingly recognized as a requirement for safe and rational use of protein drugs. The use of therapeutic strategies based on anti-TNF drug levels and ADA rather than dose-escalation has also proven to be cost-effective, as this allows individualized patient-tailored strategies rather than the current universal approach to loss of response. The objective of the present article – and the accompanying article – is to discuss the reasons for recommending assessments of circulating drug and ADA levels in patients treated with anti-TNF biopharmaceuticals and to detail some of the methodological issues that obscure cost-effective and safer therapies. PMID:25904915

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

    PubMed Central

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

    2015-01-01

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

  16. Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis

    PubMed Central

    Benucci, M; Saviola, G; Baiardi, P; Manfredi, M; Sarzi Puttini, P; Atzeni, Fabiola

    2012-01-01

    The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.610.4% vs ETA 48.415.7% vs INF 40.716.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN dont reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence. PMID:22655000

  17. Safety of Anti-TNF Therapies in Immune-Mediated Inflammatory Diseases: Focus on Infections and Malignancy.

    PubMed

    Pereira, Rui; Lago, Paula; Faria, Raquel; Torres, Tiago

    2015-12-01

    Preclinical Research The efficacy of anti-TNF agents in the treatment of multiple immune-mediated inflammatory diseases (IMIDs) has increased their daily use. However, concerns remain regarding their long-term safety profile. Using a literature-based review of the infectious and malignant complications of anti-TNF biologics in IMIDs including psoriasis, Rheumatoid Arthritis, and inflammatory bowel disease, this review presents current evidence relative to the safety of anti-TNF agents in the context infections and malignancy in adults with IMIDs. Treatment with anti-TNF biologics is an effective treatment option with known risks that can be mitigated by appreciating the safety aspects and via a thorough screening and continuous monitoring of the patient. Drug Dev Res 76 : 419-427, 2015. 2015 Wiley Periodicals, Inc. PMID:26482111

  18. Transmembrane TNF-α: structure, function and interaction with anti-TNF agents

    PubMed Central

    Mitoma, Hiroki; Harashima, Shin-ichi; Tsukamoto, Hiroshi; Shimoda, Terufumi

    2010-01-01

    Transmembrane TNF-α, a precursor of the soluble form of TNF-α, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-α-converting enzyme (TACE), the soluble form of TNF-α is cleaved from transmembrane TNF-α and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-α, but also transmembrane TNF-α is involved in the inflammatory response. Transmembrane TNF-α acts as a bipolar molecule that transmits signals both as a ligand and as a receptor in a cell-to-cell contact fashion. Transmembrane TNF-α on TNF-α-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a ligand, whereas transmembrane TNF-α also acts as a receptor that transmits outside-to-inside (reverse) signals back to the cells after binding to its native receptors. Anti-TNF agents infliximab, adalimumab and etanercept bind to and neutralize soluble TNF-α, but exert different effects on transmembrane TNF-α-expressing cells (TNF-α-producing cells). In the clinical settings, these three anti-TNF agents are equally effective for RA, but etanercept is not effective for granulomatous diseases. Moreover, infliximab induces granulomatous infections more frequently than etanercept. Considering the important role of transmembrane TNF-α in granulomatous inflammation, reviewing the biology of transmembrane TNF-α and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities. PMID:20194223

  19. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents.

    PubMed

    Horiuchi, Takahiko; Mitoma, Hiroki; Harashima, Shin-ichi; Tsukamoto, Hiroshi; Shimoda, Terufumi

    2010-07-01

    Transmembrane TNF-alpha, a precursor of the soluble form of TNF-alpha, is expressed on activated macrophages and lymphocytes as well as other cell types. After processing by TNF-alpha-converting enzyme (TACE), the soluble form of TNF-alpha is cleaved from transmembrane TNF-alpha and mediates its biological activities through binding to Types 1 and 2 TNF receptors (TNF-R1 and -R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF-alpha, but also transmembrane TNF-alpha is involved in the inflammatory response. Transmembrane TNF-alpha acts as a bipolar molecule that transmits signals both as a ligand and as a receptor in a cell-to-cell contact fashion. Transmembrane TNF-alpha on TNF-alpha-producing cells binds to TNF-R1 and -R2, and transmits signals to the target cells as a ligand, whereas transmembrane TNF-alpha also acts as a receptor that transmits outside-to-inside (reverse) signals back to the cells after binding to its native receptors. Anti-TNF agents infliximab, adalimumab and etanercept bind to and neutralize soluble TNF-alpha, but exert different effects on transmembrane TNF-alpha-expressing cells (TNF-alpha-producing cells). In the clinical settings, these three anti-TNF agents are equally effective for RA, but etanercept is not effective for granulomatous diseases. Moreover, infliximab induces granulomatous infections more frequently than etanercept. Considering the important role of transmembrane TNF-alpha in granulomatous inflammation, reviewing the biology of transmembrane TNF-alpha and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities. PMID:20194223

  20. [Preventive immunotherapy].

    PubMed

    Boquete, M; Carballada, F; Expósito, F; González, A

    2000-01-01

    Allergen specific immunotherapy has been shown to be effective in rigorous double-blind placebo-controlled clinical trials in both children and adults A recent WHO position paper stated that immunotherapy is an effective treatment for patients with allergic rhinitis/conjunctivitis, allergic asthma and allergic reactions from stinging insects and is thought to be more effective in children than in adults. When speaking about children there are several questions that are important regarding the natural course of the disease. One of the most important is whether immunotherapy can prevent asthma, either by preventing sensitisation to allergens related to the development of asthma or by preventing the inflammation in the lungs caused by allergen exposure. Another point could be to establish the differences in the long term outcome of those patients treated with immunotherapy and medication during childhood, compared to the long term outcome of those with comparable asthma features who received only antiasthmatic medication The PAT study is a European multi-center study. The end-point is to show in what capacity allergen specific subcutaneous immunotherapy can prevent the development of asthma in children who only have rhinoconjunctivitis secondary to grass or birch pollen sensitisation. Two hundred and ten children aged from 5 to 13 years were included in the study. Children were randomised to the active treatment group receiving allergen specific immunotherapy with birch and/or timothy pollen allergen extract or to the control group receiving only pharmacotherapy. It is important to highlight that the main criteria to be included was that the children should never have had any asthmatic symptom. Immunotherapy has been effective in terms of decreasing significantly the amount of symptoms in the active group compared to the control one. It was safe with no serious adverse reactions and reduced the risk of the onset of asthma. After two years of treatment more children in the control group developed clinical asthma than in the active group: p = 0.004. Des Roches et al reported the results of a prospective non randomised trial of immunotherapy with Dermatophagoides pteronyssinus in 44 asthmatic children younger than six years of age who were sensitive only to dust mites. The purpose of the study was to assess whether immunotherapy could reduce the development of new sensitisation during a period of three years of follow up. Specific immunotherapy was given with only D. Pteronyssinus extract. All 22 children in the control group developed new sensitivities as determined by skin testing and in vitro tests, while 10 (45%) of 22 children who received mite immunotherapy did not develop additional sensitivities. The findings of this study suggests that immunotherapy may alter the natural course of the allergic sensitisation reducing the risk of developing new sensitisation in mono sensitive children. A limited number of studies have examined the long terms effects of immunotherapy on the clinical presentation of asthma and rhinoconjunctivitis, and have shown a long lasting efficacy decreasing the amount of symptoms 6-10 years after termination. In a retrospective study of children treated with immunotherapy during childhood for at least three years, that were re-evaluated in early adulthood, the control patients who were treated with medication and no immunotherapy suffered almost 3.5 times more symptoms than the active group treated with immunotherapy. The current findings suggest that immunotherapy should be considered earlier in the course of allergic disease to prevent progression or to prevent the development of new sensitisation. Further studies with long term follow up particularly in children could address this possibility. PMID:10867376

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

    PubMed

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

    2012-09-01

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

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

    PubMed

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

    2009-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  4. Listeria infection in patients on anti-TNF treatment: report of two cases and review of the literature.

    PubMed

    Abreu, Cndida; Magro, Fernando; Vilas-Boas, Filipe; Lopes, Susana; Macedo, Guilherme; Sarmento, Antnio

    2013-03-01

    Listeria monocytogenes is an aerobic gram positive intracellular bacillus, predominantly affecting pregnant women, immunocompromised patients and old individuals. Invasive listeriosis, meningitis and meningoencephalitis, bacteraemia with or without joint, eye or heart focalization are clinical manifestations of the disease. Anti-TNF-? drugs blocking the host's response against various microorganisms, particularly intracellular agents like Listeria monocytogenes, increase the risk of disease. We report two cases of L. monocytogenes meningitis in ulcerative colitis patients under infliximab plus steroids. One patient is HIV-1 infected. A review of reported invasive listeriosis cases under anti-TNF drugs is also showed. PMID:22626505

  5. The relationship between body weight and inflammation: Lesson from anti-TNF-? antibody therapy.

    PubMed

    Peluso, Ilaria; Palmery, Maura

    2016-01-01

    Obesity is associated with many pathological conditions. Tumor Necrosis Factor-? (TNF-?) is one of the key mediators of inflammation involved in the obesity-related insulin resistance development. We aim to review the human evidence useful to clarify the relationship between inflammation and body weight, with particular reference to TNF-?. Genetic polymorphisms and epigenetic factors, such as diet, could affect TNF-? activity. TNF-? is associated with obesity, but also with anorexia and cachexia. Despite the role of TNF-? in obesity-related diseases, anti-TNF-? antibody therapy is associated with an increase in adiposity. In conclusion the reviewed results suggest that inflammation is more likely a consequence rather than a cause of obesity. PMID:26472017

  6. Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease.

    PubMed

    Mocci, Giammarco; Marzo, Manuela; Papa, Alfredo; Armuzzi, Alessandro; Guidi, Luisa

    2013-11-01

    The clinical introduction of tumour necrosis factor (TNF) inhibitors has deeply changed the treatment of inflammatory bowel diseases (IBD). It has demonstrated impressive efficacy as compared to alternative treatments, allowing for the chance to achieve near-remission and long-term improvement in function and quality of life and to alter the natural history of Crohn's disease (CD) and ulcerative colitis (UC). As a consequence of longer follow-up periods the number of side effects which may be attributed to treatment with biologics is growing significantly. Cutaneous reactions are among the most common adverse reactions. These complications include injection site reactions, cutaneous infections, immune-mediated complications such as psoriasis and lupus-like syndrome and rarely skin cancers. We review the recent literature and draw attention to dermatological side effects of anti-TNF therapy of inflammatory bowel disease. PMID:23453887

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

    SciTech Connect

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

    2009-07-01

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

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

    PubMed

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

    2016-04-11

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

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

    PubMed Central

    Snchez-Cano, Daniel; Callejas-Rubio, Jos Luis; Ruiz-Villaverde, Ricardo; Ros-Fernndez, Raquel; Ortego-Centeno, Norberto

    2013-01-01

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

  10. Off-label uses of anti-TNF therapy in three frequent disorders: Behet's disease, sarcoidosis, and noninfectious uveitis.

    PubMed

    Snchez-Cano, Daniel; Callejas-Rubio, Jos Luis; Ruiz-Villaverde, Ricardo; Ros-Fernndez, Raquel; Ortego-Centeno, Norberto

    2013-01-01

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

  11. 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

  12. FOXP3+ T Regulatory Cell Modifications in Inflammatory Bowel Disease Patients Treated with Anti-TNF? Agents

    PubMed Central

    Procoli, Annabella; Bonanno, Giuseppina; Martinelli, Enrica; Danese, Silvio; De Vitis, Italo; Papa, Alfredo; Armuzzi, Alessandro; Rutella, Sergio

    2013-01-01

    Treg modulation has been hypothesized as one of the mechanisms by which antitumor necrosis factor ? (TNF?) agents exert their action in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, data in IBD are still conflicting. We evaluated CD4+CD25+FOXP3+ (Tregs) by flow cytometry in peripheral blood from 32 adult IBD patient before (T0) and after the induction of anti-TNF? therapy (T1). Eight healthy controls (HCs) were included. We also evaluated the number of FOXP3+ cells in the lamina propria (LP) in biopsies taken in a subset of patients and controls. Treg frequencies were significantly increased in peripheral blood from our patients after anti-TNF? therapy compared to T0. T1 but not T0 levels were higher than HC. The increase was detectable only in clinical responders to the treatment. A negative correlation was found among delta Treg levels and the age of patients or disease duration and with the activity score of Crohn's disease (CD). No significant differences were found in LP FOXP3+ cells. Our data suggest the possibility that in IBD patients the treatment with anti-TNF? may affect Treg percentages and that Treg modifications may correlate with clinical response, but differently in early versus late disease. PMID:24063002

  13. Anti-TNF? agents and methotrexate in spondyloarthritis related uveitis in a Chinese population.

    PubMed

    Lian, Fan; Zhou, Jun; Wei, Cui; Wang, Yu; Xu, Hanshi; Liang, Liuqin; Yang, Xiuyan

    2015-11-01

    This study seeks to evaluate the clinical characteristics of spondyloarthritis (SpA)-related uveitis in a cohort from South China and to assess the efficacy and safety of therapies based on TNF blockers. SpA patients with uveitis admitted to a south China hospital were enrolled. Demographic information, clinical characteristics, laboratory findings, intraocular inflammation, visual acuity, macular thickness, and treatments were documented. Of the 1,036 SpA patients reviewed, 182 had uveitis. Ankylosing spondylitis (AS) was the most common subtype. Unilateral uveitis was found in 51 cases (51/182, 28.0%), and unilateral alternating uveitis was found in 75 cases (75/182, 41.2%). Half of the cases were recurrent uveitis (52.2%), and acute onset was common (76.4%). The most serious complication was vision loss (0.5%). No significant difference in disease activity was found between the SpA patients with or without uveitis. Predominant improvements were found in cases treated with all three anti-TNFs (infliximab, adalimumab, and etanercept) and anti-TNFs plus methotrexate (MTX). Monotherapy of methotrexate was not adequate for inducing remission. Monotherapy of etanercept was not as effective as adalimumab and infliximab, mainly in the prevention of recurrence. No significant difference in effectiveness was found among the three anti-TNFs if MTX was added. Etanercept plus MTX were well tolerated. Infliximab and adalimumab were associated with more tuberculosis and/or hepatitis flares. Uveitis is common in SpA patients. Severe complications may develop in prolonged and intractable cases. Treatments based on anti-TNFs had good clinical response, and better safety documentation were observed in etanercept plus MTX compared to the other two anti-TNF monoclonal antibodies plus MTX. PMID:26070537

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

    PubMed Central

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

    2015-01-01

    Objectives To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-? pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA). Methods In a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes. We included 538 anti-TNF nave Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses. False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status. Results Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.12.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.17.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.41.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response. The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.416.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association. Conclusions We reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA. Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5. Furthermore, we identified other candidate genes that require replication in independent cohorts. PMID:26440629

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

    PubMed

    Ros-Navarro, Cesar; de Pablo, Carmen; Collado-Diaz, Vctor; Orden, Samuel; Blas-Garcia, Ana; Martnez-Cuesta, Mara ngeles; Esplugues, Juan V; Alvarez, Angeles

    2015-10-15

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

  16. Anti-TNF?-therapy as an evidence-based treatment option for different clinical manifestations of psoriatic arthritis.

    PubMed

    Khm, Michaela; Burkhardt, Harald; Behrens, Frank

    2015-01-01

    The development programmes of different TNF-blocking agents in psoriatic arthritis (PsA) not only provided substantial evidence for the therapeutic benefits of the specific treatment options, but also enabled new insights into the differential treatment effects on distinct disease manifestations. For the first time, specific robust evidence for distinctive effects on different manifestations of PsA, as a distinct entity separate from rheumatoid arthritis (RA), has been generated in a standardized way. The clearest evidence was shown for an effect on peripheral arthritis (polyarticular) with ACR20 response rates from 45 up to 58% (vs. 9-24% for placebo), and an inhibition of radiographic progression demonstrated for the first time for a treatment principle in PsA. However, as PsA does not remain confined to the peripheral joints, it was necessary to address diverse patterns of PsA-subtypes in the outcome measurements of the anti-TNF trials. Accordingly, the results of the clinical studies on anti-TNF treatment also have demonstrated efficacy on enthesitis, dactylitis and skin psoriasis, either in sub analysis of results from phase III RCTs, or in additional prospective studies. PMID:26472504

  17. Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity

    PubMed Central

    Chen, Xin; Oppenheim, Joost J.

    2011-01-01

    Anti-TNF treatment is effective in a majority of rheumatoid arthritis (RA), however, this treatment can unexpectedly trigger the onset or exacerbate multiple sclerosis (MS). Recent progress in cellular immunology research provides a new framework to analyze the possible mechanism underlying these puzzling contradictory effects. The delicate balance of protective CD4+FoxP3+ regulatory T cells (Tregs) and pathogenic CD4+FoxP3− effector T cells (Teffs) is crucial for the outcome of anti-TNF treatment of autoimmune disease. There is convincing evidence that TNF, in addition to stimulating Teffs, is able to activate and expand Tregs through TNFR2, which is preferentially expressed by Tregs. Therefore, the contrasting effects of TNF on Tregs and Teffs are likely to determine the therapeutic effect of anti-TNF treatment. In this review, we discuss the current understanding of the general effect of TNF on the activation of T cells, and the impact of TNF on the function of Teffs and Tregs. Understanding the differential effects of TNF on Teffs and Tregs is fundamentally required for the design of more effective and safer anti-TNF or anti-TNF receptor(s) therapeutic strategy for autoimmune diseases. PMID:21513711

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

    PubMed

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

    2015-10-01

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

  19. 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

  20. 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

  1. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment.

    PubMed

    Emery, Paul

    2012-07-01

    A failure to respond to TNF inhibitors remains a serious concern for patients with RA. Although some patients experience a primary lack of drug efficacy in reducing their symptoms, others fail to maintain an initial response because of acquired drug resistance. While switching to another TNF inhibitor is a common practice for patients who are not responsive to a particular treatment, limited clinical trial data support this strategy. If more than one TNF inhibitor provides inadequate responses and/or similar tolerability issues, switching to a different class of agent may provide a more effective option. Currently four non-TNF inhibitors are approved for use in RA patients-the T-cell co-stimulation inhibitor abatacept, the B-cell-depleting mAb rituximab, the IL-1 receptor blocker anakinra and the IL-6 receptor inhibitor tocilizumab. These biologic agents have been studied in large, randomized placebo-controlled trials that demonstrate their efficacy in reducing disease activity in patients failing TNF inhibitor therapy. Results with the majority of these agents suggest that their administration may provide a greater proportion of patients with an effective, evidence-based disease-modifying approach earlier in the course of their disease than switching TNF inhibitors. PMID:22718923

  2. Melanoma immunotherapy.

    PubMed

    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

    2014-06-01

    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

  3. 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

  4. Hidradenitis suppurativa: guidelines of the Italian Society of Dermatology and Venereology (SIDeMaST) for the use of anti-TNF-? agents.

    PubMed

    Megna, M; Bettoli, V; Chimenti, S; Chiricozzi, A; Naldi, L; Virgili, A; Girolomoni, G; Monfrecola, G

    2015-12-01

    Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by nodules, abscesses and sinus tracts, primarily affecting the intertriginous areas. The occlusion of the upper part of the folliculopilosebaceous unit, leading to rupture of the sebofollicular canal with the consequent development of perifollicular lympho-histiocytic inflammation, is believed to be the initial pathogenic event in HS. Giving the chronic nature of HS, its destructive impact on social, working and daily life of patients, its management is often frustrating both for patients and physicians. The HS treatment choices are influenced by disease severity and its individual subjective impact. In this article, the Board of the Italian Society of Dermatology and Venereology (SIDeMaST) on HS has prepared a document focusing on the role of biologic drugs (anti-TNF-?) in HS management, providing also a flow-chart for HS handling and the inclusion and exclusion criteria for HS treatment with anti-TNF-?. PMID:26513043

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

    PubMed Central

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

    2013-01-01

    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

  6. Anti-TNF-? Activity of Brazilian Medicinal Plants and Compounds from Ouratea semiserrata.

    PubMed

    Campana, Priscilla R V; Mansur, Daniel S; Gusman, Grasielle S; Ferreira, Daneel; Teixeira, Mauro M; Braga, Ferno C

    2015-10-01

    Several plant species are used in Brazil to treat inflammatory diseases and associated conditions. TNF-? plays a pivotal role on inflammation, and several plant extracts have been assayed against this target, both in vitro and in vivo. The effect of 11 Brazilian medicinal plants on TNF-? release by LPS-activated THP-1 cells was evaluated. The plant materials were percolated with different solvents to afford 15 crude extracts, whose effect on TNF-? release was determined by ELISA. Among the evaluated extracts, only Jacaranda caroba (Bignoniaceae) presented strong toxicity to THP-1 cells. Considering the 14 non-toxic extracts, TNF-? release was significantly reduced by seven of them (inhibition?>?80%), originating from six plants, namely Cuphea carthagenensis (Lythraceae), Echinodorus grandiflorus (Alismataceae), Mansoa hirsuta (Bignoniaceae), Ouratea semiserrata (Ochnaceae), Ouratea spectabilis and Remijia ferruginea (Rubiaceae). The ethanol extract from O. semiserrata leaves was fractionated over Sephadex LH-20 and RP-HPLC to give three compounds previously reported for the species, along with agathisflavone and epicatechin, here described for the first time in the plant. Epicatechin and lanceoloside A elicited significant inhibition of TNF-? release, indicating that they may account for the effect produced by O. semiserrata crude extract. PMID:26094613

  7. 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

  8. Passive immunotherapy targeting amyloid-? reduces cerebral amyloid angiopathy and improves vascular reactivity.

    PubMed

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

    2016-02-01

    Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-? isoform(s) (predominantly amyloid-?40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-?40 selective antibody, to attenuate amyloid-? accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-? accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-? biochemically. We hypothesized that the reduction in vascular amyloid-?40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-?40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-?40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-? species that may otherwise be detrimental to normal vessel function. PMID:26493635

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

    NASA Astrophysics Data System (ADS)

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

    2015-07-01

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

  10. Production of anti TNF-α antibodies in eukaryotic cells using different combinations of vectors carrying heavy and light chains.

    PubMed

    Balabashin, Dmitriy; Kovalenko, Elena; Toporova, Viktoria; Aliev, Teimur; Panina, Anna; Svirshchevskaya, Elena; Dolgikh, Dmitry; Kirpichnikov, Mikhail

    2015-10-01

    Tumor necrosis factor-α (TNF-α) plays a key role in rheumatoid arthritis and some other autoimmune diseases. Therapy with anti-TNF-α recombinant antibodies (Ab) appears to be highly effective. Production of new hyper-producing eukaryotic cell lines can decrease the treatment cost, which currently is very high. However, due to the complexity of protein transcription, translation, processing, and secretion in mammalian cells, the stages at which antibody expression is affected are still poorly determined. The aim of this work was to compare the productivity of two cell lines developed in CHO DG44 cells, deficient in dihydrofolate reductase, transfected with vectors carrying either heavy (H) or light (L) chains of chimeric antibody under different combinations of selective elements. Both H and L chains were cloned either in pOptiVEC or pcDNA3.3 vectors and different combinations were used to produce HL and LH cell lines. We have shown that Ab production has been low and comparable between HL and LH cells until selection on methotrexate (MTX) when LH but not HL cells have responded with 3.5 times increased productivity. Flow cytometry analysis has demonstrated that intracellular concentration of full size Abs in LH cells was 5.6 times higher than in HL ones due to higher amount of H chain synthesis. No differences in viability between HL and LH cells have been found. We have concluded that the expression of H chain in the pOptiVEC vector, which is responsible for MTX resistance, has led to the suppression of H chain synthesis and limitation in full Ab assembly. PMID:24939591

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

    PubMed Central

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

    2015-01-01

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

  12. [Drug-induced liver injury with an autoimmune phenotype following anti-TNF Therapy - presentation of cases and review of literature].

    PubMed

    Rsner, S; Schad, A; Kittner, J; Rahman, F; Wrns, M A; Schuchmann, M; Galle, P R; Schattenberg, J M

    2014-01-01

    Therapeutic agents to inhibit tumour necrosis factor alpha (TNF-?) have dramatically improved the treatment options for patients with autoimmune diseases. Common side effects include an increased susceptibility towards infection. Hepatic side effects are less frequently observed. Elevated liver function tests, hyperbilirubinaemia reactivation of chronic viral hepatitis or even acute liver failure have been described. Some cases have exhibited an autoimmune phenotype with the emergence of autoantibodies and characteristic histological lesions. We report on three patients who received anti-TNF therapy for psoriasis and presented with elevated liver function tests in the further course. Histological and serum analysis revealed an autoimmune phenotype of liver injury. In light of the growing use of anti-TNF therapies, drug-induced liver injury (DILI) with an autoimmune phenotype is an important side effect. Since the pathophysiological mechanisms related to the autoimmune phenotype of liver injury during TNF-inhibition are not well understood, the cases detailed herein should help treating physicians to improve their understanding of the situation. PMID:24420801

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

    PubMed Central

    Sina, Mohammad; Farajzadeh, Davoud; Dastmalchi, Siavoush

    2015-01-01

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

  14. Alzheimer's disease and immunotherapy.

    PubMed

    Madeo, Jennifer; Frieri, Marianne

    2013-08-01

    Alzheimer's disease (AD) is a growing health care epidemic. It is the most common cause of dementia and its incidence is rising. Age, which influences the oxidative and inflammatory states of the brain, is the most important risk factor. Currently there is no disease modifying treatments available for this irreversible, progressive debilitating disease. Immunotherapy represents an emerging, potentially disease modifying strategy aimed at reducing the pathological lesions of AD and facilitating cognitive improvement. Many clinical trials are currently underway. This literature review highlights current knowledge regarding the physiology of aging and how it relates to the pathogenesis of AD. In addition, immunotherapy is discussed in the context of its mechanism, current studies and future goals. PMID:23936745

  15. [Guidelines in RA treatment: concepts on safety and recommendations using anti-TNF-alpha inhibitors. Grupo de Estudio de Nuevas Terapias de Enfermedades reumticas (GENTE)].

    TOXLINE Toxicology Bibliographic Information

    Daz-Jouanen E; Abud-Mendoza C; Garza-Elizondo MA; Medrano-Ramrez G; Burgos-Vargas R; Orozco-Alcalá JJ; Pacheco-Tena CF; Pineda C; Pozos-Espndola JC; Ramos-Niembro F; Robles-San-Romn M; Santana-Sahagn JE; Grupo de Estudio de Nuevas Terapias de Enfermedades reumticas (GENTE)

    2009-05-01

    Recommendations for the use of Disease-Modifying Antirheumatic Drugs (DMARD) with both conventional and biological agents in Rheumatoid Arthritis (RA) must be based on their safety profile, adverse effects, risks, and advantages. With the purpose of presenting the most updated information about the safety of tumor necrosis factor alpha (TNFalpha) antagonists, in this article we summarize the literature published during the last three years about this sort of biological agents in specific clinical situations, such as risk of developing infections, cancer, cardiovascular diseases, and autoimmunity; as well as their administration to patients who will undergo surgical procedures, pregnant and/or breast-feeding women, and patients who need immunizations. Likewise, in this analysis we offer specific recommendations, based on evidence, for the best anti-TNF-alfa management.

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

    PubMed Central

    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 LCMS 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 (R2 = 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

  17. 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; Sthle, 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

  18. Allergen-specific immunotherapy

    PubMed Central

    2011-01-01

    Allergen-specific immunotherapy is a potentially disease-modifying therapy that is effective for the treatment of allergic rhinitis/conjunctivitis, allergic asthma and stinging insect hypersensitivity. However, despite its proven efficacy in these conditions, it is frequently underutilized in Canada. The decision to proceed with allergen-specific immunotherapy should be made on a case-by-case basis, taking into account individual patient factors such as the degree to which symptoms can be reduced by avoidance measures and pharmacological therapy, the amount and type of medication required to control symptoms, the adverse effects of pharmacological treatment, and patient preferences. Since this form of therapy carries the risk of anaphylactic reactions, it should only be prescribed by physicians who are adequately trained in the treatment of allergy. Furthermore, injections must be given under medical supervision in clinics that are equipped to manage anaphylaxis. In this article, the authors review the indications and contraindications, patient selection criteria, and the administration, safety and efficacy of allergen-specific immunotherapy. PMID:22166078

  19. Tau Immunotherapy.

    PubMed

    Sigurdsson, Einar M

    2016-01-01

    In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-? (A?) pathology, greater clinical efficacy may be achieved by clearing tau than A? aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects. PMID:26551002

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

    PubMed Central

    Forsgren, Sture; Grimsholm, Ola; Daln, Tore; Rantap-Dahlqvist, Solbritt

    2011-01-01

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

  1. Subcutaneous Immunotherapy and Sublingual Immunotherapy: Comparative Efficacy, Current and Potential Indications, and Warnings-United States Versus Europe.

    PubMed

    Nelson, Harold S; Makatsori, Melina; Calderon, Moises A

    2016-02-01

    Subcutaneous immunotherapy and sublingual immunotherapy are effective for allergic rhinitis and allergic asthma and with some support for use in selected patients with atopic dermatitis. The sequence of immunologic responses is the same, irrespective of the route of administration, and similar disease modification has been demonstrated. However, there are differences between the two approaches. The most important is the greatly reduced likelihood of sublingual immunotherapy producing systemic reactions. There are major drawbacks for sublingual immunotherapy in regard to dosing. Finally, there is the question of relative clinical efficacy, with the currently available data favoring subcutaneous immunotherapy. PMID:26617224

  2. Assessing patients satisfaction with anti-TNF? treatment in Crohns disease: qualitative steps of the development of a new questionnaire

    PubMed Central

    Marant, Claire; Arnould, Benoit; Marrel, Alexia; Spizak, Cderic; Colombel, Jean-Frdric; Faure, Patrick; Hagege, Herv; Lemann, Marc; Nahon, Stphane; Tucat, Gilbert; Vandromme, Luc; Thibout, Emmanuel; Goldfarb, Grard

    2011-01-01

    Purpose: To develop a self-administered questionnaire assessing patients satisfaction with treatments in Crohns disease for use in clinical research and epidemiological studies. Patients and methods: Semi-directive interviews (16) were conducted with patients with severe Crohns disease treated with anti-tumor necrosis factor alpha (anti-TNF?). Transcripts were analyzed and concepts related to satisfaction with treatment were extracted and organized into a model. Items were generated using patients words. The resulting test version was tested for relevance and comprehension with 7 patients and revised accordingly; the new version was tested with 5 other patients and revised to provide the pilot version. A clinician advisory board was involved at each milestone of the development. Results: The test questionnaire assessed treatment satisfaction through 67 items, organized into 5 sections: treatment efficacy, side-effects, convenience and constraints, overall impact, and satisfaction. Conceptual content of the questionnaire includes comparison with prior state and with expectations, satisfaction, acceptability, and intentions. The questionnaire was generally well accepted and understood by patients; few modifications were made in the structure and item formulation. After the second round of comprehension tests, the pilot version contained 62 items; the questionnaire was named Satisfaction of PAtients in Crohns diseasE (SPACE). Conclusion: The questionnaire is a unique tool to assess treatment satisfaction in patients with Crohns disease. A scoring and validation study is currently being performed to finalize and establish its scoring, as well as its psychometric properties. PMID:21904463

  3. Tumor necrosis factor-α-mediated severity of idiopathic retinal periphlebitis in young adults (Eales’ disease): implication for anti-TNF-α therapy

    PubMed Central

    Pant, Aditya B.; Khanna, Vinay K.; Singh, Kamlesh; Shukla, Rajendra K.; Meyer, Carsten H.; Singh, Vijay K.

    2010-01-01

    Tumor necrosis factor-alpha (TNF-α) is a pleiotropic inflammatory cytokine. Tumor necrosis factor-alpha was evaluated in the serum samples of patients with idiopathic retinal periphlebitis in young adults (Eales’ disease). Retinal periphlebitis was graded according to a new grading system based on severity of inflammation (grade 1–4). Quantification of the TNF-α levels was carried out using ELISA kit in the serum samples of young adults with idiopathic retinal periphlebitis (n = 17) and healthy controls (n = 17) of similar age. Tumor necrosis factor-α level was found to be significantly raised in cases with retinal periphlebitis as compared with controls (p < 0.001). Higher levels of TNF-α were found to be associated with increased severity of retinal periphlebitis. Tumor necrosis factor-α represents a novel target for controlling inflammatory activity in idiopathic retinal periphlebitis. Higher levels of TNF-α, in association with the increased severity of retinal periphlebitis, have implications for early anti-TNF-α therapy. PMID:21139707

  4. Immunotherapy and tumor microenvironment.

    PubMed

    Tang, Haidong; Qiao, Jian; Fu, Yang-Xin

    2016-01-01

    Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases. PMID:26477683

  5. 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 118126 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

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

    PubMed Central

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

    2014-01-01

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

  7. Immunotherapy for bladder cancer.

    PubMed

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

    2015-01-01

    It is nearly 40 years since Bacillus Calmette-Gurin (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

  8. Immunotherapy for bladder cancer

    PubMed Central

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

    2015-01-01

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

  9. A randomized trial of immunotherapy for persistent genital warts

    PubMed Central

    Jardine, David; Lu, Jieqiang; Pang, James; Palmer, Cheryn; Tu, Quanmei; Chuah, John; Frazer, Ian H.

    2012-01-01

    Aim To determine whether immunotherapy with HPV6 L1 virus like particles (VLPs) without adjuvant (VLP immunotherapy) reduces recurrence of genital warts following destructive therapy. Trial design A randomized placebo controlled blinded study of treatment of recurrent genital warts amenable to destructive therapy, conducted independently in Australia and China. Methods Patients received conventional destructive therapy of all evident warts together with intramuscular administration of 1, 5 or 25 g of VLP immunotherapy, or of placebo immunotherapy (0.9% NaCl), as immunotherapy at week 0 and week 4. Primary outcome, assessed at week 8, was recurrence of visible warts. Results Of 33 protocol compliant Brisbane recipients of placebo immunotherapy, 11 were disease free at two months, and a further 9 demonstrated reduction of > 50% in total wart area. Wart area reduction following destructive treatment correlated with prior duration of disease. Among 102 protocol compliant Brisbane recipients of VLP immunotherapy, disease reduction was significantly greater than among the placebo immunotherapy (50% s.e.m. 7%) recipients for subjects receiving 5 g or 25 g of VLP immunotherapy/dose (71% s.e.m.7%) but not for those receiving 1 g VLP immunotherapy/dose (42% 7%). Of 52 protocol compliant placebo immunotherapy recipients in Wenzhou, 37 were disease free at two months, and a further 8 had > 50% disease reduction. Prior disease duration was much shorter in Wenzhou subject (8.1 1.1 mo) than in Brisbane subjects (53.7 5.5 mo). No significant reduction in mean wart area was observed for the 168 Wenzhou protocol compliant subjects who also received VLP immunotherapy. Conclusions This study confirms the findings in a previous open label trial that administration of VLP immunotherapy may assist in clearance of recurrent genital warts in patients for whom destructive therapy is unsuccessful and that unsuccessful destructive therapy is more common with increasing prior disease duration. PMID:22634446

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

    PubMed

    Erdemli, zge; zen, Seza; Keskin, Dilek; Usanmaz, Ali; Batu, Ezgi Deniz; Atilla, Blent; Tezcaner, Ay?en

    2014-10-01

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

  11. Colorectal Cancer Immunotherapy

    PubMed Central

    Xiang, Bo; Snook, Adam E.; Magee, Michael S.; Waldman, Scott A.

    2014-01-01

    Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. Here, we review the major immunotherapeutic approaches currently under investigation for colorectal cancer, including cancer vaccines and adoptive cell therapy. Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval and mainstream adoption of colorectal cancer immunotherapeutics. PMID:23725603

  12. [Melanoma immunotherapy: dendritic cell vaccines].

    PubMed

    Lozada-Requena, Ivan; Nez, Csar; Aguilar, Jos Luis

    2015-01-01

    This is a narrative review that shows accessible information to the scientific community about melanoma and immunotherapy. Dendritic cells have the ability to participate in innate and adaptive immunity, but are not unfamiliar to the immune evasion of tumors. Knowing the biology and role has led to generate in vitro several prospects of autologous cell vaccines against diverse types of cancer in humans and animal models. However, given the low efficiency they have shown, we must implement strategies to enhance their natural capacity either through the coexpression of key molecules to activate or reactivate the immune system, in combination with biosimilars or chemotherapeutic drugs. The action of natural products as alternative or adjuvant immunostimulant should not be ruled out. All types of immunotherapy should measure the impact of myeloid suppressor cells, which can attack the immune system and help tumor progression, respectively. This can reduce the activity of cellular vaccines and/or their combinations, that could be the difference between success or not of the immunotherapy. Although for melanoma there exist biosimilars approved by the Food and Drug Administration (FDA), not all have the expected success. Therefore it is necessary to evaluate other strategies including cellular vaccines loaded with tumor antigenic peptides expressed exclusively or antigens from tumor extracts and their respective adjuvants. PMID:26580940

  13. Using macrophage activation to augment immunotherapy of established tumours

    PubMed Central

    Fridlender, Z G; Jassar, A; Mishalian, I; Wang, L-CS; Kapoor, V; Cheng, G; Sun, J; Singhal, S; Levy, L; Albelda, S M

    2013-01-01

    Background: Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy. Methods: We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RTPCR). Results: In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8+ T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect. Conclusion: Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials. PMID:23481183

  14. Immunotherapy for Cervical Cancer

    Cancer.gov

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

  15. Cancer immunotherapy in children

    Cancer.gov

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

  16. Trends in Cancer Immunotherapy

    PubMed Central

    Murphy, Joseph F.

    2010-01-01

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

  17. Immunotherapy in lung cancer.

    PubMed Central

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

    1998-01-01

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

  18. Mechanisms of Aeroallergen Immunotherapy: Subcutaneous Immunotherapy and Sublingual Immunotherapy.

    PubMed

    Ozdemir, Cevdet; Kucuksezer, Umut Can; Akdis, Mbeccel; Akdis, Cezmi A

    2016-02-01

    Allergen immunotherapy (AIT) is an effective way to treat allergic disorders, targeting the underlying mechanisms and altering the disease course by inducing a long-lasting clinical and immune tolerance to allergens. Although sublingual and subcutaneous routes are used in daily practice, many novel ways to decrease side effects and duration and increase efficacy have been pursued. Further studies are needed to develop biomarkers for the identification of AIT responder patients and also to use the developed knowledge in allergy prevention studies. Future directions in AIT include treatments for autoimmune diseases, chronic infections, organ transplantation, and breaking immune tolerance to cancer cells. PMID:26617228

  19. Immunotherapy in gastric cancer

    PubMed Central

    Matsueda, Satoko; Graham, David Y

    2014-01-01

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

  20. Environmental control and immunotherapy for allergic disease.

    PubMed

    Evans, R

    1992-09-01

    Treatment for allergic disease can help prevent recurrent sinusitis. Removal of carpeting and feather bedding and use of acaricides can significantly improve symptoms caused by house dust mites or animal dander. To kill mites, wash-water temperature must be at least 58 degrees C. Patients with severe allergy should use an air-filtering vacuum cleaner and an air cleaner with a HEPA filter. Humidity should be kept at under 50%. If other measures fail, pets may have to be removed. Subcutaneous immunotherapy is effective for patients with anaphylactic reactions to insect stings, allergic rhinitis, and allergic asthma. It is ineffective for food allergy or nonallergic rhinitis or asthma. In children, immunotherapy is reserved for generalized life-threatening airway reactions. Relative indications for immunotherapy include inability to avoid the allergen and poor results or significant side effects from pharmacologic treatment. Efficacy depends on dosage, duration of treatment, and allergen selection. Low initial doses are increased at a set rate until the dose induces appropriate antibody response without significant reactions. Patients should be much improved or symptom-free for 1 to 2 years before immunotherapy is discontinued. Pollen, house dust mite, cat, and some mold spore extracts reduce symptoms and sensitivity to nasal or bronchial provocation. When used appropriately, immunotherapy is safe and effective. PMID:1527338

  1. Recent advances in immunotherapy for allergic diseases.

    PubMed

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

    2014-01-01

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

  2. What Is Recent in Pancreatic Cancer Immunotherapy?

    PubMed Central

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

    2013-01-01

    Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4–6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor response in vivo. PMID:23509731

  3. Immunotherapy for colorectal cancer

    PubMed Central

    Koido, Shigeo; Ohkusa, Toshifumi; Homma, Sadamu; Namiki, Yoshihisa; Takakura, Kazuki; Saito, Keisuke; Ito, Zensho; Kobayashi, Hiroko; Kajihara, Mikio; Uchiyama, Kan; Arihiro, Seiji; Arakawa, Hiroshi; Okamoto, Masato; Gong, Jianlin; Tajiri, Hisao

    2013-01-01

    The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms. PMID:24379570

  4. Lung Cancer Immunotherapy

    PubMed Central

    Raez, Luis E.; Fein, Steven; Podack, Eckhard R.

    2005-01-01

    Recent insights into anti-tumor immunotherapy have led to a wave of clinical trials involving immunotherapy for lung cancer. Vaccines have evolved from nonspecific immune stimulants, like Bacillus Calmette-Guerin (BCG), to much more specific and potent strategies, some of which generate active immune responses against tumor-associated antigens. Understanding the mechanisms of anti-tumor immunity and identifying target antigens will likely improve these therapeutic strategies and provide them with a niche in the future of lung cancer therapy. PMID:16303887

  5. [Immunotherapy in ovarian cancer].

    PubMed

    Weinberger, V; Minr, L

    2012-04-01

    In the last decade we have witnessed a stormy development in the field of molecular biology, immunology and genetics. Dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory agents, created new conditions and opportunities in the treatment of ovarian cancer. The review article provides an overview of the current state of immunotherapy, outlines modern trends in the development of vaccines and immunomodulatory therapies available for immediate clinical testing in cases of advanced ovaria cancer. PMID:22702073

  6. Sublingual immunotherapy: other indications.

    PubMed

    Passalacqua, Giovanni; Compalati, Enrico; Canonica, Giorgio Walter

    2011-05-01

    Sublingual immunotherapy (SLIT) represents a significant advance and it seems particularly suitable in pediatric patients. There are favorable results for food allergy in controlled trials. For latex allergy, the results of several trials are encouraging. For atopic dermatitis, previous experience with subcutaneous immunotherapy and some earlier trials suggest the possible application of SLIT in children with mild to moderate dermatitis and sensitization to dust mite, but this recommendation is considered insufficiently evidence based. In hymenoptera allergy, the only trial available is a proof-of-concept study in large local reactions that needs to be confirmed in well-controlled studies. PMID:21530820

  7. Allergen Immunotherapy: Vaccine Modification.

    PubMed

    Creticos, Peter Socrates

    2016-02-01

    There is a need for newer therapeutic agents that improve the safety of allergen immunotherapy, provide ease of delivery to patients that fosters compliance and allows access to a greater proportion of the allergic population who could benefit from this disease-modifying treatment, and achieve an acceptable therapeutic benefit for patients committing to the treatment. The advances in sublingual allergen immunotherapy are encouraging, as this offers patients a noninjectable form of treatment of inhalant allergies. The continued research and development of the novel therapeutic constructs discussed in this article holds the promise of accomplishing the aforementioned goals in the future. PMID:26617230

  8. Immunotherapy in veterinary oncology.

    PubMed

    Bergman, Philip J

    2014-09-01

    Tumor immunology and immunotherapy is one of the most exciting and rapidly expanding fields. The immune system is divided into 2 primary components: the innate immune response and the highly specific, but more slowly developing, adaptive or acquired immune response. Immune responses are separated by whether they are induced by exposure to a foreign antigen (active response) or transferred through serum or lymphocytes from an immunized individual (passive response). The ideal cancer immunotherapy agent should discriminate between cancer and normal cells (specificity), be potent enough to kill small or large numbers of tumor cells (sensitivity), and prevent recurrence of a tumor (durability). PMID:25174908

  9. Active Immunotherapy of Cancer.

    PubMed

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

    2015-11-01

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

  10. Immunotherapy for Gastrointestinal Malignancies

    PubMed Central

    Toomey, Paul G.; Vohra, Nasreen A.; Ghansah, Tomar; Sarnaik, Amod A.; Pilon-Thomas, Shari A.

    2016-01-01

    Background Gastrointestinal (GI) cancers are the most common human tumors encountered worldwide. The majority of GI cancers are unresectable at the time of diagnosis, and in the subset of patients undergoing resection, few are cured. There is only a modest improvement in survival with the addition of modalities such as chemotherapy and radiation therapy. Due to an increasing global cancer burden, it is imperative to integrate alternative strategies to improve outcomes. It is well known that cancers possess diverse strategies to evade immune detection and destruction. This has led to the incorporation of various immunotherapeutic strategies, which enable reprogramming of the immune system to allow effective recognition and killing of GI tumors. Methods A review was conducted of the results of published clinical trials employing immunotherapy for esophageal, gastroesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers. Results Monoclonal antibody therapy has come to the forefront in the past decade for the treatment of colorectal cancer. Immunotherapeutic successes in solid cancers such as melanoma and prostate cancer have led to the active investigation of immunotherapy for GI malignancies, with some promising results. Conclusions To date, monoclonal antibody therapy is the only immunotherapy approved by the US Food and Drug Administration for GI cancers. Initial trials validating new immunotherapeutic approaches, including vaccination-based and adoptive cell therapy strategies, for GI malignancies have demonstrated safety and the induction of antitumor immune responses. Therefore, immunotherapy is at the forefront of neoadjuvant as well as adjuvant therapies for the treatment and eradication of GI malignancies. PMID:23302905

  11. [Cancer immunotherapy--current status].

    PubMed

    Kundig, T M; Renner, Ch; Knuth, A

    2006-04-01

    Cancer immunotherapy includes passive and active strategies. Passive immunotherapy such as the use of therapeutic monoclonal antibodies, and in a broader sense also of other immunological effector molecules, such as interferon-alpha is clinically established. The efficacy of passive immunotherapy attests to the fact that the immune system can successfully fight cancer. The logical next step is therefore to develop strategies for active immunotherapy, i.e. "vaccines against cancer". This review focuses on the current status of active immunotherapy with respect to clinical application. Although active immunotherapy is still in the experimental stage, the data are highly encouraging and it is expected that vaccination will soon become part of cancer management. PMID:16689457

  12. Nanoparticulate immunotherapy for cancer.

    PubMed

    Kapadia, Chintan H; Perry, Jillian L; Tian, Shaomin; Luft, J Christopher; DeSimone, Joseph M

    2015-12-10

    Although surgery, radiation therapy, and chemotherapy have significantly improved as treatments for cancer, they can rarely control metastatic disease and cures remain scarce. Promising recent developments suggest that cancer immunotherapy may become a powerful new therapy that clinicians can offer cancer patients. The opportunity to orchestrate the body's own immune system to target, fight, and eradicate cancer cells without destroying healthy cells makes this an extremely attractive treatment modality. Our increased knowledge in anti-tumor immunity and the immunosuppressive tumor microenvironment (TME) has provided many therapeutic strategies to battle cancer. That combined with advancements in the field of particulate delivery systems provide a mechanism to deliver these immunotherapeutics to their specific targeted cells and the TME. In this review we will focus on the current status of immunotherapy and the potential advantages of utilizing nanocarriers within the field. PMID:26432555

  13. 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

  14. Immunotherapy in Peripheral Neuropathies.

    PubMed

    Lger, Jean-Marc; Guimares-Costa, Raquel; Muntean, Cristina

    2016-01-01

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

  15. [Immunotherapies and melanoma].

    PubMed

    Routier, milie; Robert, Caroline; Mateus, Christina

    2014-12-01

    Metastatic melanoma treatment has been radically modified over the last four years with the emergence of new and effective therapeutic strategies targeted anti-BRAF therapies as well as immunotherapy. Following this latter immunotherapy strategy, anti-CTLA4 antibody ipilimumab demonstrated a benefit in terms of overall survival in patients with metastatic melanoma and is now challenged by other checkpoint inhibitors, antibodies directed against PD-1 and PD-L1 that have extremely promising benefit/risk ratio. Adverse events as well as evaluation criteria are different from the ones associated with classical chemotherapy or targeted therapies. The challenge for the next years will be to optimize these new strategies, by possibly using these new drugs sequentially or in combination for a higher clinical benefit for our patients. PMID:25776763

  16. Targeted cancer immunotherapy.

    PubMed

    Zigler, Maya; Shir, Alexei; Levitzki, Alexander

    2013-08-01

    The understanding that the immune system plays a dual role in cancer progression has led to the recent development of targeted immunotherapies. These treatments, which aim to harness the immune system against cancer, include monoclonal antibodies, immune adjuvants, cell-based therapy and vaccines. Although numerous immune-targeted treatment modalities have entered the clinic, most have shown limited efficacy. The intrinsic heterogeneity and genomic instability of the tumor, coupled with immune suppression induced by both the tumor and its microenvironment, remain the main obstacles to the success of these therapies. We believe that the primary objective of the new generation of therapies must be to reinstate immune surveillance against primary and metastatic tumor cells, while inhibiting the immune suppressive microenvironment. Most probably this will be achieved by combining several treatment modalities. This paper will briefly review current immunotherapies and their promise, as well as the obstacles associated with them. PMID:23648271

  17. Immunotherapy of Fungal Infections.

    PubMed

    Datta, Kausik; Hamad, Mawieh

    2015-11-01

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

  18. Immunotherapy of Cancer in 2012

    PubMed Central

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

    2012-01-01

    The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy. PMID:22576456

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

    PubMed

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

    2012-01-01

    Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe's policy-makers to coordinate actions and improve individual and public health in allergy by:Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade. PMID:23110958

  20. Sublingual immunotherapy in allergic rhinitis

    PubMed Central

    Han, Doo Hee

    2011-01-01

    Current treatment options for allergic rhinitis (AR) include allergen avoidance and environmental control, pharmacotherapy, nasal surgery and immunotherapy. Among these, immunotherapy is the only therapeutic option that modifies fundamental immunologic mechanism by inducing desensitization. Specific allergen immunotherapy has been used for 1 century since 1911 and subcutaneous immunotherapy (SCIT) has been demonstrated to be effective in asthma and AR. However, SCIT has several disadvantages such as inconvenience, invasiveness and potentially severe systemic reactions. Thus, sublingual immunotherapy (SLIT) has recently received much attention around the world as a treatment for AR and is now widely used to replace the subcutaneous route. SLIT has recently been introduced in Korea and is now available for AR treatment in the Asia-Pacific region. This review offers better understanding of SLIT for AR by summarizing published articles and our previous works regarding proposed mechanisms, indication and efficacy, safety and adverse events, and compliance. PMID:22053308

  1. Regulatory T Cells as Immunotherapy

    PubMed Central

    Singer, Benjamin D.; King, Landon S.; DAlessio, 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

  2. Sublingual and oral immunotherapy.

    PubMed

    Canonica, Giorgio Walter; Compalati, Enrico; Fumagalli, Federica; Passalacqua, Giovanni

    2004-11-01

    Sublingual immunotherapy (SLIT) is a viable alternative to the subcutaneous route for the treatment of respiratory allergy, whereas the pure oral route has been abandoned because of its lack of efficacy. The main distinctive feature of SLIT is its optimal safety profile, which has been demonstrated in adults and children. The indications for SLIT are similar to those for the subcutaneous route. A long-lasting effect has been demonstrated for the sublingual route, but data are needed to determine the optimal dose and the preventive effect in asthma. PMID:15474866

  3. 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

  4. Combinatorial Cancer Immunotherapies.

    PubMed

    Hellmann, Matthew D; Friedman, Claire F; Wolchok, Jedd D

    2016-01-01

    T cell checkpoint blockade therapies are revolutionizing the treatment of patients with cancer. Highlighted by the recent success of PD-1 plus CTLA-4 blockade in patients with melanomas, synergistic immunotherapy combinations of modalities represent an important opportunity to improve responses and outcomes for patients. We review the rationale and experience with T cell checkpoint blockade in combination with targeting of other coinhibitory or costimulatory checkpoints, immunomodulatory molecules in the tumor microenvironment, and other anticancer modalities such as vaccines, chemotherapy, and radiation. PMID:26923003

  5. Prospects for immunotherapy and vaccines against Cryptosporidium

    PubMed Central

    Mead, Jan R

    2014-01-01

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

  6. Prospects for immunotherapy and vaccines against Cryptosporidium.

    PubMed

    Mead, Jan R

    2014-01-01

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

  7. Alzheimers Disease and Immunotherapy

    PubMed Central

    Madeo, Jennifer; Frieri, Marianne

    2013-01-01

    Alzheimers disease (AD) is a growing health care epidemic. It is the most common cause of dementia and its incidence is rising. Age, which influences the oxidative and inflammatory states of the brain, is the most important risk factor. Currently there is no disease modifying treatments available for this irreversible, progressive debilitating disease. Immunotherapy represents an emerging, potentially disease modifying strategy aimed at reducing the pathological lesions of AD and facilitating cognitive improvement. Many clinical trials are currently underway. This literature review highlights current knowledge regarding the physiology of aging and how it relates to the pathogenesis of AD. In addition, immunotherapy is discussed in the context of its mechanism, current studies and future goals. PMID:23936745

  8. Adherence to Sublingual Immunotherapy.

    PubMed

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

    2016-01-01

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

  9. Current status of immunotherapy.

    PubMed

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

    2016-03-01

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

  10. Immunotherapy for Resected Pulmonary Metastases.

    PubMed

    Morse, Michael A

    2016-02-01

    Micrometastatic disease following pulmonary metastasectomy is an ideal setting to test adjuvant immunotherapy, as the efficacy of immunotherapy in experimental models is greatest with the smallest tumor burdens. Although there is not a standard-of-care adjuvant immunotherapy for resected pulmonary metastases, there have been several studies using cytokines and other immunostimulatory molecules in conjunction with metastasectomies in patients with melanoma, renal cell carcinoma, sarcoma, and colorectal cancer, which have provided preliminary data that such adjuvant therapy is feasible and safe and may be useful in the future, following more rigorous testing, as routine therapy to prevent recurrences. PMID:26611512

  11. 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, Lus E. M.; Fraga, Carlos A. M.; Barreiro, Eliezer J.; Guimaraes, Marlia 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 M. 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 mol.Kg?1 LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 mol.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 mol.Kg?1 LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 711 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

  12. 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.

  13. Principles of immunotherapy.

    PubMed

    Liebelt, Brandon D; Finocchiaro, Gaetano; Heimberger, Amy B

    2016-01-01

    Gliomas are the most common primary brain tumors of the central nervous system, and carry a grim prognosis. Novel approaches utilizing the immune system as adjuvant therapy are quickly emerging as viable and effective options. Immunotherapeutic strategies being investigated to treat glioblastoma include: vaccination therapy targeted against either specific tumor antigens or whole tumor lysate, adoptive cellular therapy with cytotoxic T lymphocytes, chimeric antigen receptors and bi-specific T-cell engaging antibodies allowing circumvention of major histocompatibility complex restriction, aptamer therapy with aims for more efficient target delivery, and checkpoint blockade in order to release the tumor-mediated inhibition of the immune system. Given the heterogeneity of glioblastoma and its ability to gain mutations throughout the disease course, multifaceted treatment strategies utilizing multiple forms of immunotherapy in combination with conventional therapy will be most likely to succeed moving forward. PMID:26948354

  14. Mutanome directed cancer immunotherapy.

    PubMed

    Vormehr, Mathias; Diken, Mustafa; Boegel, Sebastian; Kreiter, Sebastian; Türeci, Özlem; Sahin, Ugur

    2016-04-01

    Somatic mutations are important drivers of cancer development. Accumulating evidence suggests that a significant subset of mutations result in neo-epitopes recognized by autologous T cells and thus may constitute the Achilles' heel of tumor cells. T cells directed against mutations have been shown to have a key role in clinical efficacy of potent cancer immunotherapy modalities, such as adoptive transfer of autologous tumor infiltrating lymphocytes and immune checkpoint inhibitors. Whereas these findings strengthen the idea of a prominent role of neo-epitopes in tumor rejection, the systematic therapeutic exploitation of mutations was hampered until recently by the uniqueness of the repertoire of mutations ('the mutanome') in every patient's tumor. This review highlights insights into immune recognition of neo-epitopes and novel concepts for comprehensive identification and immunotherapeutic exploitation of individual mutations. PMID:26716729

  15. Immunotherapy of hepatocellular carcinoma

    PubMed Central

    Pardee, Angela D.; Butterfield, Lisa H.

    2012-01-01

    Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients. PMID:22720211

  16. Immunotherapy of cancer

    PubMed Central

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

    2009-01-01

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

  17. Imaging Biomarkers in Immunotherapy

    PubMed Central

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

    2016-01-01

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

  18. Tau immunotherapy and imaging.

    PubMed

    Sigurdsson, Einar M

    2014-01-01

    Disappointing findings from recent phase III trials on amyloid-? (A?) immunotherapy for Alzheimer's disease (AD) have shifted the focus of such treatments to the tau protein. As tau pathology correlates better with the degree of dementia than A? plaque burden, it is a more attractive target once cognitive impairments are evident, while A? therapies may be better suited for the presymptomatic phase of the disease. Over 12 years ago, we initiated a tau immunotherapy program, seeking to alleviate the functional impairments associated with tau lesions in tauopathies. We have reported that various active and passive tau immunizations diminish tau pathology and improve function, including cognition, in different mouse models. Both extra- and intracellular pathways are likely involved. The antibodies may block the spread of tau pathology via microglial phagocytosis of the antibody-tau complex and facilitate lysosomal tau clearance in neurons after endosomal uptake. We have observed such antibody internalization following intracarotid injection in mice and in various culture models. These include brain slices and primary neurons from tangle mice as well as human neuroblastoma cell lines. Antibody targeting of different intracellular protein aggregates, including ?-synuclein, A? and superoxide dismutase has been reported by others. Now, several laboratories have confirmed and extended our findings using various active and passive tau immunizations in different models, thereby clearly establishing the feasibility of this approach for clinical trials. We are also working on imaging approaches to monitor tau pathology, its consequences and the efficacy of treatments. Dire need exists for such diagnostic methods for tauopathies. Overall, therapies and diagnostic tools targeting tau pathology have a great potential for AD and other tauopathies. PMID:24029727

  19. Longer durations of antitumour necrosis factor treatment are associated with reduced risk of cardiovascular events in patients with rheumatoid arthritis

    PubMed Central

    Nurmohamed, Michael; Bao, Yanjun; Signorovitch, James; Trahey, Alex; Mulani, Parvez; Furst, Daniel E

    2015-01-01

    Objective To assess the effects of treatment with antitumour necrosis factor (TNF) agents, methotrexate, or other non-biological disease-modifying antirheumatic drugs (DMARDs) on cardiovascular event risks among patients with rheumatoid arthritis (RA). Methods We conducted a retrospective study using data from the MarketScan claims database. Patients with RA with ?1 prescription for an index drug were included. Each patient's use of an index drug was calculated cumulatively as a time-varying exposure. The incidence of cardiovascular events among patients with RA was determined. Associations between drug exposures and occurrence of cardiovascular events were assessed with Cox proportional hazards models. Results Of 113?677 patients identified, 35.8%, 41.1% and 23.1% received anti-TNF agents, methotrexate and other DMARDs, respectively. Patients were treated for an average of 7.6?months; 2138 patients (1.9%) had a cardiovascular event following their index prescription. Each additional 6?months of anti-TNF therapy use versus non-use reduced the risk (HR; 95% CI) for any cardiovascular event by 12% (0.88; 0.81 to 0.95, p=0.002). Anti-TNF therapy was associated with a 13% and 12% reduction in cardiovascular events in patients aged ?50?years (0.87; 0.80 to 0.95, p=0.002) and in those without prior methotrexate use (0.88; 0.78 to 0.99, p=0.04), respectively. Cumulative use of 1, 2 or 3?years of anti-TNF therapy versus non-use is expected to reduce cardiovascular event risks by 21%, 38% and 51%, respectively. Conclusions Anti-TNF therapy was associated with a significantly lower risk of cardiovascular events among patients with RA, older patients with RA and patients without prior exposure to methotrexate. PMID:26535138

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

    PubMed Central

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

    2009-01-01

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

  1. Immunotherapy advances for glioblastoma

    PubMed Central

    Reardon, David A.; Freeman, Gordon; Wu, Catherine; Chiocca, E. Antonio; Wucherpfennig, Kai W.; Wen, Patrick Y.; Fritsch, Edward F.; Curry, William T.; Sampson, John H.; Dranoff, Glenn

    2014-01-01

    Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation. PMID:25190673

  2. Lymphoma Immunotherapy: Current Status

    PubMed Central

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

    2015-01-01

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

  3. 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

  4. IgE immunotherapy

    PubMed Central

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

    2014-01-01

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

  5. Biologic Therapy (Immunotherapy) for Kidney Cancer

    MedlinePLUS

    ... Next Topic Chemotherapy for kidney cancer Biologic therapy (immunotherapy) for kidney cancer The goal of biologic therapy ... to suppress your immune system. Newer approaches to immunotherapy Cytokines can also be used as part of ...

  6. Current status of cancer immunotherapy.

    PubMed

    Kono, K

    2014-01-01

    To prove clinical benefits of cancer vaccine is currently difficult, except for one phase III trial has documented improved overall survival with the vaccine, Sipuleucel-T, although induction of anti-tumor immune responses through cancer vaccine is theoretically promising and would be straightforward. In contrast, immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types. In addition, there is a promising novel cancer immunotherapy, CAR therapy-a personalized treatment that involves genetically modifying a patient's T-cells to make them target tumor cells. We are now facing new era of cancer immunotherapy. PMID:25075156

  7. Immunotherapy of Childhood Sarcomas

    PubMed Central

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

    2015-01-01

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

  8. Hypoallergenic molecules for subcutaneous immunotherapy.

    PubMed

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

    2016-01-01

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

  9. CCL2 Blockade Augments Cancer Immunotherapy

    PubMed Central

    Fridlender, Zvi G.; Buchlis, George; Kapoor, Veena; Cheng, Guanjun; Sun, Jing; Singhal, Sunil; Crisanti, Cecilia; Wang, Liang-Chuan S; Heitjan, Daniel; Snyder, Linda A.; Albelda, Steven M.

    2009-01-01

    Since an immuno-inhibitory environment exists within tumors, successful vaccines will likely require additional approaches to alter the tumor microenvironment. Monocyte chemoattractant proteins (such as CCL2) are produced by many tumors and have both direct and indirect immuno-inhibitory effects. We hypothesized that CCL2 blockade would reduce immunosuppression and augment vaccine immunotherapy. Anti-murine-CCL2/CCL12 monoclonal antibodies were administered in three immunotherapy models: one aimed at the HPV-E7 antigen expressed by a non-small cell lung cancer line, one targeted to mesothelin expressed by a mesothelioma cell line, and one using an adenovirus expressing Interferon-? to treat a non-immunogenic, non-small cell lung cancer line. We evaluated the effect of the combination treatment on tumor growth and assessed the mechanism of these changes by evaluating cytotoxic T cells, immunosuppressive cells, and the tumor microenvironment. Administration of anti-CCL2/CCL12 antibodies along with the vaccines markedly augmented efficacy with enhanced reduction in tumor volume and cures of approximately half of the tumors. The combined treatment generated more total intra-tumoral CD8+ T-cells that were more activated and more anti-tumor antigen specific, as measured by tetramer evaluation. Another important potential mechanism was reduction in intratumoral T-regulatory (T-reg) cells. CCL2 appears to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T cell immune response to tumors elicited by vaccines via multifactorial mechanisms. These observations suggest that combining CCL2 neutralization with vaccines should be considered in future immunotherapy trials. PMID:20028856

  10. Classification of current anticancer immunotherapies.

    PubMed

    Galluzzi, Lorenzo; Vacchelli, Erika; Bravo-San Pedro, Jos-Manuel; Buqu, 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?kov, Jitka; Gabrilovich, Dmitry I; Galon, Jrme; Garg, Abhishek; Ghiringhelli, Franois; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jger, Dirk; Kalinski, Pawel; Krre, 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; Sauts-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, Benot 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

  11. Cancer Immunotherapy Comes of Age

    PubMed Central

    Topalian, Suzanne L.; Weiner, George J.; Pardoll, Drew M.

    2011-01-01

    Cancer immunotherapy comprises a variety of treatment approaches, incorporating the tremendous specificity of the adaptive immune system (T cells and antibodies) as well as the diverse and potent cytotoxic weaponry of both adaptive and innate immunity. Immunotherapy strategies include antitumor monoclonal antibodies, cancer vaccines, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate immune cells or block immune inhibitory pathways (so-called immune checkpoints). Although clear clinical efficacy has been demonstrated with antitumor antibodies since the late 1990s, other immunotherapies had not been shown to be effective until recently, when a spate of successes established the broad potential of this therapeutic modality. These successes are based on fundamental scientific advances demonstrating the toleragenic nature of cancer and the pivotal role of the tumor immune microenvironment in suppressing antitumor immunity. New therapies based on a sophisticated knowledge of immune-suppressive cells, soluble factors, and signaling pathways are designed to break tolerance and reactivate antitumor immunity to induce potent, long-lasting responses. Preclinical models indicate the importance of a complex integrated immune response in eliminating established tumors and validate the exploration of combinatorial treatment regimens, which are anticipated to be far more effective than monotherapies. Unlike conventional cancer therapies, most immunotherapies are active and dynamic, capable of inducing immune memory to propagate a successful rebalancing of the equilibrium between tumor and host. PMID:22042955

  12. Neoepitope Vaccines Next Immunotherapy Frontier.

    PubMed

    2016-02-01

    Memorial Sloan Kettering Cancer Center has teamed up with biotechnology company Advaxis to explore development of neoepitope-based immunotherapies. The partnership is just one of several such ventures in a promising area of research that uses advanced sequencing technology to customize vaccines based on altered proteins in individual patients' tumors. PMID:26712929

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

    2014-01-01

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

  14. Engineering opportunities in cancer immunotherapy.

    PubMed

    Jeanbart, Laura; Swartz, Melody A

    2015-11-24

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

  15. Engineering opportunities in cancer immunotherapy

    PubMed Central

    Jeanbart, Laura; Swartz, Melody A.

    2015-01-01

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

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

    PubMed

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

    2016-04-01

    Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33(+) relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33(+) AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m(2) × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m(2)). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m(2) per dose), 5 at dose level 2 (6 mg/m(2) per dose), 3 at dose level 3 (7.5 mg/m(2) per dose), and 3 at dose level 4 (9 mg/m(2) per dose). Three of 14 patients received only 1 dose of GO after alloHSCT. One patient experienced grade III transaminitis, which resolved; no grade IV transaminitis, no grade III/IV hyperbilirubinemia, or sinusoidal obstructive syndrome were observed. The second dose of GO was given at median of 143 days (range, 120 to 209) after alloHSCT. Probability of grades II to IV acute and chronic graft-versus-host disease were 21% and 33.5%, respectively. Probability of overall survival after RIC alloHSCT and GO consolidation at 1 and 5 years was 78% and 61%, respectively. Probability of 5-year event-free survival after RIC alloHSCT and GO consolidation in patients in CR1 was 78%. No dose-limiting toxicities probably or directly related to GO were observed in this cohort. This preliminary data demonstrate that RIC followed by alloHSCT and consolidation with GO appears to be safe in children and adolescents with CD33(+) AML in CR1/CR2. A phase II trial is currently underway investigating this approach with a GO dose of 9 mg/m(2) per dose. PMID:26785332

  17. Cancer immunotherapy via nucleic acid aptamers.

    PubMed

    Khedri, Mostafa; Rafatpanah, Houshang; Abnous, Khalil; Ramezani, Pouria; Ramezani, Mohammad

    2015-12-01

    Over the past decade, immune therapy has become a standard treatment for a variety of cancers. Monoclonal antibodies, immune adjuvants and vaccines against oncogenic viruses are now well-established cancer therapies. Immune modulation is a principal element of supportive care for many high-dose chemotherapy regimens. Aptamers are short nucleic acids that bind to defined targets with high affinity and specificity. The first aptamers have been selected around two decades ago by an in vitro process named SELEX (systematic evolution of ligands by exponential enrichment). Since then, numerous aptamers with specificities for a variety of targets from small molecules to proteins or even whole cells have been selected. Targeting immunomodulatory ligands in the progressive tumor lesions of the patients would be prophylactic or therapeutic and may reduce drug-associated toxicities. A new class of inhibitory and agonistic ligands composed of short oligonucleotide (ODN) aptamers was developed recently that exhibited bioactivities comparable or superior to that of antibodies. This paper addressed progress in cancer immunotherapy with nucleic acid aptamers and highlighted recent developments either in immune system targeting or in immunotherapy methods involved aptamers. We discussed aptamer limitations when used as therapeutic agents for cancer treatment and suggested ways to overcome those limitations. PMID:26603636

  18. Multiple courses of immunotherapy with different immune cell types for patients with hepatocellular carcinoma after microwave ablation

    PubMed Central

    YU, MING-AN; LIANG, PING; YU, XIAO-LING; HAN, ZHI-YU; DONG, XUE-JUAN; WANG, YU; CHENG, CHAO; LI, XIN

    2015-01-01

    The aim of the present study was to investigate the therapeutic efficacy of immunotherapy after microwave ablation (MWA), which was used to improve liver function, reduce the recurrence rate and enhance survival period in patients with hepatocellular carcinoma (HCC). Between February 2009 and December 2010, 14 patients received immunotherapy after MWA (immunotherapy group) and 15 patients received MWA alone with no post-ablated adjuvant therapy (control group). Immune and liver parameters, recurrence rate and survival time were recorded. The absolute lymphocyte count in the immunotherapy group exceeded that in the control group after 3 courses of immunotherapy (P<0.05). No significant differences were detected in the lymphocyte subset distribution in the control and immunotherapy patients prior to ablation (P>0.05); however, certain cytotoxic subsets (CD3+/CD8+, CD8+CD28+ and CD3+CD16+CD56+ T cells) were over-represented and negative regulatory or helper subsets (CD4+CD8+, CD4+, CD4+CD25+) were under-represented in the immunotherapy group between 1 and 12 months after immunotherapy (P<0.05). After 2 courses of immunotherapy the proliferation rate of myeloid dendritic cells and T lymphocytes, including CD3+/CD8+ lymphocytes, significantly increased (P<0.05 and P<0.01, respectively). In addition, the level of albumin in the immunotherapy group exceeded that in the control group after 3 courses of immunotherapy (P<0.05). However, the rate of disease-free survival and overall survival within 16 months of MWA did not differ significantly between the two groups (P>0.05). In conclusion, the results of the present study indicate that immunotherapy improves the immune status and liver function of patients with HCC. PMID:26622507

  19. Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy

    PubMed Central

    De Souza Rebouas, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, Mara 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

  20. Cancer immunotherapy via dendritic cells

    PubMed Central

    Palucka, Karolina; Banchereau, Jacques

    2012-01-01

    Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called natures adjuvants and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer. PMID:22437871

  1. Oral Immunotherapy for Peanut Allergy.

    PubMed

    Anagnostou, Katherine; Clark, Andrew

    2016-01-14

    Peanut allergy is a common disease and the cause of severe, life-threatening allergic reactions and death. It is rarely outgrown; most pediatric patients carry the disease into adulthood. Peanut allergy poses a significant burden on the quality of life of sufferers and their families, which results mainly from the fear of accidental peanut ingestion but is also due to dietary and social restrictions. Current standard management involves avoidance advice, patient education, and provision of emergency rescue medication. Immunotherapy, commonly used to treat other allergic diseases, has shown promise as a disease-modifying therapy for peanut allergy. Results from studies of oral immunotherapy show high efficacy rates, improvement in quality of life, and a good safety profile. Treatment may result in sustained unresponsiveness in a proportion of patients, whereas others require ongoing treatment. PMID:26332004

  2. Oncolytic virus immunotherapy for melanoma.

    PubMed

    Dharmadhikari, Neal; Mehnert, Janice M; Kaufman, Howard L

    2015-03-01

    Melanoma is a type of skin cancer arising from melanocytes and is increasing in incidence. Although complete surgical excision of early stage lesions may be curative, metastatic melanoma continues to be a major therapeutic challenge. Advances in understanding the molecular pathways that promote tumorigenesis and the interactions between melanoma cells and the immune system have resulted in the approval of several newly targeted agents and immunotherapy strategies for the treatment of advanced disease. Oncolytic virus immunotherapy is a new approach that uses native or attenuated live viruses to selectively kill melanoma cells and induce systemic tumor-specific immune responses. A variety of viruses are now in clinical development with the attenuated oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor, known as talimogene laherparepvec, recently demonstrating an improvement in durable response rate in patients with advanced melanoma compared with granulocyte-macrophage colony stimulating factor alone. A major advantage of talimogene laherparepvec and related agents is the limited toxicity and ability to use each individual tumor as a source of antigen to generate a highly specific antitumor immune response. These agents are easily administered in the out-patient setting and may be a reasonable option for patients with limited metastatic tumor burden, those with a good performance status and without extensive prior treatment, and in those who cannot tolerate more difficult therapeutic regimens. Further investigation into the impact on overall survival as monotherapy and combination of oncolytic virus immunotherapy with other forms of immunotherapy merit high priority for further clinical application of these novel agents for the treatment of melanoma and perhaps other cancers as well. PMID:25777572

  3. 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

  4. Novel immunotherapies in lymphoid malignancies.

    PubMed

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

    2016-01-01

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

  5. [Current Approaches in Cancer Immunotherapy].

    PubMed

    Othal, P; Trn?n, M

    2015-01-01

    Methods of cancer immunotherapy have finally entered clinical medicine after years of preclinical research. Currently, there are several methods, which have proven to be very effective even in cases of incurable cancer. Antitumor monoclonal antibodies are among major therapeutic anti-cancer drugs and have been successfully used for many ears. Novel group of antibodies are immunomodulatory antibodies which can break tumor?-specific immune tolerance and induce regression of tumors by nonspecific activation of immune system. Bispecific antibodies represent a novel class of anticancer agents which can induce expansion of T cells in vivo, blinatumomab is an example of such agents and is currently available for the treatment of acute B?-cell leukemia. Cellular immunotherapy is also very effective, especially the use of Chimeric receptor modified T-cells for the therapy of B-?cell lymphoproliferative diseases. Although it is a very complicated and expensive method, it is highly effective approach which can induce remission even in previously hopeless conditions. The goal of this article is to explain the basic principles of cancer immunotherapy and summarize the newest findings in this field. PMID:26489509

  6. Immunotherapy Not Working? Check Your Microbiota.

    PubMed

    West, Nathan R; Powrie, Fiona

    2015-12-14

    Gut microbes have ascended to prominence as key modulators of host immunity, raising the possibility that they could influence the outcome of cancer immunotherapy. Two recent studies address this question byidentifying specific gut-resident bacteria as drivers of checkpoint blockade immunotherapy in pre-clinical tumor models. PMID:26678336

  7. Oral Immunotherapy for Food Allergy.

    PubMed

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

    2016-02-01

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

  8. Cancer immune contexture and immunotherapy.

    PubMed

    Becht, Etienne; Giraldo, Nicolas A; Dieu-Nosjean, Marie-Caroline; Sautès-Fridman, Catherine; Fridman, Wolf Herman

    2016-04-01

    The immune contexture that characterizes the density, the location, the organization and the functional orientation of tumor-infiltrating immune cells in cancers has a clinical impact on patient's outcome. It is, in great part, shaped by the malignant cells, as in a given cancer type, tumors presenting different oncogenic processes have different immune contextures. Moreover, the immune contexture in metastatic sites reflects that of the corresponding primary tumors. Finally, the components forming the immune contexture represent targets and markers of efficient anti-cancer immunotherapies. PMID:26708937

  9. New insights in sublingual immunotherapy.

    PubMed

    Passalacqua, Giovanni; Guerra, Laura; Compalati, Enrico; Fumagalli, Federica; Cirillo, Arianna; Canonica, Giorgio Walter

    2006-09-01

    Sublingual immunotherapy (SLIT) is accepted in the official documents and is currently used in many European countries. In recent years, new clinical data on efficacy and safety have been published, including meta-analyses in adults and children and surveys of safety in children younger than age 5 years. Moreover, it has been shown that, similar to the injection route, SLIT can prevent the onset of new sensitizations and the onset of asthma. Additionally, the mechanisms of action are beginning to be systematically studied. Some points need further investigation, such as the effect in asthma, the mechanisms of action, and the optimal dose to be administered. PMID:16899203

  10. Immunotherapy: It Takes a Village

    PubMed Central

    Pardoll, Drew

    2016-01-01

    We in the cancer immunology and immunotherapy community are thrilled that Science named “Cancer immunotherapy” as 2013’s Breakthrough of the Year (J. Couzin-Frankel, 20 December 2013, p. 1432). The rapid succession of clinical successes by blocking antibodies to two immune checkpoints, CTLA-4 and PD-1, and by chimeric antigen-receptor-transduced T cells, shows the power of basic immunology when translated to therapy. As such, I write to acknowledge some of the key scientists whose basic discoveries paved the way for the clinical successes outlined in the Breakthrough issue. PMID:24723594

  11. Immunotherapy in Neonatal Sepsis: Advances in Treatment and Prophylaxis

    PubMed Central

    Cohen-Wolkowiez, Michael; Benjamin, Daniel K.; Capparelli, Edmund

    2012-01-01

    Purpose of review Systemic infections in premature and term infants cause significant morbidity and mortality in spite of appropriate antimicrobial therapy. Consequently, immunotherapy has emerged as a potential adjuvant therapeutic modality to reduce the incidence and mortality associated with neonatal sepsis. Recent findings The most recent findings during the review period include systematic reviews of previously published trials evaluating the use of intravenous immunoglobulin and colony stimulating factors in neonatal sepsis. In addition, the most recent trials describing the use of anti-staphylococcal antibodies, probiotics, glutamine supplementation, recombinant human protein C, and lactoferrin in the prevention and treatment of neonatal sepsis have been reviewed. Summary Immunotherapy used as an adjuvant for the prevention and treatment of neonatal sepsis holds promise. Clinical trials specifically designed towards the neonatal population and appropriately powered to detect treatment differences are necessary prior to universal recommendation of these therapies in the nursery. PMID:19276977

  12. Developments in HIV-1 immunotherapy and therapeutic vaccination

    PubMed Central

    Tanner, Helen; Dalgleish, Angus

    2014-01-01

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

  13. Novel Delivery Routes for Allergy Immunotherapy: Intralymphatic, Epicutaneous, and Intradermal.

    PubMed

    Senti, Gabriela; Kndig, Thomas M

    2016-02-01

    Current allergy immunotherapy protocols suffer from two main problems: long treatment duration and systemic allergic side effects of the allergen administrations. The immunologic effects of allergen administration could be enhanced and the number of allergen administrations and treatment duration reduced by choosing a tissue for administration that contains a high density of antigen-presenting cells. Local side effects could be reduced by choosing a route characterized by a low density of mast cells, and systemic side effects could be reduced by administration to nonvascularized tissues, so that inadvertent systemic distribution of the allergen and consequent systemic allergic side effects are minimized. PMID:26617225

  14. Novel immunotherapies for hematological malignancies

    PubMed Central

    Nelson, Michelle H.; Paulos, Chrystal M.

    2014-01-01

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

  15. Potentiality of immunotherapy against hepatocellular carcinoma

    PubMed Central

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

    2015-01-01

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

  16. Immunotherapy of tuberculosis with Mycobacterium vaccae NCTC 11659.

    PubMed

    Stanford, J L; Stanford, C A

    1994-10-01

    The history of immunotherapy for tuberculosis is briefly reviewed, and the early appreciation of the importance of secreted antigens, common mycobacterial antigens and stress proteins is noted. The methods by which Mycobacterium vaccae strain NCTC 11659 was selected for special attention, and results of some of the pilot studies of its use as an immunotherapeutic for tuberculosis are reviewed. The results suggested that immunotherapy with M. vaccae may be an important step forward in the treatment and eventual control of tuberculosis. Used in combination with modern short course chemotherapy, treatment failures and deaths during treatment can be significantly reduced. Preliminary data suggests that shortened courses of chemotherapy may be possible when combined with immunotherapy, and such treatment may also be effective in patients co-infected with HIV. Studies at several centers show that M. vaccae may have an important part to play in the treatment of multi-drug resistant tuberculosis, especially when resistance is of the primary type. The mechanism by which M. vaccae achieves these results may be through adrenal endocrine influences on immunity, but remains speculative. PMID:7713570

  17. New developments of clinical trial in immunotherapy for Alzheimer's disease.

    PubMed

    Yang, Cece; Xiao, Shifu

    2015-01-01

    Active or passive immunotherapy is expected to slow or stop the pathological process of Alzheimer's disease (AD). Immunotherapy for AD has demonstrated that targeting beta-amyloid (A?) or tau protein with vaccines or antibodies can reduce AD pathologies. Active anti-A? immunization for AD includes using AN1792 and second generation vaccines such as ACC-001, CAD106 and AFFITOPE vaccines, while antibodies for passive immunization include monoclonal antibodies and intravenous immunoglobulin (IVIG). Preclinical trials have shown powerful evidence of significant advances for more than a decade; however, there are still issues that need to be addressed in clinical trials. In the phase IIa AN1792 trial, 6% of patients who received the vaccination were diagnosed with meningoencephalitis as an adverse effect. There was a high incidence of amyloid-related imaging abnormalities (ARIA) in patients treated with some monoclonal antibodies. Moreover, several phase 3 clinical trial findings of immunization targeting A? were negative. These issues require attention in order to improve the safety and efficacy of immunization strategies in AD. Prevention studies and other novel immunization strategies have the potential to dramatically impact AD care. Herein we review the recent advances in clinical trials involving immunotherapy for AD. PMID:25860060

  18. Immunotherapy

    MedlinePLUS

    ... reprogrammed to target tumor cells through a gene modification technique. The cells are then returned to the ... to them: Naked antibodies don't have another chemical or radioactive material attached. Rituximab (Rituxan®) and alemtuzumab ( ...

  19. DNA-inorganic hybrid nanovaccine for cancer immunotherapy.

    PubMed

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

    2016-03-17

    Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy. PMID:26947116

  20. [Current immunotherapy of multiple sclerosis].

    PubMed

    Paul, F; Ruprecht, K

    2015-08-01

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

  1. 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

  2. Advances in immunotherapy for melanoma.

    PubMed

    Redman, Jason M; Gibney, Geoffrey T; Atkins, Michael B

    2016-01-01

    In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients. PMID:26850630

  3. Topical immunotherapy in alopecia areata.

    PubMed

    Singh, Gurcharan; Lavanya, Ms

    2010-01-01

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

  4. Who Will Benefit from Cancer Immunotherapy?

    Cancer.gov

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

  5. Immunotherapy: Disrupting the Cancer Treatment World

    MedlinePLUS

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

  6. Immune checkpoints and immunotherapy for colorectal cancer

    PubMed Central

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

    2015-01-01

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

  7. Grass pollen immunotherapy: where are we now.

    PubMed

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

    2016-04-01

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

  8. 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.

  9. 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.

  10. 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

  11. Advances in immunotherapy for pancreatic cancer: 2013.

    PubMed

    DeVito, Nicholas C; Saif, Muhammad Wasif

    2013-07-01

    Pancreatic cancer is one of the more difficult malignancies to treat, and there is a great need for less toxic, effective regimens. Immunotherapy has shown potential in the treatment of pancreatic cancer, and at ASCO 2013 there were several progressive advances in its clinical application. Abstracts #3067, #3049, #3007, #4040, #LBA4004, and #3090 will be discussed. New developments in the field of immunotherapy are promising novel treatments for pancreatic neoplasms with tolerable side effect profiles. PMID:23846925

  12. 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

  13. Mannan-mediated gene delivery for cancer immunotherapy

    PubMed Central

    Tang, Choon K; Lodding, Jodie; Minigo, Gabriela; Pouniotis, Dodie S; Plebanski, Magdalena; Scholzen, Anja; McKenzie, Ian F C; Pietersz, Geoffrey A; Apostolopoulos, Vasso

    2007-01-01

    Recent years have seen a resurgence in interest in the development of efficient non-viral delivery systems for DNA vaccines and gene therapy. We have previously used oxidized and reduced mannan as carriers for protein delivery to antigen-presenting cells by targeting the receptors that bind mannose, resulting in efficient induction of cellular responses. In the present study, oxidized mannan and reduced mannan were used as receptor-mediated gene transfer ligands for cancer immunotherapy. In vivo studies in C57BL/6 mice showed that injection of DNA encoding ovalbumin (OVA) complexed to oxidized or reduced mannan-poly-L-lysine induced CD8 and CD4 T-cell responses as well as antibody responses leading to protection of mice from OVA+ tumours. Both oxidized and reduced mannan delivery was superior to DNA alone or DNA-poly-L-lysine. These studies demonstrate the potential of oxidized and reduced mannan for efficient receptor-mediated gene delivery in vivo, particularly as DNA vaccines for cancer immunotherapy. PMID:17328786

  14. Immunotherapy in acute myeloid leukemia.

    PubMed

    Arpinati, Mario; Curti, Antonio

    2014-01-01

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

  15. Checkpoint blockade in cancer immunotherapy.

    PubMed

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

    2006-01-01

    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

  16. LAG-3 in Cancer Immunotherapy

    PubMed Central

    Goldberg, Monica V.

    2015-01-01

    LAG-3 (CD223) is a cell surface molecule expressed on activated T cells (Huard et al. Immunogenetics 39:213217, 1994), NK cells (Triebel et al. J Exp Med 171:13931405, 1990), B cells (Kisielow et al. Eur J Immunol 35:20812088, 2005), and plasmacytoid dendritic cells (Workman et al. J Immunol 182:18851891, 2009) that plays an important but incompletely understood role in the function of these lymphocyte subsets. In addition, the interaction between LAG-3 and its major ligand, Class II MHC, is thought to play a role in modulating dendritic cell function (Andreae et al. J Immunol 168:38743880, 2002). Recent preclinical studies have documented a role for LAG-3 in CD8 T cell exhaustion (Blackburn et al. Nat Immunol 10:2937, 2009), and blockade of the LAG-3/Class II interaction using a LAG-3 Ig fusion protein is being evaluated in a number of clinical trials in cancer patients. In this review, we will first discuss the basic structural and functional biology of LAG-3, followed by a review of preclinical and clinical data pertinent to a role for LAG-3 in cancer immunotherapy. PMID:21086108

  17. Immunotherapy in Sarcoma: Future Horizons.

    PubMed

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

    2015-11-01

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

  18. 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

  19. International consensus on allergy immunotherapy.

    PubMed

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

    2015-09-01

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

  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. Combining immunotherapy and radiation for prostate cancer.

    TOXLINE Toxicology Bibliographic Information

    Finkelstein SE; Salenius S; Mantz CA; Shore ND; Fernandez EB; Shulman J; Myslicki FA; Agassi AM; Rotterman Y; DeVries T; Sims R

    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.

  2. Improving clinical benefit for prostate cancer patients through the combination of androgen deprivation and immunotherapy

    PubMed Central

    Kwilas, Anna R; Gameiro, Sofia R; Kim, Peter S; Malamas, Anthony S; Hodge, James W

    2015-01-01

    Androgen-deprivation therapy (ADT) induces prostate cancer immunogenic modulation (IM) by reducing human tumor cell expression of anti-apoptotic genes thus facilitating increased sensitivity to immune-mediated lysis. Through its stimulation of IM, ADT has been shown to synergize with active immunotherapy thereby significantly improving overall survival in a mouse model of prostate cancer. PMID:26155431

  3. Combinatorial immunotherapy strategies for hepatocellular carcinoma.

    PubMed

    Tagliamonte, Maria; Petrizzo, Annacarmen; Tornesello, Maria Lina; Ciliberto, Gennaro; Buonaguro, Franco M; Buonaguro, Luigi

    2016-04-01

    Hepatocellular carcinoma (HCC) is the most common liver malignancy. The prognosis for HCC patients greatly varies according to the stage at diagnosis. Overall it is poor, with a 5-year survival rate of approximately 5-6%. Immunotherapeutic interventions represent a novel and effective therapeutic tool. However, only few immunotherapy trials for HCC have been conducted so far with contrasting results, suggesting that significant improvements are needed. Indeed, the liver is characterized by a strong intrinsic immune suppressive microenvironment which needs to be counterbalanced with immune stimulatory approaches. Therefore, the implementation of combinatorial protocols combining immune stimulatory strategies with specific immunotherapy approaches could result in a dramatic improvement of efficacy and clinical outcome in HCC patients. The present review aims at describing the state of the art in immunotherapy strategies for HCC and future perspectives. PMID:26851637

  4. Immunotherapy in prostate cancer: challenges and opportunities.

    PubMed

    Noguchi, Masanori; Koga, Noriko; Moriya, Fukuko; Itoh, Kyogo

    2016-01-01

    Although treatment options for castration-resistant prostate cancer (CRPC) have increased over the last decade, there remains a need for strategies that can provide durable disease control and long-term benefit. Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of CRPC. To date, there are multiple strategies to target the immune system, and several approaches including therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in clinical trials. With regard to this, we report the results of the most recent clinical trials investigating immunotherapy in CRPC and discuss the future development of immunotherapy for CRPC, as well as the potential importance of biomarkers in the future progress of this field. PMID:26642100

  5. Practice parameters for sublingual immunotherapy.

    PubMed

    Ortolani, C; Agostinis, F; Amoroso, S; Ariano, R; Barbato, A; Bassi, M; Cadario, G; Campi, P; Cardinale, F; Ciprandi, G; D'Anneo, R; Di Gioacchino, M; Di Rienzo, V; Fiocchi, A; Galimberti, M; Galli, E; Giovannini, M; Incorvaia, C; La Grutta, S; Lombardi, C; Marcucci, F; Marseglia, G; Minelli, M; Musarra, A; Nettis, E; Novembre, E; Pajno, G; Patriarca, G; Pezzuto, F; Piras, P; Pucci, S; Romano, A; Romano, C; Quercia, O; Scala, G; Schiavino, D; Senna, G; Sforza, G; Tosca, M; Tripodi, S; Frati, F

    2006-03-01

    The efficacy and safety of sublingual immunotherapy (SLIT) are currently supported by clinical trials, meta-analysis and post-marketing surveys. Practice parameters for clinical use of SLIT are proposed here by a panel of Italian specialists, with reference to evidence based criteria. Indications to SLIT include allergic rhinoconjunctivitis, asthma, and isolated conjunctivitis (strength of recommendation: grade A). As to severity of the disease, SLIT is indicated in moderate/severe intermittent rhinitis, persistent rhinitis and mild to moderate asthma (grade D). SLIT may be safely prescribed also in children aged three to five years (grade B), and its use in subjects aged more than 60 years is not prevented when the indications and contraindication are ascertained (grade D). The choice of the allergen to be employed for SLIT should be made in accordance with the combination of clinical history and results of skin prick tests (grade D). Polysensitisation, i.e. the occurrence of multiple positive response does not exclude SLIT, which may be done with the clinically most important allergens (grade D). As to practical administration, co-seasonal, pre co-seasonal, and continuous schedules are available, being the latter recommended for perennial allergens or for pollens with particularly prolonged pollination, such as Parietaria (grade D). For pollens with relatively short pollination, such as grasses and trees (cypress, birch, alder, hazelnut, olive) the pre co-seasonal and perennial schedules are preferred (grade C). The build-up phases suggested by manufacturers can be safely used (grade A), but they can be modified according to the patient's tolerance (grade C). A duration of SLIT of 3-5 years is recommended to ensure a long-lasting clinical effect after the treatment has been terminated (grade C). PMID:16700194

  6. Cellular mucins: targets for immunotherapy.

    PubMed

    Apostolopoulos, V; McKenzie, I F

    1994-01-01

    Mucins are attracting great interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucin 1 (MUC1) (e.g., breast, pancreas, ovary, and others) as there is (1) a 10-fold increase in the amount in adenocarcinomas; (2) an alteration in expression where they become ubiquitous, and (3) due to altered glycosylation, new epitopes appear on the cell surface that are absent in normal tissues. These new epitopes can be carbohydrate; others are peptide in nature. The cloning of the cDNAs from mucins, particularly MUC1, has led to rapid advances being made, and it is clear that a highly immunogenic peptide exists within the variable number of tandem repeats (VNTR) found in all mucins. This peptide is immunogenic in mice, giving rise to strong antibody production, and most monoclonal antibodies made to breast cancer, which react with the protein core, react with the peptide APDTR. It is now also clear that humans with breast cancer have, in their draining lymph nodes, precursors of cytotoxic T cells that can be stimulated in vitro to react against breast cancer and indeed against the APDTR or a closely related peptide--shown from antibody-blocking studies. These CTLs are unique in that they are non-MHC restricted. The identification of suitable targets, coupled with the known immunogenicity of both the peptide and neo-carbohydrate epitopes, has led to the development of several different programs to immunize humans against breast cancer using either synthetic carbohydrates or peptides conjugated with adjuvants, and clinical trials are now in progress to evaluate their immunogenicity and anti-cancer effects. PMID:7538768

  7. Strategies of mucosal immunotherapy for allergic diseases

    PubMed Central

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

    2011-01-01

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

  8. Strategies of mucosal immunotherapy for allergic diseases.

    PubMed

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

    2011-11-01

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

  9. Human Tumor Antigens and Cancer Immunotherapy

    PubMed Central

    Vigneron, Nathalie

    2015-01-01

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

  10. Adoptive Immunotherapy for Cancer or Viruses

    PubMed Central

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

    2015-01-01

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

  11. Novel avenues in immunotherapies for colorectal cancer.

    PubMed

    Pardieck, Iris N; Jawahier, Priscilla A; Swets, Marloes; van de Velde, Cornelis J H; Kuppen, Peter J K

    2016-04-01

    Since it is known that the immune system affects tumor growth, it has been studied if immunotherapy can be developed to combat cancer. While some successes have been claimed, the increasing knowledge on tumor-immune interactions has, however, also shown the limitations of this approach. Tumors may show selective outgrowth of cells escaped from immune control. Escape variants arise spontaneously due to the genetically instable nature of tumor cells. This is one of the most obvious limitations of cancer immunotherapy. However, new therapies are becoming available, designed to respond to tumor-immune escape. PMID:26582071

  12. Allergen Immunotherapy: History and Future Developments.

    PubMed

    Passalacqua, Giovanni; Canonica, Giorgio Walter

    2016-02-01

    Allergen immunotherapy (AIT) was introduced in clinical practice more than 100 years ago. The clinical effectiveness in allergic rhinitis (and asthma) and in hymenoptera allergy was apparent early on but it was not until the mid-1900s that randomized placebo-controlled trials proved its efficacy. In the 1980s, sublingual immunotherapy (SLIT) was accepted in official guidelines. The availability of safer routes, such as SLIT, prompted increasing investigation of AIT for food allergy. The introduction of molecular-based diagnosis introduced the possibility of better targeted prescription of AIT. Other approaches are being explored, such as immunogenic peptides, recombinant allergens, and adjuvants. PMID:26617223

  13. Bacillus Calmette-Gurin immunotherapy for genitourinary cancer.

    PubMed

    Gandhi, Nilay M; Morales, Alvaro; Lamm, Donald L

    2013-08-01

    WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The administration of Bacillus Calmette-Gurin (BCG) immunotherapy has become the standard of care for high-grade non-muscle invasive bladder cancer (NMIBC) and carcinoma in-situ (CIS) in terms of prevention of recurrence and progression. While most agree on a 6 week induction cycle, various maintenance schedules (if any at all) have been implemented without a unifying consensus. This review assesses the historical emergence of BCG immunotherapy, beginning with its discovery as a vaccinatin for tuberculosis to its effect on the host immune system and potential therapeutic benefits for various oncologic conditions. The data establishing BCG immunotherapy as the standard of care for high-grade NMIBC and CIS over other bladder instillation modalities is presented in addition to the effect maintenance BCG therapy has on sustaining the immuno-protective effect. Bacillus Calmette-Gurin (BCG) immunotherapy is currently the most effective treatment of non-muscle invasive bladder cancer and one of the most successful applications of immunotherapy to the treatment of cancer. This review summarises the history and development of BCG as a modern cancer treatment, appraises current optimal application of BCG immunotherapy in bladder cancer, discusses promising new therapies closely related to BCG, and briefly explores the possibility that BCG or related treatments may have an application in other urological malignancies. BCG is a nonspecific stimulant to the reticuloendothelial system and induces a local inflammatory response with the infiltration of granulocytes followed by macrophages and lymphocytes, particularly helper T cells. The initial BCG controlled trial showed a statistically significant reduction in tumour recurrence and found the advantage increased with duration of follow-up. Similar results were reported in much higher risk patients in an independent concurrent study. Follow-up suggested that a single 6-week course of intravesical BCG provided long-term protection (up to 10 years) from tumour recurrence and even reduced disease progression. While induction BCG (six weekly instillations) reduced recurrence, progression and mortality at 10 years, this advantage was lost by 15 years, and patients remained at high risk for progression without the use of maintenance BCG. In a meta-analysis by the Cochrane group, induction BCG was found to be markedly superior to mitomycin C in high-risk patients but not in low-risk patients. Additionally, the National Comprehensive Cancer Network guidelines lists the use of intravesical BCG as preferred therapy, citing Category 1 data for high-grade Ta, all T1, and any Tis tumours. Maintenance BCG therapy may be the most important advance in BCG treatment of bladder cancer since the initial introduction. The risk of tumour recurrence and disease progression is life-long in most patients, but the immune stimulation induced by BCG wanes with time. Logarithmic dose reduction of BCG in patients with increasing side-effects will typically prevent escalation of toxicity. Simple dose reduction, appropriate antibiotics, and understanding treatment contraindications have greatly increased the safety of BCG. The 3-week maintenance schedule for 3 years has been evaluated in randomised clinical trials and appears to be the current optimal treatment. With the success achieved in bladder cancer and the relative safety and economy of BCG, consideration should be given to further research for its effectiveness in other genitourinary malignancies. PMID:23517232

  14. Stinging insect allergy: current perspectives on venom immunotherapy

    PubMed Central

    Ludman, Sian W; Boyle, Robert J

    2015-01-01

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

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

    PubMed

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

    2016-03-01

    Psychological problems may arise in connection with oncomedical treatments in three ways: 1. acute and/or 2. chronic ways, as well as 3. co-morbid psychiatric diseases that already exist must also be taken into account. Immunotherapies have the most common and also clinically relevant psychological side effects. Fatigue, anhedonia, social isolation, psychomotor slowness is reported during treatment. Anti-CTLA-4 antibody (ipilimumab) immunotherapy can present one of the most modern opportunities for adequate treatment for patients having distant metastasis or unresectable tumour. In relation to immunotherapies, acute psychological side effects (acute stress) emerging during treatments develop in a way that can mostly be linked to environmental factors, e.g. notification of diagnosis, hospitalisation, progression, deterioration in quality of life, imminent dates of control. Crisis is a temporary and threatening condition that endangers psychological balance. In such conditions, enhanced psychological vulnerability must be taken into account and doctors play a key role in the rapid recognition of the condition. Chronic psychological problems, which may arise from the depressogenic effect of the applied treatment or originated from a pre-melanoma psychiatric condition, may exceed the diagnostic and psychotherapeutic competences of a clinical psychologist. Even in case of a well-defined depressogenic biological mechanism such as the activation of the pro-inflammatory cytokine pathway, positive environmental effects can reduce symptoms and thus increase compliance. Side effects can be treated successfully using psychotherapeutic methods and/or psychiatric medicines. The application of routinely used complex psychosocial screening packages can provide the easiest method to identify worsening psychological condition during immunotherapy and give rapid feedback to the oncologist and the patient. Team work is of particular importance in a situation like this as it requires complex, interdisciplinary and high-level professional collaboration. Multidisciplinarity is the basic framework for modern tumour therapy where, under the guidance of oncologists, the work of specialist nurses, social workers, physiotherapists, dieticians and last but not least psychiatrists/psychologists are indispensable and play a significant role. PMID:26934347

  16. Biomarkers for glioma immunotherapy: the next generation.

    PubMed

    Sims, Jennifer S; Ung, Timothy H; Neira, Justin A; Canoll, Peter; Bruce, Jeffrey N

    2015-07-01

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

  17. Sublingual Immunotherapy for Allergic Fungal Sinusitis.

    PubMed

    Melzer, Jonathan M; Driskill, Brent R; Clenney, Timothy L; Gessler, Eric M

    2015-10-01

    Allergic fungal sinusitis (AFS) is a condition that has an allergic basis caused by exposure to fungi in the sinonasal tract leading to chronic inflammation. Despite standard treatment modalities, which typically include surgery and medical management of allergies, patients still have a high rate of recurrence. Subcutaneous immunotherapy (SCIT) has been used as adjuvant treatment for AFS. Evidence exists to support the use of sublingual immunotherapy (SLIT) as a safe and efficacious method of treating allergies, but no studies have assessed the utility of SLIT in the management of allergic fungal sinusitis. A record review of cases of AFS that are currently or previously treated with sublingual immunotherapy from 2007 to 2011 was performed. Parameters of interest included serum IgE levels, changes in symptoms, Lund-McKay scores, decreased sensitization to fungal allergens associated with AFS, and serum IgE levels. Ten patients with diagnosed AFS were treated with SLIT. No adverse effects related to the use of SLIT therapy were identified. Decreases in subjective complaints, exam findings, Lund-McKay scores, and serum IgE levels were observed. Thus, sublingual immunotherapy appears to be a safe adjunct to the management of AFS that may improve patient outcomes. PMID:25902841

  18. Developing Strategies in the Immunotherapy of Leukemias

    PubMed Central

    Brayer, Jason B.; Pinilla-Ibarz, Javier

    2015-01-01

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

  19. First Immunotherapy Combo Approved for Cancer.

    PubMed

    2015-12-01

    The FDA has granted accelerated approval to the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab to treat advanced melanoma, the first time the agency has approved any combination of immunotherapies to treat cancer. PMID:26482931

  20. Allergen Immunotherapy in Allergic Respiratory Diseases

    PubMed Central

    Viswanathan, Ravi K.

    2012-01-01

    Allergen-specific immunotherapy (SIT) involves the repeated administration of allergenic extracts to atopic individuals over a period of 3 to 5 years either subcutaneously (SCIT) or sublingually (SLIT) for the treatment of allergic respiratory diseases, including asthma and allergic rhinitis (AR). In studies, SCIT and SLIT have been shown to improve existing symptoms of asthma and AR and to also have the capability to cause disease-modifying changes of the underlying atopic condition so as to prevent new allergic sensitization as well as arrest progression of AR to asthma. Recent evidence suggests that immunotherapy brings about these effects through actions that use T-regulatory cells and blocking antibodies such as IgG4 and IgA2, which can then result in an immune deviation from a T-helper (Th) 2 cell pattern to a Th1 cell pattern. Numerous meta-analyses and studies have been performed to evaluate the existing data among these studies, with the consensus recommendation favoring the use of immunotherapy because of its potential to modify existing diseases. Significant adverse reactions can occur with immunotherapy, including anaphylaxis and, very rarely, death. A primary factor in considering SIT is its potential to provide long-lasting effects that are able to be sustained well after its discontinuation. Given the significant burden these allergic diseases impose on the health-care system, SIT appears to be a cost-effective adjunctive treatment in modifying the existing disease state. PMID:22553263

  1. Efficacy and safety of sublingual immunotherapy in children.

    PubMed

    Arasi, Stefania; Passalacqua, Giovanni; Caminiti, Lucia; Crisafulli, Giuseppe; Fiamingo, Chiara; Pajno, Giovanni Battista

    2016-01-01

    Allergen immunotherapy (AIT) is currently the only available disease-modifying and aetiological treatment of IgE-mediated diseases. Sublingual allergen immunotherapy (SLIT) constitutes the preferred route of administration of AIT for respiratory allergies in Europe. Recently it has also been approved in the US. Further applications are currently under evaluation, such as IgE-mediated food allergy and IgE-mediated atopic dermatitis. The SLIT safety profile is overall favourable, although local adverse events, usually mild, are described. Most of the meta-analyses confirmed the efficacy of SLIT in reducing symptoms and medication intake in children with allergic diseases. AIT, as an immune-modulating treatment, can modify the natural history of the allergic diseases: reduction of the risk of development of asthma and bronchial hyperreactivity in patients with allergic rhinitis, and reduction of the onset of new sensitizations. A great interest is now devoted to the preventive effects of AIT and, consequently, to the optimal time of initiation. PMID:26496537

  2. Use of natural killer cells as immunotherapy for leukaemia.

    PubMed

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

    2008-09-01

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

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

    PubMed

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

    2012-01-01

    Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and "perceived" business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace. PMID:22640522

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

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

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

  5. [Allergic march in children, from rhinitis to asthma: management, indication of immunotherapy].

    PubMed

    Scheinmann, P; Pham Thi, N; Karila, C; de Blic, J

    2012-03-01

    Allergic rhinitis (AR) is a common IgE dependent disorder. AR is maybe one of the steps of the allergic march, which starts with atopic dermatitis and food allergy and includes atopic asthma. AR and asthma are frequently associated. AR is frequently under-diagnosed and undertreated although it affects quality of life and school performance. Management of AR depends on its severity and will associate environmental control (best guided by environmental investigation and skin testing of specific IgE antibodies), pharmacotherapy (with antihistamines and intranasal corticosteroids as first line drugs). At present allergen immunotherapy is considered in patients with severe AR, insufficiently controlled by pharmacotherapy and who demonstrate specific IgE antibodies to relevant allergens. Sublingual immunotherapy is well tolerated. Only immunotherapy with the right allergens has the potential to alter the natural history of the allergic march, by preventing the development of new allergen sensitizations and reducing the risk for the subsequent development of asthma. This fact might extend the indications of specific allergen immunotherapy. Patients (and parents) education is of utmost importance in the management of allergic disorders. PMID:22306361

  6. A practical view of immunotherapy for food allergy

    PubMed Central

    2016-01-01

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

  7. Cancer Neoantigens and Applications for Immunotherapy.

    PubMed

    Desrichard, Alexis; Snyder, Alexandra; Chan, Timothy A

    2016-02-15

    Recent advances in immune checkpoint blockade therapy have revolutionized the treatment of cancer. Tumor-specific antigens that are generated by somatic mutation, neoantigens, can influence patient response to immunotherapy and contribute to tumor shrinkage. Recent evidence demonstrating the success of checkpoint blockade immunotherapy in boosting T-cell reactivity against patient-specific neoantigens constitutes a strong rationale for the development of personalized vaccines against these nonself peptides. With the decreasing cost of next-generation sequencing, peptide manufacturing, and improvement of in silico prediction of peptide immunogenicity, it is increasingly important to evaluate the potential use of neoantigens in both diagnosis and treatment. Specifically, these neoantigens could be useful both as predictors of immune checkpoint blockade therapy response and/or incorporated in therapeutic vaccination strategies. Clin Cancer Res; 22(4); 807-12. ©2015 AACR. PMID:26515495

  8. 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

  9. Should we encourage allergen immunotherapy during pregnancy?

    PubMed

    Lieberman, Jay

    2014-03-01

    Primary prevention of allergy is a laudable goal, but one that has unfortunately proven difficult to achieve. Many different strategies have been reported to date, but unequivocal supporting data for any single strategy does not exist. Any successful strategy must lead to immunomodulation and must be encountered very early on life, likely in utero. Reports of early bacterial and farm animal exposures lend supportive data to the concept of immune regulation via early fetal exposure, howeve attempts at clinical applications of this, such as probiotics has not been completely successful. One practical, clinical method for achieving a similar immune modulation to these exposures would be providing atopic women with allergy immunotherapy while pregnant (or perhaps even preconception). Allergy immunotherapy is associated with favorable immune modulation and some data suggest that these changes if produced in mother can influence the atopic status of offspring. PMID:24483169

  10. Advances in the Development of Cancer Immunotherapies

    PubMed Central

    Gao, Jianjun; Bernatchez, Chantale; Sharma, Padmanee; Radvanyi, Laszlo G.; Hwu, Patrick

    2012-01-01

    Manipulating the immune system in order to induce clinically relevant responses against cancer is a longstanding goal. Interventions to enhance tumor specific immunity through vaccination, sustaining effector T cell activation, or increasing the numbers of tumor specific T cells using ex vivo expansion, have all resulted in clinical successes. Here we examine recent clinical advances and major ongoing studies in the field of cancer immunotherapy. Single agents have so far benefited a limited proportion of patients and future studies combining different types of immunotherapies and other therapeutic modalities, such as drugs against specific signaling pathways driving cancer cell growth, are needed to hopefully pave the way for the development of effective anti-cancer treatments causing durable responses. PMID:23031830

  11. [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

  12. Mechanism of Anti-α-Synuclein Immunotherapy

    PubMed Central

    Lee, Jun Sung; Lee, Seung-Jae

    2016-01-01

    Immunization therapy targeting α-synuclein has emerged as a promising approach for Parkinson’s disease and perhaps for other synucleinopathies. Several antibodies have shown therapeutic effects in mouse models of synucleinopathies and have alleviated the pathological and behavioral phenotypes of these mice. The mechanisms through which the immunization therapy works were initially puzzling, especially given that α-synuclein is a typical cytosolic protein. Recent studies, however, suggested that extracellular α-synuclein is an important pathogenic entity, and hence, a target for immunotherapy. Here, we review the literature describing immunization therapy for synucleinopathies in mouse models and provide current thoughts on the potential mechanisms underlying the therapeutic effects of α-synuclein immunotherapy. PMID:26828212

  13. RNA-Based Vaccines in Cancer Immunotherapy

    PubMed Central

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

    2015-01-01

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

  14. Mechanism of Anti-α-Synuclein Immunotherapy.

    PubMed

    Lee, Jun Sung; Lee, Seung-Jae

    2016-01-01

    Immunization therapy targeting α-synuclein has emerged as a promising approach for Parkinson's disease and perhaps for other synucleinopathies. Several antibodies have shown therapeutic effects in mouse models of synucleinopathies and have alleviated the pathological and behavioral phenotypes of these mice. The mechanisms through which the immunization therapy works were initially puzzling, especially given that α-synuclein is a typical cytosolic protein. Recent studies, however, suggested that extracellular α-synuclein is an important pathogenic entity, and hence, a target for immunotherapy. Here, we review the literature describing immunization therapy for synucleinopathies in mouse models and provide current thoughts on the potential mechanisms underlying the therapeutic effects of α-synuclein immunotherapy. PMID:26828212

  15. Strategies and developments of immunotherapies in osteosarcoma

    PubMed Central

    WAN, JIA; ZHANG, XIANGHONG; LIU, TANG; ZHANG, XIANGSHENG

    2016-01-01

    Osteosarcoma (OS) is a frequently observed primary malignant tumor. Current therapy for osteosarcoma consists of comprehensive treatment. The long-term survival rate of patients exhibiting nonmetastatic OS varies between 65–70%. However, a number of OS cases have been observed to be resistant to currently used therapies, leading to disease recurrence and lung metastases, which are the primary reasons leading to patient mortality. In the present review, a number of pieces of evidence provide support for the potential uses of immunotherapy, including immunomodulation and vaccine therapy, for the eradication of tumors via upregulation of the immune response. Adoptive T-cell therapy and oncolytic virotherapy have been used to treat OS and resulted in objective responses. Immunologic checkpoint blockade and targeted therapy are also potentially promising therapeutic tools. Immunotherapy demonstrates significant promise with regard to improving the outcomes for patients exhibiting OS. PMID:26834853

  16. Personalized dendritic cell-based tumor immunotherapy

    PubMed Central

    Janikashvili, Nona; Larmonier, Nicolas; Katsanis, Emmanuel

    2010-01-01

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

  17. Immunological landscape and immunotherapy of hepatocellular carcinoma.

    PubMed

    Prieto, Jess; Melero, Ignacio; Sangro, Bruno

    2015-12-01

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

  18. Immunity to visceral leishmaniasis: implications for immunotherapy.

    PubMed

    Khadem, Forough; Uzonna, Jude E

    2014-01-01

    Visceral leishmaniasis, caused by Leishmania donovani, L. infantum (syn. Leishmania chagasi), is a globally widespread disease with a burden of about 400,000 new infections reported annually. It is the most dangerous form of human leishmaniasis in terms of mortality and morbidity and is spreading to several nonendemic areas because of migration, global traveling and military conflicts. The emergence of Leishmania-HIV co-infection and increased prevalence of drug-resistant strains have worsened the impact of the disease. The traditional low-cost drugs are often toxic with several adverse effects, highlighting the need for development of new therapeutic and prophylactic strategies. Therefore, a detailed understanding of mechanisms of protective immunity is extremely important in order to develop new therapeutics in the form of vaccines or immunotherapies. This review gives an overview of visceral leishmaniasis, with particular emphasis on the innate and adaptive immune responses, vaccine and vaccination strategies and their potentials for immunotherapy against the disease. PMID:25156379

  19. Hepatotoxicity Associated with the Use of Anti-TNF-? Agents.

    PubMed

    French, Joshua B; Bonacini, Maurizio; Ghabril, Marwan; Foureau, David; Bonkovsky, Herbert L

    2016-03-01

    Medications to inhibit the actions of tumour necrosis factor alpha have revolutionized the treatment of several pro-inflammatory autoimmune conditions. Despite their many benefits, several serious side effects exist and adverse reactions do occur from these medications. While many of the medications' potential adverse effects were anticipated and recognized in clinical trials prior to drug approval, several more rare adverse reactions were recorded in the literature as the popularity, availability and distribution of these medications grew. Of these potential adverse reactions, liver injury, although uncommon, has been observed in some patients. As case reports accrued over time and ultimately case series developed, the link became better established between this family of medicines and various patterns of liver injury. Interestingly, it appears that the majority of cases exhibit an autoimmune hepatitis profile both in serological markers of autoimmune liver disease and in classic autoimmune features seen on hepatic histopathology. Despite the growing evidence of this relationship, the pathogenesis of this reaction remains incompletely understood, but it appears to depend on characteristics of the medications and the genetic composition of the patients; it is likely more complicated than a simple medication class effect. Because of this still incomplete understanding and the infrequency of the occurrence, treatments have also been limited, although it is clear that most patients improve with cessation of the offending agent and, in certain cases, glucocorticoid use. However, more needs to be done in the future to unveil the underlying mechanisms of this adverse reaction. PMID:26692395

  20. Lymphocutaneous Sporotrichosis during Treatment with Anti-TNF-Alpha Monotherapy.

    PubMed

    Ursini, Francesco; Russo, Emilio; Leporini, Christian; Calabria, Marilena; Bruno, Caterina; Tripolino, Cesare; Naty, Saverio; Grembiale, Rosa Daniela

    2015-01-01

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

  1. Improvement of malignant pleural mesothelioma immunotherapy by epigenetic modulators.

    PubMed

    Hamaidia, Malik; Staumont, Bernard; Duysinx, Bernard; Louis, Renaud; Willems, Luc

    2016-01-01

    In the absence of a satisfactory treatment of malignant pleural mesothelioma (MPM), novel therapeutic strategies are urgently needed. Among these, immunotherapy offers a series of advantages such as tumor specificity and good tolerability. Unfortunately, MPM immunotherapy is frequently limited by incomplete cell differentiation or feedback loop regulatory mechanisms. In this review, we describe different components of the innate immune system and discuss strategies to improve MPM immunotherapy by using epigenetic modulators. PMID:26303419

  2. Prostate cancer immunotherapy: beyond immunity to curability.

    PubMed

    Simons, Jonathan W

    2014-11-01

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

  3. Predictive factors for immunotherapy in melanoma

    PubMed Central

    Gonzlez-Cao, Maria; Karachaliou, Niki; Rosell, Rafael

    2015-01-01

    Immunotherapy has emerged as an exciting strategy for cancer treatment. Therapeutic blockade of immune checkpoint regulators favors the ability of T cell responses to increase anti-tumor immunity. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) are two T cell-inhibitory receptors with independent mechanisms of action. Immune checkpoint inhibitors targeting either CTLA-4, PD-1 or its ligand PD-L1 are currently yielding promising results in terms of efficacy in several clinical studies with melanoma patients and are being developed and tested as immunotherapy agents for multiple cancer types. To date, no reliable predictors of activity and efficacy of immunotherapy have yet been identified or validated. Even so, determining which patients derive clinical benefit from immune checkpoint agents remains an important clinical question and efforts to identify predictive markers of response are ongoing. This article reviews the current potential predictive factors for CTLA-4 and PD-1/PD-L1 immune checkpoints inhibitors in melanoma. PMID:26488004

  4. Sublingual or subcutaneous immunotherapy for allergic rhinitis?

    PubMed

    Durham, Stephen R; Penagos, Martin

    2016-02-01

    Allergen immunotherapy is effective in patients with allergic rhinitis (AR) and, unlike antiallergic drugs, has been shown to modify the underlying cause of the disease, with proved long-term benefits. Subcutaneous immunotherapy (SCIT) has been the gold standard, whereas sublingual immunotherapy (SLIT) has emerged as an effective and safe alternative. Previous Cochrane systematic reviews and meta-analyses have confirmed that both SLIT and SCIT are effective in patients with seasonal AR, whereas evidence for their efficacy in patients with perennial disease has been less convincing. Recent large, adequately powered trials have demonstrated reductions in both symptoms and use of rescue medication in patients with seasonal and those with perennial AR. Here we appraise evidence for SCIT versus SLIT based on indirect evidence from Cochrane reviews and recent well-powered double-blind, randomized controlled trials versus placebo and the limited direct evidence available from randomized blind head-to-head comparisons. At present, based on an overall balance of efficacy and side effects, the patient is in equipoise. Pending definitive comparative trials, choice might be determined largely by the local availability of SCIT and SLIT products of proved value and personal (patient) preference. PMID:26853126

  5. 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. PMID:26167500

  6. Russian thistle pollinosis: form allergen characterization to specific immunotherapy treatment.

    PubMed

    Colas, Carlos; Lezaun, Apolinar

    2009-01-01

    Chenopodiacea/Amaranthacea pollen is an important cause of respiratory allergy around the world. The problem could be aggravated because in desert or desert-like countries, these weeds are used in greening programmes or as ornamental plants. As climate tendencies should maintain in future decades, relevance of Chenopodiacea/Amaranthacea pollen allergy will go up. Relationship between airborne pollen grains and symptoms may not follow conventional patterns, and a wide lag between pollen counts and symptoms has been observed. Allergens from Chenopodium album y Salsola kali are probably the best known. A mayor band protein of 40-43 kDa has been associated with the main Salsola kali allergen, named sal k 1 and now recognised as pectin methyltranspherase or glucose 3 phosphate dehidrogenase. Systemic immunotherapy is effective and safe, improving symptoms, medication intake and Quality of Life and also reduces cutaneous allergen response. PMID:19273379

  7. Crescentic glomerulonephritis associated with renal cell carcinoma after cancer immunotherapy.

    PubMed

    Kai, H; Yamagata, K; Usui, J; Shimizu, Y; Hirayama, A; Yoh, K; Mase, K; Hirayama, K; Nagase, S; Nagata, M; Kawai, K; Akaza, H; Koyama, A

    2005-01-01

    A 59 year-old woman showed rapidly progressive glomerulonephritis during immunotherapy for metastatic renal cell carcinoma. She received unilateral nephrectomy and cytotoxic T lymphocyte (CTL) therapy for the treatment of retroperitoneal lymph node metastasis of renal cell carcinoma. With CTL therapy, her retroperitoneal lymph node mass decreased in size. One year after the third round of CTL therapy, her serum creatinine was increased and massive proteinuria occurred. Her renal biopsy specimen revealed necrotizing and crescentic glomerulonephritis with immune complex deposition. Her retroperitoneal lymph node mass continued to decrease in size. Consequently, for the purpose of avoiding interfering with the CTL therapy, we performed double filtration plasmapheresis (DFPP) monotherapy for removal of immune complexes without using immunosuppressive drugs or prednisolone. After 24 sessions of DFPP, her serum IgG was reduced from 3,942 mg/dL to 2,400 mg/dL, and proteinuria (from 9.0 g/day to 0.9 g/day) and renal function (serum creatinine; from 5.6 mg/dL to 2.2 mg/dL) also improved. However, 3 months after the final DFPP, she expired due to perforation of the colon. The autopsy sample of the kidney showed that most of the glomeruli were obsolescent, but immunoglobulin depositions were reduced and necrotizing lesions were diminished. In the patients with RPGN associated with renal cell carcinoma, renal functional recovery has not been observed upon immunosuppressive treatment. Consequently, plasmapheresis is considered to be one of the effective and safe methods for patients with this association. We also discuss previous reports of RPGN associated with renal cell carcinoma, or RPGN after cancer immunotherapy. PMID:16245250

  8. Sublingual Immunotherapy for Asthmatic Children Sensitized to House Dust Mite

    PubMed Central

    Liao, Wei; Hu, Qi; Shen, Lei-Lei; Hu, Ying; Tao, Hai-feng; Li, Hui-fan; Fan, Wen-ting

    2015-01-01

    Abstract The house dust mite is one of the most common allergens worldwide. There is good evidence that house dust mite subcutaneous immunotherapy is efficacious and has long-term benefit in children. However, the evidence of the benefit of house dust mite sublingual immunotherapy (SLIT) is less convincing. The purpose of this meta-analysis was to evaluate that efficacy and safety of dust mite SLIT in children with asthma. Medical Literature Analysis and Retrieval System Online, ISI Web of Knowledge, and Cochrane Central Register of Controlled Trials databases until February 2014 were searched. The primary outcome was mean change in asthma symptom score. Secondary outcomes included mean change in serum immunoglobulin G4 (sIgG4), specific Dermatophagoides pteronyssinus, immunoglobulin E (IgE) levels, and medication score. Safety was also assessed. We found that SLIT significantly decreased asthma symptom score (P?=?0.007) and increased sIgG4 levels (P?=?0.011) greater than control in children (<18 years of age) with asthma. There was no difference between SLIT and control groups in specific D pteronyssinus IgE levels (P?=?0.076) and medication score (P?=?0.408). The safety profile was similar between groups. Our study indicates that dust mite SLIT therapy was effective in reducing asthma symptoms and in increasing sIgG4 but did not significantly reduce medication scores or specific D pteronyssinus IgE levels. Our findings are not enough to support the use of dust mite SLIT in children with asthma. PMID:26091451

  9. Specific allergen immunotherapy attenuates allergic airway inflammation in a rat model of Alstonia scholaris pollen induced airway allergy.

    PubMed

    Datta, Ankur; Moitra, Saibal; Hazra, Iman; Mondal, Somnath; Das, Prasanta Kumar; Singh, Manoj Kumar; Chaudhuri, Suhnrita; Bhattacharya, Debanjan; Tripathi, Santanu Kumar; Chaudhuri, Swapna

    2016-01-01

    Pollen grains are well established to be an important cause of respiratory allergy. Current pharmacologic therapies for allergic asthma do not cure the disease. Allergen specific immunotherapy is the only treatment method which re-directs the immune system away from allergic response leading to a long lasting effect. The mechanism by which immunotherapy achieves this goal is an area of active research world-wide. The present experimental study was designed to develop an experimental model of allergic lung inflammation based on a relevant human allergen, Alstonia scholaris pollen, and to establish the immunological and cellular features of specific allergen immunotherapy using this same pollen extract. Our results revealed that Alstonia scholaris pollen sensitization and challenge causes eosinophilic airway inflammation with mucin hypersecretion. This is associated with increased total IgE, increased expression of Fc?RI on lung mast cells and increased levels of IL-4, IL-5 & IL-13 as confirmed by ELISA, in-situ immunofluorescence and FACS assay. Allergen specific immunotherapy reduced airway inflammation and also decreased total IgE level, Fc?RI expression, IL-4, IL-5 & IL-13 levels. It was further noted that the reduction of these levels was more by intra-nasal route than by intra-peritoneal route. Thus we present a novel animal model of Alstonia scholaris pollen allergic disease and specific allergen immunotherapy which will pave the way towards the development of better treatment modalities. PMID:26667977

  10. Modulation of Anti-Tumor Necrosis Factor Alpha (TNF-?) Antibody Secretion in Mice Immunized with TNF-? Kinoid

    PubMed Central

    Semerano, Luca; Duvallet, Emilie; Delavalle, Laure; Bernier, Emilie; Laborie, Marion; Grouard-Vogel, Graldine; Larcier, Patrick; Bessis, Natacha; Boissier, Marie-Christophe

    2012-01-01

    Tumor necrosis factor alpha (TNF-?) blockade is an effective treatment for patients with TNF-?-dependent chronic inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and psoriasis. TNF-? kinoid, a heterocomplex of human TNF-? and keyhole limpet hemocyanin (KLH) (TNF-K), is an active immunotherapy targeting TNF-?. Since the TNF-K approach is an active immunization, and patients receiving this therapy also receive immunosuppressant treatment, we evaluated the effect of some immunosuppressive drugs on the generation of anti-TNF-? antibodies produced during TNF-K treatment. BALB/c mice were injected intramuscularly with TNF-K in ISA 51 adjuvant. Mice were also injected intraperitoneally with one of the following: phosphate-buffered saline, cyclophosphamide, methylprednisolone, or methotrexate. Anti-TNF-? and anti-KLH antibody levels were assessed by enzyme-linked immunosorbent assay and the anti-TNF-? neutralizing capacity of sera by L929 bioassay. Our results showed that current treatments used in rheumatoid arthritis, such as methylprednisolone and methotrexate, do not significantly alter anti-TNF-? antibody production after TNF-K immunization. In contrast, the administration of cyclophosphamide (200 mg/kg) after immunization significantly reduced anti-TNF-? antibody titers and their neutralizing capacity. PMID:22441388

  11. Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimers 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 Alzheimers 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 Alzheimers 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

  12. 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

  13. 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

  14. Immunotherapy for Melanoma: Current Status and Perspectives

    PubMed Central

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

    2012-01-01

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

  15. Novel approaches to antiviral and anticancer immunotherapy.

    PubMed

    Trnková, K; Pastoreková, S; Petrik, J

    2012-01-01

    In this review we discuss existing as well as new approaches to immunotherapy directed against infected or cancerous cells. These approaches traditionally exploit either natural components of immune system (such as cytokines, chemokines, co-stimulatory molecules and adjuvants), or monoclonal antibodies designed to target foreign agents and/or diseased cells through their molecular markers. Additional strategies in development include therapeutic vaccines, oncolytic viruses and T-cell therapies. In addition, we briefly describe a novel strategy called ReDIT (Re-Directed ImmunoTherapy), based on re-orienting the existing long-lasting immune responses (e.g. induced by measles vaccination or natural infection) towards new target molecules on the surface of infected or malignant cells. This can be principally achieved by using bi-functional protein constructs that contain an antigen carrier component and a re-directing component. The antigen carrier component can consist of the ectodomain of the measles hemagglutinin that can be recognized by antibodies and memory cells generated during previous infection or vaccination. The re-directing component consists of the specific virus- or tumor antigen-binding molecule. The fusion constructs are expected to boost existing anti-measles immunity and re-direct it against a new target, engaging the existing anti-measles immunity as an effector mechanism. Thus, ReDIT is a promising novel approach that may represent a valuable addition to immunotherapy of difficult to treat infections and tumors, as it exploits a mechanism distinct from other available therapies. PMID:23237083

  16. 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

  17. The past, present and future of immunotherapy against tumor

    PubMed Central

    Jiang, Tao

    2015-01-01

    Tumor is one of the most common lethal diseases in the world. Current progress of therapy remains insufficient survival benefit. Tumor immunotherapies have been proposed for more than a century. With the improvement in the understanding of the role of the immune system in the tumorigenesis and immune response to tumor, immunotherapy has obtained a rapid development and plays the significant role in tumor therapy nowadays. This review designs to provide a general overview of immunotherapy in tumors. We will introduce the landmark events in the past research of immunotherapy and elaborate a range of strategies using different immune response mechanism, which have been demonstrated successfully and even some of them have been approved by US Food and Drug Administration (FDA) to certain tumor therapy. Finally, we will discuss the future direction of immunotherapy so that we can predict the possible and valuable strategies for future tumor therapy. PMID:26207213

  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. Fighting cancer with magnetic nanoparticles and immunotherapy

    NASA Astrophysics Data System (ADS)

    Gutiérrez, L.; Mejías, R.; Barber, D. F.; Veintemillas-Verdaguer, S.; Serna, C. J.; Lázaro, F. J.; Morales, M. P.

    2012-03-01

    IFN-γ-adsorbed DMSA-coated magnetite nanoparticles can be used as an efficient in vivo drug delivery system for tumor immunotherapy. Magnetic nanoparticles, with adsorbed interferon-γ, were targeted to the tumor site by application of an external magnetic field. A relevant therapeutic dosage of interferon in the tumor was detected and led to a notable reduction in tumor size. In general, only 10% of the total injected nanoparticles after multiple exposures were found in tissues by AC susceptibility measurements of the corresponding resected tissues. Magnetic nanoparticle biodistribution is affected by the application of an external magnetic field.

  20. Solving the Problem of Nonadherence to Immunotherapy.

    PubMed

    Bender, Bruce G; Lockey, Richard F

    2016-02-01

    Allergen immunotherapy (AIT) can improve allergic response by modifying the underlying disease. Many patients are nonadherent, and do not achieve full benefit. Numerous studies reveal that fewer than 10% of patients complete a full course and that most abandon treatment in the first year. The development and testing of interventions to improve AIT are emerging. Data from adherence interventions in other chronic conditions provide guidance to allergists/immunologists. Evidence-based communication strategies-patient-centered care, motivational interviewing, and shared-decision making-underscore the importance of taking time to establish trust, understand patient concerns and priorities, and involve the patient in decisions regarding AIT. PMID:26617236

  1. Current state of immunotherapy for bladder cancer.

    PubMed

    Kassouf, Wassim; Kamat, Ashish M

    2004-12-01

    Bacillus Calmette-Guerin (BCG) has been shown to be the most effective agent for the treatment of superficial bladder cancer since its approval by the US Food and Drug Administration for the treatment of carcinoma in situ of the bladder in 1990. Recently, augmentation of BCG immunotherapy with interferon-alpha2b and other agents is emerging as salvage therapy for those patients who fail initial treatment. This review summarizes the role of various immunotherapeutic agents in the treatment of bladder cancer, with special emphasis on the appropriate administration and schedule of BCG therapy as well as salvage with the combination of BCG with interferon-alpha2b. PMID:15606331

  2. Immunotherapy strategies for spinal cord injury.

    PubMed

    Wang, Yong-Tang; Lu, Xiu-Min; Chen, Kai-Ting; Shu, Ya-Hai; Qiu, Chun-Hong

    2015-01-01

    Regeneration in the central nervous system (CNS) of adult mammalian after traumatic injury is limited, which often causes permanent functional motor and sensory loss. After spinal cord injury (SCI), the lack of regeneration is mainly attributed to the presence of a hostile microenvironment, glial scarring, and cavitation. Besides, inflammation has also been proved to play a crucial role in secondary degeneration following SCI. The more prominent treatment strategies in experimental models focus mainly on drugs and cell therapies, however, only a few strategies applied in clinical studies and therapies still have only limited effects on the repair of SCI. Recently, the interests in immunotherapy strategies for CNS are increasing in number and breadth. Immunotherapy strategies have made good progresses in treating many CNS degenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and multiple sclerosis (MS). However, the strategies begin to be considered to the treatment of SCI and other neurological disorders in recent years. Besides anti-inflamatory therapy, immunization with protein vaccines and DNA vaccines has emerged as a novel therapy strategy because of the simplicity of preparation and application. An inflammatory response followed by spinal cord injury, and is controled by specific signaling molecules, such as some cytokines playing a crucial role. As a result, appropriate immunoregulation, the expression of pro-inflammatory cytokines and anti-inflammatory cytokines may be an effective therapy strategy for earlier injury of spinal cord. In addition, myelinassociated inhibitors (MAIs) in the injured spinal cord, such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte- myelin glycoprotein (OMgp) are known to prevent axonal regeneration through their co-receptors, and to trigger demyelinating autoimmunity through T cell-mediated harmful autoimmune response. The antagonism of the MAIs through vaccinating with protein or DNA vaccines targeting Nogo, MAG, OMgp, and their co-receptors, may be an effective strategy for the treatment of SCI. However, immunotherapy such as anti-inflammtory therapy or vaccine targeting MAIs or their receptors, accompanied with the potential in risking autoimmune diseases. As a result, in order to optimize the anti-inflammtory therapy and design of protein or DNA vaccines for their use in the future clinical application, we need to further understand the possible mechanisms of neuroprotective immunity. This review presents recent advances in the development of immunotherapy strategies for the treatment of axonal degeneration and demyelination, and improvement of motor function after SCI. PMID:25860061

  3. [Immunotherapy in the treatment of genitourinary cancers].

    PubMed

    Gczi, Lajos; Ladnyi, Andrea; Vajdics, Tmea; Kronya, Zsfia; Br, Krisztina; Gyergyay, Fruzsina; Martin, Tams; Nagyivnyi, Krisztin

    2016-03-01

    In this clinical review we provide information regarding advance and main achievements in the immunotherapy of genitourinary, particularly renal cell and prostate cancer. Nivolumab treatment became the new standard of care in locally advanced or metastatic renal cell cancer after failure on tyrosine kinase inhibitor treatment. Sipuleucel-T prolonged survival in patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer but had no effect on progression-free survival. Based on the results of phase I/II trials anti-PD-1/PD-L1 monoclonal antibodies are a new hope in the treatment of urothelial bladder cancer. Regarding germ cell tumors basic research is ongoing. PMID:26934350

  4. Pancreatitis Secondary to Anti-Programmed Death Receptor 1 Immunotherapy Diagnosed by FDG PET/CT.

    PubMed

    Alabed, Yazan Z; Aghayev, Ayaz; Sakellis, Christopher; Van den Abbeele, Annick D

    2015-11-01

    A 57-year-old man with metastatic melanoma developed colitis secondary to ipilimumab, a known immune-related adverse event (irAE). The patient then received pembrolizumab immunotherapy, an anti-programmed-death-receptor-1 (PD-1) antibody. Restaging FDG PET/CT study following 3 cycles of therapy demonstrated diffuse increased FDG uptake throughout the body of the pancreas associated with fat stranding in the peripancreatic region, suggestive of pembrolizumab-induced pancreatitis. Although the patient was clinically asymptomatic, diagnosis was biochemically confirmed with elevated amylase and lipase levels. In the era of immunotherapy, it will be critical to recognize irAEs early to allow prompt initiation of appropriate therapy and reduce the risk of long-term sequelae. PMID:26284765

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

    PubMed

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

    2015-05-01

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

  6. Rationale for Peptide and DNA Based Epitope Vaccines for Alzheimers Disease Immunotherapy

    PubMed Central

    Ghochikyan, Anahit

    2010-01-01

    Amyloid-beta (A?) immunotherapy has received considerable attention as a promising approach for reducing the level of A? in the CNS of Alzheimers disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with A?42 developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients mat received the vaccine. Generated antibodies reduced ?-amyloid deposits in the parenchyma of patients brains, but no reduction in soluble A? or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of A? is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric A?, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for A? immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-A? antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD. PMID:19355933

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

    PubMed Central

    Leung, Joanne

    2014-01-01

    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

  8. Tecemotide: An antigen-specific cancer immunotherapy

    PubMed Central

    Wurz, Gregory T; Kao, Chiao-Jung; Wolf, Michael; DeGregorio, Michael W

    2015-01-01

    The identification of tumor-associated antigens (TAA) has made possible the development of antigen-specific cancer immunotherapies such as tecemotide. One of those is mucin 1 (MUC1), a cell membrane glycoprotein expressed on some epithelial tissues such as breast and lung. In cancer, MUC1 becomes overexpressed and aberrantly glycosylated, exposing the immunogenic tandem repeat units in the extracellular domain of MUC1. Designed to target tumor associated MUC1, tecemotide is being evaluated in Phase III clinical trials for treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC) as maintenance therapy following chemoradiotherapy. Additional Phase II studies in other indications are ongoing. This review discusses the preclinical and clinical development of tecemotide, ongoing preclinical studies of tecemotide in human MUC1 transgenic mouse models of breast and lung cancer, and the potential application of these models for optimizing the timing of chemoradiotherapy and tecemotide immunotherapy to achieve the best treatment outcome for patients. PMID:25483673

  9. A killer choice for cancer immunotherapy.

    PubMed

    Schmidt, Tobi L; Negrin, Robert S; Contag, Christopher H

    2014-05-01

    The promise of cell-based immunotherapies for the treatment of cancer offers the potential of therapeutic synergy with chemo- and radiotherapies that may overcome current limitations leading to durable responses and prevention of recurrence. There is a wide array of cell-based immunotherapies that are either poised to enter cancer clinical trials or are in clinical trials, and many are showing some success. Yet within this field, there are clear obstacles that need to be overcome, including limited access across tissue barriers, development of antigen tolerance, and the immunosuppressive microenvironment of tumors. Through an understanding of immune cell signaling and trafficking, immune cell populations can be selected for adoptive transfer, and delivery strategies can be developed that circumvent these obstacles to effectively direct populations of cells with robust anti-tumor efficacy to the target. Within the realm of immune cell therapies, cytokine-induced killer (CIK) cells have demonstrated promising trafficking patterns, effective delivery of synergistic therapeutics, and stand-alone efficacy. Here, we discuss the next generation of CIK therapies and their application for the effective treatment of a wide variety of cancers. PMID:24791943

  10. Algenpantucel-L immunotherapy in pancreatic adenocarcinoma.

    PubMed

    Coveler, Andrew L; Rossi, Gabriela R; Vahanian, Nicholas N; Link, Charles; Chiorean, E Gabriela

    2016-02-01

    Pancreatic adenocarcinoma is the 4th leading cause of cancer death in the USA and the EU. A minority of patients presents with surgically resectable and potentially curable disease, but among these, 80% are destined to relapse and overall survival rates with adjuvant chemotherapy average 24 months. Immunotherapy is a promising therapeutic option and a potential paradigm shift in the treatment of patients with pancreatic cancer, and may be particularly effective when used early in the disease course to prevent metastatic spread. Algenpantucel-L (HyperAcute Pancreas, NewLink Genetics, Ames, IA, USA) is a whole-cell immunotherapy consisting of irradiated allogeneic pancreatic cancer cells genetically engineered to express the murine enzyme ?-GT, which results in hyperacute rejection of the tumor cells with complement- and antibody-dependent cytotoxicity. Phase II clinical trial data has been encouraging, particularly for patients who demonstrated humoral immunologic responses. Here, we report preliminary results and biomarkers correlations with clinical activity of algenpantucel-L in pancreatic cancer. PMID:26787078

  11. Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies.

    PubMed

    Gastaldi, Matteo; Thouin, Anas; Vincent, Angela

    2016-01-01

    Over the last 15years it has become clear that rare but highly recognizable diseases of the central nervous system (CNS), including newly identified forms of limbic encephalitis and other encephalopathies, are likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated 1 protein and contactin-associated protein like 2, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Most importantly, the new antibody-associated diseases almost invariably respond to immunotherapies with considerable and sometimes complete recovery, and there is convincing evidence of their pathogenicity in the relatively limited studies performed so far. Treatments include first-line steroids, intravenous immunoglobulins, and plasma exchange, and second-line rituximab and cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term. This review focuses mainly on N-methyl D-aspartate receptor- and voltage-gated potassium channel complex-related Abs in adults, the clinical phenotypes, and treatment responses. Pediatric cases are referred to but not reviewed in detail. As there have been very few prospective studies, the conclusions regarding immunotherapies are based on retrospective studies. PMID:26692392

  12. Immune checkpoint?targeted cancer immunotherapies.

    PubMed

    Swatler, Julian; Koz?owska, Ewa

    2016-01-01

    Tumor cells may express on their surface various characteristic antigens that can induce antitumor immunity. However, cancer in human body may induce an immunosuppressive microenvironment that limits immune response to its antigens. For many years scientists have tried to develop an immunotherapy which would induce a potent antitumor immune response and lead to an elimination of the disease. One of the most promising immunotherapies is blockade of immune checkpoints, i.e. a group of costimulatory molecules negatively regulating the immune system. Their blockade would overcome immune tolerance in the tumor microenvironment and amplify antitumor immunity. What's more, immune checkpoint blockade may turn out even more profitable, as some of immune checkpoints and their ligands are expressed on tumor surface and on tumor infiltrating lymphocytes, contributing to the immunosuppressive cancer microenvironment. Phase III clinical trials have confirmed efficacy of an anti?CTLA?4 antibody ipilimumab, thereby leading to its acceptance for the treatment of advanced melanoma. Thanks to promising results of the phase I clinical trials, a breakthrough therapy designation and an early approval for the treatment have been granted to anti?PD?1 antibodies ? nivolumab (for the treatment of advanced melanoma and advanced non?small cell lung cancer) and pembrolizumab (for the treatment of advanced melanoma) and, in the treatment of advanced bladder cancer, an anti?PD?L1 antibody ? MPDL3280A as well. Other immune checkpoints, such as LAG?3, TIM?3, BTLA, B7?H3 and B7?H4, are also under early evaluation. PMID:26864062

  13. Personalized approaches to active immunotherapy in cancer.

    PubMed

    Ophir, Eran; Bobisse, Sara; Coukos, George; Harari, Alexandre; Kandalaft, Lana E

    2016-01-01

    Immunotherapy is emerging as a promising anti-cancer curative modality. However, in contrast to recent advances obtained employing checkpoint blockade agents and T cell therapies, clinical efficacy of therapeutic cancer vaccines is still limited. Most vaccination attempts in the clinic represent "off-the shelf" approaches since they target common "self" tumor antigens, shared among different patients. In contrast, personalized approaches of vaccination are tailor-made for each patient and in spite being laborious, hold great potential. Recent technical advancement enabled the first steps in the clinic of personalized vaccines that target patient-specific mutated neo-antigens. Such vaccines could induce enhanced tumor-specific immune response since neo-antigens are mutation-derived antigens that can be recognized by high affinity T cells, not limited by central tolerance. Alternatively, the use of personalized vaccines based on whole autologous tumor cells, overcome the need for the identification of specific tumor antigens. Whole autologous tumor cells could be administered alone, pulsed on dendritic cells as lysate, DNA, RNA or delivered to dendritic cells in-vivo through encapsulation in nanoparticle vehicles. Such vaccines may provide a source for the full repertoire of the patient-specific tumor antigens, including its private neo-antigens. Furthermore, combining next-generation personalized vaccination with other immunotherapy modalities might be the key for achieving significant therapeutic outcome. PMID:26241169

  14. A Breakthrough: Macrophage-Directed Cancer Immunotherapy.

    PubMed

    Mills, Charles D; Lenz, Laurel L; Harris, Robert A

    2016-02-01

    Successful immunotherapy of cancer is becoming a reality aided by the realization that macrophages play an important role in the growth or regression of tumors. Specifically, M2/repair-type macrophages predominate in human cancers and produce growth-promoting molecules that actively stimulate tumor growth in much the same way they help wounds heal. However, modulating M2/repair-type macrophages to M1/kill-type can slow or stop cancer growth. The effects involve direct activity of M1 kill-type as well as the ability of M1-type macrophages to stimulate Th1-type cytotoxic T cells and other effector cells. Macrophage responses can also predict cancer susceptibility; individuals with a high M1/kill to M2/repair ratio are less prone. That macrophages/innate immunity can be modulated to play a central role in directly or indirectly combating cancer is a breakthrough that seems likely to finally make successful immunotherapy of cancer a reality. Cancer Res; 76(3); 513-6. 2016 AACR. PMID:26772756

  15. [Progression of immunotherapy in gastric cancer].

    PubMed

    Wei, Xiaoli; Xu, Ruihua

    2016-02-25

    Gastric cancer is a malignant disease with high incidence and mortality. The therapeutic methods for advanced gastric cancer, including chemotherapy and targeted therapy are very limited. Immunotherapy is a new method for cancer treatment. The immune checkpoint inhibitors developed for cancer treatment mainly target the CTLA-4 and PD-1/PD-L pathways. There have already been several inhibitors approved for the treatment of melanoma and non-small cell lung cancer by the FDA, including Ipilimumab (fully human antibody against CTLA-4), Pembrolizumab (fully human antibody against PD-1) and Nivolumab (fully human antibody against PD-1). There are also many on-going clinical trials investigating the value of immune checkpoint inhibitors in treating various malignancies, including advanced gastric cancer. In KEYNOTE-012 trial, for advanced gastric and esophagogastric junction cancer anti-PD-1 therapy seemed to be safe and effective for advanced gastric cancer with PD-L1 positivity. Moreover, studies of adoptive cell therapy and tumor vaccine in gastric cancer are underway. Here the latest developments in immunotherapy for gastric cancer will be illustrated. PMID:26831889

  16. Cancer immunotherapy: Strategies for personalization and combinatorial approaches.

    PubMed

    Sathyanarayanan, Vishwanath; Neelapu, Sattva S

    2015-12-01

    The results of recent clinical trials using novel immunotherapy strategies such as immune checkpoint blockade and adoptive T-cell therapy approaches including CAR T-cell therapy have clearly established immunotherapy as an important modality for the treatment of cancer besides the traditional approaches of surgery, radiotherapy, and chemotherapy or targeted therapy. However, to date immunotherapy has been shown to induce durable clinical benefit in only a fraction of the patients. The use of combination strategies is likely to increase the number of patients that might benefit from immunotherapy. Indeed, over the last decade, the characterization of multiple immune resistance mechanisms used by the tumor to evade the immune system and the development of agents that target those mechanisms has generated a lot of enthusiasm for cancer immunotherapy. But a critical issue is to determine how best to combine such agents. This review will focus on novel immunotherapy agents currently in development and discuss strategies to develop and personalize combination cancer immunotherapy strategies. PMID:26548534

  17. Laser immunotherapy in treatment of metastatic prostate tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Ritchey, Jerry W.; Bartles, Kenneth E.; Lucroy, Michael D.; Liu, Hong; Nordquist, Robert E.

    2002-07-01

    Laser immunotherapy is a special cancer treatment modality using an intratumor injection of a special formulation consisting of a novel immunoadjuvant and a laser-absorbing dye, followed by a non-invasive near-IR laser irradiation. Our early experiments using a metastatic mammary rat tumor model showed that laser immunotherapy could cause acute selective photothermal tumor destruction and induce a systemic, long-term specific anti-tumor immunity. In the current study, laser immunotherapy was used to treat metastatic prostate tumors in Copenhagen male rats. The transplantable tumors metastasize mainly to the lung and the lung cancer is usually the cause of death. Two experimental were performed in our study. The first was to study the effect of laser immunotherapy on the tumor burdens, both the primary and the metastasis in the lung. The second was to study the effect of laser immunotherapy on the long-term survival of the tumor-bearing rats. For comparison, some rat tumors were also treated by the laser-dye combination to study the photothermal effect. Tour results showed that both the photothermal effect and the laser immunotherapy could slow the growth of primary tumors and the metastatic tumors. The laser-dye-immunoadjuvant treatment resulted in more than 20 percent long-term survival rate in tumor-bearing rats. Our experimental results indicate that the laser immunotherapy has a great potential in treating metastatic tumors.

  18. Immunotherapy coming of age: What will it take to make it standard of care for glioblastoma?

    PubMed Central

    Heimberger, Amy B.; Sampson, John H.

    2011-01-01

    With the recent approval by the FDA of an immunotherapy for prostate cancer and another positive immunotherapy trial in melanoma, immunotherapy may finally be coming of age. So what will it take for it to become part of the standard treatment for glioblastoma? To put this question into perspective, we summarize critical background information in neuro-immunology, address immunotherapy clinical trial design, and discuss a number of extrinsic factors that will impact the development of immunotherapy in neuro-oncology. PMID:21149252

  19. Talimogene laherparepvec (T-VEC) as cancer immunotherapy.

    PubMed

    Kohlhapp, F J; Zloza, A; Kaufman, H L

    2015-09-01

    Talimogene laherparepvec (T-VEC) is the first-in-class oncolytic virus immunotherapy for the treatment of cancer and was generated from an attenuated, recombinant herpes simplex virus. T-VEC has demonstrated therapeutic activity in melanoma patients and is being tested in a number of other cancers alone and in combination with standard cancer therapeutics and other immunotherapy agents. This review will discuss the current landscape of melanoma, the construction and application of T-VEC for melanoma along with other indications for T-VEC, as well as highlight some of the novel challenges with oncolytic virus immunotherapy as it enters into clinical practice. PMID:26488034

  20. Evolving synergistic combinations of targeted immunotherapies to combat cancer.

    PubMed

    Melero, Ignacio; Berman, David M; Aznar, M Angela; Korman, Alan J; Prez Gracia, Jos Luis; Haanen, John

    2015-08-01

    Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients. PMID:26205340

  1. Immunotherapy for Infectious Diseases: Past, Present, and Future.

    PubMed

    Manohar, Akshay; Ahuja, Jasmine; Crane, John K

    2015-11-01

    Passive immunotherapy for established infections, as opposed to active immunization to prevent disease, remains a tiny niche in the world of antimicrobial therapies. Many of the passive immunotherapies currently available are directed against bacterial toxins, such as botulism, or are intended for agents of bioterrorism such as anthrax, which fortunately has remained rare. The emergence of Ebola virus and multi-drug resistant pathogens, however, may breathe new life into the immunotherapy field as researchers seek non-antibiotic interventions for infectious diseases. PMID:26575462

  2. Cellular immunotherapy in multiple myeloma: lessons from preclinical models.

    PubMed

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

    2014-12-01

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

  3. Immunotherapy in multiple sclerosis, Part 2.

    PubMed

    Becker, C C; Gidal, B E; Fleming, J O

    1995-10-01

    The efficacies of corticosteroids and azathioprine (part 1) and of cyclophosphamide, immune globulin, cyclosporine, interferons, copolymer 1, and cladribine (part 2) in patients with multiple sclerosis (MS) are reviewed. MS is an inflammatory, demyelinating disease of the CNS that commonly affects young adults. The involvement of various immune mechanisms in MS suggests a role for immunomodulating therapy. The goals of immunotherapy vary with the clinical stage of the disease and include (1) improving recovery from exacerbations, (2) decreasing the number or severity of relapses, (3) preventing the development of chronic progressive disease from a relapsing-remitting course, and (4) decreasing further progression in patients with chronic progressive disease. In clinical trials, corticotropin and corticosteroids have been found to accelerate recovery from exacerbations. Tapering is often effective after high-dose induction therapy. Long-term maintenance regimens do not alter disease progression and are not recommended. Azathioprine produces modest benefits with respect to relapse rates and disease progression after two or more years of treatment; adverse effects are mild to moderate. Azathioprine should not be used in patients with aggressive disease who may approach severe disability in 6-18 months. Cyclophosphamide, because of its modest impact on disease progression and its potentially severe adverse effects, including cancer, should be reserved for patients with aggressive relapsing-remitting or chronic progressive disease in whom other treatments have failed to work; maintenance therapy is necessary after induction. Intravenous immune globulin may benefit patients with severe relapses; however, its efficacy remains unproven. Cyclosporine also cannot be recommended because of its modest efficacy, marked adverse effects, and high cost. Interferon beta-1b is a more specific immunotherapy that has been found to decrease the number and severity of relapses. This treatment should be considered in patients with relapsing-remitting disease who are having two or more exacerbations per year. Copolymer 1 and cladribine have shown some promising early results. Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progression, and some can cause serious adverse effects. Better understanding of the immunologic basis of MS may lead to more specific immunotherapies with more lasting benefits. PMID:8535945

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

    SciTech Connect

    Zhang, Han; Sonoda, Koh-Hei; Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro

    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.

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

    PubMed

    Palgan, K; Bartuzi, Z; Gotz-Zbikowska, M

    2014-01-01

    Hymenoptera venom anaphylaxis after bee or wasp sting is a common problem that affects about 1.2 percent to 3.5 percent of the general population. Venom-specific immunotherapy (VIT) is an established mode of treatment for immunoglobulin (Ig) E-mediated Hymenoptera venom allergy. However, VIT may often be associated with immediate anaphylaxis which can lead to treatment withdrawal. Several cases published in recent years suggest that omalizumab, used as add-on therapy may be able to prevent anaphylaxis during VIT. We report the case of a 30-year-old woman, suffering from mild persistent asthma, who had a history of severe anaphylactic reactions after yellow jacket sting, and after eating peanuts, contact with guinea pig hair, and i.v. administration of dexamethasone natrium phosphate. Initial specific immunotherapy had to be stopped due to severe anaphylaxis (hypotension, dyspnea, and angioedema). The immunotherapy was reintroduced accompanied by the anti-immunoglobulin (Ig) E monoclonal antibody omalizumab. Subcutaneous omalizumab 150 mg was initiated 4 weeks after the anaphylaxis incident and 1 day before the resumption of VIT. Rush treatment was uneventful, and the usual cumulative dose of 111.1 microg was successfully reached. The combination of omalizumab and VIT is a valid option of therapy for these patients and could reduce asthma and food allergy symptoms. PMID:24674685

  6. The Role of Immunotherapy in Multiple Myeloma.

    PubMed

    Kocoglu, Mehmet; Badros, Ashraf

    2016-01-01

    Multiple myeloma is the second most common hematologic malignancy. The treatment of this disease has changed considerably over the last two decades with the introduction to the clinical practice of novel agents such as proteasome inhibitors and immunomodulatory drugs. Basic research efforts towards better understanding of normal and missing immune surveillence in myeloma have led to development of new strategies and therapies that require the engagement of the immune system. Many of these treatments are under clinical development and have already started providing encouraging results. We, for the second time in the last two decades, are about to witness another shift of the paradigm in the management of this ailment. This review will summarize the major approaches in myeloma immunotherapies. PMID:26784207

  7. Engineering better immunotherapies via RNA interference.

    PubMed

    Sioud, Mouldy

    2014-01-01

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

  8. 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

  9. GD2-targeted immunotherapy and radioimmunotherapy

    PubMed Central

    Dobrenkov, Konstantin; Cheung, Nai-Kong

    2014-01-01

    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’s 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 antibody, cytokines, cells and genetically engineered products all directed at GD2 are rapidly moving into the clinic. In the review, past and present immunotherapy trials directed at GD2 will be summarized, highlighting the lessons learned and the future directions. PMID:25440605

  10. Biomarkers for Allergen Immunotherapy: A "Panoromic" View.

    PubMed

    Moingeon, Philippe

    2016-02-01

    Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials. PMID:26617233

  11. Sublingual immunotherapy for allergic rhinitis and conjunctivitis.

    PubMed

    Passalacqua, Giovanni; Garelli, Valentina; Sclif, Francesca; Canonica, Giorgio Walter

    2013-03-01

    Sublingual immunotherapy (SLIT) for allergic respiratory diseases was first described in 1986 and immediately appeared as a viable alternative to the traditional subcutaneous route. Since then, more than 60 randomized controlled trials have been published, almost all with very favorable results. The average improvement over placebo in symptom score and medication use was always greater than 20%. The results of the clinical trials were pooled in several meta-analyses, which consistently confirmed the efficacy of the treatment. SLIT is characterized by a satisfactory safety profile, its side effects being mainly limited to oral discomfort. Only six anaphylaxes and no fatalities have been so far reported. Due to the good risk:benefit ratio, SLIT is currently being investigated in diseases other than respiratory allergy, such as food allergy and atopic dermatitis. PMID:23444955

  12. Oncolytic viruses: a novel form of immunotherapy

    PubMed Central

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

    2009-01-01

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

  13. Engineering better immunotherapies via RNA interference

    PubMed Central

    Sioud, Mouldy

    2014-01-01

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

  14. Candida albicans intralesional injection immunotherapy of warts.

    PubMed

    Signore, Robert J

    2002-09-01

    Often, the treatment of verrucae is frustrating for both the physician and patient. Treatment may be painful, scarring, ineffective, and costly. The object of this study was to compare the clinical outcomes and safety of Candida albicans intralesional injection immunotherapy (CI) versus conventional wart treatment. The results of a prospective, nonrandomized, open-label, comparison study are presented. CI is a novel, simple, and inexpensive modality for the treatment of verruca vulgaris (VV), including the plantar wart (PW) type. CI appears safe and well tolerated and is well suited for multiple warts on hands and fingers, PWs, and recalcitrant warts. Uninjected warts also may regress during CI. The new phenomenon of postimmunotherapy-revealed cicatrix (PIRC) is described. CI represents an off-label usage of Candida extract. PMID:12353895

  15. Chemotherapy and immunotherapy: mapping the road ahead.

    PubMed

    Cook, Alistair M; Lesterhuis, W Joost; Nowak, Anna K; Lake, Richard A

    2016-04-01

    Cancer immunotherapy, and in particular checkpoint blockade, is now standard clinical care for a growing number of cancers. Cytotoxic drugs have been the primary weapon against cancer for a long time and have typically been understood because of their capacity to directly kill tumour cells. It is now clear that these drugs are potential partners for checkpoint blockade and different drugs can influence the immune response to cancer through a wide variety of mechanisms. Some of these relate to immunogenic cell death, whilst others relate to changes in antigen-presentation, tumour cell targeting, or depletion of immunosuppressive cells. Here, we review some recent advances in our understanding of the immunological changes associated with chemotherapy, discuss progress in combining chemotherapy with checkpoint blockade, and comment on the difficulties encountered in translating promising preclinical data into successful treatments for cancer patients. PMID:26724433

  16. Targeting nanoparticles to dendritic cells for immunotherapy.

    PubMed

    Cruz, Luis J; Tacken, Paul J; Rueda, Felix; Domingo, Joan Carles; Albericio, Fernando; Figdor, Carl G

    2012-01-01

    Dendritic cells (DCs) are key players in the initiation of adaptive immune responses and are currently exploited in immunotherapy for treatment of cancer and infectious diseases. Development of targeted nanodelivery systems carrying vaccine components, including antigens and adjuvants, to DCs in vivo represents a promising strategy to enhance immune responses. Delivering particulate vaccines specifically to DCs and preventing nonspecific uptake by other endocytotic cells are challenging. Size represents a critical parameter determining whether particulate vaccines can penetrate lymph nodes and reach resident DCs. Specific delivery is further enhanced by actively targeting DC-specific receptors. This chapter discusses the rationale for the use of particle-based vaccines and provides an overview of antigen-delivery vehicles currently under investigation. In addition, we discuss how vaccine delivery systems may be developed, focusing on liposomes, PLGA polymers, and gold nanoparticles, to obtain safe and efficacious vaccines. PMID:22568905

  17. Laser Assisted Cancer Immunotherapy: Surface Irradiation

    NASA Astrophysics Data System (ADS)

    Wilson, Joshua; Chen, Hsin-Wei; Bandyopadhyay, Pradip

    2006-03-01

    Experiments in our laboratory incorporate a non-invasive approach to treat superficial tumors in animal models. Based on the concept of Laser Assisted Cancer Immunotherapy, surface irradiation provides good information to compare to invasive alternatives. The procedure involves injecting an immunoadjuvant (Glycated Chitosan) as well as a light absorbing dye (Indocyanine Green) directly into the tumor (5 to 7 mm in diameter). The temperature of the tumor is raised using an infrared diode laser operating at 804 nm, with a silica fiber tip placed a set distance away from the surface of the tumor. We monitor the surface temperature using non-invasive (infrared detector probe) as well as the internal temperature of the tumor using invasive (micro thermocouples) methods. This study aims at the success of the surface irradiation mode to treat solid tumors. * This work is supported by a grant from The National Institute of Health.

  18. 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

  19. Development of Passive Immunotherapies for Synucleinopathies.

    PubMed

    Bergstrm, Ann-Louise; Kallunki, Pekka; Fog, Karina

    2016-02-01

    Immunotherapy using antibodies targeting alpha-synuclein has proven to be an effective strategy for ameliorating pathological and behavioral deficits induced by excess pathogenic alpha-synuclein in various animal and/or cellular models. However, the process of selecting the anti-alpha-synuclein antibody with the best potential to treat synucleinopathies in humans is not trivial. Critical to this process is a better understanding of the pathological processes involved in the synucleinopathies and how antibodies are able to influence these. We will give an overview of the first proof-of-concept studies in rodent disease models and discuss challenges associated with developing antibodies against alpha-synuclein resulting from the distribution and structural characteristics of the protein. We will also provide a status on the passive immunization approaches targeting alpha-synuclein that have entered, or are expected to enter, clinical evaluation. 2015 Movement Disorder Society. PMID:26704735

  20. Practical Approaches to Immunotherapy in the Clinic.

    PubMed

    Agarwala, Sanjiv S

    2015-12-01

    The development of immunotherapy using checkpoint blockade has altered the treatment landscape for patients who had but few options only several years ago. Currently, approved anti-checkpoint agents include ipilimumab, the first approved treatment aimed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway, and pembrolizumab and nivolumab, which inhibit the programmed death-1 (PD-1) pathway. Careful monitoring and early intervention for immune-mediated side effects is important to mitigate toxicity. Immune-mediated response patterns may differ from response associated with conventional therapies, and so it is important to use caution against early abandonment of treatment. Biomarkers as predictive and prognostic markers of efficacy are still under investigation in an attempt to guide treatment selection in patients with advanced melanoma, and additional studies are needed to provide guidance for selection of checkpoint inhibitors to be used in sequence or combination. PMID:26598056

  1. Immunotherapy for pancreatic cancer: current concepts.

    PubMed

    Kaufman, Howard L; Di Vito, Joseph; Hrig, Heidi

    2002-02-01

    Despite advances in chemotherapy and surgical technique, patients with pancreatic cancer often succumb to local recurrence or metastatic spread. The need for new therapeutic strategies for this disease coupled with a better understanding of basic immunology have led to the development of novel anti-tumor vaccines. This review focuses on the historical development of tumor vaccines emphasizing the identification of potential pancreatic tumor antigens. The role of both B-cell and T-cell responses in tumor rejection will be reviewed. Methods for antigen presentation, including peptides, recombinant viral and bacterial vectors, dendritic cells, and whole cell approaches will be discussed. The use of immune adjuvants and improved methods of vaccine delivery will also be explored. The full potential for the immunotherapy of pancreatic cancer awaits the results of early phase clinical trials. The development of pancreatic cancer vaccines represents a useful paradigm for the translation of basic research into the clinical arena. PMID:12063825

  2. Immunotherapy in miscellaneous medical disorders Graves ophthalmopathy, asthma, and regional painful syndrome.

    PubMed

    Gonzales, Michael; Fratianni, Carmel; Mamillapali, Chaitanya; Khardori, Romesh

    2012-05-01

    In Graves ophthalmopathy, immunotherapy is offering an opportunity of reducing bad outcomes that lead to disfigurement and impairment of vision. These therapies are not perfect; however, we now have a chance to achieve better outcomes. In asthma, immune therapy using passive immunity targeting key proinflammatory cytokine/chemokines and medications of their effects has opened an avenue of research into a safe and durable therapy. Omalizumab appears to be safe and effective in clinical use. In regional pain syndrome, immune mechanisms may be involved in sustaining long-standing pain, and IVIG may moderate pain sensitivity by reducing immune activation. PMID:22703859

  3. Bacteria and their toxins tamed for immunotherapy.

    PubMed

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

    2012-06-01

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

  4. Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy

    PubMed Central

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

    2014-01-01

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

  5. Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment

    PubMed Central

    Jackson, Christopher; Ruzevick, Jacob; Phallen, Jillian; Belcaid, Zineb; Lim, Michael

    2011-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite intensive treatment, the prognosis for patients with GBM remains grim with a median survival of only 14.6 months. Immunotherapy has emerged as a promising approach for treating many cancers and affords the advantages of cellular-level specificity and the potential to generate durable immune surveillance. The complexity of the tumor microenvironment poses a significant challenge to the development of immunotherapy for GBM, as multiple signaling pathways, cytokines, and cell types are intricately coordinated to generate an immunosuppressive milieu. The development of new immunotherapy approaches frequently uncovers new mechanisms of tumor-mediated immunosuppression. In this review, we discuss many of the current approaches to immunotherapy and focus on the challenges presented by the tumor microenvironment. PMID:22190972

  6. Landscape of Tumor Antigens in T Cell Immunotherapy.

    PubMed

    Ilyas, Sadia; Yang, James C

    2015-12-01

    Cancer immunotherapy is a rapidly evolving field that exploits T cell responses to tumor-associated Ags to induce tumor rejection. Molecular identification of tumor rejection Ags has helped define several classes of Ags, including tissue differentiation and tumor germline Ags. The ability to genetically engineer Ag-specific receptors into T cells provides an opportunity to translate these findings into therapies. New immunotherapy agents, notably checkpoint inhibitors, have demonstrated unprecedented efficacy in certain cancers. However, the nature of the Ags driving those beneficial immune responses remains unclear. New evidence suggests that tumors express immunogenic, tumor-specific epitopes generated from the same mutations that drive cancer development. Correlations between cancer types responding to immunotherapies and the frequency of somatic mutations may clarify what drives natural antitumor immune responses. This fusion of tumor immunology and genetics is leading to new ways to target this class of ideal tumor-specific Ags and could allow the application of immunotherapy to many cancers. PMID:26589749

  7. 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

  8. [Immunotherapy of malignant diseases--developments and prospects].

    PubMed

    Paukovits, Patricia; Himmler, Gottfried; Loibner, Hans

    2004-05-01

    Conventional strategies in cancer management, such as surgery, chemotherapy or radiation therapy are effective treatments for most tumors, but often fail in achieving complete remission. The reason for this failure is, that single tumor cells have already spread to various organs by the time the tumor is diagnosed and lead, often years later, to the development of metastases. Therefore it is insufficient to treat the tumor solely at its point of origin; tumor dissemination should be prevented too. Tumor immunotherapy is one of the treatment options that target tumor propagation. In cancer immunotherapy, the immune system of the patient is influenced such, that the tumor is recognized and attacked by the body's defences. Since these therapies specifically aim at tumor cells, they cause fewer adverse events and improve the quality of life of patients. This review outlines previous developments in cancer immunotherapies with a focus on active immunotherapies and vaccination strategies. PMID:15244049

  9. Rapid Isolation of Central Memory T Cells for Adoptive Immunotherapy

    Cancer.gov

    The National Cancer Institute (NCI), Surgery Branch is seeking parties interested in collaborative research to further co-develop a methodology for the isolation of memory T cells for adoptive immunotherapy.

  10. Immunotherapy for small-cell lung cancer: emerging evidence.

    PubMed

    Reck, Martin; Heigener, David; Reinmuth, Niels

    2016-04-01

    Treatment for small-cell lung cancer (SCLC) has changed little over the past few decades; available therapies have failed to extend survival in advanced disease. In recent years, immunotherapy with treatments such as interferons, TNFs, vaccines and immune checkpoint inhibitors has advanced and shown promise in the treatment of several tumor types. Immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab, durvalumab, tremelimumab and ulocuplumab are at the forefront of immunotherapy and have achieved approvals for certain cancer types, including melanoma (ipilimumab, nivolumab and pembrolizumab), non-SCLC (nivolumab and pembrolizumab) and renal cell carcinoma (nivolumab). Clinical trials are investigating different immunotherapies in patients with other solid and hematologic malignancies, including SCLC. We review emerging evidence supporting the use of immunotherapy in SCLC patients. PMID:26882955

  11. Immunotherapy: Critical Appraisal, Effectiveness and Cost/Benefit Ratio

    PubMed Central

    Saint-Amant, Serge

    1986-01-01

    A critical appraisal of the literature shows that allergy skin testing is safe, economical and useful when correlated by a meticulous medical history and physical examination. Immunotherapy is beneficial in appropriately selected patients, if properly performed using licensed and preferably standardized allergenic extracts. This article reviews the labelling and standardization of those extracts, the guidelines in determining their degree of effectiveness, their current status and their different nature through inhalation, contact, injection or ingestion. It emphasizes the basic steps in dealing with potential allergic complaints, enumerating the specific indications for immunotherapy, in which conditions it gives results and the extent of these results. The cost/benefit ratio of immunotherapy and the future prospects for allergy skin testing and immunotherapy are discussed. PMID:21274249

  12. Future directions in bladder cancer immunotherapy: towards adaptive immunity.

    PubMed

    Smith, Sean G; Zaharoff, David A

    2016-03-01

    The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed. PMID:26860539

  13. Immunotherapy for pancreatic ductal adenocarcinoma: an overview of clinical trials

    PubMed Central

    Paniccia, Alessandro; Merkow, Justin; Edil, Barish H.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and current therapeutic strategies are often unsatisfactory. Identification and development of more efficacious therapies is urgently needed. Immunotherapy offered encouraging results in preclinical models during the last decades, and several clinical trials have explored its therapeutic application in PDAC. The aim of this review is to summarize the results of clinical trials conducted to evaluate the future perspective of immunotherapy in the treatment of PDAC. PMID:26361407

  14. Sugar-carrying Polystyrenes Facilitate Harvesting of APCs from MLRs: Possible Application of Sugar-carrying Polystyrenes to Immunotherapy.

    PubMed

    Imaizumi, Akira; Onishi, Hideya; Yamasaki, Akio; Kawamoto, Makoto; Morisaki, Takashi; Goto, Mitsuaki; Iwama, Masamichi; Akaike, Toshihiro; Hasumi, Kenichiro

    2016-02-01

    Antigen-presenting cells (APCs) play a pivotal role in cancer immunotherapy. APCs in conventionally used flasks are harvested by enzymatic digestion or cell scraping for application to cancer immunotherapy. However, these methods may impair functional molecules expressed on the APC surface and reduce their effects in cancer immunotherapy. Recently, we found that APCs could be harvested by shaking at 4C in flasks coated with poly[N-p-vinylbenzyl-O-2-acetoamide-2-deoxy-?-D-glucopyranosyl-(1?4)-2-acetoamide-2-deoxy-?-D-gluconamide] (PVGlcNAc) or a copolymer consisting of sulfonylurea (SU) linked to poly[N-p-vinyl-benzyl-4-O-?-D-galactopyranosyl-D-gluconamide] [P(VLA-co-SU)]. In the present study, we compared the functions of cytotoxic T-lymphocytes (CTLs) induced by APCs generated in PVGlcNAc- or P(VLA-co-SU)-coated flasks and conventional flasks. APCs from PVGlcNAc- or P(VLA-co-SU)-coated flasks showed higher expression of cluster of differentiation (CD)80/86, CD11c, and major histocompatibility complex class II alloantigen I-A(d), and higher cytotoxicity than APCs from conventional flasks. These results suggest that the use of PVGlcNAc- or P(VLA-co-SU)-coated flasks is optimal for harvesting APCs. The generated APCs also have a higher antigen-presenting ability compared to those generated in conventional flasks. Our results may contribute to the development of effective cancer immunotherapies. PMID:26851023

  15. Recent advances in the field of anti-cancer immunotherapy

    PubMed Central

    Neves, Henrique; Kwok, Hang Fai

    2015-01-01

    Background The main goal of anti-cancer therapy is to specifically inhibit the malignant activity of cancer cells, while leaving healthy cells unaffected. As such, for every proposed therapy, it is important to keep in mind the therapeutic index — the ratio of the toxic dose over the therapeutic dose. The use of immunotherapy has allowed a means to both specifically block protein–protein interaction and deliver cytotoxic events to a tumor-specific antigen. Review scope It is the objective of this review to give an overview on current immunotherapy treatment for cancers using monoclonal antibodies. We demonstrate three exciting targets for immunotherapy, TNF-α Converting Enzyme (TACE), Cathepsin S and Urokinase Plasmogen Activator and go over the advances made with one of the most used monoclonal antibodies in cancer therapy, Rituximab; as well as Herceptin, which is used for breast cancer therapy. Furthermore, we touch on other venues of immunotherapy, such as adaptive cell transfer, the use of nucleic acids and the use of dendritic cells. Finally, we summarize some ongoing studies that spell tentative advancements for anti-cancer immunotherapy. General significance Immunotherapy is at the forefront of anti-cancer therapies, allying both a high degree of specificity to general high effectiveness and fewer side-effects. PMID:26673349

  16. Allergen hybrids next generation vaccines for Fagales pollen immunotherapy

    PubMed Central

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

    2013-01-01

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

  17. Clinical and histopathological evaluation of the effect of addition of immunotherapy with Mw vaccine to standard chemotherapy in borderline leprosy.

    PubMed

    Kamal, R; Natrajan, M; Katoch, K; Arora, M

    2012-01-01

    This study reports detailed analysis of clinical parameters and clearance of granuloma in borderline leprosy patients treated with immunotherapy and chemotherapy. It aims to assess the additive effect of immunotherapy (Mwvaccine) with standard MDT on clinical status of untreated borderline leprosy cases and on granuloma fraction of untreated borderline leprosy cases. Patients attending the OPD were serially recruited in two groups. A total of 150 cases in one treatment (trial) group (Mw vaccine plus MDT) and 120 cases in another treatment (control) group (MDT only) of border line leprosy have been included. After the formal written consent, detailed clinical examination, charting, smear examination of all untreated borderline patients of both groups was done, biopsies were taken from the active lesions of all patients of both groups at start of therapy and every six month thereafter till the completion of therapy. The same procedure was repeated every six months during the follow-up period. Standard MDT was given to all the patients of both groups according to type of disease. Mw vaccine 0.1 ml (0.5 x 10(9) bacilli) was injected intra-dermally at the start of therapy and every six months in addition to chemotherapy to the treatment group. The BT cases were followed up after 6 doses of MDT and 2 doses of Mw vaccine, and, the BB, BL cases were followed up after 24 doses of MDT plus 5 doses of Mw vaccine. Clinically, greater and faster improvement was observed in all the clinical parameters, faster attainment of smear negativity and two episodes of lepra reaction occurred in cases treated with combined chemotherapy and immunotherapy, as compared to controls (chemotherapy alone) wherein clinical improvement was slower in all parameters, slower attainment of smear negativity in bacillary index and seven showed the occurrence of reactions, histipathologically in addition to more rapid clearance of granuloma in immunotherapy treated group, a significant finding was an increase in the epithelioid cells population in this group. This suggests a possible immunoactivation of the macrophages especially in BB/BL immunotherapy group. Overall comparison of regression induced by chemotherapy alone with that induced by combined chemotherapy and immunotherapy shows a greater reduction in clinical parameters as well as granuloma fraction in BT cases as well as in BB/BL cases. This trial shows the potential usefulness of this approach of addition of immunotherapy to standard chemotherapy in borderline leprosy cases which leads to in faster recovery from disease reduced chances of reactions and faster granuloma clearance. Such information is expected to be useful in improving the immunotherapeutic approaches for treatinggranulomatous conditions in general and in leprosy in particular. PMID:23720894

  18. Sublingual immunotherapy: World Allergy Organization position paper 2013 update

    PubMed Central

    2014-01-01

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

  19. 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

  20. [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

  1. Immunotherapy for advanced melanoma: fulfilling the promise.

    PubMed

    Gogas, Helen; Polyzos, Aristidis; Kirkwood, John

    2013-12-01

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

  2. 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-β, 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

  3. Optimal vaccine scheduling in cancer immunotherapy

    NASA Astrophysics Data System (ADS)

    Piccoli, B.; Castiglione, F.

    2006-10-01

    Cancer immunotherapy aims at stimulating the immune system to react against cancer stealth capabilities. It consists of repeatedly injecting small doses of a tumor-associated molecule one wants the immune system to recognize, until a consistent immune response directed against the tumor cells is observed. We have applied the theory of optimal control to the problem of finding the optimal schedule of injections of an immunotherapeutic agent against cancer. The method employed works for a general ODE system and can be applied to find the optimal protocol in a variety of clinical problems where the kinetics of the drug or treatment and its influence on the normal physiologic functions have been described by a mathematical model. We show that the choice of the cost function has dramatic effects on the kind of solution the optimization algorithm is able to find. This provides evidence that a careful ODE model and optimization schema must be designed by mathematicians and clinicians using their proper different perspectives.

  4. Recommendations for appropriate sublingual immunotherapy clinical trials.

    PubMed

    Passalacqua, Giovanni

    2014-01-01

    Sublingual immunotherapy is currently considered a viable alternative to the subcutaneous route. The body of evidence of its efficacy is based on the results of 77 clinical trials and 7 meta-analyses, that have been published so far. Nonetheless, the experimental evidence is partially weak due to the large heterogeneity of studies, namely: doses, regimens, patient selection, duration of treatment, outcomes and reporting. In addition, it is virtually impossible to compare the potency of extracts produced by different manufacturers. Also, there is large variability in reporting and in the classification of adverse events, either systemic or local, so that only a rough estimate can be provided. Considering all these aspects, efforts are needed to harmonize the methodology, outcome measures and reporting of SLIT clinical trials, to achieve the ability of comparing the results of various studies. International societies and the World Allergy Organization have recently provided general recommendations on how to design and conduct trials which can provide more interpretable and homogeneous data. PMID:25309678

  5. Effects of laser immunotherapy on tumor microenvironment

    NASA Astrophysics Data System (ADS)

    Acquaviva, Joseph T.; Wood, Ethan W.; Hasanjee, Aamr; Chen, Wei R.; Vaughan, Melville B.

    2014-02-01

    The microenvironments of tumors are involved in a complex and reciprocal dialog with surrounding cancer cells. Any novel treatment must consider the impact of the therapy on the microenvironment. Recently, clinical trials with laser immunotherapy (LIT) have proven to effectively treat patients with late-stage, metastatic breast cancer and melanoma. LIT is the synergistic combination of phototherapy (laser irradiation) and immunological stimulation. One prominent cell type found in the tumor stroma is the fibroblast. Fibroblast cells can secrete different growth factors and extracellular matrix modifying molecules. Furthermore, fibroblast cells found in the tumor stroma often express alpha smooth muscle actin. These particular fibroblasts are coined cancer-associated fibroblast cells (CAFs). CAFs are known to facilitate the malignant progression of tumors. A collagen lattice assay with human fibroblast cells is used to elucidate the effects LIT has on the microenvironment of tumors. Changes in the contraction of the lattice, the differentiation of the fibroblast cells, as well as the proliferation of the fibroblast cells will be determined.

  6. Combining radiotherapy and immunotherapy: A revived partnership

    SciTech Connect

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

  7. Antibody-based immunotherapy of cryptosporidiosis.

    PubMed

    Crabb, J H

    1998-01-01

    Passive antibody immunotherapy (PAI) for cryptosporidiosis is a treatment strategy that has been actively pursued in laboratory studies and early-stage clinical studies for the last decade. Several experimental approaches have been initiated, including use of bovine colostrum and colostral antibodies (hyperimmune and natural), monoclonal antibodies, chicken egg yolk antibodies, and even orally administered human plasma antibodies. Most studies have employed oral administration to treat or prevent this intestinal infection. The interest in this treatment strategy has been sparked by the lack of an effective or approved therapy, increased awareness of the widespread nature of this parasite, epidemiological evidence that humoral immunity plays an important role in host resistance, and several early case reports of antibody therapy in which remarkable resolution of the disease was observed. Most studies using a variety of preparations of antibodies administered to animals and humans have shown some degree of efficacy, though the responses have been, for the most part, partial rather than complete resolution of the disease. This chapter examines critically the scientific rationale and the evidence for PAI for cryptosporidiosis, including practical considerations and future approaches. PMID:9554072

  8. Allergen Immunotherapy: Past, Present, and Future.

    PubMed

    Jutel, Marek; Kosowska, Anna; Smolinska, Sylwia

    2016-05-01

    Allergen-specific immunotherapy (AIT), although in clinical use for more than a century, is still the only causal treatment of allergic diseases. The safety and efficacy of AIT has been demonstrated in a large number of clinical trials. In addition to allergy symptom reduction AIT plays an essential role in preventing new allergies and asthma and shows long-term effects after discontinuation of treatment. Ideally, it is capable of curing allergy. However, AIT is not effective in all allergic individuals and is not equally effective in the treatment of various hypersensitivities to different allergens. For many years, the route of administration and the vaccine compositions have been evolving. Still there is a strong need for research in the field of new AIT modalities to increase its effectiveness and safety. Growing evidence on immunological effects of AIT, especially new T cell subsets involved in antigen/allergen tolerance, provides novel concepts for safer and more effective vaccination. Pharmacoeconomic studies have demonstrated a clear advantage of AIT over pharmacologic therapies. PMID:26922928

  9. Cellular immunotherapy for pediatric solid tumors

    PubMed Central

    HEGDE, MEENAKSHI; MOLL, ALEXANDER; BYRD, TIARA T.; LOUIS, CHRYSTAL U.; AHMED, NABIL

    2015-01-01

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

  10. 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, 2550% 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

  11. Toll-like Receptors in Tumor Immunotherapy

    PubMed Central

    Paulos, Chrystal M.; Kaiser, Andrew; Wrzesinski, Claudia; Hinrichs, Christian S.; Cassard, Lydie; Boni, Andrea; Muranski, Pawel; Sanchez-Perez, Luis; Palmer, Douglas C.; Yu, Zhiya; Antony, Paul A.; Gattinoni, Luca; Rosenberg, Steven A.; Restifo, Nicholas P.

    2007-01-01

    Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory Tcells (Treg) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as sinks for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression. PMID:17875756

  12. Humoral-targeted immunotherapies in multiple sclerosis.

    PubMed

    Lulu, Sabeen; Waubant, Emmanuelle

    2013-01-01

    The continuous improvements of our understanding of the pathophysiological changes that occur in multiple sclerosis (MS) have translated into many novel therapeutic agents at different stages of development. These agents target more specifically the innate or the adaptive immune response. We will review agents available or under development that target the humoral pathways of the adaptive immune response. As such, humoral targeted immunotherapies that are being developed for MS are discussed herein: rituximab, ocrelizumab, and ofatumumab show promise as B-cell depleting agents. Other agents, such as atacicept were suspended during development in MS due to increased inflammatory activity versus the placebo. Although most agents were tested in relapsing-remitting forms of MS, rituximab and ocrelizumab have both been studied in progressive MS, whereas ocrelizumab only is currently moving forward in primary progressive MS trials. We provide an overview of agents available and under development that target the humoral response and include their mechanisms of action, safety profiles, and results of clinical trials. PMID:23208729

  13. Effect of laser immunotherapy and surgery on the treatment of mouse mammary tumors

    NASA Astrophysics Data System (ADS)

    Chen, Vivian A.; Le, Henry; Li, Xiaosong; Wolf, Roman F.; Ferguson, Halie; Sarkar, Akhee; Liu, Hong; Nordquist, Robert E.; Chen, Wei R.

    2010-02-01

    Laser immunotherapy using laser photothermal therapy and immunological stimulation could achieve tumor-specific immune responses, as indicated by our previous pre-clinical and preliminary clinical studies. To further study the effect of laser immunotherapy, we conducted an investigation combining laser immunotherapy and surgery. After laser immunotherapy, treated tumors were surgically removed at different time points. The survival rates of treated mice were compared among different groups. Furthermore, the cured mice were rechallenged to test the immunity induced by laser immunotherapy. Our results showed that the mice treated with surgical removal one week after laser immunotherapy had the highest survival rate (77%). When the tumors were removed immediately after laser immunotherapy treatment, the survival rate was 57%. Most cured mice withstood tumor rechallenges, indicating an induction of tumor immunity by laser immunotherapy. The differentiations between different surgery groups indicate that the treated tumors have contributed to the immunological responses of the hosts.

  14. Undertreatment of allergy: exploring the utility of sublingual immunotherapy.

    PubMed

    Emanuel, Ivor A; Parker, Michael J; Traub, Oren

    2009-05-01

    Allergic syndromes are highly prevalent and are comprised of a wide variety of clinical problems, including rhinitis, conjunctivitis, atopic dermatitis and urticaria, asthma, and food allergies. Numerous studies have shown that allergic syndromes are both underdiagnosed and undertreated. This is related to many factors, including trivialization of allergic conditions by physicians and patients, failure to adhere to diagnostic and treatment guidelines, and dissatisfaction with conventional pharmacologic treatments. Immunotherapy involves the administration of allergen extracts in an attempt to induce immunologic tolerance and has been used for the treatment of allergic syndromes and the prevention of long-term complications. Conventional subcutaneous immunotherapy is effective but is also associated with a risk of serious adverse events, requires administration by a trained health care professional, and is contraindicated in certain populations. By contrast, sublingual immunotherapy has been used extensively in Europe and possesses most of the benefits of subcutaneous immunotherapy along with increased safety, tolerability, and convenience. This narrative review explores data from selected clinical studies and concludes that sublingual immunotherapy may be well suited to fill the gap posed by the undertreatment of allergic syndromes in the United States. PMID:19393398

  15. Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy.

    PubMed

    Anguille, Sbastien; Smits, Evelien L; Bryant, Christian; Van Acker, Heleen H; Goossens, Herman; Lion, Eva; Fromm, Phillip D; Hart, Derek N; Van Tendeloo, Viggo F; Berneman, Zwi N

    2015-10-01

    Although the earliestrudimentaryattempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy. PMID:26240218

  16. Allergenic Characterization of New Mutant Forms of Pru p 3 as New Immunotherapy Vaccines

    PubMed Central

    Gmez-Casado, C.; Garrido-Arandia, M.; Gamboa, P.; Blanca-Lpez, N.; Canto, G.; Varela, J.; Cuesta-Herranz, J.; Pacios, L. F.; Daz-Perales, A.; Tordesillas, L.

    2013-01-01

    Nowadays, treatment of food allergy only considered the avoidance of the specific food. However, the possibility of cross-reactivity makes this practice not very effective. Immunotherapy may exhibit as a good alternative to food allergy treatment. The use of hypoallergenic molecules with reduced IgE binding capacity but with ability to stimulate the immune system is a promising tool which could be developed for immunotherapy. In this study, three mutants of Pru p 3, the principal allergen of peach, were produced based on the described mimotope and T cell epitopes, by changing the specific residues to alanine, named as Pru p 3.01, Pru p 3.02, and Pru p 3.03. Pru p 3.01 showed very similar allergenic activity as the wild type by in vitro assays. However, Pru p 3.02 and Pru p 3.03 presented reduced IgE binding with respect to the native form, by in vitro, ex vivo, and in vivo assays. In addition, Pru p 3.03 had affected the IgG4 binding capacity and presented a random circular dichroism, which was reflected in the nonrecognition by specific antibodies anti-Pru p 3. Nevertheless, both Pru p 3.02 and Pru p 3.03 maintained the binding to IgG1 and their ability to activate T lymphocytes. Thus, Pru p 3.02 and Pru p 3.03 could be good candidates for potential immunotherapy in peach-allergic patients. PMID:24324505

  17. A modified ultrarush insect venom immunotherapy protocol for children.

    PubMed

    Steiss, Jens-Oliver; Jödicke, Birgit; Lindemann, Hermann

    2006-01-01

    The prevalence of insect venom allergy in the European population is approximately 5%. Hymenoptera venom allergy is an important epidemiological problem. Ten to 40 deaths are reported annually in Germany. In contrast to conventional dose increase schedules lasting a minimum of 5 days, shorter protocols reduce the patient's stay in the hospital and provide an earlier protection toward stings. Clinical studies on ultrarush protocols have been published for adult patients, but very little data are currently available for children. Therefore, we investigated the safety and tolerability of a shortened insect venom immunotherapy (VIT) in children and adolescents. Forty-three children and adolescents (aged 4-18 years) with insect venom allergy were treated in this study. Five children were hyposensitized according to the ultrarush protocol with nine injections (as suggested by Brehler et al. (Safety of a two-day ultrarush insect VIT protocol in comparison with protocols of longer duration and involving a larger number of injections. J Allergy Clin Immunol 105:1231-1235,2000); 38 children received the modified ultrarush schedules with only eight subcutaneous injections. With both protocols the maintenance dose (100 microg) was achieved in 24 hours. Twenty-five patients (58.1%) showed no reaction after the injections. In 11 patients (25.6%), extensive erythema (>5 cm, maximum of 20 cm) was found at the injection site. Erythema and edema (>5 cm, maximum of 15 cm) were observed in seven patients (16.2%). The maintenance dose was well tolerated, with no systemic reaction in any patient. The modified ultrarush protocol for insect VIT used in this study showed very good tolerability and safety in children and adolescents. This dose regimen can increase compliance by shortening inpatient stay and reduces hospital costs. PMID:16724635

  18. Intravesical chemo-immunotherapy in non muscle invasive bladder cancer.

    PubMed

    Leopardo, D; Cecere, S C; Di Napoli, M; Cavaliere, C; Pisano, C; Striano, S; Marra, L; Menna, L; Claudio, L; Perdon, S; Setola, S; Berretta, M; Franco, R; Tambaro, R; Pignata, S; Facchini, G

    2013-08-01

    Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed. PMID:23893180

  19. Cellular and Antibody Based Approaches for Pediatric Cancer Immunotherapy

    PubMed Central

    Huang, Michael A.; Krishnadas, Deepa K.; Lucas, Kenneth G.

    2015-01-01

    Progress in the use of traditional chemotherapy and radiation-based strategies for the treatment of pediatric malignancies has plateaued in the past decade, particularly for patients with relapsing or therapy refractory disease. As a result, cellular and humoral immunotherapy approaches have been investigated for several childhood cancers. Several monoclonal antibodies are now FDA approved and commercially available, some of which are currently considered standard of practice. There are also several new cellular immunotherapy approaches under investigation, including chimeric antigen receptor (CAR) modified T cells, cancer vaccines and adjuvants, and natural killer (NK) cell therapies. In this review, we will discuss previous studies on pediatric cancer immunotherapy and new approaches that are currently being investigated in clinical trials. PMID:26587548

  20. Past, present and future targets for immunotherapy in ovarian cancer

    PubMed Central

    Schwab, Carlton L; English, Diana P; Roque, Dana M; Pasternak, Monica; Santin, Alessandro D

    2015-01-01

    Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions. PMID:25524384

  1. Cancer Immunotherapy: Selected Targets and Small-Molecule Modulators.

    PubMed

    Weinmann, Hilmar

    2016-03-01

    There is a significant amount of excitement in the scientific community around cancer immunotherapy, as this approach has renewed hope for many cancer patients owing to some recent successes in the clinic. Currently available immuno-oncology therapeutics under clinical development and on the market are mostly biologics (antibodies, proteins, engineered cells, and oncolytic viruses). However, modulation of the immune system with small molecules offers several advantages that may be complementary and potentially synergistic to the use of large biologicals. Therefore, the discovery and development of novel small-molecule modulators is a rapidly growing research area for medicinal chemists working in cancer immunotherapy. This review provides a brief introduction into recent trends related to selected targets and pathways for cancer immunotherapy and their small-molecule pharmacological modulators. PMID:26836578

  2. Immunotherapy for myeloid leukemias: current status and future directions

    PubMed Central

    el-Shami, K; Smith, BD

    2011-01-01

    Myeloid leukemias, although a heterogeneous group of hematopoietic stem cell neoplasms, are arguably among the most suited for active specific immunotherapy. Nevertheless, clinical development of myeloid leukemia vaccine lagged behind similar approaches in other solid and hematological malignancies. The recent identification of apparently specific leukemia antigens and advances in understanding the fundamentals of tumor immunology have helped initiate a number of early phase clinical studies evaluating the safety and clinical efficacy of this approach. Here we review the recently identified and characterized putative leukemia antigens, the main vaccination strategies employed by most investigators and the results of clinical studies of immunotherapy of myeloid leukemias. Although these studies are early and often difficult to interpret, they offer evidence that effective immunity to leukemia could be induced following vaccination, and that clinical benefit can sometimes be observed, thus setting the stage for future development of this strategy and in the combinatorial approaches to treatment of myeloid leukemias that incorporate immunotherapy. PMID:18563174

  3. Propionibacterium acnes in the pathogenesis and immunotherapy of acne vulgaris.

    PubMed

    Liu, Pei-Feng; Hsieh, Yao-Dung; Lin, Ya-Ching; Two, Aimee; Shu, Chih-Wen; Huang, Chun-Ming

    2015-01-01

    Acne vulgaris, a multi-factorial disease, is one of the most common skin diseases, affecting an estimated 80% of Americans at some point during their lives. The gram-positive and anaerobic Propionibacterium acnes (P. acnes) bacterium has been implicated in acne inflammation and pathogenesis. Therapies for acne vulgaris using antibiotics generally lack bacterial specificity, promote the generation of antibiotic-resistant bacterial strains, and cause adverse effects. Immunotherapy against P. acnes or its antigens (sialidase and CAMP factor) has been demonstrated to be effective in mice, attenuating P. acnes-induced inflammation; thus, this method may be applied to develop a potential vaccine targeting P. acnes for acne vulgaris treatment. This review summarizes reports describing the role of P. acnes in the pathogenesis of acne and various immunotherapy-based approaches targeting P. acnes, suggesting the potential effectiveness of immunotherapy for acne vulgaris as well as P. acnes-associated diseases. PMID:26264195

  4. Peptide-based immunotherapy for multiple myeloma: current approaches.

    PubMed

    Zhou, Fu-Ling; Meng, Shan; Zhang, Wang-Gang; Wei, Yong-Chang; Cao, Xing-Mei; Bai, Gai-Gai; Wang, Bai-Yan

    2010-08-23

    Multiple myeloma (MM) is a clonal B-cell malignancy with many fatal clinical sequelae. Despite extensive therapeutic approaches, cures remain rare exceptions. A recent promising area of investigation is the development of immunotherapeutic approaches that target and eliminate myeloma cells more selectively. Because of its potential to promote the destruction of cancerous cells via cytotoxic T-cell responses, peptide-based immunotherapy is one of these strategies to have attracted considerable attention. Furthermore, many studies were carried out to identify the best epitope peptides, the optimal vaccine formulation and schedule, and the preferable clinical situation for vaccination. Based on these results, various epitope peptides have been identified that may be selectively targeted by host immunity, and various approaches have been used to enhance the immune responses of peptides. This chapter focuses on reviewing previous immunotherapy trials, describing the current strategies for peptide-based immunotherapy, and discussing the achievable prospects in MM. PMID:20619381

  5. Treatment planning for radio-immunotherapy

    NASA Astrophysics Data System (ADS)

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

    1996-10-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

    Silvestri, Ida; Cattarino, Susanna; Aglian, 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. PMID:26161414

  8. Immunotherapy of autoimmunity and cancer: the penalty for success

    PubMed Central

    Caspi, Rachel R.

    2009-01-01

    Advances in our understanding of autoimmunity and tumour immunity have led to improvements in immunotherapy for these diseases. Ironically, effective tumour immunity requires the induction of the same responses that underlie autoimmunity, whereas autoimmunity is driven by dysregulation of the same mechanisms that are involved in host defence and immune surveillance. Therefore, as we manipulate the immune system to treat cancer or autoimmunity, we inevitably unbalance the vital mechanisms that regulate self tolerance and antimicrobial resistance. This Science and Society article aims to dissect the conundrum that is inherent to the concept of immunotherapy and highlights the need for new and more specific therapeutic approaches. PMID:19008897

  9. Prolonged overall survival in gastric cancer patients after adoptive immunotherapy

    PubMed Central

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

    2015-01-01

    AIM: To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes (EAALs) in gastric cancer. METHODS: An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients, of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment (control group). EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination. Clinical data including age, gender, clinical stage, chemotherapeutic regimens, hospitalization, surgical, radiotherapy, and survival data were collected along with EAAL therapy details and side effects. Patients were followed and the relationship between treatment and overall survival (OS) data obtained for the immunotherapy and control groups were compared retrospectively. The safety of EAAL immunotherapy was also evaluated. RESULTS: After in vitro culture and proliferation, the percentages of CD3+, CD3+CD8+, CD8+CD27+, CD8+CD28+, and CD3+CD16+/CD56+ cells increased remarkably (P < 0.05), while the percentages of CD3+CD4+, CD4+CD25+, and CD3-CD16+/CD56+ (natural killer cells) were overtly decreased (P < 0.05); no significant change was observed in CD4+CD25+CD127- cells (P = 0.448). Interestingly, OS in the immunotherapy group was significantly higher than that in the control group, with 27.0 and 13.9 mo obtained for the two groups, respectively (P = 0.028, HR = 0.573, 95%CI: 0.347-0.945). These findings indicated a 42.7% decrease in the risk of death. In addition, we found that clinical stage and application of EAAL immunotherapy were independent prognostic factors for gastric cancer patients. Indeed, the OS in stage IIIc and IV patients that had received surgery was prolonged after EAAL immunotherapy (P < 0.05). Importantly, in vitro induction and proliferation of EAAL were easy and biologically safe. CONCLUSION: Overall, EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients. PMID:25759549

  10. Universes Collide: Combining Immunotherapy with Targeted Therapy for Cancer

    PubMed Central

    Wargo, Jennifer A.; Cooper, Zachary A.; Flaherty, Keith T.

    2014-01-01

    There have been significant advances in the past several years with regard to targeted therapy and immunotherapy for cancer. This is highlighted in melanoma, where treatment with targeted therapy (against the BRAF oncogene) results in responses in the majority of patients, though duration of response is limited. In contrast, treatment with immunotherapy results in a lower response rate, but ones that tend to be more durable. Insights regarding mechanisms of response and potential synergy between these treatment strategies for melanoma are a focus of this review, with opportunities to extend these insights to the treatment of other cancers. PMID:25395294

  11. Vaccines versus immunotherapy: overview of approaches in deciding between options.

    PubMed

    Dalgleish, Angus G

    2014-01-01

    This review compares the optimal use of vaccines vs. other forms of immunotherapy, which includes cytokines, such as IL-2, monoclonal antibodies, such as the 'checkpoint inhibitors', against CTLA-4 and PD-1. The review includes both prophylactic and therapeutic vaccines using a variety of technologies. It is already established that vaccines can be enhanced by other immunotherapies, such as cytokines (IL-2) and there is scope for combining both of these with the 'checkpoint' antibodies. Moreover, both can be enhanced with other modalities, such as radiotherapy, ablative therapy and both high and low dose chemotherapies. PMID:25625932

  12. The Use of Adjuvants for Enhancing Allergen Immunotherapy Efficacy.

    PubMed

    Chesn, Julie; Schmidt-Weber, Carsten B; Esser von-Bieren, Julia

    2016-02-01

    One key approach to increase the efficacy and the safety of immunotherapy is the use of adjuvants. However, many of the adjuvants currently in use can cause adverse events, raising concerns regarding their clinical use, and are geared toward productive immune responses but not necessarily tolerogenic responses. Thus, novel adjuvants for immunotherapy are needed and are being developed. Essential is their potential to boost appropriate tolerogenic adaptive immune responses to allergens while limiting side effects. This review provides an overview of adjuvants currently in clinical use or under development and discusses their therapeutic effect in enhancing allergen-induced tolerance. PMID:26617231

  13. T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy.

    PubMed

    Chung, David J; Pronschinske, Katherine B; Shyer, Justin A; Sharma, Sneh; Leung, Samantha; Curran, Shane A; Lesokhin, Alexander M; Devlin, Sean M; Giralt, Sergio A; Young, James W

    2016-01-01

    Multiple myeloma is the most common indication for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and lenalidomide maintenance after transplant is now standard. Although lenalidomide doubles progression-free survival, almost all patients eventually relapse. Posttransplant immunotherapy to improve outcomes after ASCT therefore has great merit but first requires delineation of the dynamics of immune reconstitution. We evaluated lymphocyte composition and function after ASCT to guide optimal timing of immunotherapy and to identify potential markers of relapse. Regulatory T cells (Treg) decline as CD8(+) T cells expand during early lymphocyte recovery after ASCT, markedly reducing the Treg:CD8(+) effector T-cell ratio. These CD8(+) T cells can respond to autologous dendritic cells presenting tumor antigen in vitro as early as day +12 after transplant, becoming antigen-specific cytolytic T-lymphocyte effectors and thereby demonstrating preservation of cellular reactivity. CD4(+) and CD8(+) T cells express the negative regulatory molecules, CTLA-4, PD-1, LAG-3, and TIM-3, before and after ASCT. A subpopulation of exhausted/senescent CD8(+) T cells, however, downregulates CD28 and upregulates CD57 and PD-1, characterizing immune impairment and relapse after ASCT. Relapsing patients have higher numbers of these cells at +3 months after transplant, but before detection of clinical disease, indicating their applicability in identifying patients at higher risk of relapse. PD-1 blockade also revives the proliferation and cytokine secretion of the hyporesponsive, exhausted/senescent CD8(+) T cells in vitro. Collectively, these results identify T-cell exhaustion/senescence as a distinguishing feature of relapse and support early introduction of immunotherapy to stimulate antitumor immunity after ASCT. Cancer Immunol Res; 4(1); 61-71. 2015 AACR. PMID:26464015

  14. Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy

    PubMed Central

    Kwilas, Anna R.; Donahue, Renee N.; Tsang, Kwong Y.; Hodge, James W.

    2015-01-01

    Combination therapy for the treatment of cancer is becoming increasingly essential as we gain improved understanding of the complexity of cancer progression and the mechanisms by which cancer cells become resistant to single-agent therapy. Recent studies, both clinical and preclinical, have suggested that immunotherapy is a promising approach to the treatment of cancer; however, strategies to improve its clinical efficacy are still needed. A number of recent studies have indicated that antiangiogenic tyrosine kinase inhibitors (TKIs) target multiple components of the tumor microenvironment and are an ideal class of agents for synergizing with cancer immunotherapy. TKIs are well known to modulate tumor endothelial cells, leading to vascular normalization; however, these agents have also been recently shown to decrease tumor compactness and tight junctions, thereby reducing solid tumor pressure and allowing for improved perfusion of collapsed vessels and increased tumor oxygenation. In addition, some TKIs are capable of inducing immunogenic modulation, whereby tumor cells are sensitized to killing by T lymphocytes. Moreover, a number of TKIs have been shown to be involved in immune subset conditioning, increasing the frequency and function of effector immune elements, while decreasing the number and function of immune suppressor cells. The alteration of the immune landscape, direct modification of tumor cells, and improved vascular perfusion leads to improved antitumor efficacy when antiangiogenic TKIs are combined with immunotherapy. Collectively, the data presented in this review support the clinical combination of multi-targeted antiangiogenic TKIs, including but not limited to cabozantinib, sunitinib, and sorafenib, as well as to other antiangiogenic therapies, such as the anti-VEGF antibody bevacizumab, with cancer vaccines for improved treatment of solid tumors. PMID:26005708

  15. Microneedle delivery of autoantigen for immunotherapy in type 1 diabetes.

    PubMed

    Zhao, Xin; Birchall, James C; Coulman, Sion A; Tatovic, Danijela; Singh, Ravinder K; Wen, Li; Susan Wong, F; Dayan, Colin M; Hanna, Stephanie J

    2016-02-10

    Antigen specific immunotherapy mediated via the sustained generation of regulatory T cells arguably represents the ideal therapeutic approach to preventing beta cell destruction in type 1 diabetes. However, there is a need to enhance the efficacy of this approach to achieve disease modification in man. Previous studies suggest that prolonged expression of self-antigen in skin in a non-inflammatory context is beneficial for tolerance induction. We therefore sought to develop a dry-coated microneedle (MN) delivery system and combine it with topical steroid to minimise local inflammation and promote prolonged antigen presentation in the skin. Here we show that a combination of surface-modified MNs coated with appropriate solvent systems can deliver therapeutically relevant quantities of peptide to mouse and human skin even with hydrophobic peptides. Compared to conventional "wet" intradermal (ID) administration, "dry" peptide delivered via MNs was retained for longer in the skin and whilst topical hydration of the skin with vehicle or steroid accelerated loss of ID-delivered peptide from the skin, MN delivery of peptide was unaffected. Furthermore, MN delivery resulted in enhanced presentation of antigen to T cells in skin draining lymph nodes (LNs) both 3 and 10days after administration. Repeated administration of islet antigen peptide via MN was effective at reducing antigen-specific T cell proliferation in the pancreatic LN, although topical steroid therapy did not enhance this. Taken together, these data show auto-antigenic peptide delivery into skin using coated MNs results in prolonged retention and enhanced antigen presentation compared to conventional ID delivery and this approach may have potential in individuals identified as being at a high risk of developing type 1 diabetes and other autoimmune diseases. PMID:26739548

  16. Advances in the Treatment of Food Allergy: Sublingual and Epicutaneous Immunotherapy.

    PubMed

    Sindher, Sayantani; Fleischer, David M; Spergel, Jonathan M

    2016-02-01

    Food allergies continue to increase in prevalence. Standard care is a strict elimination diet, but life-threatening reactions still occur. Allergen immunotherapy has the most potential in treating food allergy. Subcutaneous immunotherapy has not been adopted into food allergy therapy. Oral immunotherapy has a high rate of adverse reactions. Sublingual immunotherapy (SLIT) uses the tolerogenic environment of the oral mucosa and epicutaneous immunotherapy (EPIT) uses the immune cells of the epidermis to transport antigens to afferent lymph nodes to activate immune responses. SLIT and EPIT can successfully desensitize patients. More research is needed to define optimal doses and administration protocols. PMID:26617226

  17. Early gene expression changes with rush immunotherapy

    PubMed Central

    2011-01-01

    Background To examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC) from allergic patients undergoing rush immunotherapy (RIT) that might be manifest within the first few months of treatment. Methods For this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI) expression and T-regulatory cell frequency as detected by expression of CD3+CD4+CD25bright cells at each timepoint using flow cytometry. Results In comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ?1.5-fold expression change (p less than or equal to 0.05, BH-FDR), we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR), we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1?, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints. Conclusions We observed significant changes in gene expression early in peripheral blood samples from allergic patients undergoing RIT. Moreover, serum levels for allergen specific IgG4 also increased over the course of treatment. These studies suggest that RIT induces rapid and dynamic alterations in both innate and adaptive immunity which can be observed in the periphery of allergic patients. These alterations could be directly related to the therapeutic shift in the allergen-specific class of immunoglobulin. PMID:21961521

  18. Cancer immunotherapy: are we there yet?

    PubMed

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

    2013-01-01

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

  19. A review of allergoid immunotherapy: is cat allergy a suitable target?

    PubMed

    Nguyen, Nhung T; Raskopf, Esther; Shah-Hosseini, Kija; Zadoyan, Gregor; Msges, Ralph

    2016-03-01

    To modify the course of allergy, different types of specific allergen immunotherapy have been developed such as sublingual immunotherapy and subcutaneous immunotherapy with native allergens or subcutaneous immunotherapy with polymerized allergoids. However, the optimal specific immunotherapy, especially for cat allergy, remains undetermined. Few studies investigating immunotherapy in cat allergy have been published, and the risk of serious adverse reactions and systemic reactions has often been an important issue. Monomeric allergoids have lower allergenic potential while their immunogenicity remains constant, resulting in excellent safety with notable efficacy. Specific immunotherapy with monomeric allergoids could, therefore, be of high value, especially in cat allergy as well as other types of allergy, and bring relief to a great community of patients. PMID:26860435

  20. [Monoclonal immunotherapy with human monoclonal antibody(CLN-IgG) in glioma patients].

    PubMed

    Kubo, Osami; Takakura, Kintomo

    2002-03-01

    It is well recognized that malignant gliomas escape an immune response by hiding behind the blood-brain barrier and by producing proteins that suppress systemic immunity. However, if gliomas can be made to be more immunogenic or if a tumor vaccine can be produced, then access to all tumor cells including those that infiltrate into the brain can be achieved through the patient's immune response. Several strategies have been investigated for immunotherapy. Laboratory studies and animal models have shown that these immune cells will attack the tumor cell, reduce the size of implanted tumors, and that the immune memory is sufficient to suppress tumor growth when the animal is rechallenges with a tumor implant. Since the development of hybridoma technology, monoclonal antibodies against human cancer cells have been produced and antigens have been identified. Hagiwara reported the production of a human monoclonal antibody, CLN-IgG, made by fusing UC 729-6, human lymphoblastoid B-cell line, with lymphocytes obtained from a patient with the cervical carcinoma. It has been reported that CLN-IgG recognized the antigen expressed in various histological types of human cancers including malignant gliomas. The effect of human monoclonal antibody(CLN-IgG) on malignant brain tumors was evaluated in patients with malignant glioma. Early phase II study was concluded that this specific immunotherapy with CLN-IgG is safe and effective therapy in patients with malignant glioma. We treated 10 cases of malignant gliomas with CLN-IgG. All patients had received radiotherapy and chemotherapy before this immunotherapy using the human monoclonal antibody. The human monoclonal antibody(CLN-IgG) was administered intravenously once or twice/week during 24 weeks. Six cases of glioblastoma, 1 medulloblastoma and 3 cases of potine glioma histologically unverified, were treated. Five cases of 6 glioblastomas died 4 to 12 months after this treatment, 3 cases of pontine glioma showed good responses, 2 cases showed marked decrease of tumor size and 1 case showed no regrowth of tumor on MRI imaging. For the above reasons, Human monoclonal antibody(CLN-IgG) might be useful as an immunotherapy of malignant gliomas. PMID:11904965

  1. NK Cell-based Immunotherapies in Pediatric Oncology

    PubMed Central

    McDowell, Kimberly A.; Hank, Jacquelyn A.; DeSantes, Kenneth B.; Capitini, Christian M.; Otto, Mario; Sondel, Paul M.

    2015-01-01

    The past decade has seen several anti-cancer immunotherapeutic strategies transition from “promising preclinical models” to treatments with proven clinical activity or benefit. In 2013, the journal Science selected the field of Cancer Immunotherapy as the overall number-1 breakthrough for the year in all of scientific research. In the setting of cancer immunotherapy for adult malignancies, many of these immunotherapy strategies have relied on the cancer patient’s endogenous anti-tumor T cell response. While much promising research in pediatric oncology is similarly focused on T cell reactivity, several pediatric malignancies themselves, or the chemo-radiotherapy used to achieve initial responses, can be associated with profound immune suppression, particularly of the T cell system. A separate component of the immune system, also able to mediate anti-tumor effects and less suppressed by conventional cancer treatment, is the NK cell system. In recent years, several distinct immunotherapeutic approaches that rely on the activity of NK cells have moved from preclinical development into clinical testing, and some have shown clear antitumor benefit. This review provides an overview of NK cell-based immunotherapy efforts that are directed towards childhood malignancies, with an emphasis on protocols that are already in clinical testing. PMID:25590232

  2. Toward effective immunotherapy for the treatment of malignant brain tumors

    PubMed Central

    Mitchell, Duane A.; Sampson, John H.

    2009-01-01

    The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this reinvigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included in order to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors. PMID:19560742

  3. Immunotherapy for multiple myeloma: Current status and future directions.

    PubMed

    Ayed, Ayed O; Chang, Lung-Ji; Moreb, Jan S

    2015-12-01

    Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies and has been in the limelight of fast-track development of novel drugs that have contributed to the transformation of a rapidly lethal disease into a chronic illness with significant improvement in quality of life. Nonetheless, MM remains an incurable disease in many patients. Immunotherapy has been one of the approaches that had the highest hope for curing this disease. More than two decades of research and clinical trials in immunotherapy for MM have however resulted in very little impact on patient survival. The various immunotherapy approaches that have been attempted over the last two decades but were fraught with failure have already been extensively summarized in many published reviews. Nevertheless, in view of better understanding of the immune checkpoints, the innate immune system, and improved biotechnology, there is renewed hope. In this review, we will briefly discuss the unsuccessful approaches and emphasize the lessons learned, highlight the challenges that lie ahead, and discuss the more promising approaches, that already exist or being developed such as use of allogeneic stem cell transplants (allo-SCT) as a form of cellular immunotherapy, new monoclonal antibodies, chimeric antigen receptor (CAR) T-cell adoptive therapy, and NK cell therapy. PMID:26153389

  4. Immunotherapy for glioma: from illusion to realistic prospects?

    PubMed

    Dietrich, Pierre-Yves; Dutoit, Valrie; Walker, Paul R

    2014-01-01

    There is now evidence that the rules established for tumor immunology and immunotherapy in general are relevant for brain tumors. Treatment strategies explored have mainly involved vaccines using either tumor cells or components, and vaccines with defined synthetic peptides. This latter approach offers the advantage to select well-characterized antigens with selective or preferential expression on glioma. This is a prerequisite because collateral damage to the brain is not allowed. A second strategy which is reaching clinical trials is T cell therapy using the patients' own lymphocytes engineered to become tumor reactive. Tumor specificity can be conferred by forced expression of either a high-avidity T cell receptor or an antitumor antibody (the latter cells are called chimeric antigen receptors). An advantage of T cell engineering is the possibility to modify the cells to augment cellular activation, in vivo persistence and resistance to the tumor immunosuppressive milieu. A direct targeting of the hostile glioma microenvironment will additionally be required for achieving potent immunotherapy and various trials are assessing this issue. Finally, combining immunotherapy with immune checkpoint inhibitors and chemotherapy must be explored within rigorous clinical trials that favor constant interactions between the bench and bedside. Regarding immunotherapy for glioma patients, what was an unrealistic dream a decade ago is today a credible prospect. PMID:24857060

  5. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy.

    PubMed

    Swift, Stephanie L; Stojdl, David F

    2016-01-01

    Large-scale assays, such as microarrays, next-generation sequencing and various "omics" technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy-from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse-has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system. PMID:26861383

  6. Immunotherapy: Using the Immune System to Treat Cancer

    Cancer.gov

    Immunotherapies are treatments that restore or enhance the immune systems 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.

  7. Novel technologies and emerging biomarkers for personalized cancer immunotherapy.

    PubMed

    Yuan, Jianda; Hegde, Priti S; Clynes, Raphael; Foukas, Periklis G; Harari, Alexandre; Kleen, Thomas O; Kvistborg, Pia; Maccalli, Cristina; Maecker, Holden T; Page, David B; Robins, Harlan; Song, Wenru; Stack, Edward C; Wang, Ena; Whiteside, Theresa L; Zhao, Yingdong; Zwierzina, Heinz; Butterfield, Lisa H; Fox, Bernard A

    2016-01-01

    The culmination of over a century's work to understand the role of the immune system in tumor control has led to the recent advances in cancer immunotherapies that have resulted in durable clinical responses in patients with a variety of malignancies. Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, not all patients respond to immunotherapy and even those that do often experience toxicities. Thus, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of the mechanisms underlying the complex interactions between the immune system and cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) reconvened an Immune Biomarkers Task Force to review state of the art technologies, identify current hurdlers, and make recommendations for the field. As a product of this task force, Working Group 2 (WG2), consisting of international experts from academia and industry, assembled to identify and discuss promising technologies for biomarker discovery and validation. Thus, this WG2 consensus paper will focus on the current status of emerging biomarkers for immune checkpoint blockade therapy and discuss novel technologies as well as high dimensional data analysis platforms that will be pivotal for future biomarker research. In addition, this paper will include a brief overview of the current challenges with recommendations for future biomarker discovery. PMID:26788324

  8. Towards Curative Cancer Immunotherapy: Overcoming Posttherapy Tumor Escape

    PubMed Central

    Zhou, Gang; Levitsky, Hyam

    2012-01-01

    The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction. PMID:22778760

  9. Cancer immunotherapy highlights from the 2014 ASCO Meeting.

    PubMed

    Harshman, Lauren C; Drake, Charles G; Wargo, Jennifer A; Sharma, Padmanee; Bhardwaj, Nina

    2014-08-01

    The promise of cancer immunotherapy was validated officially in March 2011 when the FDA approved Yervoy (ipilimumab; Bristol-Myers Squibb) for the treatment of unresectable or metastatic melanoma. The approval was based on results of a randomized, double-blind clinical trial establishing that ipilimumab (a humanized anti-CTLA-4 monoclonal antibody) treatment extended the overall survival of patients with advanced melanoma. CTLA-4 is a member of the so-called family of checkpoint regulators, which are expressed on immune cells that activate or inhibit an immune response. An increasing number of immune checkpoint regulators are now being identified and targeted for immunotherapy. At the 2014 meeting of the American Society of Clinical Oncology (ASCO), it was reported that checkpoint blockade as a monotherapy or combination therapy was used successfully to treat advanced melanoma and non-small cell lung cancer. Checkpoint blockade immunotherapy was also used successfully for the treatment of other cancers, most notably genitourinary cancers such as urothelial bladder cancer and metastatic renal cell carcinoma. This report is a compiled summary of cancer immunotherapy highlights presented at the 2014 ASCO meeting by various investigators. PMID:25092813

  10. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    PubMed Central

    Swift, Stephanie L.; Stojdl, David F.

    2016-01-01

    Large-scale assays, such as microarrays, next-generation sequencing and various “omics” technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy—from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse—has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system. PMID:26861383

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

    PubMed Central

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

    2015-01-01

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

  12. Neuropathology and Amyloid-? Spectrum in a Bapineuzumab Immunotherapy Recipient

    PubMed Central

    Roher, Alex E.; Maarouf, Chera L.; Daugs, Ian D.; Kokjohn, Tyler A.; Hunter, Jesse M.; Sabbagh, Marwan N.; Beach, Thomas G.

    2011-01-01

    The field of Alzheimers disease (AD) research eagerly awaits the results of a large number of Phase III clinical trials that are underway to investigate the effectiveness of anti-amyloid-? (A?) immunotherapy for AD. In this case report, we review the pertinent clinical history, examine the neuropathology, and characterize the A? profile of an AD patient who received bapineuzumab immunotherapy. The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of A? due to immunotherapy. The A? species profile of this case was compared with non-immunized AD cases and non-demented controls and found to be similar to non-immunized AD cases. SELDI-TOF mass spectrometric analysis revealed the presence of full-length A?1-42 and truncated A? peptides demonstrating species with and without bapineuzumab specific epitopes. These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment. PMID:21263194

  13. Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax.

    PubMed

    Huang, Bruce; Xie, Tao; Rotstein, David; Fang, Hui; Frucht, David M

    2015-10-01

    The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay. PMID:26426050

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

    PubMed Central

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

    2013-01-01

    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

  15. Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax

    PubMed Central

    Huang, Bruce; Xie, Tao; Rotstein, David; Fang, Hui; Frucht, David M.

    2015-01-01

    The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay. PMID:26426050

  16. Immunotherapy of acute radiation syndromes with antiradiation gamma G globulin.

    NASA Astrophysics Data System (ADS)

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

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

  17. 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

  18. 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

  19. Bacterial vectors for active immunotherapy reach clinical and industrial stages

    PubMed Central

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

    2012-01-01

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

  20. Cellular-Based Immunotherapies for Patients with Glioblastoma Multiforme

    PubMed Central

    Xu, Xun; Stockhammer, Florian; Schmitt, Michael

    2012-01-01

    Treatment of patients with glioblastoma multiforme (GBM) remains to be a challenge with a median survival of 14.6?months following diagnosis. Standard treatment options include surgery, radiation therapy, and systemic chemotherapy with temozolomide. Despite the fact that the brain constitutes an immunoprivileged site, recent observations after immunotherapies with lysate from autologous tumor cells pulsed on dendritic cells (DCs), peptides, protein, messenger RNA, and cytokines suggest an immunological and even clinical response from immunotherapies. Given this plethora of immunomodulatory therapies, this paper gives a structure overview of the state-of-the art in the field. Particular emphasis was also put on immunogenic antigens as potential targets for a more specific stimulation of the immune system against GBM. PMID:22474481

  1. Overview of Cellular Immunotherapy for Patients with Glioblastoma

    PubMed Central

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

    2010-01-01

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

  2. Is Sublingual Immunotherapy the Final Answer? Implications for the Allergist

    PubMed Central

    2008-01-01

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

  3. Novel targets for natural killer/T-cell lymphoma immunotherapy.

    PubMed

    Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

    2016-01-01

    Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL. PMID:26642249

  4. FcγR requirements leading to successful immunotherapy.

    PubMed

    Dahal, Lekh N; Roghanian, Ali; Beers, Stephen A; Cragg, Mark S

    2015-11-01

    Monoclonal antibody (mAb) immunotherapy is currently experiencing an unprecedented amount of success, delivering blockbuster sales for the pharmaceutical industry. Having experienced several false dawns and overcoming technical issues which limited progress, we are now entering a golden period where mAbs are becoming a mainstay of treatment regimes for diseases ranging from cancer to autoimmunity. In this review, we discuss how these mAbs are most likely working and focus in particular on the key receptors that they interact with to precipitate their therapeutic effects. Although their targets may vary, their engagement with Fcγ receptors (FcγRs) on numerous immune effector cells is almost universal, and here we review their roles in delivering successful immunotherapy. PMID:26497516

  5. Management of polysensitized patient: from molecular diagnostics to biomolecular immunotherapy.

    PubMed

    Ciprandi, Giorgio; Incorvaia, Cristoforo; Frati, Franco

    2015-01-01

    A panel of Italian allergists gathered to discuss the issue concerning the management of polysensitized patients. The main conclusions were as follows: polysensitization is a relevant clinical characteristic as it affects about 70-80% of the global allergic population; the diagnostic pathway needs the use of an adequate and thorough methodology, based on the demonstration of consistency between history and documented sensitization; polysensitization and polyallergy are not synonymous: true allergy should always be demonstrated; polysensitization does not constitute a limitation to allergen immunotherapy prescription, as 1-2 allergen extracts could be effective in polysensitized patients; the allergen immunotherapy product characteristics should include the following: high efficacy and optimal safety profile, standardized production, and documented presence and titration of the major allergen. PMID:26144241

  6. Current role of immunotherapy for the treatment of prostate cancer.

    PubMed

    Porfyris, O; Kalomoiris, P

    2013-01-01

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

  7. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade

    PubMed Central

    Emens, Leisha A

    2013-01-01

    Breast cancer is immunogenic, and infiltrating immune cells in primary breast tumors convey important clinical prognostic and predictive information. Furthermore, the immune system is critically involved in clinical responses to some standard cancer therapies. Early breast cancer vaccine trials have established the safety and bioactivity of breast cancer immunotherapy, with hints of clinical activity. Novel strategies for modulating regulators of immunity, including regulatory T cells, myeloid-derived suppressor cells and immune checkpoint pathways (monoclonal antibodies specific for the cytotoxic T-lymphocyte antigen-4 or programmed death), are now available. In particular, immune checkpoint blockade has enormous therapeutic potential. Integrative breast cancer immunotherapies that strategically combine established breast cancer therapies with breast cancer vaccines, immune checkpoint blockade or both should result in durable clinical responses and increased cures. PMID:23253225

  8. Mutanome Engineered RNA Immunotherapy: Towards Patient-Centered Tumor Vaccination

    PubMed Central

    Vormehr, Mathias; Schrrs, Barbara; Boegel, Sebastian; Lwer, Martin; Treci, zlem; Sahin, Ugur

    2015-01-01

    Advances in nucleic acid sequencing technologies have revolutionized the field of genomics, allowing the efficient targeting of mutated neoantigens for personalized cancer vaccination. Due to their absence during negative selection of T cells and their lack of expression in healthy tissue, tumor mutations are considered as optimal targets for cancer immunotherapy. Preclinical and early clinical data suggest that synthetic mRNA can serve as potent drug format allowing the cost efficient production of highly efficient vaccines in a timely manner. In this review, we describe a process, which integrates next generation sequencing based cancer mutanome mapping, in silico target selection and prioritization approaches, and mRNA vaccine manufacturing and delivery into a process we refer to as MERIT (mutanome engineered RNA immunotherapy). PMID:26844233

  9. Immunotherapy and targeted therapy for cervical cancer: an update.

    PubMed

    Menderes, Gulden; Black, Jonathan; Schwab, Carlton L; Santin, Alessandro D

    2016-01-01

    The prognosis of patients with metastatic cervical cancer is poor with a median survival of 8-13 months. Despite the potency of chemotherapeutic drugs, this treatment is rarely curative and should be considered palliative only. In the last few years, a better understanding of Human papillomavirus tumor-host immune system interactions and the development of new therapeutics targeting immune check points have renewed interest in the use of immunotherapy in cervical cancer patients. Moreover, next generation sequencing has emerged as an attractive option for the identification of actionable driver mutations and other markers. In this review, we provide background information on the molecular biology of cervical cancer and summarize immunotherapy studies, targeted therapies, including those with angiogenesis inhibitors and tyrosine kinase inhibitors recently completed or currently on-going in cervical cancer patients. PMID:26568261

  10. Genetic modification of natural killer cells for adoptive cellular immunotherapy.

    PubMed

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

    2009-07-01

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

  11. [Progress in monoclonal antibody-based immunotherapy for cancer treatment].

    PubMed

    Guo, Yajun

    2015-06-01

    More than 100 years ago, Paul Ehrlich first proposed the "magic bullets" concept in which antibody targeting disease related antigen can fight against human disease. Since then, with the development of hybridoma technology for monoclonal antibody production and cancer serum therapy, immunotherapy based monoclonal antibody bas been used in chinical practice to treat hematological and solid tumor. Up to now, more than 20 recombinant antibody drugs were approved for cancer treatment worldwide. In recent years, the next-generation antibody drug, including immune checkpoint antagonists, bi-specific antibody, and antibody drug conjugates have successfully cured various malignant tumor. This review recalled the history of monoclonal antibody as potent immunotherapy of cancer firstly, and focused on the next-generation antibody drug's mechanism of action, construction strategies, and the side effects in clinic. Lastly, the future trend of anti-tumor antibody drug was also discussed. PMID:26672362

  12. Nanotechnology to augment immunotherapy for the treatment of glioblastoma multiforme.

    PubMed

    Ung, Nolan; Yang, Isaac

    2015-07-01

    Glioblastoma multiforme (GBM) is characterized as one of the most common and most deadly malignant primary brain tumors. Current treatment modalities include the use of surgical resection and adjuvant chemotherapy and radiation therapy, though survival is still limited. Because of this, new treatment strategies are needed to improve overall survival. Immunotherapy has emerged as a potential treatment, but still possesses certain limitations to have a substantial clinical effect. In addition, nanotechnology has emerged as potent treatment effectors that have been shown to augment the effects of therapies including chemotherapy, gene therapy, and more. Nanoparticles possess a novel approach due to the myriad of functional groups that can create targeted treatments, though further optimization is still required. In this review, the authors will present the current uses and abilities of nanotechnology and its implication for use with immunotherapy in the treatment of GBM. PMID:26070553

  13. [Self defense instead of offense - Immunotherapy in lung cancer].

    PubMed

    Moldvay, Judit; Ostoros, Gyula

    2016-03-01

    Lung cancer is the leading cause of cancer death worldwide and also in Hungary, therefore new therapeutic strategies are of great importance. Among immunotherapeutic approaches immune checkpoint inhibition appears to be the most promising. Recent studies have shown efficacy of immunotherapy, especially in squamous cell lung cancer, which is a big step forward in the treatment of this histological subtype. Unlike in the molecularly targeted therapies, the patient selection method has not yet been developed, although some studies indicate the predictive value of tumor cell PD-L1 immunopositivity, especially in lung adenocarcinoma. Introduction of immunotherapy carries challenge for clinicians regarding the radiological assessment of therapeutic efficiency as well as the management of side effects of new profile. The favorable results of recent studies, however, provide hope in this malignancy still presenting a major therapeutic challenge. PMID:26934348

  14. Current advances in T-cell-based cancer immunotherapy

    PubMed Central

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

    2015-01-01

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

  15. Cytomegalovirus-targeted immunotherapy and glioblastoma: hype or hope?

    PubMed

    Ferguson, Sherise D; Srinivasan, Visish M; Ghali, Michael Gz; Heimberger, Amy B

    2016-04-01

    Malignant gliomas, including glioblastoma (GBM), are the most common primary brain tumors. Despite extensive research only modest gains have been made in long-term survival. Standard of care involves maximizing safe surgical resection followed by concurrent chemoradiation with temozolomide. Immunotherapy for GBM is an area of intense research in recent years. New immunotherapies, although promising, have not been integrated into standard practice. Human cytomegalovirus (HCMV) is a DNA virus of the family Herpesviridae. Human seroprevalence is approximately 80%, and in most cases, is associated with asymptomatic infection. HCMV may be an important agent in the initiation, promotion and/or progression of tumorigenesis. Regardless of a possible etiologic role in GBM, interest has centered on exploiting this association for development of immunomodulatory therapies. PMID:26973123

  16. New Strategies in Bladder Cancer: A Second Coming for Immunotherapy.

    PubMed

    Ghasemzadeh, Ali; Bivalacqua, Trinity J; Hahn, Noah M; Drake, Charles G

    2016-02-15

    Urothelial bladder cancer (UBC) remains one of the most common and deadly cancers worldwide, and platinum-based chemotherapy, which has been the standard-of-care in metastatic bladder cancer, has had limited success in improving outcomes for patients. The recent development and translation of therapeutic strategies aimed at harnessing the immune system have led to durable and prolonged survival for patients with several different cancers, including UBC. In this review, we discuss new findings in bladder cancer immunotherapy, including recent successes with immune checkpoint blockade. We also discuss therapeutic cancer vaccines and highlight several additional immunotherapy modalities in early stages of development. Clin Cancer Res; 22(4); 793-801. ©2015 AACR. PMID:26683632

  17. The failure of immunotherapy with dinitrochlorobenzene and Rhus extract for recurrent conjunctival squamous papillomas.

    PubMed

    Novick, N L; Bosniak, S L

    1986-06-01

    A 25-year-old white male is described who presented with recurrent conjunctival squamous papillomata. Despite prior reports of successful dinitrochlorobenzene use for tropical immunotherapy, its failure in our patient, and the first documented attempt to employ Rhus oleoresin (poison ivy/oak) extract for topical conjunctival immunotherapy is reported. The role of topical immunotherapy in treating recurrent conjunctival papillomas is discussed. PMID:2940277

  18. Is immunotherapy an opportunity for effective treatment of drug addiction?

    PubMed

    Zalewska-Kaszubska, Jadwiga

    2015-11-27

    Immunotherapy has a great potential of becoming a new therapeutic strategy in the treatment of addiction to psychoactive drugs. It may be used to treat addiction but also to prevent neurotoxic complications of drug overdose. In preclinical studies two immunological methods have been tested; active immunization, which relies on the administration of vaccines and passive immunization, which relies on the administration of monoclonal antibodies. Until now researchers have succeeded in developing vaccines and/or antibodies against addiction to heroin, cocaine, methamphetamine, nicotine and phencyclidine. Their effectiveness has been confirmed in preclinical studies. At present, clinical studies are being conducted for vaccines against nicotine and cocaine and also anti-methamphetamine monoclonal antibody. These preclinical and clinical studies suggest that immunotherapy may be useful in the treatment of addiction and drug overdose. However, there are a few problems to be solved. One of them is controlling the level of antibodies due to variability between subjects. But even obtaining a suitable antibody titer does not guarantee the effectiveness of the vaccine. Additionally, there is a risk of intentional or unintentional overdose. As vaccines prevent passing of drugs through the blood/brain barrier and thereby prevent their positive reinforcement, some addicted patients may erroneously seek higher doses of psychoactive substances to get "high". Consequently, vaccination should be targeted at persons who have a strong motivation to free themselves from drug dependency. It seems that immunotherapy may be an opportunity for effective treatment of drug addiction if directed to adequate candidates for treatment. For other addicts, immunotherapy may be a very important element supporting psycho- and pharmacotherapy. PMID:26432911

  19. Treg infiltration in glioma: a hurdle for antiglioma immunotherapy.

    PubMed

    Vandenberk, Lien; Van Gool, Stefaan W

    2012-07-01

    Tregs play a crucial role in glioma-mediated immunosuppression; hence, tackling the Treg population in patients with malignant glioma could improve the clinical success rate of antiglioma immunotherapy. Therefore, it is of high importance to elucidate the mechanisms responsible for Treg recruitment and retention within the glioma microenvironment. The current paper demonstrates that, in addition to preferential chemoattraction, glioma-derived soluble factors can also induce preferential Treg proliferation and survival. These data identify new targets for Treg modulating strategies. PMID:22853753

  20. Mechanistic basis of immunotherapies for type 1 diabetes mellitus.

    PubMed

    Chen, Wenhao; Xie, Aini; Chan, Lawrence

    2013-04-01

    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. 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

  1. Advances in chimeric antigen receptor immunotherapy for neuroblastoma.

    PubMed

    Heczey, Andras; Louis, Chrystal U

    2013-12-01

    Neuroblastoma (NBL) is the most common extracranial pediatric solid tumor and has heterogeneous biology and behavior. Patients with high-risk disease have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. Immunotherapy is a novel therapeutic approach that harnesses the inherent activity of the immune system to control and eliminate malignant cells. One form of immunotherapy uses chimeric antigen receptors (CAR) to target tumor-associated antigens. CARs are derived from the antigen-binding domain of a monoclonal antibody (MAb) coupled with the intracellular signaling portion of the T cell receptor. CARs can combine the specificity and effectiveness of MAbs with the active bio-distribution, direct cytotoxicity, and long-term persistence of T cells. NBL provides an attractive target for CAR immunotherapy as many of its tumor-associated antigens are not expressed at significant levels on normal tissues, thus decreasing potential treatment related toxicity. Two previous clinical trials utilizing L1-cell adhesion molecule (L1-CAM) and disialoganglioside (GD2) specific CARs (GD2-CAR) have demonstrated safety and anti-tumor efficacy in heavily pretreated relapsed/refractory neuroblastoma patients. Based on these promising results and on improved techniques that can further potentiate CAR therapies, two clinical trials are currently investigating the use of GD2-CARs in children with NBL. Several approaches may further enhance anti-tumor activity and persistence of CAR modified cells, and if these can be safely translated into the clinic, CAR-based immunotherapy could become a viable adjunct or potential alternative to conventional treatment options for patients with NBL. PMID:24333408

  2. Advances in Chimeric Antigen Receptor Immunotherapy for Neuroblastoma

    PubMed Central

    Heczey, Andras; Louis, Chrystal U.

    2014-01-01

    Neuroblastoma (NBL) is the most common extracranial pediatric solid tumor and has heterogeneous biology and behavior. Patients with high-risk disease have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. Immunotherapy is a novel therapeutic approach that harnesses the inherent activity of the immune system to control and eliminate malignant cells. One form of immunotherapy uses chimeric antigen receptors (CAR) to target tumor-associated antigens. CARs are derived from the antigen-binding domain of a monoclonal antibody (MAb) coupled with the intracellular signaling portion of the T cell receptor. CARs can combine the specificity and effectiveness of MAbs with the active bio-distribution, direct cytotoxicity, and long-term persistence of T cells. NBL provides an attractive target for CAR immunotherapy as many of its tumor-associated antigens are not expressed at significant levels on normal tissues, thus decreasing potential treatment related toxicity. Two previous clinical trials utilizing L1-cell adhesion molecule (L1-CAM) and disialoganglioside (GD2) specific CARs (GD2-CAR) have demonstrated safety and anti-tumor efficacy in heavily pretreated relapsed/refractory neuroblastoma patients. Based on these promising results and on improved techniques that can further potentiate CAR therapies, two clinical trials are currently investigating the use of GD2-CARs in children with NBL. Several approaches may further enhance anti-tumor activity and persistence of CAR modified cells, and if these can be safely translated into the clinic, CAR-based immunotherapy could become a viable adjunct or potential alternative to conventional treatment options for patients with NBL. PMID:24333408

  3. Preliminary Evaluation of a Bunyavirus Vector for Cancer Immunotherapy.

    PubMed

    Oreshkova, N; Spel, L; Vloet, R P M; Wichgers Schreur, P J; Moormann, R J M; Boes, M; Kortekaas, J

    2015-09-01

    Replicon particles of Rift Valley fever virus, referred to as nonspreading Rift Valley fever virus (NSR), are intrinsically safe and highly immunogenic. Here, we demonstrate that NSR-infected human dendritic cells can activate CD8(+) T cells in vitro and that prophylactic and therapeutic vaccinations of mice with NSR encoding a tumor-associated CD8 peptide can control the outgrowth of lymphoma cells in vivo. These results suggest that the NSR system holds promise for cancer immunotherapy. PMID:26085169

  4. Assessing T-cell responses in anticancer immunotherapy

    PubMed Central

    Escors, David; Liechtenstein, Therese; Perez-Janices, Noemi; Schwarze, Julia; Dufait, Ines; Goyvaerts, Cleo; Lanna, Alessio; Arce, Frederick; Blanco-Luquin, Idoia; Kochan, Grazyna; Guerrero-Setas, David; Breckpot, Karine

    2013-01-01

    Since dendritic cells operate as professional antigen-presenting cells (APCs) and hence are capable of jumpstarting the immune system, they have been exploited to develop a variety of immunotherapeutic regimens against cancer. In the few past years, myeloid-derived suppressor cells (MDSCs) have been shown to mediate robust immunosuppressive functions, thereby inhibiting tumor-targeting immune responses. Thus, we propose that the immunomodulatory activity of MDSCs should be carefully considered for the development of efficient anticancer immunotherapies. PMID:24244902

  5. Immunotherapy for Prostate Cancer – Recent Developments and Future Challenges

    PubMed Central

    Schweizer, Michael T.; Drake, Charles G.

    2014-01-01

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

  6. Immunomonitoring in glioma immunotherapy: current status and future perspectives.

    PubMed

    Lamano, Jonathan B; Ampie, Leonel; Choy, Winward; Kesavabhotla, Kartik; DiDomenico, Joseph D; Oyon, Daniel E; Parsa, Andrew T; Bloch, Orin

    2016-03-01

    Given the continued poor clinical outcomes and refractory nature of glioblastoma multiforme to traditional interventions, immunotherapy is gaining traction due to its potential for specific tumor-targeting and long-term antitumor protective surveillance. Currently, development of glioma immunotherapy relies on overall survival as an endpoint in clinical trials. However, the identification of surrogate immunologic biomarkers can accelerate the development of successful immunotherapeutic strategies. Immunomonitoring techniques possess the potential to elucidate immunological mechanisms of antitumor responses, monitor disease progression, evaluate therapeutic effect, identify candidates for immunotherapy, and serve as prognostic markers of clinical outcome. Current immunomonitoring assays assess delayed-type hypersensitivity, T cell proliferation, cytotoxic T-lymphocyte function, cytokine secretion profiles, antibody titers, and lymphocyte phenotypes. Yet, no single immunomonitoring technique can reliably predict outcomes, relegating immunological markers to exploratory endpoints. In response, the most recent immunomonitoring assays are incorporating emerging technologies and novel analysis techniques to approach the goal of identifying a competent immunological biomarker which predicts therapy responsiveness and clinical outcome. This review addresses the current status of immunomonitoring in glioma vaccine clinical trials with emphasis on correlations with clinical response. PMID:26638171

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

    PubMed Central

    Pandolfi, F.; Cianci, R.; Pagliari, D.; Casciano, F.; Bagal, 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

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

    PubMed

    Fierabracci, A

    2011-01-01

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

  9. Recent advances in immunotherapy and vaccine development for peanut allergy

    PubMed Central

    2015-01-01

    Peanut allergy is a common problem and can be the cause of severe, life-threatening allergic reactions. It rarely resolves, with the majority of patients carrying the disease onto adulthood. Peanut allergy poses a significant burden on the quality of life of sufferers and their families, which results mainly from the fear of accidental peanut ingestion, but is also due to dietary and social restrictions. Current standard management involves avoidance, patient education and provision of emergency medication, for use in allergic reactions, when they occur. Efforts have been made to develop a vaccine for peanut allergy. Recent developments have also highlighted the use of immunotherapy, which has shown promise as an active form of treatment and may present a disease-modifying therapy for peanut allergy. So far, results, especially from oral immunotherapy studies, have shown good efficacy in achieving desensitization to peanut with a good safety profile. However, the capacity to induce long-term tolerance has not been demonstrated conclusively yet and larger, phase III studies are required to further investigate safety and efficacy of this intervention. Peanut immunotherapy is not currently recommended for routine clinical use or outside specialist allergy units. PMID:26288733

  10. Can Alzheimer disease be prevented by amyloid-beta immunotherapy?

    PubMed

    Lemere, Cynthia A; Masliah, Eliezer

    2010-02-01

    Alzheimer disease (AD) is the most common form of dementia. The amyloid-beta (Abeta) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive Abeta immunotherapies have been shown to lower cerebral Abeta levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 Abeta vaccine was stopped when approximately 6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive Abeta immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active Abeta vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, Abeta immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Abeta immunization. PMID:20140000

  11. Immunotherapy for Brain Cancer: Recent Progress and Future Promise

    PubMed Central

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

    2016-01-01

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

  12. Immunotherapy in Multiple Myeloma Using Cancer-Testis Antigens

    PubMed Central

    Ghafouri-Fard, Soudeh; Seifi-Alan, Mahnaz; Shamsi, Roshanak; Esfandiary, Ali

    2015-01-01

    Context: Multiple myeloma (MM) is a B-cell malignancy characterized by monoclonal expansion of abnormal plasma cells in the bone marrow. It accounts for 10% of hematological malignancies. Although patients respond to a wide range of anticancer modalities, relapse occurs in a significant number of the cases. Immunotherapeutic approaches have been evolved to tackle this problem. Cancer-testis antigens CTAs as a group of tumor-associated antigens are appropriate targets for cancer immunotherapy as they have restricted expression pattern in normal tissues except for testis which is an immune-privileged site. Expression of these antigens has been assessed in different malignancies including MM. Evidence Acquisition: We performed a computerized search of the MEDLINE/PubMed databases with key words: multiple myeloma, cancer-testis antigen, and cancer stem cell and immunotherapy. Results: Several CTAs including NY-ESO-1, MAGE and GAGE family have been shown to be expressed in MM patients. Cellular and humoral immune responses against these antigens have been detected in MM patients. Conclusions: The frequent and high expression level of CTAs in MM patients shows that these antigens can be applied as cancer biomarkers as well as targets for immunotherapy in these patients. PMID:26634107

  13. Imaging the immune response to monitor tumor immunotherapy.

    PubMed

    Wang, Qin; Ornstein, Moshe; Kaufman, Howard L

    2009-10-01

    The goal of cancer immunotherapy is to promote antitumor immunity, and novel approaches include vaccination, adoptive transfer of tumor-reactive T cells, and administration of monoclonal antibodies and small molecules that target immune regulatory pathways. The molecular and cellular events responsible for tumor rejection are not completely defined and correlative studies have been used to help understand the mechanisms and extent of immune activation and tumor regression with these approaches. The real-time monitoring of immune responses to immunotherapy has been challenging as specific cell subsets may be difficult to define, and molecular pathways have evolved functionally diverse outcomes in different cells and in different tissues. Recently, improvements in optics and digital imaging have led to novel imaging techniques that make it possible to track the migration of individual immune cells ex vivo and in vivo, and to detect the dynamic interactions between T cells and antigen-presenting cells or tumor cells within complex microenvironments, including lymphoid tissue and established tumors. This review will explain some of the more established imaging techniques and discuss their role in monitoring the immune response in patients treated with various tumor immunotherapy approaches. PMID:19803763

  14. Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy.

    PubMed

    Maio, Michele; Covre, Alessia; Fratta, Elisabetta; Di Giacomo, Anna Maria; Taverna, Pietro; Natali, Pier Giorgio; Coral, Sandra; Sigalotti, Luca

    2015-09-15

    Epigenetic regulation allows heritably modulating gene expression profiles without modifying the primary sequence of gDNA. Under physiologic conditions, epigenetic patterns determine tissue-specific gene expression landscapes, gene imprinting, inactivation of chromosome X, and preservation of genomic stability. The most characterized mediators of epigenetic inheritance are gDNA methylation and histone posttranslational modifications that cooperate to alter chromatin state and genome transcription. According to these notions, it is not surprising that cancer cells invariantly deploy epigenetic alterations to achieve gene expression patterns required for neoplastic transformation and tumor progression. In this context, the recently uncovered use of epigenetic alterations by cancer cells to become stealth from the host's immune recognition has significant immunobiologic relevance in tumor progression, and it appears to have potential clinical usefulness. Indeed, immune evasion is among the major obstacles to further improve the efficacy of cancer immunotherapies and to increase long-lasting disease control. Luckily, different "epigenetic drugs" able to revert these "epimutations" are available, some of which have already been approved for clinical use. Here, we summarize the immunomodulatory activities of epigenetic drugs that lead to improved immune recognition of cancer cells and focus on the potential of this class of agents in improving the anticancer activity of novel immunotherapies through combinatorial epigenetic immunotherapy approaches. PMID:26374074

  15. Bubble-Assisted Ultrasound: Application in Immunotherapy and Vaccination.

    PubMed

    Escoffre, Jean-Michel; Deckers, Roel; Bos, Clemens; Moonen, Chrit

    2016-01-01

    Bubble-assisted ultrasound is a versatile technology with great potential in immunotherapy and vaccination. This technology involves the exposure of immune cells (i.e., dendritic cells, lymphocytes) in-vitro or diseased tissues (i.e., brain, tumor) in-vivo to ultrasound treatment with gas bubbles. Bubble destruction leads to physical forces that induce the direct delivery of weakly permeant immuno-stimulatory molecules either into the cytoplasm of immune cells, or through the endothelial barrier of diseased tissues. Hence, therapeutic antibodies (i.e., antibody-based immunotherapy) and cytokine-encoding nucleic acids (i.e., cytokine gene therapy) can be successfully delivered into diseased tissues, thus improving immune responses. In addition, protein antigens, as well as antigen-encoding nucleic acids (pDNA, mRNA), can be delivered into dendritic cells (i.e., dendritic cell-based vaccines), thus leading to a long-lasting prophylactic or therapeutic immunization. This chapter focuses on the state-of-the-art of bubble-assisted ultrasound in the field of immunotherapy and vaccination. PMID:26486342

  16. Possible role of laser phototherapy in laser immunotherapy

    NASA Astrophysics Data System (ADS)

    Hode, Tomas; Hode, Lars

    2009-02-01

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

  17. Laser immunotherapy: a novel approach for metastatic tumors

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Korbelik, Mladen; Bartels, Kenneth E.; Liu, Hong; Nordquist, Robert E.

    2004-08-01

    The ideal treatment modality for tumors, particularly for those that metastasize to multiple remote sites, should eradicate the primary tumor and elicit a systemic, tumor-specific response leading to elimination of metastases and to long-term tumor immunity. Using the selective photothermal interaction as a precursor, laser immunotherapy was developed by introducing a novel immunoadjuvant administered in conjunction with the laser-absorbing dye. Specifically, an 805-nm laser and indocyanine green (ICG) was used for the selective photothermal interaction, and a novel immunoadjuvant, glycated chitosan (GC), was used as the immunological stimulant. The laser-ICG-GC combinations has been resulted in the following results in animal studies. (1) Selective destruction of deep target tumor target has been achieved; (2) Eradication of treated primary tumors and regression and disappearance of untreated distant metastases have been observed; (3) Long-term survival of tumor-bearing rats have been resulted; (4) Long-term immunity for resistance to repeated, dose-escalated subsequent tumor challenges has been induced; (5) Tumor-specific immunological responses, after laser immunotherapy treatment, have been detected at cellular and molecular levels. The procedure of laser immunotherapy and major results in animal studies will be summarized and some new results using the immunological enhancement for photodynamic therapy treatment will be presented.

  18. Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy.

    PubMed

    Pilon-Thomas, Shari; Kodumudi, Krithika N; El-Kenawi, Asmaa E; Russell, Shonagh; Weber, Amy M; Luddy, Kimberly; Damaghi, Mehdi; Wojtkowiak, Jonathan W; Mulé, James J; Ibrahim-Hashim, Arig; Gillies, Robert J

    2016-03-15

    Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation. Cancer Res; 76(6); 1381-90. ©2015 AACR. PMID:26719539

  19. Sublingual allergen immunotherapy in HIV-positive patients.

    PubMed

    Iemoli, E; Borgonovo, L; Fusi, A; Magni, C; Ricci, E D; Rizzardini, G; Piconi, S

    2016-03-01

    HIV infection is a relative contraindication for allergic immunotherapy (AIT). In the last decade, highly active antiretroviral therapy (HAART) has improved the immune function and life expectancy in HIV-infected patients whose respiratory allergic incidence is similar to the general population. We evaluated the safety and clinical effectiveness of sublingual immunotherapy in a group of grass pollen-allergic HAART-treated HIV-positive patients. Thirteen patients received sublingual immunotherapy (SLIT) tablet (Oralair, Stallergenes©) and symptomatic therapy and were compared with nine patients receiving symptomatic therapy alone. Clinical benefits were evaluated by the analysis of total combined score (TCS), sum of symptom-medication score, and a quality of life (QoL) questionnaire. HIV viral load and peripheral TCD4 lymphocytes were analyzed at the beginning and at the end of the study. Clinical efficacy data showed a significant improvement in SLIT-treated patients compared to controls (TCS: P = 0.0001; QoL: P = 0.03). We did not observe any significant alteration of TCD4 cell counts and viral load (VL) in both groups. Our preliminary data showed that SLIT therapy in viro-immunological controlled HAART treated HIV positive patients was efficacious, safe and well tolerated. PMID:26228482

  20. Cancer immunotherapy in veterinary medicine: Current options and new developments.

    PubMed

    Regan, Daniel; Guth, Amanda; Coy, Jonathan; Dow, Steven

    2016-01-01

    Excitement in the field of tumor immunotherapy is being driven by several remarkable breakthroughs in recent years. This review will cover recent advances in cancer immunotherapy, including the use of T cell checkpoint inhibitors, engineered T cells, cancer vaccines, and anti-B cell and T cell antibodies. Inhibition of T cell checkpoint molecules such as PD-1 and CTLA-4 using monoclonal antibodies has achieved notable success against advanced tumors in humans, including melanoma, renal cell carcinoma, and non-small cell lung cancer. Therapy with engineered T cells has also demonstrated remarkable tumor control and regression in human trials. Autologous cancer vaccines have recently demonstrated impressive prolongation of disease-free intervals and survival times in dogs with lymphoma. In addition, caninized monoclonal antibodies targeting CD20 and CD52 just recently received either full (CD20) or conditional (CD52) licensing by the United States Department of Agriculture for clinical use in the treatment of canine B-cell and T-cell lymphomas, respectively. Thus, immunotherapy for cancer is rapidly moving to the forefront of cancer treatment options in veterinary medicine as well as human medicine. PMID:26545847

  1. 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

  2. Current status of immunotherapy in B cell malignancies.

    PubMed

    Kofler, D M; Mayr, C; Wendtner, C-M

    2006-10-01

    Conventional treatment of hematologic malignancies mainly consists of chemotherapeutic agents or a combination of both, chemotherapy and monoclonal antibodies. Despite recent advances, chemotherapeutic treatments often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore the evaluation of novel therapeutic options is of great interest. B cell malignancies, in particularly follicular lymphomas, chronic lymphocytic leukemia and multiple myeloma, represent the most immune-responsive types of all human cancer. Several immunotherapeutic strategies are presently employed to combat these B-cell malignancies. Active immunotherapies include vaccination strategies with dendritic cells (DCs) and genetically-modified tumor cell preparations as well as DNA and protein vaccination. Most of these vaccines target the tumor-specific immunoglobulin idiotype and have already demonstrated some anti-lymphoma activity in early phase clinical trials while their definitive impact is evaluated in ongoing phase III randomized trials. In contrast to these active immunizations, T cells transduced with chimeric antigen receptors and donor leukocyte infusions (DLI) represent adoptive (passive) immunotherapies. Recent advances of gene transduction technologies enabled improvement of immunotherapeutic strategies based on genetic modification of malignant cells or adoptive T cells. Current early phase clinical trials are investigating the potential of these innovative approaches. At the moment it remains unclear if the novel immunotherapeutic strategies will be able to play a similar role in the treatment of B cell malignancies than the already established antibody-based immunotherapy. PMID:17073599

  3. 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

  4. 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

  5. Oral and sublingual immunotherapy for food allergy: current progress and future directions

    PubMed Central

    Moran, Timothy P; Vickery, Brian P; Burks, A Wesley

    2014-01-01

    Food allergies are increasing in prevalence and present an emerging epidemic for westernized countries. Strict dietary avoidance is the only approved management for food allergy, but accidental exposures regularly occur, leading to significant patient anxiety and decreased quality of life. Over the past decade, oral and sublingual immunotherapies have emerged as potential treatments for food allergy. While several small clinical trials have demonstrated that immunotherapy can desensitize food-allergic individuals, strategies for further enhancing safety and definitively establishing long-term efficacy are needed. This review presents an overview of recent oral and sublingual immunotherapy trials, and provides a glimpse into what the next generation of food immunotherapy may entail. PMID:23972904

  6. Effect of Immunotherapy on Seizure Outcome in Patients with Autoimmune Encephalitis: A Prospective Observational Registry Study

    PubMed Central

    Jung, Keun-Hwa; Sunwoo, Jun-Sang; Moon, Jangsup; Lim, Jung-Ah; Lee, Doo Young; Shin, Yong-Won; Kim, Tae-Joon; Lee, Keon-Joo; Lee, Woo-Jin; Lee, Han-Sang; Jun, Jinsun; Kim, Dong-Yub; Kim, Man-Young; Kim, Hyunjin; Kim, Hyeon Jin; Suh, Hong Il; Lee, Yoojin; Kim, Dong Wook; Jeong, Jin Ho; Choi, Woo Chan; Bae, Dae Woong; Shin, Jung-Won; Jeon, Daejong; Park, Kyung-Il; Jung, Ki-Young; Chu, Kon; Lee, Sang Kun

    2016-01-01

    Objective To evaluate the seizure characteristics and outcome after immunotherapy in adult patients with autoimmune encephalitis (AE) and new-onset seizure. Methods Adult (age ≥18 years) patients with AE and new-onset seizure who underwent immunotherapy and were followed-up for at least 6 months were included. Seizure frequency was evaluated at 2–4 weeks and 6 months after the onset of the initial immunotherapy and was categorized as “seizure remission”, “> 50% seizure reduction”, or “no change” based on the degree of its decrease. Results Forty-one AE patients who presented with new-onset seizure were analysed. At 2–4 weeks after the initial immunotherapy, 51.2% of the patients were seizure free, and 24.4% had significant seizure reduction. At 6 months, seizure remission was observed in 73.2% of the patients, although four patients died during hospitalization. Rituximab was used as a second-line immunotherapy in 12 patients who continued to have seizures despite the initial immunotherapy, and additional seizure remission was achieved in 66.6% of them. In particular, those who exhibited partial response to the initial immunotherapy had a better seizure outcome after rituximab, with low adverse events. Conclusion AE frequently presented as seizure, but only 18.9% of the living patients suffered from seizure at 6 months after immunotherapy. Aggressive immunotherapy can improve seizure outcome in patients with AE. PMID:26771547

  7. Escalating immunotherapy of multiple sclerosis.Austrian-German- Swiss Multiple Sclerosis Therapy Consensus Group [MSTCG].

    PubMed

    Rieckmann, P; Toyka, K V

    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 even hampered by monetary restrictions or reluctance of the medical community to adjust their approach to new treatments. After an initial inquiry had shown that less than 50% of eligible patients received any active immunomodulating treatment, a consensus group of Austrian, German and Swiss MS societies was formed in order to prepare a report of the current treatment options in MS. The aim of this report is to present the consensus on a new concept of escalating immunotherapy in MS. Future updates of the report are planned on a yearly basis or whenever substantial new evidence becomes available. PMID:10529535

  8. [Immunotherapy of Urothelial Carcinoma of the Bladder-? from BCG Vaccines to Targeted Therapy].

    PubMed

    Matoukov, M

    2015-01-01

    Bladder cancer has high prevalence in men and women. Bladder cancer usually originates from urothelium. More than 75% of cases are classified as nonmuscle?invasive bladder cancer. Urothelial bladder carcinoma is usually managed by transurethral resection of the bladder tumor. Role of transurethral resection of the bladder tumor is also essential in bladder cancer staging. Local prophylaxis is used in nonmuscle?invasive bladder cancer to reduce risk of recurrence. While local chemoprophylaxis is sufficient in low and middle risk patients, intravesical instillation of Mycobacterium bovis bacillus CalmetteGuerin (BCG) is preferred in high risk bladder cancer. Chemotherapy alone or in combination with locoregional treatment is used in advanced bladder cancer. New immunotherapy modalities have proven their efficacy in several clinical studies in advanced bladder cancer. PMID:26647897

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

    PubMed Central

    Rutella, Sergio; Locatelli, Franco

    2012-01-01

    Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome. PMID:22567028

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

    NASA Astrophysics Data System (ADS)

    Dewi, C.; Trisilowati

    2015-03-01

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

  11. Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer.

    PubMed

    Rosalia, Rodney A; Arenas-Ramirez, Natalia; Bouchaud, Grgory; Raeber, Miro E; Boyman, Onur

    2014-12-01

    The use of interleukin-2 (IL-2) for the stimulation of an effector immune response against metastatic cancer dates back to the early 1980s. Administration of unmodified IL-2, either alone or together with antigen-specific approaches, has resulted in remarkably long-term survival of some patients suffering from metastatic melanoma. However, such treatment is usually hampered by the appearance of toxic adverse effects, which has motivated the engineering of modified IL-2 formulations showing reduced toxicity while being more potent at stimulating anti-tumor effector immune cells. In this review we summarize and discuss the features and biological relevance of several enhanced IL-2 formulations, compare these to IL-15-based therapeutics, and try to foreshadow their potential in immunological research and immunotherapy. PMID:25271022

  12. A cell membrane modification technique using domain 4 of intermedilysin for immunotherapy against cancer.

    PubMed

    Nagamune, Hideaki; Ohkura, Kazuto; Umezu, Kazunori; Shouji, Hidekatsu; Kourai, Hiroki

    2004-01-01

    Rapid cell membrane modification techniques are currently being sought in order to develop gene therapy and cellular immunotherapy modalities against cancer and other diseases. We developed a novel technique using the non-toxic portion of intermedilysin, a streptolysin O family cytolysin with a high affinity for human cell membranes, as a cell membrane adaptor module. Domain 4 recombinants of intermedilysin with linker sites at the N-terminus were designed. These modules are able to bind tightly to human cells after simple incubation and have no harmful effects. The modules were conjugated with the partially reduced or unreduced F(ab')2 of an anti-carcinoembryonic antigen monoclonal antibody. Erythrocytes bound to these conjugates were shown to specifically target a carcinoembryonic antigen-positive cell line, TT, in vitro. This is a promising technique for the development of convenient and effective anticancer treatment methods. PMID:15515433

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

    PubMed Central

    2008-01-01

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

  14. 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 saponintreated 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 saponintreated 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

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

    PubMed

    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 (Aβ), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against Aβ leads to the clearance of deposits in transgenic mice expressing human Aβ. 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-Aβ antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (FcγR) 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 FcγR by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that FcγR 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 FcγR 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 FcγR in the healthy and diseased brain. Here we review the literature on FcγR 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

  16. 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

  17. Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy

    PubMed Central

    Kersten, Kelly; Salvagno, Camilla; de Visser, Karin E.

    2015-01-01

    Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer immunotherapy strategies aimed at maximizing success of immunotherapy. Here, we discuss how tumors orchestrate an immunosuppressive microenvironment, which contributes to their escape from immune attack. Relieving the immunosuppressive networks in cancer patients is an attractive strategy to extend the clinical success of cancer immunotherapy. Since the clinical availability of drugs specifically targeting immunosuppressive cells or mediators is still limited, an alternative strategy is to use conventional chemotherapy drugs with immunomodulatory properties to improve cancer immunotherapy. We summarize the preclinical and clinical studies that illustrate how the anti-tumor T cell response can be enhanced by chemotherapy-induced relief of immunosuppressive networks. Treatment strategies aimed at combining chemotherapy-induced relief of immunosuppression and T cell-boosting checkpoint inhibitors provide an attractive and clinically feasible approach to overcome intrinsic and acquired resistance to cancer immunotherapy, and to extend the clinical success of cancer immunotherapy. PMID:26500653

  18. Addition of Interleukin-21 for Expansion of T-Cells for Adoptive Immunotherapy of Murine Melanoma

    PubMed Central

    Zoon, Christine Kathryn; Wan, Wen; Graham, Laura; Bear, Harry D.

    2015-01-01

    We previously demonstrated that interleukin (IL)-7/15 was superior to IL-2 for expansion of T cells in vitro for adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Nave T cell receptor (TcR) transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I) for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and metastases counted 14 days after treatment. Culturing lymphocytes in IL-7/15/21 increased expansion compared to IL-2 or IL-7/15. IL-21 and IL-7/15/21 increased CD8+ cells compared to IL-2 or IL-7/15. IL-21 preferentially expanded a CD8+CD44?CD62L+ T nave population, whereas IL-7/15/21 increased CD8+CD44+CD62Lhigh central-memory T cells. T cells grown in IL-7/15/21 were more effective at reducing metastases than IL-2. The addition of IL-21 to IL-7/15 induced greater expansion of lymphocytes in culture and increased the yield of CD8+ T central-memory cells vs. IL-7/15 alone. This may have significant impact on future clinical trials of adoptive immunotherapy, particularly for generating adequate numbers of lymphocytes for treatment. PMID:25903148

  19. Addition of interleukin-21 for expansion of T-cells for adoptive immunotherapy of murine melanoma.

    PubMed

    Zoon, Christine Kathryn; Wan, Wen; Graham, Laura; Bear, Harry D

    2015-01-01

    We previously demonstrated that interleukin (IL)-7/15 was superior to IL-2 for expansion of T cells in vitro for adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Nave T cell receptor (TcR) transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I) for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and metastases counted 14 days after treatment. Culturing lymphocytes in IL-7/15/21 increased expansion compared to IL-2 or IL-7/15. IL-21 and IL-7/15/21 increased CD8+ cells compared to IL-2 or IL-7/15. IL-21 preferentially expanded a CD8+CD44-CD62L+ T "nave" population, whereas IL-7/15/21 increased CD8+CD44+CD62Lhigh central-memory T cells. T cells grown in IL-7/15/21 were more effective at reducing metastases than IL-2. The addition of IL-21 to IL-7/15 induced greater expansion of lymphocytes in culture and increased the yield of CD8+ T central-memory cells vs. IL-7/15 alone. This may have significant impact on future clinical trials of adoptive immunotherapy, particularly for generating adequate numbers of lymphocytes for treatment. PMID:25903148

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

    PubMed Central

    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

    2014-01-01

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

  1. 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

  2. Venom immunotherapy in patients with mastocytosis and hymenoptera venom anaphylaxis.

    PubMed

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

    2011-05-01

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

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

    PubMed

    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

  4. Dendritic Cell-Based Immunotherapy for Myeloid Leukemias

    PubMed Central

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

    2013-01-01

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

  5. 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.

  6. 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

  7. Subcutaneous Immunotherapy Improves the Symptomatology of Allergic Rhinitis

    PubMed Central

    Lourenço, Edmir Américo; Caldeira, Eduardo José; Carvalho, César Alexandre Fabrega; Cunha, Marcelo Rodriques; Carvalho, Marcus Vinícius Henriques; Passos, Saulo Duarte

    2015-01-01

    Introduction The relevance of allergic rhinitis is unquestionable. This condition affects people's quality of life and its incidence has increased over the last years. Objective Thus, this study aims to analyze the effectiveness of subcutaneous injectable immunotherapy in cases of nasal itching, sneeze, rhinorrhea and nasal congestion in allergic rhinitis patients. Methods In the present study, the same researcher analyzed the records of 281 patients. Furthermore, the researchers identified allergens through puncture cutaneous tests using standardized extracts containing acari, fungi, pet hair, flower pollen, and feathers. Then, the patients underwent treatment with subcutaneous specific immunotherapy, using four vaccine vials for desensitization, associated with environmental hygiene. The authors analyzed conditions of nasal itching, sneeze, rhinorrhea, and nasal congestion throughout the treatment, and assigned them with a score ranging from zero (0), meaning absence of these symptoms to three (3), for severe cases. The symptoms were statistically compared in the beginning, during, and after treatment. Results In this study, authors analyzed the cases distribution according to age and the evolution of symptomatology according to the scores, comparing all phases of treatment. The average score for the entire population studied was 2.08 before treatment and 0.44 at the end. These results represent an overall improvement of ∼79% in symptomatology of allergic rhinitis in the studied population. Conclusion The subcutaneous immunotherapy as treatment of allergic rhinitis led to a reduction in all symptoms studied, improving the quality of life of patients, proving itself as an important therapeutic tool for these pathological conditions. PMID:26722338

  8. 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

  9. Subcutaneous Immunotherapy Improves the Symptomatology of Allergic Rhinitis.

    PubMed

    Lourenço, Edmir Américo; Caldeira, Eduardo José; Carvalho, César Alexandre Fabrega; Cunha, Marcelo Rodriques; Carvalho, Marcus Vinícius Henriques; Passos, Saulo Duarte

    2016-01-01

    Introduction The relevance of allergic rhinitis is unquestionable. This condition affects people's quality of life and its incidence has increased over the last years. Objective Thus, this study aims to analyze the effectiveness of subcutaneous injectable immunotherapy in cases of nasal itching, sneeze, rhinorrhea and nasal congestion in allergic rhinitis patients. Methods In the present study, the same researcher analyzed the records of 281 patients. Furthermore, the researchers identified allergens through puncture cutaneous tests using standardized extracts containing acari, fungi, pet hair, flower pollen, and feathers. Then, the patients underwent treatment with subcutaneous specific immunotherapy, using four vaccine vials for desensitization, associated with environmental hygiene. The authors analyzed conditions of nasal itching, sneeze, rhinorrhea, and nasal congestion throughout the treatment, and assigned them with a score ranging from zero (0), meaning absence of these symptoms to three (3), for severe cases. The symptoms were statistically compared in the beginning, during, and after treatment. Results In this study, authors analyzed the cases distribution according to age and the evolution of symptomatology according to the scores, comparing all phases of treatment. The average score for the entire population studied was 2.08 before treatment and 0.44 at the end. These results represent an overall improvement of ∼79% in symptomatology of allergic rhinitis in the studied population. Conclusion The subcutaneous immunotherapy as treatment of allergic rhinitis led to a reduction in all symptoms studied, improving the quality of life of patients, proving itself as an important therapeutic tool for these pathological conditions. PMID:26722338

  10. Sublingual grass and ragweed immunotherapy: Clinical considerations-a PRACTALL consensus report.

    PubMed

    Li, James T; Bernstein, David I; Calderon, Moises A; Casale, Thomas B; Cox, Linda; Passalacqua, Giovanni; Pfaar, Oliver; Papadopoulos, Nikolaos G

    2016-02-01

    Sublingual allergen immunotherapy provides a new option for patients with allergic rhinitis in the United States. The efficacy of these sublingual immunotherapy tablets in the treatment of allergic rhinitis has been firmly established in large multicenter clinical trials. In addition, the clinical benefits of sublingual immunotherapy might persist after treatment is discontinued. Local reactions, such as gastrointestinal or oropharyngeal symptoms, are common. However, severe anaphylaxis is rare, and therefore the immunotherapy tablets can be administered at home. Sublingual immunotherapy for allergic rhinitis has been used successfully for years in Europe, and these products might be appropriate for patients who do not do well with standard drug therapy or for those who prefer a disease-modifying approach. PMID:26371843

  11. How can nanotechnology help membrane vesicle-based cancer immunotherapy development?

    PubMed Central

    Tian, Xin; Zhu, Motao; Nie, Guangjun

    2013-01-01

    Exosomes are nanosized vesicles originating from endosomal compartments and secreted by most living cells. In the past decade, exosomes have emerged as potent tools for cancer immunotherapy due to their important roles in modulation of immune responses, and promising results have been achieved in exosome-based immunotherapy. The recent rapid progress of nanotechnology, especially on tailored design of nanocarriers for drug delivery based on both passive and active targeting strategies, sheds light on re-engineering native membrane vesicles for enhanced immune regulation and therapy. Applications of nanotechnology toolkits might provide new opportunity not only for value-added therapeutic or diagnostic strategies based on exosomes in cancer immunotherapy, but also new insights for biogenesis and biological relevance of membrane vesicles. This commentary focuses on the recent development and limitations of using exosomes in cancer immunotherapy and our perspectives on how nanomaterials with potential immune regulatory effects could be introduced into exosome-based immunotherapy. PMID:23108359

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

    PubMed

    Yatsuda, Junji; Eto, Masatoshi

    2014-12-01

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

  13. 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

  14. 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

  15. Allergen-specific sublingual immunotherapy for respiratory allergy.

    PubMed

    Passalacqua, G; Canonica, G W

    2001-01-01

    Present knowledge regarding the clinical efficacy and safety of sublingual immunotherapy (SLIT) for the treatment of respiratory allergy is reviewed. Allergen-specific immunotherapy is presently considered a 'biological response modifier' for the treatment of respiratory allergy, to be used in association with drug therapy and allergen avoidance. Its value in the treatment of these conditions has been established in position papers from the World Health Organization and the European Academy of Allergology and Clinical Immunology. Immunotherapy is usually administered subcutaneously (SCIT), and with this route several severe adverse events and fatalities have been described. Therefore, in the last 15 years, novel and safer routes of administration (local routes) have been developed. SLIT, in particular, has been investigated in 18 randomised controlled clinical trials. SLIT's clinical efficacy (improvement in symptoms and reduction in drug intake) in both asthma and rhinitis has been clearly assessed in 16 of these studies and for the most common allergens. SLIT's safety profile, derived from the clinical trials and from post-marketing surveillance studies, was shown to be satisfactory in both adults and children. The most frequently reported adverse events are gastrointestinal complaints, which can be avoided through appropriate dosage adjustment. For these reasons, SLIT has been accepted as a viable alternative to SCIT in recent position papers. The main advantages of SLIT are its safety (no severe systemic adverse event has ever been described) and good patient acceptance, especially in children; in addition, SLIT is a self-administered treatment that can be carried out at home by the patient. In contrast to injection immunotherapy, knowledge of the mechanisms of action of SLIT is still developing, albeit rapidly, although interesting data about its pharmacokinetics in humans are available. Data are also required concerning the possible preventive and long-lasting effects. SLIT is a viable alternative to SCIT, with the same rationale and indications. It is intended to be used in association with proper pharmacological treatment, at the earliest stages of the disease, for optimal management of respiratory allergy. PMID:11543692

  16. Sublingual immunotherapy for allergic respiratory diseases: efficacy and safety.

    PubMed

    Passalacqua, Giovanni; Canonica, Giorgio Walter

    2011-05-01

    Subcutaneous immunotherapy (SCIT) is effective and safe when properly prescribed and administered. However, a certain risk of severe side effects exists, even when the reaction is managed correctly. These potential adverse effects stimulated the search for new administration routes (nasal, bronchial, oral, sublingual), which were expected to be safer. Not all of these alternative routes provided an improved benefit-safety profile compared with SCIT. The sublingual route (SLIT) seemed to be a good candidate for the clinical practice because of its satisfactory safety profile and is now considered an acceptable alternative to SCIT in adults and children. PMID:21530819

  17. Adoptive cell transfer: a clinical path to effective cancer immunotherapy.

    PubMed

    Rosenberg, Steven A; Restifo, Nicholas P; Yang, James C; Morgan, Richard A; Dudley, Mark E

    2008-04-01

    Adoptive cell therapy (ACT) using autologous tumour-infiltrating lymphocytes has emerged as the most effective treatment for patients with metastatic melanoma and can mediate objective cancer regression in approximately 50% of patients. The use of donor lymphocytes for ACT is an effective treatment for immunosuppressed patients who develop post-transplant lymphomas. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment. PMID:18354418

  18. The journey from discoveries in fundamental immunology to cancer immunotherapy.

    PubMed

    Miller, Jacques F A P; Sadelain, Michel

    2015-04-13

    Recent advances in cancer immunotherapy have directly built on 50 years of fundamental and technological advances that made checkpoint blockade and Tcell engineering possible. In this review, we intend to show that research, not specifically designed to bring relief or cure to any particular disease, can, when creatively exploited, lead to spectacular results in the management of cancer. The discovery of thymus immune function, Tcells, and immune surveillance bore the seeds for today's targeted immune interventions and chimeric antigen receptors. PMID:25858803

  19. Allergen Immunotherapy Outcomes and Unmet Needs: A Critical Review.

    PubMed

    Caimmi, Davide; Calderon, Moises A; Bousquet, Jean; Demoly, Pascal

    2016-02-01

    Allergen immunotherapy (AIT) has been evaluated throughout several studies over the last years. A position paper from the European Academy of Allergy and Clinical Immunology highlighted the total combined symptoms score as the method to record the primary end point in AIT studies for allergic rhinitis, but this score still needs to be formally validated and more work done for other allergic diseases. These aspects still seem to be the main unmet need in the evaluation of AIT clinical outcomes in clinical trials. PMID:26617234

  20. Immunotherapy for Head and Neck Squamous Cell Carcinoma.

    PubMed

    Schoppy, David W; Sunwoo, John B

    2015-12-01

    Although head and neck squamous cell carcinoma has traditionally been considered to be a very immunosuppressive, or at least nonimmunogenic, tumor type, recent results from clinical studies of immune checkpoint blockade strategies have led to resurgence in the enthusiasm for immunotherapeutic approaches. Additional strategies for immunotherapy that are under active investigation include enhancement of cetuximab-mediated antibody-dependent cell-mediated cytotoxicity, tumor vaccines, and engineered T cells for adoptive therapy. All of these studies have early-phase clinical trials under way, and the next several years will be exciting as the results of these studies are reported. PMID:26568546

  1. Developing T cell cancer immunotherapy in the dog with lymphoma.

    PubMed

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

    2014-01-01

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

  2. 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 1821 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

  3. Hematopoietic stem cell transplant as a platform for tumor immunotherapy.

    PubMed

    Fuchs, Ephraim J; Whartenby, Katharine A

    2004-02-01

    Blood or marrow transplantation (BMT) has been utilized as a cancer therapy with varying levels of success. While it has been an important option for many hematological malignancies, it has met with less success in solid tumors. More recently, new combinations of therapies with BMT have been developed to enhance the efficacy of this therapy and to expand the number of target tumors. This review highlights current uses of BMT, rationales for experimental approaches using BMT alone or as a part of a combination therapy, and reviews some of the novel therapies that have been developed in tumor immunotherapy with BMT, in addition to the implications for translation. PMID:15011781

  4. Production of Monoclonal Antibodies in Plants for Cancer Immunotherapy

    PubMed Central

    Moussavou, Ghislain; Ko, Kisung; Lee, Jeong-Hwan; Choo, Young-Kug

    2015-01-01

    Plants are considered as an alternative platform for recombinant monoclonal antibody (mAb) production due to the improvement and diversification of transgenic techniques. The diversity of plant species offers a multitude of possibilities for the valorization of genetic resources. Moreover, plants can be propagated indefinitely, providing cheap biomass production on a large scale in controlled conditions. Thus, recent studies have shown the successful development of plant systems for the production of mAbs for cancer immunotherapy. However, their several limitations have to be resolved for efficient antibody production in plants. PMID:26550566

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

    PubMed Central

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

    2014-01-01

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

  6. Combination immunotherapy and photodynamic therapy for cancer

    NASA Astrophysics Data System (ADS)

    Hamblin, Michael R.; Castano, Ana P.; Mroz, Pawel

    2006-02-01

    Cancer is a leading cause of death among modern people largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with minimal toxicity towards normal tissue. This is best accomplished by priming the body's immune system to recognize the tumor antigens so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species leading to vascular shutdown and tumor cell death. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins. Combination regimens using PDT and immunostimulating treatments are likely to even further enhance post-PDT immunity. These immunostimulants are likely to include products derived from pathogenic microorganisms that are effectively recognized by Toll-like receptors and lead to upregulation of transcription factors for cytokines and inflammatory mediators. The following cascade of events causes activation of macrophages, dendritic and natural killer cells. Exogenous cytokine administration can be another way to increase PDT-induced immunity as well as treatment with a low dose of cyclophosphamide that selectively reduces T-regulatory cells. Although so far these combination therapies have only been used in animal models, their use in clinical trials should receive careful consideration.

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

    PubMed Central

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

    2009-01-01

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

  8. Novel IL-2-Poly(HPMA)Nanoconjugate Based Immunotherapy.

    PubMed

    Votavova, Petra; Tomala, Jakub; Subr, Vladimir; Strohalm, Jiri; Ulbrich, Karel; Rihova, Blanka; Kovar, Marek

    2015-09-01

    Interleukin-2 (IL-2) possesses a strong stimulatory activity for activated T and NK cells and it is an attractive molecule for immunotherapy. Nevertheless, extremely short half-life and severe toxicities associated with high-dose IL-2 treatment are serious and limiting drawbacks. In order to increase IL-2 half-life in vivo, we covalently conjugated synthetic semitelechelic polymeric carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) to IL-2. Thus, we synthesized IL-2-poly(HPMA) conjugate containing 2-3 polymer chains per IL-2 molecule in average. Such conjugate has lower biologic activity in comparison to IL-2 in vitro. However, it exerts much higher activity than IL-2 in vivo as shown by expansion of memory CD8+ T, NK, NKT, ??T and Treg cells. Moreover, IL-2-poly(HPMA) extremely effectively potentiates CD8+ T cell peptide-based vaccination. IL-2-poly(HPMA) shows also much longer half-time in circulation than IL-2 (-4 h versus -5 min). Collectively, modification of IL-2 with poly(HPMA) chains dramatically improves its potency and pharmacologic features in vivo, which have implications for immunotherapy. To our knowledge, this is the first proof-of-concept report of the use of polymer/protein modification of IL-2 to obtain more pronounced biological activity. PMID:26485935

  9. TAP-ing into TIEPPs for cancer immunotherapy.

    PubMed

    Kiessling, Rolf

    2016-02-01

    Cancer immunotherapy in which cytotoxic T cells (CTLs) target tumor-specific antigens complexed to MHC-I molecules has been used successfully for several types of cancer; however, MHC-I is frequently downregulated in tumors, resulting in CTL evasion. Recently, it has been shown that MHC-Ilo tumors produce a set of T cell epitopes associated with impaired peptide processing (TEIPP) that have potential to be exploited for immunotherapy. TEIPP-specific CTLs recognize tumors defective in antigen presentation machinery (APM) but not those with intact APM. In this issue of the JCI, Doorduljn et al. evaluated thymus selection and peripheral behavior of TEIPP-specific T cells, using a unique T cell receptor (TCR) transgenic mouse model. They demonstrated that TEIPP-specific T cells in TAP-deficient mice have largely been deleted by central tolerance, while the same T cells in WT mice are naive and sustained. The results of this study suggest that TIEPPs have potential to be successful targets for elimination of MHC-Ilo tumors. PMID:26784539

  10. Immunotherapy for non-small cell lung cancer

    PubMed Central

    Kelly, Ronan J.; Gulley, James L.; Giaccone, Giuseppe

    2012-01-01

    Developing effective immunotherapy for lung cancer is a daunting but hugely attractive challenge. Until recently, non-small cell lung cancer was thought of as a non-immunogenic tumor, but there is now evidence highlighting the integral role played by both inflammatory and immunological responses in lung carcinogenesis. Despite recent encouraging preclinical and phase I/II data, there is a paucity of phase III trials showing a clear clinical benefit for vaccines in lung cancer. There are many difficulties to overcome prior to the development of a successful therapy. Perhaps a measurable immune response may not translate into a clinically meaningful or radiological response. Patient selection may also be a problem for ongoing clinical studies. The majority of trials for lung cancer vaccines are focused on patients with advanced-stage disease, while the ideal candidates may be patients with a lower tumor burden stage I or II disease. Selecting the exact antigens to target is also difficult. It will likely require multiple epitopes of a diverse set of genes restricted to multiple haplotypes to generate a truly effective vaccine that is able to overcome the various immunologic escape mechanisms that tumors employ. This review discusses active immunotherapy employing protein/peptide vaccines, whole cell vaccines, and dendritic cell vaccines and examines the current data on some novel immunomodulating agents. PMID:20630824

  11. Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors

    PubMed Central

    De Felice, Francesca; Marchetti, Claudia; Palaia, Innocenza; Musio, Daniela; Muzii, Ludovico; Tombolini, Vincenzo; Panici, Pierluigi Benedetti

    2015-01-01

    Ovarian cancer is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies to improve the outcomes. Advances in understanding the role of immune system in the pathogenesis of cancer have led to the rapid evolvement of immunotherapy, which might establish a sustained immune system response against recurring cancer cells. Recently, it has emerged that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called immune checkpoints, which turn off the immune system. Similarly, cancer cells are able to use these checkpoints to avoid immune control and rejection. Inhibition of these inhibitory pathways represents a potent strategy in the fight against cancer and is currently under investigation with encouraging results in some cancers, such as melanoma. In ovarian cancer researches are still in an early phase, but with promising results. In this review we will explore the rationale of immunotherapy in ovarian cancer with a special focus on these emerging molecules. PMID:26236750

  12. 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

  13. Observations in immunotherapy of lymphoma and melanoma patients.

    PubMed Central

    Thomas, J W; Plenderleith, I H; Clements, D V; Landi, S

    1975-01-01

    Maintenance of remission solely by repeated BCG vaccinations in seven patients with non-Hodgkin's lymphoma who had achieved a complete clinical remission with initial standard therapy has provided sufficient encouragement to begin a randomized clinical trial. In vitro lymphocyte responses to mitogens and PPD used as parameters of cell-mediated immunity have not proved to be of value in predicting early or late recurrence in six pre-trial and trial patients. Eight out of twenty-one patients with malignant melanoma have shown a satisfactory clinical response (10-34 months) to immunotherapy. Those who respond must show immunological reactivity to the stimulating agent, however the best clinical responses were not associated with the highest degrees of in vivo and in vitro sensitization. The skin reactivity and the in vitro lymphocyte response to PPD as well as a 2-3-fold increase in the appearance of colony-forming units in the peripheral blood following the intratumour injection of BCG or PPD are helpful in prognosis and management of these patients. All patients with malignant melanoma who presented with a PHA response less than 40% of normal made a poor response to immunotherapy. Autopsies performed on seven patients dying with extensive melanocarcinomatous disease failed to show any serious adverse toxic reactions or infections from oral and intratumour injections of BCG. PMID:1102163

  14. Immunotherapy for neurodegenerative diseases: focus on α-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 (Aβ) protein in AD is a secreted molecule that circulates in blood and is readably recognized by antibodies. In contrast, α-synuclein (α-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 α-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 Aβ, α-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 α-synucleinopathies. PMID:23384597

  15. Langerhans cells as targets for immunotherapy against skin cancer

    PubMed Central

    Stoitzner, Patrizia; Sparber, Florian; Tripp, Christoph H

    2010-01-01

    Cancer is the second most common cause of death in the world. Treatment of cancer is very challenging and immunotherapy has been developed as a potential way to fight cancer. The main obstacle with immunotherapy is that cancer cells evolve from healthy body cells in response to an accumulation of genetic mutations. As a consequence, the immune system struggles to detect the abnormal cells as they are mainly recognized as self. This implies that equipping the immune system to eliminate cancer cells is tricky, yet represents a very efficient way to constrain the growth of tumors. We became interested in developing immunotherapeutical strategies against skin cancer in the context of our observations that Langerhans cells (LC) are very potent antigen presenting cells and are able to incorporate protein antigens and present them to CD4+ and CD8+ T cells in the skin-draining lymph nodes. As a consequence, we developed an immunization strategy through the skin, termed epicutaneous immunization. Protein antigen applied onto barrier-disrupted skin induces long-lasting cytotoxic T-cell responses, potent enough to control and inhibit tumor growth. In this review, we suggest that immunization strategies through the skin could be a promising new approach for the treatment of skin cancer. PMID:20351746

  16. Sublingual immunotherapy for pediatric allergic rhinitis: The clinical evidence.

    PubMed

    Poddighe, Dimitri; Licari, Amelia; Caimmi, Silvia; Marseglia, Gian Luigi

    2016-02-01

    Allergic rhinitis is estimated to affect 10%-20% of pediatric population and it is caused by the IgE-sensitization to environmental allergens, most importantly grass pollens and house dust mites. Allergic rhinitis can influence patient's daily activity severely and may precede the development of asthma, especially if it is not diagnosed and treated correctly. In addition to subcutaneous immunotherapy, sublingual immunotherapy (SLIT) represents the only treatment being potentially able to cure allergic respiratory diseases, by modulating the immune system activity. This review clearly summarizes and analyzes the available randomized, double-blinded, placebo-controlled trials, which aimed at evaluating the effectiveness and the safety of grass pollen and house dust mite SLIT for the specific treatment of pediatric allergic rhinitis. Our analysis demonstrates the good evidence supporting the efficacy of SLIT for allergic rhinitis to grass pollens in children, whereas trials regarding pediatric allergic rhinitis to house dust mites present lower quality, although several studies supported its usefulness. PMID:26862501

  17. Use of lectin-functionalized particles for oral immunotherapy

    PubMed Central

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

    2013-01-01

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

  18. Engulfing tumors with synthetic extracellular matrices for cancer immunotherapy

    PubMed Central

    Hori, Yuki; Stern, Patrick; Hynes, Richard O.; Irvine, Darrell J.

    2009-01-01

    Local immunotherapies are under investigation for treatment of unresectable tumors and sites of solid tumor resection to prevent local recurrence. Successful local therapy could also theoretically elicit systemic immune responses against cancer. Here we explored the delivery of therapeutic dendritic cells (DCs), cytokines, or other immunostimulatory factors to tumors via the use of self-gelling hydrogels based on the polysaccharide alginate, injected peritumorally around established melanoma lesions. Peritumoral injection of alginate matrices loaded with DCs and/or an interleukin-15 superagonist (IL-15SA) around 14-day established ova-expressing B16F0 murine melanoma tumors promoted immune cell accumulation in the peritumoral matrix, and matrix infiltration correlated with tumor infiltration by leukocytes. Single injections of IL-15SA-carrying gels concentrated the cytokine in the tumor site ~40-fold compared to systemic injection and enabled a majority of treated animals to suppress tumor growth for a week or more. Further, we found that single injections of alginate matrices loaded with IL-15SA and the Toll-like receptor ligand CpG or two injections of gels carrying IL-15SA alone could elicit comparable anti-tumor activity without the need for exogenous DCs. Thus, injectable alginate gels offer an attractive platform for local tumor immunotherapy and facilitates combinatorial treatments designed to promote immune responses locally at a tumor site while limiting systemic exposure to potent immunomodulatory factors. PMID:19766305

  19. Potentiating Cancer Immunotherapy Using Papaya Mosaic Virus-Derived Nanoparticles.

    PubMed

    Lebel, Marie-Ève; Chartrand, Karine; Tarrab, Esther; Savard, Pierre; Leclerc, Denis; Lamarre, Alain

    2016-03-01

    The recent development of novel immunotherapies is revolutionizing cancer treatment. These include, for example, immune checkpoint blockade, immunomodulation, or therapeutic vaccination. Although effective on their own, combining multiple approaches will most likely be required in order to achieve the maximal therapeutic benefit. In this regard, the papaya mosaic virus nanoparticle (PapMV) has shown tremendous potential as (i) an immunostimulatory molecule, (ii) an adjuvant, and (iii) a vaccine platform through its intrinsic capacity to activate the innate immune response in an IFN-α-dependent manner. Here, we demonstrate that intratumor administration of PapMV significantly slows down melanoma progression and prolongs survival. This correlates with enhanced chemokine and pro-inflammatory-cytokine production in the tumor and increased immune-cell infiltration. Proportions of total and tumor-specific CD8(+) T cells dramatically increase following PapMV treatment whereas those of myeloid-derived suppressor cells (MDSC) concomitantly decrease. Moreover, systemic PapMV administration prevents metastatic tumor-implantation in the lungs. Importantly, PapMV also synergistically improves the therapeutic benefit of dendritic cell (DC)-based vaccination and PD-1 blockade by potentiating antitumor immune responses. This study illustrates the immunostimulatory potential of a plant virus-derived nanoparticle for cancer therapy either alone or in conjunction with other promising immunotherapies in clinical development. PMID:26891174

  20. New Approaches to Immunotherapy for HPV Associated Cancers

    PubMed Central

    Bergot, Anne-Sophie; Kassianos, Andrew; Frazer, Ian H; Mittal, Deepak

    2011-01-01

    Cervical cancer is the second most common cancer of women worldwide and is the first cancer shown to be entirely induced by a virus, the human papillomavirus (HPV, major oncogenic genotypes HPV-16 and -18). Two recently developed prophylactic cervical cancer vaccines, using virus-like particles (VLP) technology, have the potential to prevent a large proportion of cervical cancer associated with HPV infection and to ensure long-term protection. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and do not prevent their progression to HPV-associated malignancy. In animal models, therapeutic vaccines for persisting HPV infection can eliminate transplantable tumors expressing HPV antigens, but are of limited efficacy in inducing rejection of skin grafts expressing the same antigens. In humans, clinical trials have reported successful immunotherapy of HPV lesions, providing hope and further interest. This review discusses possible new approaches to immunotherapy for HPV associated cancer, based on recent advances in our knowledge of the immunobiology of HPV infection, of epithelial immunology and of immunoregulation, with a brief overview on previous and current HPV vaccine clinical trials. PMID:24212964

  1. Rationale for anti-CD137 cancer immunotherapy.

    PubMed

    Makkouk, Amani; Chester, Cariad; Kohrt, Holbrook E

    2016-02-01

    The consideration of the complex interplay between the tumour microenvironment (TME) and the immune response is the key for designing effective immunotherapies. Therapeutic strategies that harness co-stimulatory receptors have recently gained momentum in the clinic. One such strategy with promising clinical applications is the targeting of CD137, a member of the tumour necrosis factor receptor superfamily. Its expression on both innate and adaptive immune cells, coupled with its unique ability to potentiate antitumour responses through modulating the TME and to ameliorate autoimmune responses, has established it as an appealing target. In this review, we will discuss the various CD137-targeted immunotherapeutics that have reached clinical development, with a focus on recent advances and novel modalities such as CD137 chimeric antigen receptors and CD137 bispecific antibodies. We will also highlight the effect of CD137 targeting on the TME and discuss the importance of probing TME changes for predicting and testing the efficacy of CD137-mediated immunotherapy. PMID:26751393

  2. Antigen-specific immunotherapies for acute myeloid leukemia.

    PubMed

    Buckley, Sarah A; Walter, Roland B

    2015-12-01

    Antigen-specific immunotherapies have emerged as important components of curative treatment algorithms for many cancers. In acute myeloid leukemia (AML), success has been less obvious. Nonetheless, among the few drugs shown to improve survival in recent randomized trials is the CD33 antibody-drug conjugate gemtuzumab ozogamicin. Significant antileukemic activity is also well documented for radioimmunoconjugates targeting CD33, CD45, or CD66. These therapeutics can intensify conditioning before hematopoietic cell transplantation, but their effect on patient outcomes needs clarification. Emerging data now suggest clinical antileukemic activity of several novel antibodies and perhaps some adoptive T-cell immunotherapies and vaccines. In parallel, numerous other agents targeting a wider variety of antigens are currently being explored. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that antigen-directed therapies become an effective tool in AML, a disease for which outcomes with standard "3 + 7"-based chemotherapy have remained unsatisfactory in many patients. PMID:26637776

  3. 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

  4. 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

  5. A novel nanoparticulate adjuvant for immunotherapy with Lolium perenne.

    PubMed

    Gmez, Sara; Gamazo, Carlos; San Roman, Beatriz; Grau, Alicia; Espuelas, Socorro; Ferrer, Marta; Sanz, Maria L; Irache, Juan M

    2009-08-31

    Specific immunotherapy implies certain drawbacks which could be minimized by the use of appropriate adjuvants, capable of amplifying the right immune response with minimal side effects. In this context, previous studies of our group have demonstrated the adjuvant capacity of Gantrez AN nanoparticles, which can effectively enhance the immune response. In this work, two types of nanoparticles (with and without LPS of Brucella ovis as immunomodulator) with encapsulated Lolium perenne extract are tested in a model of sensitized mice to this allergenic mixture. The results we obtained showed that Lolium-Gantrez nanoparticles with LPS of B. ovis were able to induce significative Th1 responses, characterized by the IgG(2a) isotype. Furthermore, in the challenge experiment of the sensitized mice, differences in the mortality rate and in the mMCP-1 levels were found between the treated groups and the control. Under the experimental conditions of this model of pre-sensitized mice to L. perenne, Gantrez AN nanoparticles appeared to be a good strategy for immunotherapy. PMID:19545572

  6. Current Clinical Trials Testing Combinations of Immunotherapy and Radiation

    PubMed Central

    Crittenden, M.; Kohrt, H.; Levy, R.; Jones, J.; Camphausen, K.; Dicker, A.; Demaria, S.; Formenti, S.

    2014-01-01

    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, 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

  7. Sublingual immunotherapy for pediatric allergic rhinitis: The clinical evidence

    PubMed Central

    Poddighe, Dimitri; Licari, Amelia; Caimmi, Silvia; Marseglia, Gian Luigi

    2016-01-01

    Allergic rhinitis is estimated to affect 10%-20% of pediatric population and it is caused by the IgE-sensitization to environmental allergens, most importantly grass pollens and house dust mites. Allergic rhinitis can influence patient’s daily activity severely and may precede the development of asthma, especially if it is not diagnosed and treated correctly. In addition to subcutaneous immunotherapy, sublingual immunotherapy (SLIT) represents the only treatment being potentially able to cure allergic respiratory diseases, by modulating the immune system activity. This review clearly summarizes and analyzes the available randomized, double-blinded, placebo-controlled trials, which aimed at evaluating the effectiveness and the safety of grass pollen and house dust mite SLIT for the specific treatment of pediatric allergic rhinitis. Our analysis demonstrates the good evidence supporting the efficacy of SLIT for allergic rhinitis to grass pollens in children, whereas trials regarding pediatric allergic rhinitis to house dust mites present lower quality, although several studies supported its usefulness. PMID:26862501

  8. Clinical contraindications to allergen immunotherapy: an EAACI position paper.

    PubMed

    Pitsios, C; Demoly, P; Bil, M B; Gerth van Wijk, R; Pfaar, O; Sturm, G J; Rodriguez del Rio, P; Tsoumani, M; Gawlik, R; Paraskevopoulos, G; Ruff, F; Valovirta, E; Papadopoulos, N G; Caldern, M A

    2015-08-01

    Clinical indications for allergen immunotherapy (AIT) in respiratory and Hymenoptera venom allergy are well established; however, clinical contraindications to AIT are not always well documented. There are some discrepancies when classifying clinical contraindications for different forms of AIT as 'absolute' or 'relative'. EAACI Task Force on 'Contraindications to AIT' was created to evaluate and review current literature on clinical contraindications, and to update recommendations for both sublingual and subcutaneous AIT for respiratory and venom immunotherapy. An extensive review of the literature was performed on the use of AIT in asthma, autoimmune disorders, malignant neoplasias, cardiovascular diseases, acquired immunodeficiencies and other chronic diseases (including mental disorders), in patients treated with ?-blockers, ACE inhibitors or monoamine oxidase inhibitors, in children under 5years of age, during pregnancy and in patients with poor compliance. Each topic was addressed by the following three questions: (1) Are there any negative effects of AIT on this concomitant condition/disease? (2) Are more frequent or more severe AIT-related side-effects expected? and (3) Is AIT expected to be less efficacious? The evidence, for the evaluation of these clinical conditions as contraindications, was limited, and most of the conclusions were based on case reports. Based on an extended literature research, recommendations for each medical condition assessed are provided. The final decision on the administration of AIT should be based on individual evaluation of any medical condition and a risk/benefit assessment for each patient. PMID:25913519

  9. Immunotherapy with mutated onchocystatin fails to enhance the efficacy of a sub-lethal oxytetracycline regimen against Onchocerca ochengi.

    PubMed

    Bah, Germanus S; Tanya, Vincent N; Makepeace, Benjamin L

    2015-08-15

    Human onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, has been successfully controlled by a single drug, ivermectin, for over 25 years. Ivermectin prevents the disease symptoms of severe itching and visual impairment by killing the microfilarial stage, but does not eliminate the adult parasites, necessitating repeated annual treatments. Mass drug administration with ivermectin does not always break transmission in forest zones and is contraindicated in individuals heavily co-infected with Loa loa, while reports of reduced drug efficacy in Ghana and Cameroon may signal the development of resistance. An alternative treatment for onchocerciasis involves targeting the essential Wolbachia symbiont with tetracycline or its derivatives, which are adulticidal. However, implementation of antibiotic therapy has not occurred on a wide scale due to the prolonged treatment regimen required (several weeks). In the bovine Onchocerca ochengi system, it has been shown previously that prolonged oxytetracycline therapy increases eosinophil counts in intradermal nodules, which kill the adult worms by degranulating on their surface. Here, in an "immunochemotherapeutic" approach, we sought to enhance the efficacy of a short, sub-lethal antibiotic regimen against O. ochengi by prior immunotherapy targeting onchocystatin, an immunomodulatory protein located in the adult female worm cuticle. A key asparagine residue in onchocystatin was mutated to ablate immunomodulatory activity, which has been demonstrated previously to markedly improve the protective efficacy of this vaccine candidate when used as an immunoprophylactic. The immunochemotherapeutic regimen was compared with sub-lethal oxytetracycline therapy alone; onchocystatin immunotherapy alone; a gold-standard prolonged, intermittent oxytetracycline regimen; and no treatment (negative control) in naturally infected Cameroonian cattle. Readouts were collected over one year and comprised adult worm viability, dermal microfilarial density, anti-onchocystatin IgG in sera, and eosinophil counts in nodules. Only the gold-standard antibiotic regimen achieved significant killing of adult worms, a profound reduction in microfilarial load, and a sustained increase in local tissue eosinophilia. A small but statistically significant elevation in anti-onchocystatin IgG was observed for several weeks after immunisation in the immunotherapy-only group, but the antibody response in the immunochemotherapy group was more variable. At 12 weeks post-treatment, only a transient and non-significant increase in eosinophil counts was apparent in the immunochemotherapy group. We conclude that the addition of onchocystatin immunotherapy to a sub-lethal antibiotic regimen is insufficient to induce adulticidal activity, although with booster immunisations or the targeting of additional filarial immunomodulatory proteins, the efficacy of this strategy could be strengthened. PMID:26100152

  10. Sublingual immunotherapy (SLIT) - indications, mechanism, and efficacy Position paper prepared by the Section of Immunotherapy, Polish Society of Allergy.

    PubMed

    Jutel, Marek; Bartkowiak-Emeryk, Małgorzata; Bręborowicz, Anna; Cichocka-Jarosz, Ewa; Emeryk, Andrzej; Gawlik, Radosław; Gonerko, Paweł; Rogala, Barbara; Nowak-Węgrzyn, Anna; Samoliński, Bolesław; Pta, And Other Members Of It Section

    2016-03-01

    SLIT (sublingual immunotherapy,) induces allergen-specific immune tolerance by sublingual administration of a gradually increasing dose of an allergen. The mechanism of SLIT is comparable to those during SCIT (subcutaneous immunotherapy), with the exception of local oral dendritic cells, pre-programmed to elicit tolerance. In the SLIT dose, to achieve the same efficacy as in SCIT, it should be 50-100 times higher with better safety profile. The highest quality evidence supporting the efficacy of SLIT lasting 1 - 3 years has been provided by the large scale double-blind, placebo-controlled (DBPC) trials for grass pollen extracts, both in children and adults with allergic rhinitis. Current indications for SLIT are allergic rhinitis (and conjunctivitis) in both children and adults sensitized to pollen allergens (trees, grass, Parietaria), house dust mites (Dermatophagoides pteronyssinus, Dermatophagoides farinae), cat fur, as well as mild to moderate controlled atopic asthma in children sensitized to house dust mites. There are positive findings for both asthma and new sensitization prevention. Severe adverse events, including anaphylaxis, are very rare, and no fatalities have been reported. Local adverse reactions develop in up to 70 - 80% of patients. Risk factors for SLIT adverse events have not been clearly identified. Risk factors of non-adherence to treatment might be dependent on the patient, disease treatment, physician-patient relationship, and variables in the health care system organization. PMID:27012173

  11. Clinical significance of immunotherapy with combined three kinds of cells for operable colorectal cancer.

    PubMed

    Du, Xiao-Hui; Liu, Hai-Liang; Li, Li; Xia, Shao-You; Ning, Ning; Zou, Zhen-Yu; Teng, Da; Xiao, Chun-Hong; Li, Rong; Xu, Ying-Xin

    2015-07-01

    Surgery, chemotherapy, and radiotherapy have presented with the ability of killing tumor cells, as well as damaging the immune function, which can be corrected by the immunotherapy. The purpose of this perspective cohort study was to evaluate the efficacy of postoperative immunotherapies of tumor lysate-loaded dendritic cells (DC), in vitro DC-activated T (DC-AT), and activated T cells (ATC) combined with chemotherapy on the survival of patients with operable colorectal cancer. A total of 253 patients with primary colorectal cancer resection including 181 patients receiving postoperative simple chemotherapy (control group) and 72 patients receiving immunotherapies of DC, DC-AT, and ATC combined with chemotherapy during the corresponding period (immunotherapy group) were enrolled in this perspective cohort study. The survival of these patients was analyzed. The immunotherapy group presented a higher 5-year overall survival rate than the control group (75.63 vs 67.81 %, P = 0.035), as well as 3-year overall survival rate (87.07 vs 74.80 %, P = 0.045). For patients with advanced cancer (TNM stages III and IV), immunotherapy significantly promotes mean survival than control subjects (59.74 ± 3.21 vs 49.99 ± 2.54 years, P = 0.034). Patients who received more than three cycles of immunotherapies had a higher 5-year overall survival rate than those with less than three cycles (82.10 vs 69.90 %, P = 0.035). No serious adverse effect was observed in the immunotherapy group. Postoperative immunotherapies with DC, DC-AT, and ATC combination can promote the survival of patients with operable colorectal cancer (Clinical Trials, ChiCTR-OCH-12002610). PMID:25764087

  12. Leveraging immunotherapy for the treatment of gynecologic cancers in the era of precision medicine.

    PubMed

    Zamarin, Dmitriy; Jazaeri, Amir A

    2016-04-01

    During the past decade significant progress in the understanding of stimulatory and inhibitory signaling pathways in immune cells has reinvigorated the field of immuno-oncology. In this review we outline the current immunotherapy based approaches for the treatment of gynecological cancers, and focus on the emerging clinical data on immune checkpoint inhibitors, adoptive cell therapies, and vaccines. It is anticipated that in the coming years biomarker-guided clinical trials, will provide for a better understanding of the mechanisms of response and resistance to immunotherapy, and guide combination treatment strategies that will extend the benefit from immunotherapy to patients with gynecologic cancers. PMID:27016233

  13. Autologous cytokine-induced killer (CIK) immunotherapy in a case of disseminated tuberculosis.

    PubMed

    Ping, Xu; Junchi, Xu; Xinnian, Chen; Zhijian, Ye; Meiying, Wu

    2015-01-01

    A 23-year-old woman had dry cough, fever and chest tightness for 1 months. Through thoracic CT scan and serological examination, the patient was clinically diagnosed as disseminated tuberculosis. she was given anti-tuberculosis therapy combined with autologous cytokine-induced killer (CIK) immunotherapy. Through the close follow-ups we found that after immunotherapy Her condition would have a swift improvement and she do not appear liver damage after a large doses of antibiotic therapy. In conclusion, adjuvant autologous CIK immunotherapy is an effective approach for disseminated tuberculosis. PMID:26237360

  14. An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression.

    PubMed

    Rice, A E; Latchman, Y E; Balint, J P; Lee, J H; Gabitzsch, E S; Jones, F R

    2015-09-01

    We have investigated if immunotherapy against human papilloma virus (HPV) using a viral gene delivery platform to immunize against HPV 16 genes E6 and E7 (Ad5 [E1-, E2b-]-E6/E7) combined with programmed death-ligand 1 (PD-1) blockade could increase therapeutic effect as compared to the vaccine alone. Ad5 [E1-, E2b-]-E6/E7 as a single agent induced HPV-E6/E7 cell-mediated immunity. Immunotherapy using Ad5 [E1-, E2b-]-E6/E7 resulted in clearance of small tumors and an overall survival benefit in mice with larger established tumors. When immunotherapy was combined with immune checkpoint blockade, an increased level of anti-tumor activity against large tumors was observed. Analysis of the tumor microenvironment in Ad5 [E1-, E2b-]-E6/E7 treated mice revealed elevated CD8(+) tumor infiltrating lymphocytes (TILs); however, we observed induction of suppressive mechanisms such as programmed death-ligand 1 (PD-L1) expression on tumor cells and an increase in PD-1(+) TILs. When Ad5 [E1-, E2b-]-E6/E7 immunotherapy was combined with anti-PD-1 antibody, we observed CD8(+) TILs at the same level but a reduction in tumor PD-L1 expression on tumor cells and reduced PD-1(+) TILs providing a mechanism by which combination therapy favors a tumor clearance state and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in future clinical trials. PMID:26337747

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

    PubMed Central

    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

  16. International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics.

    PubMed

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

    2016-02-01

    This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal. The conclusions below focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein. PMID:26853128

  17. Challenges and future perspectives of T cell immunotherapy in cancer.

    PubMed

    de Aquino, Maria Teresa P; Malhotra, Anshu; Mishra, Manoj K; Shanker, Anil

    2015-08-01

    Since the formulation of the tumour immunosurveillance theory, considerable focus has been on enhancing the effectiveness of host antitumour immunity, particularly with respect to T cells. A cancer evades or alters the host immune response by various ways to ensure its development and survival. These include modifications of the immune cell metabolism and T cell signalling. An inhibitory cytokine milieu in the tumour microenvironment also leads to immune suppression and tumour progression within a host. This review traces the development in the field and attempts to summarize the hurdles that the approach of adoptive T cell immunotherapy against cancer faces, and discusses the conditions that must be improved to allow effective eradication of cancer. PMID:26096822

  18. Allergen extracts for immunotherapy: to mix or not to mix?

    PubMed

    Nony, Emmanuel; Martelet, Armelle; Jain, Karine; Moingeon, Philippe

    2016-03-01

    Allergen immunotherapy (AIT) is established as a curative treatment for allergic rhinitis, asthma, as well as insect venom allergy. AIT is based on the administration of natural allergen extracts via the subcutaneous or sublingual routes to reorient the immune system towards tolerogenic mechanisms. In this regard, since many patients are poly-allergic, mixtures of allergen extracts are often used with a potential risk to cause allergen degradation, thereby affecting treatment efficacy. Herein, we discuss the advantages and drawbacks of mixing homologous (i.e., related) or heterogeneous (i.e., unrelated) allergen extracts. We provide evidence for incompatibilities between mixes of grass pollen and house dust mite extracts containing bodies and feces, and summarize critical points to consider when mixing allergen extracts for AIT. PMID:26652799

  19. Genetic engineering of T cells for adoptive immunotherapy

    PubMed Central

    Varela-Rohena, Angel; Carpenito, Carmine; Perez, Elena E.; Richardson, Max; Parry, Richard V.; Milone, Michael; Scholler, John; Hao, Xueli; Mexas, Angela; Carroll, Richard G.; June, Carl H.

    2009-01-01

    To be effective for the treatment of cancer and infectious diseases, T cell adoptive immunotherapy requires large numbers of cells with abundant proliferative reserves and intact effector functions. We are achieving these goals using a gene therapy strategy wherein the desired characteristics are introduced into a starting cell population, primarily by high efficiency lentiviral vector-mediated transduction. Modified cells are then expanded using ex vivo expansion protocols designed to minimally alter the desired cellular phenotype. In this article, we focus on strategies to (1) dissect the signals controlling T cell proliferation; (2) render CD4 T cells resistant to HIV-1 infection; and (3) redirect CD8 T cell antigen specificity. PMID:18841331

  20. Immunotherapy for liver tumors: present status and future prospects

    PubMed Central

    Matar, Pablo; Alaniz, Laura; Rozados, Viviana; Aquino, Jorge B; Malvicini, Mariana; Atorrasagasti, Catalina; Gidekel, Manuel; Silva, Marcelo; Scharovsky, O Graciela; Mazzolini, Guillermo

    2009-01-01

    Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field. PMID:19272130