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

    PubMed

    Genre, Fernanda; López-Mejías, Raquel; Miranda-Filloy, José A; Ubilla, Begoña; Mijares, Verónica; Carnero-López, Beatriz; Gómez-Acebo, Inés; Dierssen-Sotos, Trinidad; Remuzgo-Martínez, Sara; Blanco, Ricardo; Pina, Trinitario; González-Juanatey, Carlos; Llorca, Javier; González-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

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

    PubMed Central

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

    2015-01-01

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

  3. [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

  4. 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

  5. Anti-TNF alpha: new therapy for Crohn's disease.

    PubMed

    Mikula, C A

    1999-01-01

    Immunological technology has paved the way for a promising new therapy for patients suffering from chronic active Crohn's disease. Neutralization of tumor necrosis factor-alpha (TNF alpha), a cytokine secreted by cells in the immune system, may prove useful in decreasing bowel inflammation and aid in the closure of fistulae. Two multicenter, randomized, double-blinded, placebo-controlled trials were conducted to evaluate the safety and efficacy of inflixmab (Remicade [Centocor]), a chimeric monoclonal antibody form of anti-TNF alpha, hypothesized to provide a prolonged therapeutic effect in chronic inflammation. The 5 mg/kg dose regimen of infliximab was the lowest effective dose and produced a high degree of benefit lasting 8 weeks to 3 months. Infusion preparation, cost, and patient indications bear special considerations. Further investigation is needed in long-term safety and efficacy for chronic administration of infliximab. PMID:10855120

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

    PubMed Central

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

    2014-01-01

    Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) ?, interleukin- (IL-) 1?, and IL-6. However, although biological treatment with anti-TNF-? agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-? blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium. PMID:25061259

  7. 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 1998–2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared HZ incidence between new anti-TNF users and patients initiating non-biologic disease modifying drugs (DMARDs) within each inflammatory disease cohort (last participant follow-up Dec 31, 2007). Within these cohorts, we used Cox regression models to compare propensity-score adjusted HZ incidence between new anti-TNF and non-biologic DMARD users while controlling for baseline corticosteroid use. Main Outcome Measure Incidence of herpes zoster cases occurring after initiation of new anti- TNF or non-biologic DMARD therapy Results Among 32,208 new users of anti-TNF therapy, we identified 310 HZ cases. Crude incidence rates among anti-TNF users for RA, IBD, and PsO-PsA-AS were 12.1/1000 pt-yrs, (95% CI 10.7–13.6), 11.3/1000 (95% CI 7.7–16.7), and 4.4/1000 (95% CI 2.8–7.0) respectively. Baseline use of corticosteroids of > 10mg/day was associated with elevated risk [adjusted HR 2.13 (1.64, 2.75) compared with no baseline use. For RA patients, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators [adjusted HR 1.00 (95% CI 0.77–1.29) and comparable between all three anti-TNF therapies studied. Conclusions and Relevance Among patients with RA and other select inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk for HZ compared to patients who initiated non-biologic treatment regimens. PMID:23462785

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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; Sørensen, 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

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

    PubMed Central

    Go?dzialska, Anna; Lipko-Godlewska, Sylwia; Obtu?owicz, Aleksander; Su?owicz, Joanna; Podolec, Katarzyna; Wojas-Pelc, Anna

    2015-01-01

    Introduction The tumor necrosis factor (TNF-?) was initially described as lymphotoxin or cachectin. The discovery of therapies blocking the action of TNF-?, in 1988, started a new era in the therapy. One of often reported adverse effects related to the use of TNF-? 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

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

    PubMed

    Restrepo, Juan Pablo; Molina, María del Pilar

    2014-01-01

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

  15. 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

  16. 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

  17. CDKAL1 gene variants affect the anti-TNF response among Psoriasis patients.

    PubMed

    Coto-Segura, Pablo; Batalla, Ana; González-Fernández, Daniel; Gómez, Juan; Santos-Juanes, Jorge; Queiro, Rubén; Alonso, Belén; Iglesias, Sara; Coto, Eliecer

    2015-12-01

    The heterogeneous response to anti-TNF biological drugs among Psoriasis (Psor) patients might be explained by gene variants linked to the risk for Psor. Common variants in the CDKAL1 gene have been associated with the risk of developing Psor. Our hypothesis was that these variants could also influence the response to anti-TNFs among Psor-patients. A reduction of at least 75% in the Psoriasis area and severity index (PASI 75) at week 24 was considered a positive response to treatment. A total of 116 patients (78 responders and 38 non-responders) were genotyped for the CDKAL1 rs6908425, rs4712523, rs111739077, and rs77152992 (p.P409L) single nucleotide polymorphisms. Allele and genotype frequencies differed between the two response groups, with the highest difference for the rs6908425: CC homozygotes were significantly more common among responders (72% vs. 45%; p=0.005; OR=3.14, 95%CI=1.40-7.05). In conclusion, our data suggested that CDKAL1 gene variants have a significant effect on the response to anti-TNF therapies among Psor patients. If confirmed on other large cohorts of patients, the genotyping of these variants might help to predict the biological response. PMID:26563541

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

    PubMed

    Vande Casteele, Niels; Gils, Ann

    2015-03-01

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

  19. 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

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

    PubMed

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

    2013-12-01

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

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

    PubMed

    Persi?, Mladen

    2013-04-01

    Since the early occurrence of inflammatory bowel diseases in young people, the role of pregnancy on disease course, and the influence of different therapies on pregnancy, fetal development and the safety of breastfeeding have been one of the important questions. Biological therapy has been increasingly used and all the above mentioned questions seem to be of a great interest. The majority of research indicate that the possibility of conception in patients with IBD are the same as in a healthy population, although there is an increased risk for the child in terms of prematurity or low birth weight. Pregnancy in IBD patient should be considered as a high risk. Most medications used to achieve or maintain remission are safe in pregnancy and breastfeeding. Exceptions are thalidomide and methotrexate that are absolutely contraindicated. Anti-TNF drugs are safe but it is advised to stop the treatment after 30-32 weeks of pregnancy due to the possibility of placental transfer of medications. Infliximab is excreted into breast milk in small quantities and breastfeeding is assumed to be safe. Pregnancy in IBD patients should be planned in advance so that the medications that are contraindicated could be excluded on time and further possible complication could be prevented by constant monitoring of pregnancy. Prospective studies of monitoring throughout pregnancy and short-term and long-term forecasts of development of children whose mothers were pregnant when suffered from inflammatory bowel disease are necessary. PMID:24471298

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

    PubMed Central

    Sánchez-Cano, Daniel; Callejas-Rubio, José Luis; Ruiz-Villaverde, Ricardo; Ríos-Fernández, 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: Behçet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series. PMID:23983404

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

    PubMed

    Sánchez-Cano, Daniel; Callejas-Rubio, José Luis; Ruiz-Villaverde, Ricardo; Ríos-Fernández, 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: Behçet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series. PMID:23983404

  4. 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

  5. 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

  6. 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

  7. Predicting Hemagglutinin MHC-II Ligand Analogues in Anti-TNF? Biologics: Implications for Immunogenicity of Pharmaceutical Proteins

    PubMed Central

    Cauley, Brianna; O’Donnell, Lauren A.; Meng, Wilson S.

    2015-01-01

    The purpose of this study was to evaluate the extent of overlapping immunogenic peptides between three pharmaceutical biologics and influenza viruses. Clinical studies have shown that subsets of patients with rheumatoid arthritis (RA) develop anti-drug antibodies towards anti-TNF? biologics. We postulate that common infectious pathogens, including influenza viruses, may sensitize RA patients toward recombinant proteins. We hypothesize that embedded within infliximab (IFX), adalimumab (ADA), and etanercept (ETN) are ligands of class II major histocompatibility complex (MHC-II) that mimic T cell epitopes derived from influenza hemagglutinin (HA). The rationale is that repeated administration of the biologics would reactivate HA-primed CD4 T cells, stimulating B cells to produce cross-reactive antibodies. Custom scripts were constructed using MATLAB to compare MHC-II ligands of HA and the biologics; all ligands were predicted using tools in Immune Epitope Database and Resources (IEDB). We analyzed three HLA-DR1 alleles (0101, 0401 and 1001) that are prominent in RA patients, and two alleles (0103 and 1502) that are not associated with RA. The results indicate that 0401 would present more analogues of HA ligands in the three anti-TNF? biologics compared to the other alleles. The approach led to identification of potential ligands in IFX and ADA that shares sequence homology with a known HA-specific CD4 T cell epitope. We also discovered a peptide in the complementarity-determining region 3 (CDR-3) of ADA that encompasses both a potential CD4 T cell epitope and a known B cell epitope in HA. The results may help generate new hypotheses for interrogating patient variability of immunogenicity of the anti-TNF? drugs. The approach would aid development of new recombinant biologics by identifying analogues of CD4 T cell epitopes of common pathogens at the preclinical stage. PMID:26270649

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

    PubMed

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

    2015-10-15

    Enhanced leukocyte recruitment is an inflammatory process that occurs during early phases of the vascular dysfunction that characterises atherosclerosis. We evaluated the impact of anti-TNF-? (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

  9. 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 naïve Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses. False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status. Results Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1–2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1–7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4–1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response. The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4–16.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association. Conclusions We reproduced previously reported associations between 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

  10. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-? treatment

    PubMed Central

    British, T

    2005-01-01

    Guidelines have been compiled by The Joint Tuberculosis Committee of the British Thoracic Society to quantify the risks of reactivation of tuberculosis with anti-tumour necrosis factor ? (anti-TNF-?) treatment. These guidelines are intended to inform respiratory physicians, gastroenterologists, rheumatologists and dermatologists, together with specialist nurses in those disciplines. PMID:16055611

  11. 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

  12. 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

  13. 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

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

    PubMed

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

    2015-01-01

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

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

  16. First update of the international ASAS consensus statement for the use of anti?TNF agents in patients with ankylosing spondylitis

    PubMed Central

    Braun, J; Davis, J; Dougados, M; Sieper, J; van der Linden, S; van der Heijde, D

    2006-01-01

    Objective To update the international recommendations for use of anti?tumour necrosis factor (TNF) agents in the treatment of ankylosing spondylitis. Methods The published recommendations on anti?TNF treatment in ankylosing spondylitis formed the basis of the update. A questionnaire was sent to the ASAS (assessment in ankylosing spondylitis) members before the final decisions were agreed upon at an international meeting of the ASAS working group. Results Only minor changes to the original consensus statement were required. For the initiation of anti?TNF treatment, there should be: a diagnosis of definitive ankylosing spondylitis (normally based on modified New York criteria); active disease for at least four weeks, as defined by a sustained Bath ankylosing spondylitis disease activity index (BASDAI) of ?4 on a 0–10 scale and expert opinion based on clinical findings; refractory disease, defined by failure of at least two non?steroidal anti?inflammatory drugs during a three month period, failure of intra?articular steroids (if indicated), and failure of sulfasalazine in patients with predominantly peripheral arthritis; and application of the usual precautions and contraindications for biological treatment. For monitoring anti?TNF treatment: both the ASAS core set for clinical practice and the BASDAI should be followed after the initiation of treatment. Discontinuation of anti?TNF treatment in non?responders should be considered after 6–12?weeks. Response is defined by improvement of at least 50% or 2 units (on a 0–10 scale) of the BASDAI. Conclusions This updated consensus statement is recommended in guiding clinical practice and as a basis for developing national guidelines. Evaluation and regular update of this consensus statement is subject to further research by the ASAS group. PMID:16096329

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

    PubMed Central

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

    2015-01-01

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

  18. Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-? 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-? treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P?anti-TNF-? treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-? treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis.

  19. Sarcoma Immunotherapy

    PubMed Central

    Gouw, Launce G.; Jones, Kevin B.; Sharma, Sunil; Randall, R. Lor

    2011-01-01

    Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis. PMID:24213130

  20. [Treatment of rheumatoid arthritis (RA) with anti-TNF-alpha antibody (Remicade). Individual monitoring of bioavailability and immunogenicity--secondary publication].

    PubMed

    Bendtzen, Klaus; Geborek, Pierre; Svenson, Morten; Larsson, Lotta; Kapetanovic, Meliha C; Saxne, Tore

    2007-01-29

    Remicade/infliximab is effective in rheumatoid arthritis (RA), but response failure is frequent. Sera from 106 RA patients were monitored using an RIA for functional infliximab and an RIA for anti-infliximab antibody (Ab). S-infliximab varied considerably, e.g. 0-22 microg/ml before the 3rd infusion, and 44% were Ab-positive after 6 months. Low s-infliximab was associated with Ab development and later therapeutic failure, and high Ab levels could be related to dose increases, side-effects and cessation of therapy. Pharmacological monitoring should help optimize anti-TNF therapies. PMID:17280636

  1. 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

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

    PubMed

    Rösner, S; Schad, A; Kittner, J; Rahman, F; Wörns, 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

  3. 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

  4. LC–MS 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 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 (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

  5. 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

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

    PubMed Central

    2013-01-01

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

  7. Immunotherapy for bladder cancer

    PubMed Central

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

    2015-01-01

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

  8. Clinical and Contrast-Enhanced Ultrasound Echography Outcomes in Psoriatic Arthritis Patients after One Year of Continuous Therapy with Anti-TNF Drugs.

    PubMed

    Bonifati, Claudio; Elia, Fulvia; Graceffa, Dario; Ceralli, Fabrizio; Maiani, Elisa; De Mutiis, Carlo; Solivetti, Francesco M

    2014-01-01

    Background. We wanted to verify retrospectively the proportion of patients with psoriatic arthritis who were in remission after 1 year of continuous therapy with either etanercept or adalimumab. Remission was defined as the absence of both clinical and contrast-enhanced ultrasound (CEUS) findings suggestive of joint inflammation. Patients and Methods. The data of twenty-five patients with psoriatic arthritis were available for the clinical and CEUS evaluations before and after 1 year of continuous therapy with etanercept or adalimumab. The count of swollen (ACR66), tender (ACR68), and active inflamed joints (AJC) was used to measure the severity of joint involvement. PASI was used to score the severity of psoriasis. HAQ, DLQI, VAS pain, and VAS itching were administered to each patient before starting therapy and every 3 months, up to 1 year. Results. Eight (32%) out of twenty-five patients were in remission after 1 year of therapy with etanercept or adalimumab. A significant reduction of all clinical variables analysed was seen during the course of therapy. Conclusion. Although a significant proportion of patients achieved remission of arthritis after 1 year of effective anti-TNF therapy, the majority of them continued to have either clinical or CEUS findings suggestive of persistence of joint inflammation. PMID:24653837

  9. Clinical and Contrast-Enhanced Ultrasound Echography Outcomes in Psoriatic Arthritis Patients after One Year of Continuous Therapy with Anti-TNF Drugs

    PubMed Central

    Elia, Fulvia; Ceralli, Fabrizio; Maiani, Elisa; De Mutiis, Carlo; Solivetti, Francesco M.

    2014-01-01

    Background. We wanted to verify retrospectively the proportion of patients with psoriatic arthritis who were in remission after 1 year of continuous therapy with either etanercept or adalimumab. Remission was defined as the absence of both clinical and contrast-enhanced ultrasound (CEUS) findings suggestive of joint inflammation. Patients and Methods. The data of twenty-five patients with psoriatic arthritis were available for the clinical and CEUS evaluations before and after 1 year of continuous therapy with etanercept or adalimumab. The count of swollen (ACR66), tender (ACR68), and active inflamed joints (AJC) was used to measure the severity of joint involvement. PASI was used to score the severity of psoriasis. HAQ, DLQI, VAS pain, and VAS itching were administered to each patient before starting therapy and every 3 months, up to 1 year. Results. Eight (32%) out of twenty-five patients were in remission after 1 year of therapy with etanercept or adalimumab. A significant reduction of all clinical variables analysed was seen during the course of therapy. Conclusion. Although a significant proportion of patients achieved remission of arthritis after 1 year of effective anti-TNF therapy, the majority of them continued to have either clinical or CEUS findings suggestive of persistence of joint inflammation. PMID:24653837

  10. Assessing patients’ satisfaction with anti-TNF? treatment in Crohn’s disease: qualitative steps of the development of a new questionnaire

    PubMed Central

    Marant, Claire; Arnould, Benoit; Marrel, Alexia; Spizak, Céderic; Colombel, Jean-Frédéric; Faure, Patrick; Hagege, Hervé; Lemann, Marc; Nahon, Stéphane; Tucat, Gilbert; Vandromme, Luc; Thibout, Emmanuel; Goldfarb, Gérard

    2011-01-01

    Purpose: To develop a self-administered questionnaire assessing patients’ satisfaction with treatments in Crohn’s disease for use in clinical research and epidemiological studies. Patients and methods: Semi-directive interviews (16) were conducted with patients with severe Crohn’s 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 Crohn’s diseasE (SPACE©). Conclusion: The questionnaire is a unique tool to assess treatment satisfaction in patients with Crohn’s disease. A scoring and validation study is currently being performed to finalize and establish its scoring, as well as its psychometric properties. PMID:21904463

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

    PubMed Central

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

    1994-01-01

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

  12. [Melanoma immunotherapy: dendritic cell vaccines].

    PubMed

    Lozada-Requena, Ivan; Núñez, César; Aguilar, José Luis

    2015-09-01

    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. 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 ?=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

  14. 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

  15. 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.

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

    PubMed

    Ozdemir, Cevdet; Kucuksezer, Umut Can; Akdis, Mübeccel; 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

  17. 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

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

    PubMed Central

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

    2006-01-01

    Background Inflammation represents an early and key event in the development of both the cutaneous psoriasis and psoriatic arthritis. Compelling evidences indicate that the production of TNF-? plays a central role in psoriasis by sustaining the inflammatory process in the skin as well as in the joints. Among the multiple effects produced by TNF-? on keratinocytes, the induction of matrix metalloproteinase-9 (MMP-9), a collagenase implicated in joint inflammatory arthritis which acts as an angiogenesis promoting factor, might represent a key mechanism in the pathogenesis of the disease. Aims of the present study were to investigate a) the role of MMP-9 in the development of psoriasis by assessing the presence of MMP-9 in lesional skin and in sera of psoriatic patients; b) the association of MMP-9 with the activity of the disease; c) the relationship between MMP-9 and TNF-? production. Methods Eleven psoriatic patients, clinically presenting joint symptoms associated to the cutaneous disease, were included in a therapeutic protocol based on the administration of anti-TNF-? monoclonal antibody (Infliximab). Sera and skin biopsies were collected before treatment and after 6 weeks of therapy. Tissues were kept in short term cultures and production soluble mediators such as TNF-?, MMP-9, MMP-2, VEGF and E-Selectin, which include angiogenic molecules associated to the development of plaque psoriasis, were measured in the culture supernatants by immunoenzymatic assays (ng/ml or pg/ml per mg of tissue). MMP-9 concentrations were also measured in the sera. The cutaneous activity of disease was evaluated by the Psoriasis Area and Severity Index (PASI). Results Clinical and laboratory assessment indicated that all but one patients had a significant improvement of the PASI score after three months of therapy. The clinical amelioration was associated to a significant decrease of MMP-9 (P = 0.017), TNF-? (P = 0.005) and E-selectin (P = 0.018) levels, spontaneously released by lesional biopsies before and after therapy. In addition, significant correlations were found between the PASI measurements and TNF-? (r2 = 0.33, P = 0.005), MMP-9 (r2 = 0.25, P = 0.017), E-selectin (r2 = 0.24, P = 0.018) production. MMP-9 levels were significantly correlated with those of TNF-? (r2 = 0.30, P = 0.008). A significant decrease of MMP-9 in the sera, associated to the clinical improvement was also found. Conclusion Our findings show the existence of a direct relationship between MMP-9 and TNF-? production strongly suggesting that MMP-9 may play a key role in the skin inflammatory process in psoriasis. PMID:17022813

  19. 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

  20. 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

  1. Principles of immunotherapy.

    PubMed

    Olszanski, Anthony J

    2015-05-01

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

  2. Targeted cancer immunotherapy

    PubMed Central

    Müller, Dafne

    2012-01-01

    Under physiological conditions, the trans-presentation of interleukin-15 (IL-15) by the IL-15 receptor ? on the cell surface allows to confine and tune the IL-15-mediated immune responses. Therefore, targeting strategies that mimic this situation at the tumor sites appear especially promising for anticancer immunotherapy. PMID:23170284

  3. 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

  4. [Immunotherapies and melanoma].

    PubMed

    Routier, Émilie; 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

  5. 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

  6. 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

  7. 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-?2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy. PMID:22576456

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

    PubMed

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

    2012-01-01

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

  9. Regulatory T Cells as Immunotherapy

    PubMed Central

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

    2014-01-01

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

  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. Intravesical immunotherapy in nonmuscle invasive bladder cancer

    PubMed Central

    Jokisch, Jan-Friedrich; Karl, Alexander; Stief, Christian

    2015-01-01

    Introduction: Nonmuscle invasive urothelial cell carcinoma is the most frequent malignancy of the urinary bladder. The high recurrence rate (up to 80%) and risk of progression (up to 30%) reflect the need for long-term follow-up and sometimes multiple interventions. To reduce the rate of recurrences and tumor progression, intravesical immunotherapy, especially the use of Bacille Calmette-Guerin (BCG), represents the gold standard adjuvant treatment of high-risk nonmuscle invasive bladder cancer (NMIBC). This article reviews the role of BCG therapy and several promising new immunotherapeutic approaches such as mycobacterium phlei cell wall-nucleic acid complex, interleukin-10 (IL-10) antibody, vaccine-based therapy, alpha-emitter therapy, and photodynamic therapy checkpoint inhibitors. Methods: A systematic literature review was performed using the terms (immunotherapy, NMIBC, BCG, and intravesical) using PubMed and Cochrane databases. Results: BCG represents the most common intravesical immunotherapeutic agent for the adjuvant treatment of high-risk NMIBC. Its use is associated with a significant reduction of recurrence and progression. Patients with NMIBC of intermediate and high-risk benefit the most from BCG therapy. To achieve maximal efficacy, an induction therapy followed by a maintenance schedule should be used. Full-dose BCG is recommended to obtain ideal antitumoral activity and there is no evidence of a reduction of side effects in patients treated with a reduced dose. There are multiple new approaches and agents in immunotherapy with potential and promising antineoplastic effects. Conclusions: The beneficial effect of BCG is well documented and established. To reduce the tumor specific mortality, it is essential to follow guideline-based treatment. In patients with BCG-failure, there are new promising alternatives other than BCG but BCG remains the gold standard at this stage. PMID:26604441

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Immunotherapy for Alzheimer's Disease

    PubMed Central

    Wisniewski, Thomas; Goni, Fernando

    2014-01-01

    Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid ? (sA?) peptide is converted into oligomeric/fibrillar A?. The oligomeric forms of A? are thought to be the most toxic, while fibrillar A? becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only A? has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen. PMID:24412277

  18. 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

  19. Classification of current anticancer immunotherapies.

    PubMed

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

    2014-12-30

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

  20. 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

  1. Classification of current anticancer immunotherapies

    PubMed Central

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

    2014-01-01

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

  2. 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

  3. 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

  4. 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

  5. Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy

    PubMed Central

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

    2012-01-01

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

  6. 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

  7. [Current Approaches in Cancer Immunotherapy].

    PubMed

    Otáhal, P; Trn?ný, 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

  8. 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

  9. 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

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

    PubMed

    Antony, S; Kuttan, R; Kuttan, G

    1999-01-01

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

  11. 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 by identifying specific gut-resident bacteria as drivers of checkpoint blockade immunotherapy in pre-clinical tumor models. PMID:26678336

  12. 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

  13. 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

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

    PubMed

    Senti, Gabriela; Kündig, 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

  15. 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

  16. 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

  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

    ... CSF) Interleukin-2 (IL-2) Interferon Donor lymphocyte infusion Some blood cancer patients, especially those with chronic ... from an immune cell treatment called donor lymphocyte infusion. During this procedure, doctors transfer lymphocytes (a type ...

  19. [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

  20. Engineering persistent interleukin-2 for cancer immunotherapy

    E-print Network

    Gai, Shuning

    2012-01-01

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

  1. 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.

  2. 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

  3. 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 ...

  4. Lung cancer: potential targets for immunotherapy.

    PubMed

    Tartour, Eric; Zitvogel, Laurence

    2013-09-01

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

  5. 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.

  6. Reiter's syndrome following intravesical BCG immunotherapy

    PubMed Central

    Hogarth, M; Thomas, S; Seifert, M; Tariq, S

    2000-01-01

    A 71 year old woman developed conjunctivitis, asymmetrical oligoarthritis, and cystitis (Reiter's syndrome) secondary to intravesical BCG treatment for transitional cell carcinoma of the bladder. She received oral prednisolone, izoniazid, and pyridoxine and made a full recovery. Increasing use of BCG as immunotherapy will lead to an increase in the incidence of BCG associated reactive arthritis. Prompt recognition and early diagnosis will facilitate treatment and recovery.???Keywords: arthritis; BCG immunotherapy; Reiter's syndrome PMID:11085772

  7. 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.

  8. 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

  9. 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

  10. 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 39:213–217, 1994), NK cells (Triebel et al. J Exp Med 171:1393–1405, 1990), B cells (Kisielow et al. Eur J Immunol 35:2081–2088, 2005), and plasmacytoid dendritic cells (Workman et al. J Immunol 182:1885–1891, 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 168:3874–3880, 2002). Recent preclinical studies have documented a role for LAG-3 in CD8 T cell exhaustion (Blackburn et al. Nat Immunol 10:29–37, 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

  11. 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

  12. 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

  13. 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

  14. Advances in the understanding of cancer immunotherapy.

    PubMed

    Shore, Neal D

    2015-09-01

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

  15. Combining immunotherapy and radiation for prostate cancer.

    PubMed

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

    2015-02-01

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

  16. 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

  17. The progress of immunotherapy for glioblastoma.

    PubMed

    Zhou, Qiangyi; Wang, Yu; Ma, Wenbin

    2015-11-01

    Glioblastoma is the most common primary brain tumor in adults, accounting for about half of all primary brain tumors. Despite multiple therapeutic interventions such as surgical resection, radiotherapy, and systemic chemotherapy, the prognosis for glioblastoma remains poor. Due to the scientific community's enhanced understanding of the CNS immune system and significant achievements in tumor immunotherapy in recent years, immunotherapy has become a promising GBM treatment. In vaccine therapy, a number of clinical trials have achieved encouraging results. In antibody therapy, antibodies are used to target immune checkpoints such as ipilimumab and nivolumab. Bioengineering technology has also lead to a new field of tumor immunotherapy, whereby genetically modified tumor-specific T cells are reintroduced into a patient's body. PMID:26308501

  18. 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

  19. 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

  20. 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

  1. 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

  2. The biochemical aftermath of anti-amyloid immunotherapy

    PubMed Central

    2010-01-01

    Background Active and passive immunotherapy in both amyloid-beta precursor protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the A? peptide 1-42 (AN-1792) and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC) cases. Results All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of A? species remnants by ELISA suggested that total A? levels may have been reduced, although because the amounts of A? peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric A? peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of A?-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-? levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups. Conclusions Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques by AN-1792 was impressive, proportionate alterations in the clinical progression of AD were not evident. The fact that plaque elimination did not alter the trajectory of decline into dementia suggests the likelihood that these deposits alone are not the underlying cause of dementia. PMID:20929585

  3. 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

  4. 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

  5. A 'fit' microbiota to potentiate cancer immunotherapy.

    PubMed

    Rescigno, Maria

    2015-01-01

    Cancer immunotherapy is very effective and leads to a long-term response in certain patients. Yet, the variability observed in this response indicates that additional factors related to the host must influence the activity of the treatments. Recent research suggests that the microbiota might play an important part in this variability. PMID:26689196

  6. 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

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

    PubMed Central

    2012-01-01

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

  8. 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.

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

    PubMed Central

    Choi, Jae Woo; Cho, Soyun

    2011-01-01

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

  10. 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

  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. 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

  13. 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

  14. Immunotherapy for the Treatment of Glioblastoma

    PubMed Central

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

    2012-01-01

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

  15. Predictive factors for immunotherapy in melanoma

    PubMed Central

    González-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

  16. Predictive factors for immunotherapy in melanoma.

    PubMed

    Teixidó, Cristina; González-Cao, Maria; Karachaliou, Niki; Rosell, Rafael

    2015-09-01

    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

  17. Yeast-based vaccine approaches to cancer immunotherapy

    E-print Network

    Howland, Shanshan W

    2008-01-01

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

  18. The biochemical aftermath of anti-amyloid immunotherapy

    E-print Network

    2010-01-01

    with mixed and vascular dementia. Dement Geriatr Cogn Disorddeterioration, such as vascular dementia, dementia with Lewyvascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia

  19. 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

  20. Anti-Mesothelin Cancer Immunotherapy

    Cancer.gov

    Researchers at the NCI's Laboratory of Molecular Biology have created an immunoconjugate using an anti-mesothelin antibody (SS1) as the targeting moiety and IL12 as the payload molecule. This allows the localized concentration of IL12 at cancer cells, reducing the toxic effects seen with systemic IL12 administration.

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

    PubMed Central

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

    2014-01-01

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

  2. Effects of venom immunotherapy on serum level of CCL5/RANTES in patients with Hymenoptera venom allergy.

    PubMed

    Gawlik, Radoslaw; Glück, Joanna; Jawor, Barbara; Rogala, Barbara

    2015-01-01

    Hymenoptera venoms are known to cause life-threatening IgE-mediated anaphylactic reactions in allergic individuals. Venom immunotherapy is a recommended treatment of insect allergy with still the mechanism not being completely understood. We decided to assess the serum CCL5/RANTES level in patients who experienced severe anaphylactic reaction to Hymenoptera venom and to find out changes in the course of immunotherapy. Twenty patients (9 men, 11 women, mean age: 31.91?±?7.63 years) with history of anaphylactic reaction after insect sting were included into the study. Diagnosis was made according to sIgE and skin tests. All of them were enrolled into rush venom immunotherapy with bee or wasp venom extracts (Pharmalgen, ALK-Abello, Horsholm, Denmark). Serum levels of CCL5/RANTES were measured using a commercially available ELISA kit (R&D Systems, Minneapolis, MN). CCL5/RANTES serum concentration are higher in insect venom allergic patients than in healthy controls (887.5?±?322.77 versus 387.27?±?85.11?pg/ml). Serum concentration of CCL5/RANTES in insect venom allergic patient was significantly reduced in the course of allergen immunotherapy already after 6 days of vaccination (887.5?±?322.77 versus 567.32?±?92.16?pg/ml). CCL5/RANTES serum doesn't correlate with specific IgE. Chemokine CCL5/RANTES participates in allergic inflammation induced by Hymenoptera venom allergens. Specific immunotherapy reduces chemokine CCL5/RANTES serum level already after initial days of venom immunotherapy. PMID:26181651

  3. Prolactin as an Adjunct for Type 1 Diabetes Immunotherapy.

    PubMed

    Hyslop, Colin M; Tsai, Sue; Shrivastava, Vipul; Santamaria, Pere; Huang, Carol

    2016-01-01

    Type 1 diabetes is caused by autoimmune destruction of ?-cells. Although immunotherapy can restore self-tolerance thereby halting continued immune-mediated ?-cell loss, residual ?-cell mass and function is often insufficient for normoglycemia. Using a growth factor to boost ?-cell mass can potentially overcome this barrier and prolactin (PRL) may fill this role. Previous studies have shown that PRL can stimulate ?-cell proliferation and up-regulate insulin synthesis and secretion while reducing lymphocytic infiltration of islets, suggesting that it may restore normoglycemia through complementary mechanisms. Here, we test the hypothesis that PRL can improve the efficacy of an immune modulator, the anticluster of differentiation 3 monoclonal antibody (aCD3), in inducing diabetes remission by up-regulating ?-cell mass and function. Diabetic nonobese diabetic (NOD) mice were treated with a 5-day course of aCD3 with or without a concurrent 3-week course of PRL. We found that a higher proportion of diabetic mice treated with the aCD3 and PRL combined therapy achieved diabetes reversal than those treated with aCD3 alone. The aCD3 and PRL combined group had a higher ?-cell proliferation rate, an increased ?-cell fraction, larger islets, higher pancreatic insulin content, and greater glucose-stimulated insulin release. Lineage-tracing analysis found minimal contribution of ?-cell neogenesis to the formation of new ?-cells. Although we did not detect a significant difference in the number or proliferative capacity of T cells, we observed a higher proportion of insulitis-free islets in the aCD3 and PRL group. These results suggest that combining a growth factor with an immunotherapy may be an effective treatment paradigm for autoimmune diabetes. PMID:26512750

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

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

    PubMed Central

    Ursini, Francesco; 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

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

    PubMed

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

    2014-09-01

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

  14. A critical review of immunotherapy of disseminated renal adenocarcinoma.

    PubMed

    Montie, J E; Bukowski, R M; James, R E; Straffon, R A; Stewart, B H

    1982-09-01

    Sixty patients with renal adenocarcinoma have been treated with five different immunotherapy trials consisting of 1) Transfer Factor (TF), 2) TF and Bacillus Calmette-Guerin (BCG), 3) TF, BCG, Chloroethyl-cyclohexy-nitrosurea (CCNU) and megestrol acetate (Megase), 4) BCG, CCNU, and Megase, or 5) BCG. Using strict response criteria for measurable disease, objective responses were seen in 14-22% of cases. While this nonspecific immunotherapy of renal adenocarcinoma has been associated with documented regression of metastases, response rates are similar to that obtained with hormonal therapy alone. Objective responses support the concept of further trials in this disease with more sophisticated immunotherapy. PMID:7109637

  15. 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

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

    PubMed

    Melero, Ignacio; Berman, David M; Aznar, M Angela; Korman, Alan J; Pérez Gracia, José 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

  17. 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.

  18. 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

  19. Safety of engineered allergen-specific immunotherapy vaccines

    PubMed Central

    Focke-Tejkl, Margarete; Valenta, Rudolf

    2015-01-01

    Purpose of review The purpose of the review is to summarize and comment on recent developments regarding the safety of engineered immunotherapy vaccines. Recent findings In the last 2 years, several studies were published in which allergy vaccines were developed on the basis of chemical modification of natural allergen extracts, the engineering of allergen molecules by recombinant DNA technology and synthetic peptide chemistry, allergen genes, new application routes and conjugation with immune modulatory molecules. Several studies exemplified the general applicability of hypoallergenic vaccines on the basis of recombinant fusion proteins consisting of nonallergenic allergen-derived peptides fused to allergen-unrelated carrier molecules. These vaccines are engineered to reduce both, immunoglobulin E (IgE) as well as allergen-specific T cell epitopes in the vaccines, and thus should provoke less IgE and T-cell-mediated side-effects. They are made to induce allergen-specific IgG antibodies against the IgE-binding sites of allergens with the T-cell help of the carrier molecule. Summary Several interesting examples of allergy vaccines with potentially increased safety profiles have been published. The concept of fusion proteins consisting of allergen-derived hypoallergenic peptides fused to allergen-unrelated proteins that seems to be broadly applicable for a variety of allergens appears to be of particular interest because it promises not only to reduce side-effects but also to increase efficacy and convenience of allergy vaccines. PMID:22885888

  20. 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

  1. 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

  2. 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

  3. [Cancer immunotherapy in head and neck region].

    PubMed

    Eura, M

    2001-04-01

    There is no one common immunotherapy for the treatment of head and neck cancer (H&N cancer). A streptococcal agent, OK-432, which is classified as a biological response modifier (BRM), is occasionally used by means of local administration for recurrent H&N cancer, and the response rate is approximately 18%. In regard to specific immunotherapy, a murine monoclonal antibody (named mAb 225) against the epidermal growth factor receptor (FGFR) that is frequently overexpressed in H&N cancer has been produced in the U.S.A. Furthermore, to obviate human anti-mouse antibody responses, a chimeric human-to-murine version of mAb 225 (C225) was developed by exchanging the constant regions of mAb 225 to counterparts in human immune globulin. Phase I clinical trials of C225 in the U.S.A. demonstrated that treatment with C225 was well tolerated and that C225 given in combination with cisplatin has biologic activity. On the other hand, many tumor antigens recognized by cytotoxic T lymphocytes (CTL) have been identified from a variety of malignant tumors and some of them, including the MAGE-3 antigen, are frequently expressed in H&N cancer. We identified an MAGE-3-derived epitope recognized by HLA-A24-restricted CTL from peripheral blood mononuclear cells (PBMC). In contrast we failed to generate CTL specific for MAGE-3+/HLA-A24+ tumors from PBMC in any of 5 HLA-A24+ cancer patients whose tumors expressed the MAGE-3 gene. Therefore, we did not apply MAGE-3-derived CTL epitope in clinical uses such as peptide vaccine and peptide pulsed dendritic cell infusion for H&N cancer. PMID:11329779

  4. 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.

  5. Immunotherapy for food allergies: a myth or a reality?

    PubMed

    Praticò, Andrea D; Leonardi, Salvatore

    2015-01-01

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

  6. 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

  7. Peptide immunotherapy in models of allergic airways disease 

    E-print Network

    MacKenzie, Karen Joan

    2011-11-25

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

  8. 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

  9. 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

  10. Optimizing dendritic cell-based approaches for cancer immunotherapy.

    PubMed

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

    2014-12-01

    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

  11. 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

  12. What's eating you? Bees, Part 2: Venom immunotherapy and mastocytosis.

    PubMed

    Lewis, Felisa S; Smith, Laurie J

    2007-07-01

    Bee stings are common in the United States. In part 1 of this series, we reviewed the characteristics of bumblebees, honeybees, and Africanized honeybees; the types and pathophysiology of sting reactions; and the medical management and prevention of bee stings. In this article, we review the concepts and practice of venom immunotherapy. We further discuss the diagnosis of systemic mastocytosis, initially presenting as anaphylaxis, and the efficacy of immunotherapy in patients with mastocytosis. PMID:17725061

  13. 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-? 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

  14. 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

  15. An Examination of Clinical and Immunologic Outcomes in Food Allergen Immunotherapy by Route of Administration.

    PubMed

    Chiang, David; Berin, M Cecilia

    2015-06-01

    Allergen immunotherapy for the treatment of food allergy has been a subject of intensive study within the last 10 years. After an unsuccessful attempt with subcutaneous immunotherapy for peanut allergy, other routes with varying degrees of safety and efficacy have been tested for peanut, milk, and egg allergies. In this review, we summarize the results to date with oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy for the treatment of food allergy. While results of immunotherapy trials are promising, increases in efficacy are commonly associated with an increased side effect profile. There is a need for additional research beginning at the preclinical level to develop safe and effective treatments for food allergy. PMID:26141581

  16. Why has active immunotherapy not worked in lung cancer?

    PubMed

    Thomas, A; Giaccone, G

    2015-11-01

    Vaccines that rely on active specific stimulation of the host immune system have the potential to trigger durable antitumor responses with minimal toxicity. However, in nonsmall-cell lung cancer (NSCLC), several large phase III trials of vaccines reported within the last year have yielded disappointing results. Compared with placebo, belagenpumatucel-L (an allogenic tumor cell vaccine), tecemotide (a peptide vaccine targeting MUC-1) and melanoma-associated antigen-A3 (a protein-based vaccine) did not improve outcomes in NSCLC. The lack of clinically significant outcomes, despite their ability to prime and expand tumor antigen-specific T cells could at least partly be attributed to the inability of vaccine-induced T-cell responses to overcome the tumoral mechanisms of immune escape which limit the clonal expansion of T cells following vaccination. A number of such mechanisms have been recognized including reduced antigen presentation, antigenic loss, cytokines, immunosuppressive cells and immune checkpoints. Strategies aimed at modulating the immune checkpoints have shown promise and are on the verge of revolutionizing the therapeutic landscape of metastatic NSCLC. Overcoming immune tolerance and improving the activation of antitumor T cells via combinatorial approaches may represent a new and more promising therapeutic application for active immunotherapies in NSCLC. PMID:26232492

  17. Primer on tumor immunology and cancer immunotherapy

    PubMed Central

    2013-01-01

    Individualized cancer therapy is a central goal of cancer biologists. Immunotherapy is a rational means to this end—because the immune system can recognize a virtually limitless number of antigens secondary to the biology of genetic recombination in B and T lymphocytes. The immune system is exquisitely structured to distinguish self from non-self, as demonstrated by anti-microbial immune responses. Moreover the immune system has the potential to recognize self from “altered-self”, which is the case for cancer. However, the immune system has mechanisms in place to inhibit self-reactive responses, many of which are usurped by evolving tumors. Understanding the interaction of cancer with the immune system provides insights into mechanisms that can be exploited to disinhibit anti-tumor immune responses. Here, we summarize the 2012 SITC Primer, reviewing past, present, and emerging immunotherapeutic approaches for the treatment of cancer—including targeting innate versus adaptive immune components; targeting and/or utilizing dendritic cells and T cells; the role of the tumor microenvironment; and immune checkpoint blockade. PMID:24829749

  18. 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.

  19. 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.

  20. 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.

  1. Sarcoma Immunotherapy: Past Approaches and Future Directions

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Gómez-Casado, C.; Garrido-Arandia, M.; Gamboa, P.; Blanca-López, N.; Canto, G.; Varela, J.; Cuesta-Herranz, J.; Pacios, L. F.; Díaz-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

  3. 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

  4. Folate receptor ?: a storied past and promising future in immunotherapy.

    PubMed

    Clifton, Guy T; Sears, Alan K; Clive, Kevin S; Holmes, Jarrod P; Mittendorf, Elizabeth A; Ioannides, Constantine G; Ponniah, Sathibalan; Peoples, George E

    2011-02-01

    Folate receptor alpha (FR ?) is a membrane-bound transport protein with several features which make it an attractive target for cancer immunotherapy. FR ? is largely shielded from the immune system in normal tissue but exposed while expressed on a variety of malignancies; it is functionally active in cancer pathogenesis; and it is immunogenic. A variety of different immunotherapeutic methods targeting FR ? are being explored to treat cancer. Passive immunotherapy includes monoclonal antibodies, antibodies modified to deliver treatments, and modified T cell therapy. Active immunotherapy has focused on using FR ? to increase the immunogenicity of cancer or to generate active FR ?-directed immunity through a range of vaccination techniques. We will review the rationale behind targeting immunotherapy to FR ? and cover the various techniques designed to do this. Folate receptor alpha (FR?) is a unique tumor-associated antigen (TAA) with many characteristics that make it an attractive target for immunotherapy in cancer. Many different immunotherapeutic modalities utilizing FR? are being explored to treat cancer. The research is in various stages: some are just beyond conception, others have been tried and abandoned, and others still are progressing through human clinical trials. This review will cover immunotherapeutic methods, both active and passive, that target FR?. PMID:21321484

  5. Optimal control in a model of dendritic cell transfection cancer immunotherapy

    E-print Network

    Piccoli, Benedetto

    to the venom. Another example, which is relevant to us, is the immunotherapy applied to cancer. Of courseOptimal control in a model of dendritic cell transfection cancer immunotherapy Castiglione F as immunotherapeutic agent. Keywords. Optimal control, necessary conditions, cancer, immuno-therapy, autologous

  6. 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

  7. Combining Immunotherapy and Targeted Therapies in Cancer Treatment

    PubMed Central

    Vanneman, Matthew; Dranoff, Glenn

    2014-01-01

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

  8. 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

  9. 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

  10. 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.

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

    PubMed

    Chesné, 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

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

    PubMed Central

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

    2015-01-01

    Prostate cancer (PCa) is the second most common cancer in men. As well in many other human cancers, inflammation and immune suppression have an important role in their development. We briefly describe the host components that interact with the tumor to generate an immune suppressive environment involved in PCa promotion and progression. Different tools provide to overcome the mechanisms of immunosuppression including vaccines and immune checkpoint blockades. With regard to this, we report results of most recent clinical trials investigating immunotherapy in metastatic PCa (Sipuleucel-T, ipilimumab, tasquinimod, Prostvac-VF, and GVAX) and provide possible future perspectives combining the immunotherapy to the traditional therapies. PMID:26161414

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

    PubMed

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

    2015-03-01

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

  14. 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

  15. 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

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

  18. Immunotherapy: Using the Immune System to Treat Cancer

    Cancer.gov

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

  19. 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

  20. [Scleroderma related to specific immunotherapy. A report of a case].

    PubMed

    Morfín Maciel, Blanca María; Castillo Morfín, Blanca María

    2009-01-01

    It has been described two main phenotypes of helper T cells. On activation, the immune system develops the most effective Th response. Whereas Th1 cells promote cell-mediate immunity against intracellular pathogens and an over expression could favor autoimmune diseases; Th2 cells develop humoral immunity against extracellular pathogens promoting allergic response. Normally, the two profiles coexist in the same individual with different grades of expression. Recently, it has been described a new subset: Th17, which is related to tissue injury in autoimmune diseases. Then, allergic and autoimmune diseases result from an unbalanced response of the immune system. Allergen-specific immunotherapy is the only curative treatment of a specific allergy, which leads to a life-long tolerance against allergens. There are no controlled studies about the effectiveness or risks associated with allergen-specific immunotherapy in patients with autoimmune disorders. On the other hand, scleroderma is an autoimmune chronic systemic disorder of unknown etiology characterized by excess collagen deposition in the skin and viscera, along with vascular injury. We report a girl with allergic asthma and with a second degree family history of systemic sclerosis who developed localized scleroderma during allergen specific immunotherapy. Because allergy vaccination alter the balance between effector and regulatory T-cell populations, which regulate immune tolerance, a positive family history of autoimmunity in first or second degree, could be a contraindication for allergen-specific immunotherapy. PMID:19768975

  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. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    PubMed

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy. PMID:26469159

  3. Novel mechanisms and approaches in immunotherapy for brain tumors.

    PubMed

    Finocchiaro, Gaetano; Pellegatta, Serena

    2015-01-01

    Converging data indicate that the immune system is able to recognize cancer epitopes as non-self and mount an immune reaction that may erase, or temporarily block, tumor growth. The immune pressure supports the amplification of immune resistant tumor clones, creating an immune suppressive environment that leads to the formation of a clinically relevant tumor. These general observations also apply to brain tumors and specifically to gliomas. Cancer immunotherapy strategies are aimed at reverting such immune suppression. Two approaches are already used in the clinics. The first one, peptide immunotherapy, has been oriented to the most aggressive glioma, glioblastoma (GBM) where, in the context of EGFR (epidermal growth factor receptor) amplification, a large deletion arises and creates a novel, cancer-specific antigen, EGFRvIII. The second one is dendritic cell immunotherapy. Dendritic cells are potent antigen presenting cells that can be pulsed with autologous tumor lysate or peptide pp65 from cytomegalovirus (CMV) that is present in GBM but not in normal brain. Antigen presentation by dendritic cells is bolstered by preconditioning their injection site with the tetanus/diphtheria toxoid. The third approach is adoptive cell therapy (ACT) in which tumor-specific T cells can be amplified ex vivo and subsequently re-injected to the patient to lyse cells expressing tumor antigens, increasing survival durably in a fraction of melanoma patients. ACT may also be based on T cell transduction of tumor specific receptors or chimeric antigen receptors (CARs). CARs are powerful tools for immunotherapy but off-target toxicity may be an issue as they do not request MHC presentation for activation. Upcoming clinical trial results will clarify the most effective direction for cancer immunotherapy in gliomas and other cancers with poor prognosis. PMID:26321082

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. Novel approaches and mechanisms of immunotherapy for glioblastoma.

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    2014-08-01

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

  13. Oral Immunotherapy for Food Allergy: Towards a New Horizon

    PubMed Central

    Khoriaty, Evelyne

    2013-01-01

    Food allergy has increased dramatically in prevalence over the past decade in westernized countries, and is now a major public health problem. Unfortunately for patients with food allergy, there is no effective therapy beyond food allergen avoidance, and rapid medical treatment for accidental exposures. Recently, oral immunotherapy (OIT) has been investigated as a treatment for this problem. In this review, we will discuss the progress in developing OIT for food allergy, including a novel approach utilizing Xolair (anti-IgE monoclonal antibody, omalizumab) in combination with OIT. This combination may enhance both the safety and efficacy of oral immunotherapy, and could lead to a widely available and safe therapy for food allergy. PMID:23277873

  14. 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

  15. 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

  16. 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

  17. 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

  18. Immunotherapy and the concept of a clinical cure.

    PubMed

    Eggermont, Alexander M M; Kroemer, Guido; Zitvogel, Laurence

    2013-09-01

    Immunotherapy has entered a new phase in its history, i.e. the phase of being broadly accepted as a key component of therapeutic strategies to control and cure cancer. Immune-modulation by checkpoint inhibitors have demonstrated to be capable of inducing long lasting tumour responses. Breaking tolerance by ipilimumab has been a crucial event in the past recent years, but PD-1/PD-L1 antibodies have forever changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. High response rates of high quality with prolonged duration have been demonstrated in melanoma, renal cancer and in lung cancer. The broad potential is now being explored across a wide range of tumours. Importantly, synergy with ipilimumab has been demonstrated in melanoma, indicating a bright further future. Long term tumour control now seems achievable and thus the concept of a "clinical cure" is emerging. These antibodies bring immunotherapy to the forefront and indicate that immune-modulation will be a key component of therapeutic strategies from now on. All these observations indicate that "clinical cures" can only be achieved when the immune system is involved, and so the true renaissance of immunotherapy has arrived. PMID:23890942

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

    PubMed

    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

  20. 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

  1. 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

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

    PubMed Central

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

    2015-01-01

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

  3. Oncogenic cancer/testis antigens: prime candidates for immunotherapy

    PubMed Central

    Gjerstorff, Morten F.; Andersen, Mads H.; Ditzel, Henrik J.

    2015-01-01

    Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival. PMID:26158218

  4. 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

  5. Non-infectious cholecystopathy secondary to high-dose IL-2 cancer immunotherapy

    PubMed Central

    Kuppler, Kevin; Jeong, Daniel

    2015-01-01

    Interleukin-2 (IL-2) associated cholecystopathy is a rare manifestation of IL-2 drug toxicity in the setting of cancer immunotherapy. While the imaging data and clinical presentation can easily mimic acute cholecystitis, the correct diagnosis can be made with the particular clinical history, thus avoiding inappropriate surgical management. As more cancer immunotherapies become standard oncologic treatments, specific immunotherapy-associated side effects are also expected to be encountered more frequently in the future and should be recognized as such. We present a case of IL-2-associated cholecystopathy in the setting of renal cell carcinoma immunotherapy. PMID:26576289

  6. 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.

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

    PubMed

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

    2012-10-15

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

  8. 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

  9. Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy

    PubMed Central

    Vasilevko, Vitaly; Passos, Giselle; Quiring, Daniel; Head, Elizabeth; Fisher, Mark; Cribbs, David H.

    2010-01-01

    Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical aging secondary role in many neurodegenerative diseases, including Alzheimer’s disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood brain barrier (BBB) lesions. The accumulation of amyloid beta (A?) in the cerebrovascular system is a significant risk factor for intracerebral hemorrhage (ICH), and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-A? immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits, but have been plagued by CAA-associated adverse events. While management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of beta-amyloidosis in the cerebral vasculature. PMID:20955427

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  12. 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

  13. Bounded immune response in immunotherapy described by deterministic delay Kirschner-Panetta model

    E-print Network

    Tsygvintsev, Alexey V.

    Bounded immune response in immunotherapy described by deterministic delay Kirschner-Panetta model immune system behavior. Keywords: Delay Kirschner-Panetta model, Tumors, Immunotherapy, Boundedness. 1-field versions [7]. In some cases, the role of a delayed immune-response in the presence of stochastic processes

  14. 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. Naïve 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 “naïve” 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

  15. 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

  16. NK cell-based immunotherapy for malignant diseases

    PubMed Central

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

    2013-01-01

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

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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

  3. [Combination of Targeted Therapy and Immunotherapy for Cancer].

    PubMed

    Kadowaki, Norimitsu

    2015-09-01

    Targeted therapies and immunotherapies attack tumor cells through different mechanisms. In addition, these therapies exhibit quick and delayed effects, respectively, and therefore, these therapies are complementary. Furthermore, targeted therapies may enhance the function of immune cells, and therefore, both the therapies are expected to have a synergistic effect. Antitumor immune responses comprise several steps including dendritic cell activation, T cell activation, and dampening tumor-induced immunosuppression; targeted drugs that work at each step have been reported. Clinical trials of rational combinations of both therapies, while avoiding severe adverse events, will greatly advance cancer treatments in the near future. PMID:26469160

  4. 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

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

    PubMed Central

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

    2013-01-01

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

  6. 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

  7. 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

  8. 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.

  9. Clinical Development of Listeria monocytogenes–Based Immunotherapies

    PubMed Central

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

    2013-01-01

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

  10. A novel nanoparticulate adjuvant for immunotherapy with Lolium perenne.

    PubMed

    Gómez, 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. The importance of animal models in tumor immunity and immunotherapy

    PubMed Central

    Budhu, Sadna; Wolchok, Jedd; Merghoub, Taha

    2014-01-01

    The clinical success and US FDA approval of two immunotherapies (sipuleucel-T and ipilimumab) have brought tumor immunology to the forefront of cancer research. It has been long recognized that the immune system can infiltrate and survey the tumor microenvironment. The field of tumor immunology has been actively examining this phenomenon since the 1890s when William Coley first treated patients with live pathogenic bacteria and observed occasional regressions leading to long term survival. Recent progress in understanding mechanisms of immune activation and tolerance has led to the development of novel therapies that aim to either overcome inhibitory pathways (i.e. checkpoint blockade such as anti-CTLA-4 and anti-PD-1) or stimulate immune cell activation (i.e. co-stimulation such as anti-GITR and anti-OX40). A major part of the success of immunotherapy has been the development of appropriate mouse models. This review will outline the history and the major findings leading to the accomplishments of modern day immunology with specific attention to the usefulness of animal models. PMID:24657536

  16. 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

  17. A? immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy.

    PubMed

    Sakai, Kenji; Boche, Delphine; Carare, Roxana; Johnston, David; Holmes, Clive; Love, Seth; Nicoll, James A R

    2014-12-01

    A? immunotherapy for Alzheimer's disease (AD) results in the removal of A? plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the A? transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after A? immunotherapy. 12 A?42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for A?42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. A? immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of A?42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of A? to the cerebral vasculature induced by A? immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of A?. ARIA occurring in some current trials of A? immunotherapy may reflect an extreme form of these vascular changes. PMID:25195061

  18. 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

  19. Artificial antigen presenting cells for use in adoptive immunotherapy

    PubMed Central

    Turtle, Cameron J.; Riddell, Stanley R.

    2010-01-01

    The observation that T cells can recognize and specifically eliminate cancer cells has spurred interest in the development of efficient methods to generate large numbers of T cells with specificity for tumor antigens that can be harnessed for use in cancer therapy. Recent studies have demonstrated that during encounter with tumor antigen, the signals delivered to T cells by professional antigen presenting cells can affect T cell programming and their subsequent therapeutic efficacy. This has stimulated efforts to develop artificial antigen presenting cells that allow optimal control over the signals provided to T cells. In this review, we will discuss the advantages and disadvantages of cellular and acellular artificial antigen presenting cell systems and their use in T cell adoptive immunotherapy for cancer. PMID:20693850

  20. Immunotherapy for Cancer: Synthetic Carbohydrate-based Vaccines

    PubMed Central

    Buskas, Therese; Thompson, Pamela

    2009-01-01

    Aberrant glycosylation of glycoproteins and glycolipids of cancer cells, which correlates with poor survival rates, is being exploited for the development of immunotherapies for cancer. In particular, advances in the knowledge of cooperation between the innate and adaptive system combined with the implementation of efficient synthetic methods for assembly of oligosaccharides and glycopeptides is providing avenues for the rationale design of vaccine candidates. In this respect, fully synthetic vaccine candidates show great promise because they incorporate only those elements requires for relevant immune responses, and hence do not suffer from immune suppression observed with classical carbohydrate-protein conjugate vaccines. Such vaccines are chemically well-defined and it is to be expected that they can be produced in a reproducible fashion. In this review article, recent advances in the development of fully synthetic sub-unit carbohydrate-based cancer vaccines will be discussed. PMID:19724783

  1. Immunotherapy strategies for multiple myeloma: the present and the future.

    PubMed

    Locke, Frederick L; Nishihori, Taiga; Alsina, Melissa; Kharfan-Dabaja, Mohamed A

    2013-09-01

    Growing knowledge of the complexities of the immune system have led to a better understanding of how it can be harnessed for the purpose of anticancer therapy. Moreover, recent success with immunotherapies for solid tumors, combined with novel therapeutic strategies against myeloma, heighten excitement at the prospect of improving clinical outcomes for myeloma by improving antitumor immunity. Increased understanding of myeloma tumor-associated antigens, availability of more potent vaccines, expanded immune-modulating therapies, development of agents that block immune-suppressive pathways, increased sophistication of adoptive cell therapy techniques and capitalization upon standard autologous transplant are all important standalone or combination strategies that might ultimately improve prognosis of patients with multiple myeloma. PMID:23998734

  2. Allergen Immunotherapy in an HIV+ Patient with Allergic Fungal Rhinosinusitis

    PubMed Central

    Myles, Ian A.; Gada, Satyen

    2015-01-01

    Patients with HIV/AIDS can present with multiple types of fungal rhinosinusitis, fungal balls, granulomatous invasive fungal rhinosinusitis, acute or chronic invasive fungal rhinosinusitis, or allergic fungal rhinosinusitis (AFRS). Given the variable spectrum of immune status and susceptibility to severe infection from opportunistic pathogens it is extremely important that clinicians distinguish aggressive fungal invasive fungal disease from the much milder forms such as AFRS. Here we describe a patient with HIV and AFRS to both remind providers of the importance of ruling out invasive fungal disease and outline the other unique features of fungal sinusitis treatment in the HIV-positive population. Additionally we discuss the evidence for and against use of allergen immunotherapy (AIT) for fungal disease in general, as well as the evidence for AIT in the HIV population. PMID:25954557

  3. A microfluidic approach towards hybridoma generation for cancer immunotherapy.

    PubMed

    Lu, Yen-Ta; Pendharkar, Gaurav Prashant; Lu, Chung-Huan; Chang, Chia-Ming; Liu, Cheng-Hsien

    2015-11-17

    Dendritic cells/tumor fusions have shown to elicit anti-cancer immunity in different cancer types. However, the application of these vaccines for human cancer immunotherapy are limited by the instable quality and insufficient quanity of fusion cells. We present a cell electrofusion chip fabricated using soft lithography technique, which combines the rapid and precise cell pairing microstructures and the high yield electrofusion micro-electrodes to improve the cell fusion. The design uses hydrodynamic trapping in combination with positive dielectrophoretic force (pDEP) to achieve cell fusion. The chip consists of total 960 pairs of trapping channels, which are capable of pairing and fusing both homogeneous and heterogeneous types of cells. The fused cells can be easily taken out of the chip that makes this device a distinguishable from other designs. We observe pairing efficiency of 68% with fusion efficiency of 64%. PMID:26462149

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

    PubMed

    Ciprandi, G

    2015-03-01

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

  5. Strategies for combining immunotherapy with radiation for anticancer therapy.

    PubMed

    Seyedin, Steven N; Schoenhals, Jonathan E; Lee, Dean A; Cortez, Maria A; Wang, Xiaohong; Niknam, Sharareh; Tang, Chad; Hong, David S; Naing, Aung; Sharma, Padmanee; Allison, James P; Chang, Joe Y; Gomez, Daniel R; Heymach, John V; Komaki, Ritsuko U; Cooper, Laurence J; Welsh, James W

    2015-09-01

    Radiation therapy controls local disease but also prompts the release of tumor-associated antigens and stress-related danger signals that primes T cells to promote tumor regression at unirradiated sites known as the abscopal effect. This may be enhanced by blocking inhibitory immune signals that modulate immune activity through a variety of mechanisms. Indeed, abscopal responses have occurred in patients with lung cancer or melanoma when given anti-CTLA4 antibody and radiation. Other approaches involve expanding and reinfusing T or NK cells or engineered T cells to express receptors that target specific tumor peptides. These approaches may be useful for immunocompromised patients receiving radiation. Preclinical and clinical studies are testing both immune checkpoint-based strategies and adoptive immunotherapies with radiation. PMID:26310908

  6. Epidermal growth factor receptor and variant III targeted immunotherapy

    PubMed Central

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

    2014-01-01

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

  7. Analogue peptides for the immunotherapy of human acute myeloid leukemia.

    PubMed

    Hofmann, Susanne; Mead, Andrew; Malinovskis, Aleksandrs; Hardwick, Nicola R; Guinn, Barbara-Ann

    2015-11-01

    The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies. PMID:26438084

  8. Antigen-based immunotherapy (AIT) for autoimmune and allergic disease.

    PubMed

    MacLeod, Megan K L; Anderton, Stephen M

    2015-08-01

    Autoimmune and allergic diseases are major causes of morbidity. Antigen-based immunotherapy (AIT) is immunologically the most satisfying means of specifically targeting only those T cells driving disease, thereby inducing antigen-specific immune tolerance, with the lowest adverse risk profile. AIT is highly effective in rodent models of T cell-driven inflammation and is now in clinical trials. The range of approaches to applying AIT in the clinic prevents a consensus on the molecular basis for this form of tolerance. In particular, there has been a paucity of information on how pre-activated effector and memory T cells respond to AIT. New, advanced murine models of AIT are beginning to deliver such information at the cellular, biochemical, transcriptional and epigenetic levels. PMID:26004365

  9. Trial Watch: Adoptive cell transfer for anticancer immunotherapy.

    PubMed

    Vacchelli, Erika; Eggermont, Alexander; Fridman, Wolf Hervé; Galon, Jérôme; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2013-05-01

    Adoptive cell transfer (ACT) represents a prominent form of immunotherapy against malignant diseases. ACT is conceptually distinct from dendritic cell-based approaches (which de facto constitute cellular vaccines) and allogeneic transplantation (which can be employed for the therapy of hematopoietic tumors) as it involves the isolation of autologous lymphocytes exhibiting antitumor activity, their expansion/activation ex vivo and their reintroduction into the patient. Re-infusion is most often performed in the context of lymphodepleting regimens (to minimize immunosuppression by host cells) and combined with immunostimulatory interventions, such as the administration of Toll-like receptor agonists. Autologous cells that are suitable for ACT protocols can be isolated from tumor-infiltrating lymphocytes or generated by engineering their circulating counterparts for the expression of transgenic tumor-specific T-cell receptors. Importantly, lymphocytes can be genetically modified prior to re-infusion for increasing their persistence in vivo, boosting antitumor responses and minimizing side effects. Moreover, recent data indicate that exhausted antitumor T lymphocytes may be rejuvenated in vitro by exposing them to specific cytokine cocktails, a strategy that might considerably improve the clinical success of ACT. Following up the Trial Watch that we published on this topic in the third issue of OncoImmunology (May 2012), here we summarize the latest developments in ACT-related research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of this form of cellular immunotherapy. PMID:23762803

  10. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.

    PubMed

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

    2014-11-27

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

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

    E-print Network

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

    2008-01-01

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

  12. Development and potential of HMGB1-derived immunostimulatory peptides as adjuvants in cancer immunotherapy

    E-print Network

    Saenz, Rebecca Kathleen

    2011-01-01

    vaccine-based active immunotherapies that aim to stimulate the patient’s immune systemimmune system of newborns or immunodeficient patients, and whole inactivated pathogens contain reactogenic components that can cause undesirable vaccine

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

    E-print Network

    Stachowiak, Agnieszka (Agnieszka N.)

    2007-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  15. New strategies in immunotherapy for non-small cell lung cancer

    PubMed Central

    Gold, Kathryn A.

    2015-01-01

    Treatment for the most common form of cancer (lung cancer) has historically involved use of cytotoxic chemotherapy. With the advent of mutation analysis, more therapies beyond traditional cytotoxics have been discovered. Most recently, the use of immunotherapy has entered the treatment arsenal of non-small cell lung cancer (NSCLC). This review aims to summarize the current and future use of immunotherapy in the treatment of NSCLC.

  16. Decreased amyloid-? and increased neuronal hyperactivity by immunotherapy in Alzheimer's models.

    PubMed

    Busche, Marc Aurel; Grienberger, Christine; Keskin, Aylin D; Song, Beomjong; Neumann, Ulf; Staufenbiel, Matthias; Förstl, Hans; Konnerth, Arthur

    2015-12-01

    Among the most promising approaches for treating Alzheimer´s disease is immunotherapy with amyloid-? (A?)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to A? used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies. PMID:26551546

  17. Antigen-specific immunotherapy against allergic rhinitis: the state of the art.

    PubMed

    Fujimura, Takashi; Okamoto, Yoshitaka

    2010-03-01

    Allergic rhinitis is the most prevalent type I allergy in industrialized countries. Pollen scattering from trees or grasses often induces seasonal allergic rhinitis, which is known as pollinosis or hay fever. The causative pollen differs across different areas and times of the year. Impaired performance due to pollinosis and/or medication used for treating pollinosis is considered to be an important reason for the loss of concentration and productivity in the workplace. Antigen-specific immunotherapy is an only available curative treatment against allergic rhinitis. Subcutaneous injection of allergens with or without adjuvant has been commonly used as an immunotherapy; however, recently, sublingual administration has come to be considered a safer and convenient alternative administration route of allergens. In this review, we focus on the safety and protocol of subcutaneous and sublingual immunotherapy against seasonal allergic rhinitis. We also describe an approach to selecting allergens for the vaccine so as to avoid secondary sensitization and adverse events. The biomarkers and therapeutic mechanisms for immunotherapy are not fully understood. We discuss the therapeutic biomarkers that are correlated with the improvement of clinical symptoms brought about by immunotherapy as well as the involvement of Tr1 and regulatory T cells in the therapeutic mechanisms. Finally, we focus on the current immunotherapeutic approach to treating Japanese cedar pollinosis, the most prevalent pollinosis in Japan, including sublingual immunotherapy with standardized extract, a transgenic rice-based edible vaccine, and an immunoregulatory liposome encapsulating recombinant fusion protein. PMID:20093851

  18. Local immunotherapy via delivery of interleukin-10 and transforming growth factor ? antagonist for treatment of chronic kidney disease.

    PubMed

    Rodell, Christopher B; Rai, Reena; Faubel, Sarah; Burdick, Jason A; Soranno, Danielle E

    2015-05-28

    Obstructive nephropathy is the leading cause of kidney disease in children. The tissue injury resulting from initial dilation precipitates a deleterious cascade of macrophage infiltration, apoptosis, and fibrosis to produce a resultant dysfunctional tissue. We propose to abate this tissue remodeling process through immunotherapy administered via the local and sustained delivery of interleukin-10 (IL-10; anti-inflammatory) and anti-transforming growth factor ? (anti-TGF?; anti-fibrotic). Shear-thinning, injectable hyaluronic acid (HA) hydrogels were formed through supramolecular guest-host interactions and used to contain IL-10, anti-TGF?, or both molecules together. Degradation assays demonstrated that diffusive molecule release was associated with concurrent hydrogel erosion and was sustained for up to 3weeks in vitro. Erosion was likewise monitored in vivo by non-invasive optical imaging, where gel localization to the affected tissue was observed with near complete clearance by day 18. Hydrogels were applied to a murine model of chronic kidney disease, with subcapsular hydrogel injections acting as a delivery depot. Quantitative histological analysis (days 7, 21, and 35) was used to evaluate treatment efficacy. Notably, results demonstrated reduced macrophage infiltration beyond day 7 in treatment groups and reduced apoptosis at day 21, relative to untreated unilateral ureteral obstruction disease model. Fibrosis was reduced at the 35day timepoint in groups treated with IL-10 or anti-TGF? alone, but not with the combination therapy. Rather, dual delivery of IL-10 and anti-TGF? resulted in a paradoxical hastening of fibrosis, warranting further investigation. Localized immunotherapy is a novel approach to treat kidney disease and shows promise as a translatable therapy. PMID:25804871

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

    PubMed

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

    2015-07-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  2. Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy.

    PubMed

    Niedoszytko, M; de Monchy, J; van Doormaal, J J; Jassem, E; Oude Elberink, J N G

    2009-09-01

    The most important causative factor for anaphylaxis in mastocytosis are insect stings. The purpose of this review is to analyse the available data concerning prevalence, diagnosis, safety and effectiveness of venom immunotherapy (VIT) in mastocytosis patients. If data were unclear, authors were contacted personally for further information. Quality of evidence (A: high, B: moderate, C: low and D: very low) and strength of recommendation (strong 1 and weak 2) concerning VIT in mastocytosis patients are assessed according to the Grading of Recommendations Assessment, Development and Evaluation and are marked in square brackets. Results of VIT were described in 117 patients to date. The mean rate of side-effects during treatment in studies published so far is 23.9% (7.6% requiring adrenaline) with an overall protection rate of 72%. Based on the review we conclude that (1) mastocytosis patients have a high risk of severe sting reactions in particular to yellow jacket, (2) VIT could be suggested [2] in mastocytosis, (3) probably should be done life long [2], (4) VIT in mastocytosis is accompanied by a higher frequency of side-effects, so (5) special precautions should be taken into account notably during the built up phase of the therapy [2], (6) VIT is able to reduce systemic reactions, but to a lesser extent compared to the general insect venom allergic population [2], so (7) patients should be warned that the efficacy of VIT might be less than optimal and they should continue carrying two adrenaline auto injectors [2]. PMID:19627278

  3. Successful immunotherapy with matrix metalloproteinase-derived peptides in adjuvant arthritis depends on the timing of peptide administration

    PubMed Central

    van Bilsen, Jolanda HM; Wagenaar-Hilbers, Josée PA; van der Cammen, Maarten JF; van Dijk, Mariska EA; van Eden, Willem; Wauben, Marca HM

    2002-01-01

    We have recently found that matrix metalloproteinases (MMPs) are targets for T-cell and B-cell reactivity in experimental arthritis. In the present article, we investigate whether modulation of MMP-specific T-cell responses could influence the course of adjuvant arthritis (AA). Lewis rats were treated nasally with MMP peptides prior to or after AA induction. Administration of the MMP-10 or the MMP-16 peptide prior to AA induction reduced the arthritic symptoms. In contrast, administration of the MMP-10 peptide after AA induction aggravated the arthritic symptoms. The present study shows the possible usefulness of MMP peptides for immunotherapy. However, a clear understanding of proper timing of peptide administration is crucial for the development of such therapies. PMID:12106501

  4. Effect of high-dose sublingual immunotherapy on respiratory infections in children allergic to house dust mite

    PubMed Central

    Barberi, Salvatore; Verduci, Elvira; D'Auria, Enza; Poli, Piercarlo; Pietra, Benedetta; Incorvaia, Cristoforo; Buttafava, Serena; Frati, Franco; Riva, Enrica

    2015-01-01

    Background Allergic rhinitis is characterized by eosinophil inflammation. Allergic inflammation may induce susceptibility to respiratory infections (RI). House dust mite (HDM) sensitization is very frequent in childhood. Allergen immunotherapy may cure allergy as it restores a physiologic immune and clinical tolerance to allergen and exerts anti-inflammatory activity. Objective This study investigated whether six-month high-dose, such as 300 IR (index of reactivity), HDM-sublingual immunotherapy (SLIT) could affect RI in allergic children. Methods Globally, 40 HDM allergic children (18 males; mean age, 9.3 years) were subdivided in 2 groups: 20 treated by symptomatic drugs (group 1) and 20 by high-dose HDM-SLIT (group 2), since September 2012 to April 2013. The daily maintenance dose of HDM-SLIT was 4 pressures corresponding to 24, 4.8, and 60 µg, respectively of the major allergens Dermatophagoides pteronyssinus (Der p) 1, Der p 2, and Dermatophagoides farinae (Der f) 1. RI was diagnosed when at least 2 symptoms or signs, and fever were present for at least 48 hours. A family pediatrician provided diagnosis on a clinical ground. Results SLIT-treated children had significantly (p = 0.01) less RI episodes (3.5) than control group (5.45). About secondary outcomes, SLIT-treated children had less episodes of pharyngo-tonsillitis (p < 0.05) and bronchitis (p < 0.005), and snoring (p < 0.05) than control group. In addition, SLIT-treated children had less fever (p < 0.01) and took fewer medications, such as antibiotics (p < 0.05) and fever-reducers (p < 0.01), than control group. Conclusion This preliminary study might suggest that also a short course (6 months) of high-dose SLIT, titrated in µg of major allergens, could reduce RI in allergic children. PMID:26240793

  5. The Application of Natural Killer Cell Immunotherapy for the Treatment of Cancer

    PubMed Central

    Rezvani, Katayoun; Rouce, Rayne H.

    2015-01-01

    Natural killer (NK) cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack non-hematopoietic tissues, suggesting that an NK-mediated antitumor effect can be achieved in the absence of graft-vs.-host disease. Despite reports of clinical efficacy, a number of factors limit the application of NK cell immunotherapy for the treatment of cancer, such as the failure of infused NK cells to expand and persist in vivo. Therefore, efforts to enhance the therapeutic benefit of NK cell-based immunotherapy by developing strategies to manipulate the NK cell product, host factors, and tumor targets are the subject of intense research. In the preclinical setting, genetic engineering of NK cells to express CARs to redirect their antitumor specificity has shown significant promise. Given the short lifespan and potent cytolytic function of mature NK cells, they are attractive candidate effector cells to express CARs for adoptive immunotherapies. Another innovative approach to redirect NK cytotoxicity towards tumor cells is to create either bispecific or trispecific antibodies, thus augmenting cytotoxicity against tumor-associated antigens. These are exciting times for the study of NK cells; with recent advances in the field of NK cell biology and translational research, it is likely that NK cell immunotherapy will move to the forefront of cancer immunotherapy over the next few years. PMID:26635792

  6. Immunotherapy of gram-negative infections in oncological patients.

    PubMed

    Glauser, M P

    1989-09-01

    While it is widely recognized that gram-negative bacteria (GNB) are a leading cause of morbidity and mortality among patients whose immune defenses are compromised both by their underlying malignancy as well as by its treatment, efforts to prevent or to treat such infections by immunological means have been hampered for several reasons. First, the natural anatomical barriers are often disrupted either by the tumor itself, by the chemotherapeutic agents, or, as recognized more recently, by viral (herpetic) or fungal infections, so that entrance of the gram-negative flora into the host tissue and blood stream is greatly facilitated. Efforts to diminish the bacterial load by means of oral decontamination, be it selective or not, to prevent such ingress have brought limited success. Second, active immunization is not likely to elicit a useful response in these patients, so that mainly passive immunotherapy has been considered and studied. However, since the most immunocompromised cancer patients are very often leucopenic, the opsono-phagocytic function of passively administered antibodies is not likely to help the patients to get rid of the invading gram-negative bacteria. This latter observation has been particularly well established in the case of Pseudomonas aeruginosa infections in leukemic patients (Young LS, Stevens P, Ingram J. J Clin Invest 1975, 56, 850-861). PMID:2680515

  7. Specific Immunotherapy of Experimental Myasthenia Gravis by A Novel Mechanism

    PubMed Central

    Luo, Jie; Kuryatov, Alexander; Lindstrom, Jon

    2009-01-01

    Objective Myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG), are antibody-mediated autoimmune diseases, in which autoantibodies bind to and cause loss of muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. To develop a specific immunotherapy of MG, we treated rats with ongoing EAMG by intraperitoneal injection of bacterially-expressed human muscle AChR constructs. Methods Rats with ongoing EAMG received intraperitoneal treatment with the constructs weekly for 5 weeks beginning after the acute phase. Autoantibody concentration, subclassification, and specificity were analyzed to address underlying therapeutic mechanism. Results EAMG was specifically suppressed by diverting autoantibody production away from pathologically relevant specificities directed at epitopes on the extracellular surface of muscle AChRs toward pathologically irrelevant epitopes on the cytoplasmic domain. A mixture of subunit cytoplasmic domains was more effective than a mixture containing both extracellular and cytoplasmic domains or than only the extracellular domain of ?1 subunits. Interpretation Therapy using only cytoplasmic domains, which lack pathologically relevant epitopes, avoids the potential liability of boosting the pathological response. Use of a mixture of bacterially-expressed human muscle AChR cytoplasmic domains for antigen-specific immunosuppression of myasthenia gravis has the potential to be specific, robust, and safe. PMID:20437579

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

    PubMed Central

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

    2012-01-01

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

  9. Vaccine immunotherapy in lung cancer: Clinical experience and future directions.

    PubMed

    Freeman-Keller, Morganna; Goldman, Jamie; Gray, Jhanelle

    2015-09-01

    Lung cancer remains the most common cause of cancer-related deaths in the United States, with SEER data showing lung cancer accounting for 29% of all male-related cancer mortality and 26% of all female-related mortality. Patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) who have localized disease both have 5-year survival rates of 52.2%, whereas patients with metastatic disease have 5-year survival rates of only 3.7%. Traditional anti-cancer therapies (surgery, radiotherapy, and chemotherapy) have limited effectiveness in curbing progression. However, advances in immunology and molecular biology in the past two decades have resulted in improved prognosis for those with SCLC and NSCLC, although novel therapies are still needed to make significant improvements in median overall and progression-free survival rates. Notable progress on the importance of tumor immunology has included work on immune surveillance, antigenic targets, and immune checkpoints. Immunotherapies, including vaccines, which can induce antitumor responses by harnessing the power of the immune system, may help to fill this void, and the cancer vaccine continues to be studied as adjunctive therapy. Here, we review recently reported results from clinical trials as well as the possible future roles of vaccine therapy in the treatment of SCLC and NSCLC patients. PMID:25989231

  10. Allergen immunotherapy with nanoparticles containing lipopolysaccharide from Brucella ovis.

    PubMed

    Gómez, Sara; Gamazo, Carlos; San Roman, Beatriz; Ferrer, Marta; Sanz, Maria Luisa; Espuelas, Socorro; Irache, Juan M

    2008-11-01

    The adjuvant and protective capacity against anaphylactic shock of the association between rough lipopolysaccharide of Brucella ovis (LPS) coencapsulated with ovalbumin (OVA), as a model allergen, in Gantrez AN nanoparticles was investigated. Several strategies were performed in order to study the adjuvant effect of the LPS either encapsulated or coating the nanoparticles. OVA, as well as LPS, was incorporated either during the manufacturing process (OVA-encapsulated or LPS-encapsulated nanoparticles, respectively) or after the preparation (OVA-coated or LPS-coated nanoparticles, respectively). After the administration of 10 microg of OVA incorporated in the different formulations, all the nanoparticles, with or without LPS, were capable of amplifying the immune response (IgG(1) and IgG(2a)). However, in a model of sensitized mice to OVA, the formulation with OVA and LPS-entrapped inside the nanoparticles administered intradermally in three doses of 3 microg of OVA each was the only treatment that totally protected the mice from death after a challenge with an intraperitoneal injection of OVA. In contrast, the control group administered with OVA adsorbed onto a commercial alhydrogel adjuvant showed 80% mortality. These results are highly suggestive for the valuable use of Gantrez nanoparticles combined with rough LPS of B. ovis in immunotherapy. PMID:18582571

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

    PubMed Central

    Spencer, Brian; Masliah, Eliezer

    2014-01-01

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

  12. Beta-amyloidbased immunotherapy as a treatment of Alzheimers disease.

    PubMed

    Solomon, Beka

    2007-05-01

    The pathology of Alzheimer's disease shows a significant correlation between beta-amyloid peptide conformation and the clinical severity of dementia. For many years efforts have been focused on the development of inhibitors of beta-amyloid formation and its related neurotoxic effects. A new concept has been developed which shows that site-directed antibodies may modulate formation of beta-amyloid. The performance of anti-beta-amyloid antibodies in transgenic mice models of Alzheimer's disease showed that they are delivered to the central nervous system, preventing in vivo formation of beta-amyloid. Moreover, those antibodies dissolve beta-amyloid plaques and protect the mice from learning and age-related memory deficits. Experimental active immunization with beta-amyloid (1-42) in humans was stopped in phase II of their clinical trials. However, several new preparations, able to provide antibodies against beta-amyloid by either active or passive routes, have been formulated and have reached clinical testing. The data presented support the hypothesis that beta-amyloid peptide plays a central role in Alzheimer's disease, and antibodies which modulate beta-amyloid conformation may lead to immunotherapy of the disease. PMID:17724499

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

    PubMed

    Takaiwa, Fumio

    2011-03-01

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

  14. STRATEGIES TO OVERCOME OBSTACLES TO SUCCESSFUL IMMUNOTHERAPY OF MELANOMA

    PubMed Central

    Pandolfi, F.; Cianci, R.; Lolli, S.; Dunn, I.S.; Newton, E.E.; Haggerty, T.J.; Boyle, L.A.; Kurnick, J.T.

    2010-01-01

    Summary The immunogenicity of Malignant Melanomas has been recognized by the observed recruitment of tumor-specific cytotoxic T-cells (CTL), leading to the identification of several melanoma associated antigen (MAA). However, numerous strategies to treat melanoma with immunotherapy have resulted in only partial success. In this review, we discuss recent data related to the ability of tumors to elude immune responses. In response, we discuss different strategies to induce a clinically effective immune response. These approaches include 1) immunostimulation: including peptide/protein based vaccines, dendritic cell vaccines, and adoptive cell transfer; and 2) overcoming immunosuppression: including targeting of checkpoint molecules such as CTLA-4, circumventing the activity of Tregs, and assuring antigen expression by tumor cells (thwarting antigen silencing). Finally, we discuss recent advances in gene therapy, including adoptive therapy with engineered TCRs. These issues lead to the conclusion that successful immotherapy in malignant melanoma will require a combination of strategies aimed at both inducing immunostimulation and blocking immunosuppression. PMID:18831916

  15. Assays for predicting and monitoring responses to lung cancer immunotherapy

    PubMed Central

    Teixidó, Cristina; Karachaliou, Niki; González-Cao, Maria; Morales-Espinosa, Daniela; Rosell, Rafael

    2015-01-01

    Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway. PMID:26175924

  16. Efficacy of sublingual immunotherapy for house dust mite allergic rhinitis.

    PubMed

    Cingi, Cemal; Bayar Muluk, Nuray; Ulusoy, Seçkin; Acar, Mustafa; ?irin, Seher; Çobano?lu, Bengü; Birdane, Leman; Kalayc?k, Çi?dem; Çak?r, Burak Ömür; O?han, Fatih; Aynac?, Sevilay; Erdo?mu?, Nagehan; Y?ld?r?m, Ömürsen; ?ahin, Ethem; Bulut, Fuat; Aksoy, Mehmet Akif; Türe, Nurullah; Bal, Cengiz

    2015-11-01

    In the present study, we investigated the outcomes of sublingual immunotherapy (SLIT) in house dust mite-induced allergic rhinitis (HDM-AR) patients. In this prospective, multicentric study, 186 patients with AR who had positive skin prick test results for HDMs were included. The patients were administered SLIT using Staloral 300 for 1 year. Evaluation of the patients regarding symptom scores, clinical findings and Rhinitis Quality of Life Questionnaire (RQLQ) scores was performed at baseline, and then at 6 and 12 months of therapy. Our results showed that, for all of the evaluated items (symptom scores, clinical findings and RQLQ scores), 12-month values were significantly lower than those at 6 months and baseline. Similarly, 6-month values were significantly lower than those at baseline. There were no complications in any of our patients. SLIT for HDM-AR is a treatment modality that can be used safely. We obtained better results than expected, and the treatment showed a positive psychological effect; the patients believed that SLIT was the final step of treatment and, which made them feel better. PMID:25516223

  17. Rationale for anti-OX40 cancer immunotherapy.

    PubMed

    Aspeslagh, Sandrine; Postel-Vinay, Sophie; Rusakiewicz, Sylvie; Soria, Jean-Charles; Zitvogel, Laurence; Marabelle, Aurélien

    2016-01-01

    Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade -based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials. Accumulating preclinical evidence supports their clinical development. However, conflicting results and controversies between in vitro and in vivo data point to the need for comprehensive ancillary studies to be performed in upcoming clinical trials to better understand the mechanism of action of anti-OX40 mAbs-based therapy. PMID:26645943

  18. Assays for predicting and monitoring responses to lung cancer immunotherapy.

    PubMed

    Teixidó, Cristina; Karachaliou, Niki; González-Cao, Maria; Morales-Espinosa, Daniela; Rosell, Rafael

    2015-06-01

    Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway. PMID:26175924

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

    PubMed Central

    2013-01-01

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

  20. Lentiviral vectors for cancer immunotherapy and clinical applications.

    PubMed

    Liechtenstein, Therese; Perez-Janices, Noemi; Escors, David

    2013-09-01

    The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(?-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and ?-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells. PMID:24078865

  1. Glypican-3: a new target for cancer immunotherapy.

    PubMed

    Ho, Mitchell; Kim, Heungnam

    2011-02-01

    Hepatocellular carcinoma (HCC) remains a common malignant cancer worldwide. There is an urgent need to identify new molecular targets for the development of novel therapeutic approaches. Herein, we review the structure, function and biology of glypican-3 (GPC3) and its role in human cancer with a focus on its potential as a therapeutic target for immunotherapy. GPC3 is a cell-surface protein that is over-expressed in HCC. Loss-of-function mutations of GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS), a rare X-linked overgrowth condition. GPC3 binds Wnt and Hedgehog (Hh) signalling proteins. GPC3 is also able to bind basic growth factors such as fibroblast growth factor 2 through its heparan sulphate glycan chains. GPC3 is a promising candidate for liver cancer therapy given that it shows high expression in HCC. An anti-GPC3 monoclonal antibody has shown anti-cancer activity in mice and its humanised IgG molecule is currently undergoing clinical evaluation in patients with HCC. There is also evidence that soluble GPC3 may be a useful serum biomarker for HCC. PMID:21112773

  2. Definition of a target for immunotherapy and results of the first Peptide vaccination study in chronic lymphocytic leukemia.

    PubMed

    Tabarkiewicz, J; Giannopoulos, K

    2010-10-01

    Results of bone marrow transplantation, as well as remission phenomena after viral infections, suggest that chronic lymphocytic leukemia (CLL) might be targeted effectively by T-cell-based immunotherapy. Antigen-targeted immunotherapies represent novel treatments for CLL patients. Earlier, we screened the mRNA expression of several tumor associated antigens (TAAs), observing the presence of RHAMM/CD168, fibromodulin, syntaxin, and NY-Ren60 in 55%-90% of CLL patients. RHAMM/CD168, fibromodulin, PRAME, and MPP11 were expressed in CLL patients but not in healthy volunteers. Quantitative reverse transcriptase polymerase chain reaction revealed higher RHAMM expression in high-risk CLL patients as well as in advanced stages of the disease. CLL cases with higher RHAMM expressions showed significantly shorter median treatment-free survivals. Among patients with mutated IgVH genes, an analysis of RHAMM expression enabled us to distinguish a subgroup of patients with a favorable prognosis. In lymph nodes, RHAMM staining correlated with a higher Ki-67 index and CD40L expression. Functionally, stimulation with CD40L enhanced RHAMM expression in CLL. Because of the exquisite tissue expression of RHAMM and its high expression frequency in CLL patients, we further characterized RHAMM-specific CD8+ T cells in these patients. CD8+ T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)A2, lysed RHAMM+ CLL cells. Therefore, we initiated a Phase I clinical trial of R3 peptide vaccination. Four patients exhibited reduced white blood cell counts during the vaccination process. In 5/6 patients, R3-specific CD8+ T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in 4/5 patients using ELISpot assays. In conclusion, RHAMM expression seems to be of prognostic value, and may reflect the proliferative capacity of CLL cells; it may therefore represent an interesting target for immunotherapy. Peptide vaccination in CLL patients was safe eliciting specific CD8+ T-cell responses against the tumor antigen RHAMM. PMID:20970674

  3. Role of miR-146a in Enforcing Effect of Specific Immunotherapy on Allergic Rhinitis.

    PubMed

    Liu, Hong-Jun; Zhang, Ai-Fen; Zhao, Na; Li, Xue-Zhong

    2016-01-01

    Allergic rhinitis (AR) is one of the common disorders in airway allergic inflammation. The pathogenesis of AR is unclear. It is accepted that immune deregulation is associated with the pathogenesis of AR. Recent reports suggest that a large number of micro RNAs (miR) can regulate immune functions. This study aims to investigate the role of miR-146a in an enforcing immunotherapy of AR. In this study, a mouse AR model was created. The levels of miR-146a in the mouse nasal mucosa were assessed by real time RT-PCR. A specific immunotherapy was performed in AR mice. The results showed that the AR mice had an AR-like inflammation in the nasal mucosa. Compared with naïve mice, markedly lower levels of miR-146a were detected in AR mice. The co-administration with miR-146a significantly enforced the effect of ovalbumin (OVA)-specific immunotherapy on inhibition of AR inflammation in the nasal mucosa. Further analysis showed that miR-146a induced transforming growth factor-? in dendritic cells; the latter induced naïve CD4(+) T cells to differentiate into regulatory T cells. In conclusion, miR-146a can enforce OVA-specific immunotherapy via inducing antigen-specific regulatory T cells. miR-146a may have therapeutic potential to be used in the immunotherapy of allergic diseases. PMID:26700406

  4. Allergen immunotherapy extract treatment set preparation: making a safer and higher quality product for patients.

    PubMed

    Nelson, Michael R; Petersen, Maureen M; Wolverton, Wayne O; Mikita, Cecilia P

    2013-08-01

    The best possible allergen immunotherapy clinical outcomes require the provision of high quality and safe allergen immunotherapy extract preparations. Evolving national guidelines and regulatory bodies have devoted special attention to the safe compounding of sterile products, including allergen extracts. It is incumbent upon allergists preparing extract treatment sets for patients to be familiar with and adopt training, procedures and safety measures that lead to standardized high quality products. Preparers and supervisors must maintain ongoing competency in aseptic technique and prescribing principles, such as probable effective dose ranges, allergen cross-reactivity, and separation of high protease-containing extracts from susceptible extracts. Accordingly, knowledge and application of vial labeling, diluent selection, standard operating procedures, mixing log documentation, and mixing condition principles are a necessity. Although there have been no instances of infectious complications from allergen immunotherapy in a century of clinical practice, continued vigilance in the use of measures that ensure extract sterility is paramount. A review of allergen immunotherapy preparation recommendations and best practices based on published national guidelines is presented. Further study of preparation measures and prescribing principles will continue to advance the practice of allergen immunotherapy and offer opportunities for refinement of current recommendations. PMID:23881510

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

    PubMed Central

    2013-01-01

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

  6. Differences in the effects of host suppression on the adoptive immunotherapy of subcutaneous and visceral tumors

    SciTech Connect

    Chang, A.E.; Shu, S.Y.; Chou, T.; Lafreniere, R.; Rosenberg, S.A.

    1986-07-01

    A syngeneic transplantable sarcoma induced in C57BL/6 mice, MCA 105, was used in studies to examine host suppression on the adoptive immunotherapy of established intradermal and experimentally induced pulmonary and hepatic metastases. Fresh immune splenocytes were generated from mice immunized to the MCA 105 tumor by a mixture of viable tumor cells and Corynebacterium parvum. The adoptive immunotherapy of intradermal MCA 105 tumor with immune cells required prior immunosuppression of the recipient by sublethal irradiation with 500 R or T-cell depletion. The effect of whole-body sublethal irradiation appeared to eliminate a systemic host suppression mechanism, since partialbody irradiation involving the tumor-bearing area did not permit successful immunotherapy. Host irradiation was not required to achieve successful immunotherapy of experimentally induced pulmonary or hepatic metastases. In nonirradiated recipients bearing both intradermal and pulmonary tumors, host suppression did not affect the function of transferred immune cells to induce regression of pulmonary metastases. Thus, suppression of adoptive immunotherapy appears to be relevant to tumors confined to the skin and subcutaneous tissue but not to tumor in visceral sites, such as the lung and liver.

  7. Vaccine-Mediated Immunotherapy Directed Against a Transcription Factor Driving the Metastatic Process

    PubMed Central

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

    2015-01-01

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

  8. Self Antigens Expressed by Solid Tumors Do Not Efficiently Stimulate Naive or Activated T Cells: Implications for Immunotherapy

    PubMed Central

    Speiser, Daniel E.; Miranda, Renata; Zakarian, Arsen; Bachmann, Martin F.; McKall-Faienza, Kim; Odermatt, Bernhard; Hanahan, Douglas; Zinkernagel, Rolf M.; Ohashi, Pamela S.

    1997-01-01

    Induction and maintenance of cytotoxic T lymphocyte (CTL) activity specific for a primary endogenous tumor was investigated in vivo. The simian virus 40 T antigen (Tag) expressed under the control of the rat insulin promoter (RIP) induced pancreatic ?-cell tumors producing insulin, causing progressive hypoglycemia. As an endogenous tumor antigen, the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) was introduced also under the control of the RIP. No significant spontaneous CTL activation against GP was observed. However, LCMV infection induced an antitumor CTL response which efficiently reduced the tumor mass, resulting in temporarily normalized blood glucose levels and prolonged survival of double transgenic RIP(GP × Tag2) mice (137 ± 18 d) as opposed to control RIP-Tag2 mice (88 ± 8 d). Surprisingly, the tumor-specific CTL response was not sustained despite the facts that the tumor cells continued to express MHC class I and LCMV-GP–specific CTLs were present and not tolerized. Subsequent adoptive transfer of virus activated spleen cells into RIP(GP × Tag2) mice further prolonged survival (168 ± 11 d), demonstrating continued expression of the LCMV-GP tumor antigen and MHC class I. The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo. Therefore, repetitive immunizations are necessary for prolonged antitumor immunotherapy. In addition, the data suggest that the risk for induction of chronic autoimmune diseases is limited, which may encourage immunotherapy against antigens selectively but not exclusively expressed by the tumor. PMID:9271580

  9. Current state and perspectives of dendritic cell vaccination in cancer immunotherapy.

    PubMed

    Farkas, A; Conrad, C; Tonel, G; Borbenyi, Z; Kemeny, L; Dobozy, A; Nestle, F O

    2006-01-01

    Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination. PMID:16612139

  10. Immunotherapy for Primary Brain Tumors: No Longer a Matter of Privilege

    PubMed Central

    Fecci, Peter E.; Heimberger, Amy B.; Sampson, John H.

    2014-01-01

    Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor whose standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviews modalities that have been currently employed or are undergoing active investigation. Tumor immunosuppressive counter measures, peculiarities of CNS immune access, and opportunities for rational treatment design are discussed. PMID:25398845

  11. Rare adverse events due to house dust mite sublingual immunotherapy in pediatric practice: two case reports.

    PubMed

    Galip, Nilufer; Bahceciler, Nerin

    2015-12-01

    Sublingual route, a noninjective way of allergen administration appears to be associated with a lower incidence of severe systemic reactions compared with the subcutaneous route. Local adverse reactions are reported which resolve spontaneously within a few days without need for discontinuation of treatment. Hereby, we report two pediatric cases, one with persistent asthma and the other one with persistent allergic rhinitis. Both were treated by house dust mite sublingual immunotherapy, one of whom developed severe wheezing (grade 2 systemic reaction based on World Allergy Organization subcutaneous systemic reaction grading system) and the other intractable vomiting (grade 3 local reaction based on World Allergy Organization sublingual immunotherapy local adverse events grading system) at the end of the build-up phase which repeated on re-administration of the same dose. Both of those two cases completed their 3-year immunotherapy successfully by patient-based adjustment of the highest tolerated dose of the maintenance. PMID:26427747

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

    PubMed Central

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

    2015-01-01

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

  13. Regulatory Dendritic Cells for Immunotherapy in Immunologic Diseases

    PubMed Central

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

    2013-01-01

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

  14. Immunotherapies for NSCLC: Are We Cutting the Gordian Helix?

    PubMed

    Dempke, Wolfram C M; Sellmann, Ludger; Fenchel, Klaus; Edvardsen, Klaus

    2015-11-01

    Chemotherapy is currently the standard-of-care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Molecular-targeted therapies have provided improvement in outcomes. However, these treatments only offer a clear benefit in subsets of tumors harbouring the appropriate genomic alteration (mutation, amplification, translocation). Recent advances in immunotherapy have highlighted the potential of immuno-oncology-based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. Blocking inhibitory pathways such as the cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) checkpoint pathways with monoclonal antibodies has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand-1(PD-L1) antibodies have shown durable responses in NSCLC, with a favourable safety profile and manageable side-effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naïve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted-agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. The emerging data not only offer the hope of a better cancer therapy but also provide evidence that changes our understanding on how the host immune system interacts with human cancer. It is therefore conceivable that agents blocking the CTLA-4/PD-1/PD-L1 axis will provide valuable additions to the growing armamentarium of targeted-agents. PMID:26503995

  15. Theiler's Murine Encephalomyelitis Virus as a Vaccine Candidate for Immunotherapy

    PubMed Central

    Pavelko, Kevin D.; Girtman, Megan A.; Mitsunaga, Yoshihiro; Mendez-Fernandez, Yanice V.; Bell, Michael P.; Hansen, Michael J.; Allen, Kathleen S.; Rodriguez, Moses; Pease, Larry R.

    2011-01-01

    The induction of sterilizing T-cell responses to tumors is a major goal in the development of T-cell vaccines for treating cancer. Although specific components of anti-viral CD8+ immunity are well characterized, we still lack the ability to mimic viral CD8+ T-cell responses in therapeutic settings for treating cancers. Infection with the picornavirus Theiler's murine encephalomyelitis virus (TMEV) induces a strong sterilizing CD8+ T-cell response. In the absence of sterilizing immunity, the virus causes a persistent infection. We capitalized on the ability of TMEV to induce strong cellular immunity even under conditions of immune deficiency by modifying the virus to evaluate its potential as a T-cell vaccine. The introduction of defined CD8+ T-cell epitopes into the leader sequence of the TMEV genome generates an attenuated vaccine strain that can efficiently drive CD8+ T-cell responses to the targeted antigen. This virus activates T-cells in a manner that is capable of inducing targeted tissue damage and glucose dysregulation in an adoptive T-cell transfer model of diabetes mellitus. As a therapeutic vaccine for the treatment of established melanoma, epitope-modified TMEV can induce strong cytotoxic T-cell responses and promote infiltration of the T-cells into established tumors, ultimately leading to a delay in tumor growth and improved survival of vaccinated animals. We propose that epitope-modified TMEV is an excellent candidate for further development as a human T-cell vaccine for use in immunotherapy. PMID:21625449

  16. Intratumorally implanted mesenchymal stromal cells potentiate peripheral immunotherapy against malignant rat gliomas.

    PubMed

    Ströjby, Salina; Eberstål, Sofia; Svensson, Andreas; Fritzell, Sara; Bexell, Daniel; Siesjö, Peter; Darabi, Anna; Bengzon, Johan

    2014-09-15

    Bone marrow-derived mesenchymal stromal cells (MSCs) target glioma extensions and micro-satellites efficiently when implanted intratumorally. Here, we report that intratumoral implantation of MSCs and peripheral immunotherapy with interferon-gamma (IFN?) producing tumor cells improve the survival of glioma-bearing rats (54% cure rate) compared to MSC alone (0% cure rate) or immunotherapy alone (21% cure rate) by enforcing an intratumoral CD8(+) T cell response. Further analysis revealed that the MSCs up-regulate MHC classes I and II in response to IFN? treatment in vitro and secrete low amounts of immunosuppressive molecules prostaglandin E2 and interleukin-10. PMID:25086876

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

    PubMed Central

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

    2015-01-01

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

  18. 6-Thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumor-bearing mice.

    PubMed

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

    2015-08-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2003-03-01

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

  20. Stability of Myrmecia pilosula (Jack Jumper) Ant venom for use in immunotherapy.

    PubMed

    Wiese, Michael D; Davies, Noel W; Chataway, Tim K; Milne, Robert W; Brown, Simon G A; Heddle, Robert J

    2011-01-25

    Allergy to Myrmecia pilosula (Jack Jumper Ant) venom is common in Australia, affecting ?2.7% of some communities. Venom immunotherapy is a highly effective treatment, but for the venom to be widely distributed for clinical use, the stability and shelf-life of formulated Jack Jumper Ant venom must be demonstrated. HPLC-UV, ELISA Inhibition, SDS-PAGE and SDS-PAGE Immunoblot were used to assess venom stability under conditions of varying temperature, pH and in the presence of various stabilising agents. Optimal stability occurred between pH 8 and 10, however the presence of benzyl alcohol within this pH range resulted in a cloudy appearance within 3 days, so a pH of 6 was used. Increasing polysorbate 80 concentrations accelerated the degradation of allergenic peptides in 100 ?g/mL venom, but improved stability at concentrations of 1 ?g/mL or less. Sucrose reduced degradation of allergens Myr p 1 and Myr p 3, whilst glycerol was destabilizing. In the presence of 22% sucrose, 1.1mg/mL Jack Jumper Ant venom was stable at -18 °C and 4 °C for 12 months; following dilution to 100 ?g/mL with 0.9% sodium chloride, 10mM phosphate (pH 6), 0.05% polysorbate 80 and 0.9% benzyl alcohol (giving 2% sucrose), venom was stable for 7 days when stored at 4 °C. Concentrated Jack Jumper Ant venom can be stored in 22% sucrose for 12 months, and after dilution to 100 ?g/mL for clinical use, it should be discarded after 7 days. PMID:20869831

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

    PubMed Central

    Pender, Michael P; Burrows, Scott R

    2014-01-01

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

  2. Replication-Competent Foamy Virus Vaccine Vectors as Novel Epitope Scaffolds for Immunotherapy

    PubMed Central

    Lei, Janet; Osen, Wolfram; Gardyan, Adriane; Hotz-Wagenblatt, Agnes; Wei, Guochao; Gissmann, Lutz; Eichmüller, Stefan; Löchelt, Martin

    2015-01-01

    The use of whole viruses as antigen scaffolds is a recent development in vaccination that improves immunogenicity without the need for additional adjuvants. Previous studies highlighted the potential of foamy viruses (FVs) in prophylactic vaccination and gene therapy. Replication-competent FVs can trigger immune signaling and integrate into the host genome, resulting in persistent antigen expression and a robust immune response. Here, we explored feline foamy virus (FFV) proteins as scaffolds for therapeutic B and T cell epitope delivery in vitro. Infection- and cancer-related B and T cell epitopes were grafted into FFV Gag, Env, or Bet by residue replacement, either at sites of high local sequence homology between the epitope and the host protein or in regions known to tolerate sequence alterations. Modified proviruses were evaluated in vitro for protein steady state levels, particle release, and virus titer in permissive cells. Modification of Gag and Env was mostly detrimental to their function. As anticipated, modification of Bet had no impact on virion release and affected virus titers of only some recombinants. Further evaluation of Bet as an epitope carrier was performed using T cell epitopes from the model antigen chicken ovalbumin (OVA), human tyrosinase-related protein 2 (TRP-2), and oncoprotein E7 of human papillomavirus type 16 (HPV16E7). Transfection of murine cells with constructs encoding Bet-epitope chimeric proteins led to efficient MHC-I-restricted epitope presentation as confirmed by interferon-gamma enzyme-linked immunospot assays using epitope-specific cytotoxic T lymphocyte (CTL) lines. FFV infection-mediated transduction of cells with epitope-carrying Bet also induced T-cell responses, albeit with reduced efficacy, in a process independent from the presence of free peptides. We show that primate FV Bet is also a promising T cell epitope carrier for clinical translation. The data demonstrate the utility of replication-competent and -attenuated FVs as antigen carriers in immunotherapy. PMID:26397953

  3. Optimization of Dendritic Cell Loading With Tumor Cell Lysates for Cancer Immunotherapy

    PubMed Central

    Hatfield, Paul; Merrick, Alison E.; West, Emma; O’Donnell, Dearbhaile; Selby, Peter; Vile, Richard; Melcher, Alan A.

    2014-01-01

    Summary: The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stress-associated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw “necrotic” lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to well-established maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-?, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-?B pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy. PMID:18600182

  4. Endemic fungal infections in inflammatory bowel disease associated with anti-TNF antibody therapy.

    PubMed

    Ordonez, Miguel E; Farraye, Francis A; Di Palma, Jack A

    2013-10-01

    Patients with inflammatory bowel disease are susceptible to complications from pharmacologic treatment of their disease. Tumor necrosis factor (TNF)-? inhibitors are being used increasingly in the treatment of inflammatory bowel disease and can be associated with adverse events, including common infections, and rarely the development of serious life-threatening opportunistic infections. TNF-? inhibitors have the ability to prevent an effective patient granulomatous response, and this may be associated with an increased risk of developing mycobacterial and certain fungal infections, including histoplasmosis, blastomycosis, and coccidioidomycosis, endemic in several parts of the United States. The concern for invasive fungal infection was realized during clinical trials and further demonstrated after the marketing of TNF-? inhibitors. Because of this awareness, the Food and Drug Administration developed an adverse event-reporting system to capture cases of infections associated with the use of TNF-? inhibitors. These opportunistic fungi have a great degree of regional variability, and it has been very difficult to quantify the incidence of infection in patients treated with TNF-? inhibitors. Currently, there are no formal guidelines regarding the use of TNF-? inhibitors and these fungal infections. Considering that gastroenterologists have embraced the use TNF-? inhibitors as a valuable armamentarium in the treatment of inflammatory bowel disease, they must be aware of therapy-related infectious complications, including appropriate diagnostic, therapeutic, and preventive strategies. In this article, we explore the association of these fungal entities in relation to the TNF-? inhibitor therapy by considering information provided in the gastroenterology, infectious diseases, rheumatology, and transplant literature. Finally, we provide some recommendations on diagnosis and treatment. PMID:23694943

  5. Disseminated Tuberculosis in a Patient Taking Anti-TNF Therapy for Crohn's Disease

    PubMed Central

    Liu, Xiuli; Shen, Bo

    2015-01-01

    A man in his sixth decade with Crohn's colitis and who had been taking infliximab for 18 months presented with fever and weight loss. Chest CT showed numerous nodules in both lungs, and sputum culture grew Mycobacterium tuberculosis. Colonoscopy showed circumferential ulcerations from the cecum to the descending colon, and biopsies showed extensive granulomas with central necrosis, positive for acid-fast bacteria. Brain MRI revealed a thalamic ring-enhanced mass with edema, consistent with tuberculoma. Clinicians should be aware of the appropriate screening and close monitoring of tuberculosis before and during anti-tumor necrosis factor (TNF) therapy. PMID:26504878

  6. A patient with hyper-IgD syndrome responding to anti-TNF treatment.

    PubMed

    Demirkaya, Erkan; Caglar, M Kazim; Waterham, Hans R; Topaloglu, Rezan; Ozen, Seza

    2007-10-01

    The hyperimmunoglobulinemia D periodic fever syndrome (HIDS) is caused by recessive mutations in the mevalonate kinase gene, which encodes an enzyme involved in cholesterol and nonsterol isoprenoid biosynthesis. The pathogenesis and treatment remains unclear. We describe a 6-year-old Turkish girl with severe disease. Her clinical features were accompanied with very high acute-phase reactants including a very high serum amyloid A level. The patient responded well to anti-tumor necrosis factor treatment. Our findings support the use of this anti-cytokine treatment in HIDS. PMID:17171314

  7. From Peyer's patches to tonsils. Specific stimulation with ribosomal immunotherapy.

    PubMed

    Béné, M C; Faure, G C

    1997-01-01

    Ribosomal immunotherapy has been successfully used since the 1960s to boost the immune system and provide protection against microbial infections. We have investigated both whether and how these immunostimulants behave as natural immunogens in the mucosa-associated immune system. According to current understanding of the physiology of the mucosal immune response, intestinal Peyer's patches and the related solitary nodules are the primary inductive sites involved in the immune protection of all mucosal surfaces. Sensitised lymphocytes generated at these sites reach the general circulation through lymphatic drainage and relocate in mucosal areas by means of specialised 'high endothelial venules'. We hypothesised that orally administered ribosomal preparations would yield sensitised B cells specific for bacterial antigens from the parent strains. These cells should then be detectable in the peripheral blood after ribosomal intake, and identifiable as plasma cells in mucosae-associated tissues after completing their terminal differentiation. Ultimately, specific IgA should appear in secretions. To this end, we studied the immune responses generated in children and adults after 'Ribomunyl' administration, according to various consecutive protocols. The initial hypothesis was confirmed by the identification of specific B cells in the peripheral blood, plasma cells in the tonsillar tissue and specific IgA in the saliva. An animal model involving the use of twin sheep enabled detection of the specific cells in mesenteric and cervical lymph nodes. Analysis of these data indicates that ribosomal preparations trigger the production of lymphocytes specific for both ribosomes themselves and whole bacterial antigens. This supports the fact that small antigenic motifs are carried as partly synthesised peptides on the ribosomal particles. Therefore, ribosomes boost an array of B cells that are specific for many antigenic determinants of the bacteria from which they are extracted. We were also able to show that the stimulation provided was specific, since no response to other bacteria could be detected. Finally, analysis of the kinetics of this stimulation confirmed that oral immunisation generates rapid and transient secretory responses, building increased numbers of memory cells that are readily available to respond to further challenges by either more ribosomal preparations or potential pathogens. PMID:9378075

  8. Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era.

    PubMed

    Martin, S D; Coukos, G; Holt, R A; Nelson, B H

    2015-12-01

    Owing to recent advances in genomic technologies, personalized oncology is poised to fundamentally alter cancer therapy. In this paradigm, the mutational and transcriptional profiles of tumors are assessed, and personalized treatments are designed based on the specific molecular abnormalities relevant to each patient's cancer. To date, such approaches have yielded impressive clinical responses in some patients. However, a major limitation of this strategy has also been revealed: the vast majority of tumor mutations are not targetable by current pharmacological approaches. Immunotherapy offers a promising alternative to exploit tumor mutations as targets for clinical intervention. Mutated proteins can give rise to novel antigens (called neoantigens) that are recognized with high specificity by patient T cells. Indeed, neoantigen-specific T cells have been shown to underlie clinical responses to many standard treatments and immunotherapeutic interventions. Moreover, studies in mouse models targeting neoantigens, and early results from clinical trials, have established proof of concept for personalized immunotherapies targeting next-generation sequencing identified neoantigens. Here, we review basic immunological principles related to T-cell recognition of neoantigens, and we examine recent studies that use genomic data to design personalized immunotherapies. We discuss the opportunities and challenges that lie ahead on the road to improving patient outcomes by incorporating immunotherapy into the paradigm of personalized oncology. PMID:26371284

  9. Differential Plasma-cell evolution is linked with Dermatophagoides pteronyssinus immunotherapy response

    PubMed Central

    Fernández, Tahia D.; Gómez, Enrique; Doña, Inmaculada; Campo, Paloma; Rondon, Carmen; Gonzalez, Miguel; Gomez, Francisca; Palomares, Francisca; Salas, Maria; Blanca, Miguel; Mayorga, Cristobalina; Torres, Maria J.

    2015-01-01

    Allergic rhinitis is highly prevalent worldwide. Immunotherapy has been shown to control its symptoms, however, up to 30% of patients may not respond. Previous studies of the immunological mechanisms involved in allergen-immunotherapy (AIT) have focused on the humoral and T-cell response and several studies have evaluated some B-cell subpopulations during AIT and their role in immunological tolerance. However, although B and plasma-cell subpopulations are two of the most important cellular subtypes involved in allergic reactions, their relation with AIT efficacy remains unelucidated. The objective was to analyze the effects of immunotherapy on different B and plasma-cell subpopulations and whether these changes correlate with the clinical response to the treatment. Although no changes are found in B-cell subpopulations, responder patients show increased levels of memory B-cells even before the beginning of treatment. Changes in plasma-cell subpopulations are found, mainly in circulating inflammatory plasma-cells that could affect the response to the allergen. Moreover, an early increase of specific-IgG4 and IgG4 secreting-cells was found. All these suggest that the determination of the memory B-cells before the initiation of the treatment, and the quantification of IgG4 and IgG4-secreting-cells in the first months of immunotherapy, could serve as markers for the clinical response to treatment. PMID:26416023

  10. The development of new immunotherapies for the treatment of cancer using interleukin-2. A review.

    PubMed Central

    Rosenberg, S A

    1988-01-01

    Recent increases in knowledge of cellular immunology, combined with developments in biotechnology, have provided new opportunities for the development of immunotherapies for the treatment of cancer in humans. One approach to therapy is that of adoptive immunotherapy, that is, the transfer to the tumor bearing host of lymphoid cells with antitumor reactivity that can mediate antitumor responses. Several lymphocyte subpopulations have now been identified that may be suitable for use in adoptive immunotherapy. Resting lymphocytes incubated in interleukin-2 (IL-2) give rise to lymphokine activated killer (LAK) cells that can lyse malignant cells, but not normal cells. Clinical studies in patients with advanced cancer have revealed that treatment with high dose IL-2 alone or in combination with LAK cells can mediate the complete or partial regression of cancer in selected patients. Other approaches are currently undergoing investigation, including the adoptive transfer of tumor infiltrating lymphocytes, which, in animal models, have antitumor reactivity 50-100 times more potent than do LAK cells. Other new approaches to immunotherapy include the use of combination of lymphokines, such as the use of tumor necrosis factor or alpha interferon in conjunction with IL-2. The availability of recombinant lymphokines that provide large amounts of biologically active materials can hopefully lead to the development of effective new therapies for cancer in humans. Images Fig. 4. Fig. 5. Figs. 6A and B. Fig. 7. Figs. 8A and B. Fig. 9. Fig. 10. Fig. 11. Figs. 12A and B. Figs. 13. Fig. 14. Fig. 15. PMID:3041925

  11. New strategies for melanoma immunotherapy: How to overcome immunosuppression in the tumor microenvironment.

    PubMed

    Umansky, Viktor

    2012-08-01

    Using ret transgenic mouse model of spontaneous melanoma, we showed an accumulation of melanoma antigen-specific memory T cells. However, their antitumor effects could be blocked by myeloid-derived suppressor cells, tolerogenic dendritic cells and regulatory T cells. We suggest that effective melanoma immunotherapy should include the neutralization of immunosuppressive tumor microenvironment. PMID:22934276

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  13. Combinations of Radiotherapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

    PubMed Central

    Barker, Christopher A.; Postow, Michael A.

    2015-01-01

    Radiotherapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiotherapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiotherapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiotherapy. The cytokines interferon-alpha and interleukin-2 have been combined with radiotherapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiotherapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested radiotherapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiotherapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study. PMID:24661650

  14. Combinations of Radiation Therapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

    SciTech Connect

    Barker, Christopher A.; Postow, Michael A.

    2014-04-01

    Radiation therapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiation therapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiation therapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiation therapy. The cytokines interferon-? and interleukin-2 have been combined with radiation therapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiation therapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested that radiation therapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiation therapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study.

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

    PubMed Central

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

    2014-01-01

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

  16. Allergen-Specific Immunotherapy in Patients 55 Years and Older: Results and Review of Literature

    PubMed Central

    Baptistella, Eduardo; Maniglia, Sergio; Malucelli, Diego Augusto; Rispoli, Daniel; Pruner de Silva, Thanara; Tsuru, Fernanda Miyoko; Becker, Renata Vecentin; Bernardi, Gustavo; Dranka, Daniela; Ferraz, Bruno

    2013-01-01

    Introduction?Over the years the immune system suffers many morphologic and functional alterations, which result in a peak of function in puberty and a gradual decrease in the elderly. Aim?Treat patients 55 years or older with allergic rhinitis with immunotherapy and then analyze the response to allergens. Materials and Methods?From June 2009 to July 2010, 104 charts of patients 55 years or older with allergic complaints were evaluated. The patients were selected by anamnesis, physical examination, and otorhinolaryngologic exam. The patients had cutaneous test for mites before and after 1?year of sublingual specific immunotherapy. The cutaneous response was classified as negative (absent), light, moderate, or severe. Results?Before vaccination, 42 (40.4%) patients were classified as having a severe form of allergy and 62 (59.6%) as having a moderate allergy. After the specific therapy, 40 (38.4%) patients were classified as negative (absent), 37 (35.6%) as light, 19 (18.3%) as moderate, and 8 (7.7%) as severe responses. Conclusion?Immunotherapy, a desensitization technique, is indicated in cases which patients cannot avoid the exposure to allergens and in situations where pharmacologic therapy is not ideal. Specific immunotherapy to treat the allergic rhinitis in elderly patients was efficient and had no collateral effects, and in addition to the clinical benefit, improvement in the cutaneous test could also be observed. PMID:25992039

  17. ABSTRACT Cancer immunotherapy is rapidly emerging as a self-standing therapeutic domain

    E-print Network

    ABSTRACT Cancer immunotherapy is rapidly emerging as a self-standing therapeutic domain in oncology, set to revolutionize the treatment of cancer. Cancer vaccines with defined antigens are now commonly potential in promoting antigen-specific T cell responses of magnitudes relevant to combating cancer

  18. Request Information Download PDF Permalink Print GlyTR Immunotherapy for Cancer

    E-print Network

    Heydari, Payam

    Request Information Download PDF Permalink Print GlyTR Immunotherapy for Cancer Tech ID technology that directs the immune system to kill cancer cells. GlyTRTM is a novel bispecific molecule that targets a very large and diverse number of cancer types, including both blood and solid cancers

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

    SciTech Connect

    Wada, Satoshi; Harris, Timothy J.; Tryggestad, Erik; Yoshimura, Kiyoshi; Zeng, Jing; Yen, Hung-Rong; Getnet, Derese; Grosso, Joseph F.; Bruno, Tullia C.; De Marzo, Angelo M.; and others

    2013-11-15

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

  20. Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity.

    PubMed

    Maus, Marcela V; Powell, Daniel J

    2015-01-01

    The durable remission of B-cell leukemia and lymphoma following chimeric antigen receptor (CAR) T-cell therapy has brought this new form of adoptive immunotherapy to center stage with the expectation that CAR T-cell therapy may provide similar efficacy in other hematologic and solid cancers. Herein, we review recent advances in the areas of CAR design that improve CAR T-cell proliferation, engraftment, and efficacy, as well as clinical application strategies that are designed to improve clinical efficacy while reducing the risk of toxicity and broaden patient access to this promising form of cancer immunotherapy. PMID:26588679

  1. Efficacy of intraperitoneal thermochemotherapy and immunotherapy in intraperitoneal recurrence after gastrointestinal cancer resection

    PubMed Central

    Fu, Qing-Guo; Meng, Fan-Dong; Shen, Xiao-Dong; Guo, Ren-Xuan

    2002-01-01

    AIM: To investigate the prophylactic and therapeutic efficacy of intraperitoneal IL-2 immunotherapy following intraperitoneal thermochemotherapy in the metastasis and recurrence of gastric and colorectal cancer after operation. METHODS: Forty-two gastric cancer patients at T3II-T4IIIB stages and 96 patients with colorectal cancer at B to D stages admitted from January 1996 to October 1998 were randomly divided into control group (group I, 65 cases) receiving intraperitoneal thermochemotherapy, and group II(73 cases) receiving both intraperitoneal thermochemotherapy and intraperitoneal IL-2 immunotherapy. Distilled water at 43-45 °C containing 5-Fu 0.5 g/L and MMC 8 mg/L was perfused into peritoneal cavity before closure at the end of operation for 1 h, and from the third day, IL-2 10 million IU in 500 mL 0.9% sodium chloride was intraperitoneally administrated daily for 10 times. One month after operation, all the patients underwent regular intravenous chemotherapy. Before and after the IL-2 immunotherapy, some Th1 type cytokines in the peripheral blood of the patients in the two groups were detected by ELISA, and the intraperitoneal recurrence and liver metastasis rates and the 3-year survival rate were statistically evaluated after intensive follow-up. RESULTS: IL-2 intraperitoneal immunotherapy significantly elevated the level of some Th1 type cytokines (P < 0.01 compared with that of control group), and the 3-year survival rate of group II was 18.1% higher and the rates of intraperitoneal recurrence and liver metastasis were 16.9% and 6.0% lower than those of group I significantly (P < 0.05-0.01). CONCLUSION: The combination of intraperitoneal IL-2 immunotherapy and thermochemotherapy could promote Th1 immune paradigm and enforce anti-tumor activity of bodies, which plays a positive role in preventing gastric and colorectal cancer from intraperitoneal recurrence and development. PMID:12439917

  2. Humoral and cellular immunotherapy in ALL in children, adolescents, and young adults.

    PubMed

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

    2014-09-01

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

  3. Disparities in the early adoption of chemo-immunotherapy for diffuse large B-cell lymphoma in the United States

    PubMed Central

    Flowers, Christopher R.; Fedewa, Stacey A.; Chen, Amy Y.; Nastoupil, Loretta J; Lipscomb, Joseph; Brawley, Otis W.; Ward, Elizabeth M.

    2014-01-01

    Background Since the 1970s, CHOP chemotherapy has been the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL). In 2002, randomized trials changed this standard by demonstrating that adding rituximab immunotherapy to CHOP improved survival. However, how these results influenced chemo-immunotherapy adoption in clinical practice remains unclear. Methods Using the National Cancer Database to compare chemo-immunotherapy use with chemotherapy alone, we collected data on demographics, stage, health insurance, area-level socio-economic status (SES), facility characteristics, and type of treatment for DLBCL patients diagnosed in the United States 2001-2004. Multivariable log binomial models examined associations between race, insurance, and treatment allocation, adjusting for covariates. Results Among 38,002 patients with DLBCL, 27% received chemo-immunotherapy and 50% chemotherapy alone. Patients who had localized disease, were diagnosed in 2001, black, uninsured/Medicaid insured, or lower SES were less likely to receive any form of chemotherapy (all p<0.0001). Patients who were diagnosed 2001, black [relative risk (RR) 0.83, 95% Confidence Interval (CI) 0.78-0.89], >60 years (RR 0.94, 95% CI 0.90-0.98), or had localized disease (RR 0.89, 95% CI 0.86-0.92) were less likely to receive chemo-immunotherapy. Receiving treatment at high DLBCL volume teaching/research facilities was associated with the greatest likelihood of chemo-immunotherapy (RR 1.69, 95% CI 1.52-1.89). Conclusions Black DLBCL patients were less likely to receive chemotherapy or chemo-immunotherapy during this period. Impact This large national cohort study demonstrates disparities in the diffusion of chemo-immunotherapy for DLBCL. Improving DLBCL outcomes will require efforts to extend access to proven advances in therapy to all segments of the population. PMID:22771484

  4. Estimation of health-related utility (EQ-5D index) in subjects with seasonal allergic rhinoconjunctivitis to evaluate health gain associated with sublingual grass allergen immunotherapy

    PubMed Central

    2014-01-01

    Background Grass allergen immunotherapy (AIT) reduces symptom severity in seasonal allergic rhinoconjunctivitis (ARC) but its impact on general health-related utility has not been characterised for the purposes of economic evaluation. The aim of this study was to model the preferred measure of utility, EQ-5D index, from symptom severity and estimate incremental quality adjusted life years (QALYs) associated with SQ-standardised grass immunotherapy tablet (GRAZAX®, 75,000 SQ-T/2,800 BAU, ALK, Denmark). Methods Data were analysed from five consecutive pollen seasons in a randomised placebo controlled trial of GRAZAX®. Binomial and Gaussian mixed effects modelling related weekly EQ-5D index score to daily symptom and medication scores (DSS & DMS respectively). In turn, daily EQ-5D index was estimated from ARC symptoms and medication use. Results DSS and DMS were the principal predictors of ‘perfect’ health (EQ-5D?=?1.000; binomial) and ‘imperfect’ health (EQ-5D?reduced the odds of ‘perfect’ health (EQ-5D?=?1.000) by 27% and 16% respectively, and reduced ‘imperfect’ health by 0.17 and 0.13, respectively. Gender remained the only other significant main fixed effect (Male odds ratio [OR]?=?1.82). Incremental estimated EQ-5D index utility for GRAZAX® was observed from day -30 to day +70 of the pooled pollen season; mean daily utility for GRAZAX®?=?0.938 units (95%CI 0.932-0.943) vs. 0.914 (0.907-0.921) for placebo, an incremental difference of 0.0238 (p?

  5. The usefulness of immunotherapy in pediatric neurodegenerative disorders: A systematic review of literature data.

    PubMed

    Vitaliti, Giovanna; Tabatabaie, Omidreza; Matin, Nassim; Ledda, Caterina; Pavone, Piero; Lubrano, Riccardo; Serra, Agostino; Di Mauro, Paola; Cocuzza, Salvatore; Falsaperla, Raffaele

    2015-12-01

    Immunotherapeutic strategies to treat neurodegenerative disorders have inspired the scientific community. The aim of our review is to address the translational aspects of neuroimmunology to describe the efficacy of immunotherapy in the treatment of pediatric neurodegenerative disorders. In the studies we analyzed IVIG were found to be efficient in the treatment of post-streptococcal neurodegenerative disorders, even if in PANDAS, plasma-exchange (PE) showed a higher efficiency. IVIG were also successfully used in ADEM and Guillan-Barré syndrome. In Sydenham Chorea the use of methylprednisolone was found in most cases as efficient as IVIG, while in Tourette's Syndrome, Colecoxib was successfully used in one patient. Pediatric Multiple Sclerosis seems to respond better to immunosuppressant agents (Mitoxantrone, Cyclophosphamide, Natalizumab), as well as Neuromyelitis optica (Rituximab, Mycofenolate). The importance of this review relies in the attempt to draw standardized guidelines for immunotherapy in pediatric neurodegeneratve disorders. PMID:26266339

  6. Effects of interstitial laser immunotherapy for the treatment of metastatic cancer

    NASA Astrophysics Data System (ADS)

    Bahavar, Cody; Goddard, Jessica; Sikes, Allie; Boarman, Ellen; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2013-02-01

    Laser immunotherapy (LIT) uses laser irradiation and immunological stimulation to treat metastatic cancers. The current mode of operation of LIT is through dye-enhanced non-invasive irradiation. Although this treatment has given promising results, there are still a number of challenges with this method, such as limited light penetration for deep tumors and strong light absorption by highly pigmented skins. Interstitial laser immunotherapy (ILIT), using a cylindrical diffuser, is designed to overcome these limitations. In this study, rat tumors were treated by ILIT with an 805 nm laser and varying doses of glycated chitosan, an immunological stimulant. The goal was to observe the effects of differing doses of the stimulant on the survival of the tumor-bearing rats. The results suggested that the optimal dose of glycated chitosan is in the range of 0.1 to 0.3 ml per rat tumor.

  7. Cytokine Responses to Specific Immunotherapy in House Dust Mite-Induced Allergic Rhinitis Patients.

    PubMed

    Li, Hong; Xu, Enxiu; He, Mingqiang

    2015-12-01

    Allergen-specific immunotherapy is the only immunomodulatory treatment that may alter the natural course of allergic disease. However, cytokine responses accompanying sublingual immunotherapy (SLIT) responder phenotypes have not been fully understood. Herein, we examined the level of crucial plasma cytokines during SLIT and evaluated whether their changes correlated to symptom scores. We observed that the levels of interleukin (IL)-17 and complement components C3a and C5a as well as IL-4 at year 3 of SLIT were significantly decreased than those at baseline. In contrast, there was no significant difference in the levels of IL-5, IL-13, and interferon (IFN)-?. Notably, a significant positive correlation was found between the levels of IL-17 and the symptom scores at year 3. These results suggest that IL-17 could be considered a potential biomarker for the therapeutic effect of SLIT in allergic rhinitis caused by house dust mite. PMID:26122703

  8. Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants.

    PubMed

    Klein, Florian; Nogueira, Lilian; Nishimura, Yoshiaki; Phad, Ganesh; West, Anthony P; Halper-Stromberg, Ariel; Horwitz, Joshua A; Gazumyan, Anna; Liu, Cassie; Eisenreich, Thomas R; Lehmann, Clara; Fätkenheuer, Gerd; Williams, Constance; Shingai, Masashi; Martin, Malcolm A; Bjorkman, Pamela J; Seaman, Michael S; Zolla-Pazner, Susan; Karlsson Hedestam, Gunilla B; Nussenzweig, Michel C

    2014-11-17

    Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian-human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants. PMID:25385756

  9. Combination delivery of TGF-? inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

    NASA Astrophysics Data System (ADS)

    Park, Jason; Wrzesinski, Stephen H.; Stern, Eric; Look, Michael; Criscione, Jason; Ragheb, Ragy; Jay, Steven M.; Demento, Stacey L.; Agawu, Atu; Licona Limon, Paula; Ferrandino, Anthony F.; Gonzalez, David; Habermann, Ann; Flavell, Richard A.; Fahmy, Tarek M.

    2012-10-01

    The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-? (TGF-?), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-? inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

  10. Office immunotherapy in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy.

    PubMed

    Dyck, Peter J; Taylor, Bruce V; Davies, Jenny L; Mauermann, Michelle L; Litchy, William J; Klein, Christopher J; Dyck, P James B

    2015-10-01

    Intravenous immunoglobulin [IVIg], plasma exchange [PE], and corticosteroids are efficacious treatment in chronic inflammatory demyelinating polyneuropathy [CIDP]. IVIg is effective in multifocal motor neuropathy [MMN]. NIS, NIS-weakness, sum scores of raw amplitudes of motor fiber (CMAPs) amplitudes, and Dyck/Rankin score provided reliable measures to detect and scale abnormality and reflect change; they are therefore ideal for office management of response-based immunotherapy (R-IRx) of CIDP. Using efficacious R-IRx, a large early and late therapeutic response (? one-fourth were in remission or had recovered) was demonstrated in CIDP. In MMN only an early improvement with late non-significant worsening was observed. The difference in immunotherapy response supports a fundamental difference between CIDP (immune attack on Schwann cells and myelin) and MMN (attack on nodes of Ranvier and axons). PMID:25976871

  11. Safety and effect on reported symptoms of depigmented polymerized allergen immunotherapy: a retrospective study of 2927 paediatric patients

    PubMed Central

    Pfaar, Oliver; Sager, Angelika; Robinson, Douglas S

    2015-01-01

    Background Allergen immunotherapy (AIT) is effective treatment for allergic diseases, and subcutaneous use of depigmented polymerized extracts may allow rapid up-dosing and safe therapy. To date, there is little information on their safety and clinical effects for children and adolescents with allergic disease. Methods We performed a retrospective survey of patient notes of 2927 children and adolescents across 136 centres who had received subcutaneous AIT (SCIT) with depigmented polymerized extracts to pollen or mite allergens for at least 1 yr to collect documentation on safety and clinical symptoms. Results 16.3% percent of patients had local reactions, of these 148 were larger than 12 cm in diameter. Systemic reactions were documented in 1.6% of children and in 0.8% of adolescents. There were no documented cases of anaphylactic shock. There were significant reductions in the frequency of patients with recorded nasal symptoms over time of treatment. Moreover, the prescribing rate of rescue medication was reduced over the course of SCIT. Conclusion These ‘real-life’ data from a large retrospective analysis including 2927 children and adolescents with pollen- and/or mite-induced allergic rhinoconjunctivitis with/or without allergic asthma indicate that AIT with depigmented polymerized extracts is well tolerated, and they are compatible with clinical response. PMID:25640879

  12. DC-Based Immunotherapy Combined with Low-Dose Methotrexate Effective in the Treatment of Advanced CIA in Mice

    PubMed Central

    Park, Jun-Eui; Jang, Jinah; Choi, Ji-Hye; Kang, Mi-sun; Woo, Yun-Ju; Seong, Young-Rim; Choi, Chan-Bum; Lee, Hye-Soon; Bae, Sang-Cheol; Bae, Yong-Soo

    2015-01-01

    We have previously demonstrated that semimature dendritic cell- (smDC-) based immunotherapy is effective for the treatment of collagen-induced arthritis (CIA) prior to disease onset. In the present study, we examined the efficacy of combination therapy with smDCs and methotrexate (MTX) in advanced CIA with a score of 2-3. Combination therapy with low-dose MTX and type II collagen- (CII-) pulsed smDCs (CII-smDCs) was more effective in inhibiting disease progression than high or low-dose MTX alone or a combination of high dose MTX and CII-smDCs. The effect of CII-smDCs alone was also comparable to the combination therapy. CD4+Foxp3+ Treg populations and IL-10 secretion markedly increased, and CII-specific autoreactive T cells decreased in mice treated with CII-smDCs alone or in combination with MTX. Combination therapy reduced the secretion of interferon-? (IFN-?) and IL-17 with little influence on the IL-4 secretion in the mixed leukocyte reaction. These results imply that the combination therapy with low-dose MTX and smDCs is effective in controlling advanced CIA by enhancing Treg population and suppresses antigen-specific Th1/Th17 immunity, rather than initiating Th1 to Th2 immune deviation. Our findings provide a better understanding of the DC therapy in combination with MTX for the treatment of patients with rheumatoid arthritis (RA). PMID:26221616

  13. Chitosan thermogels for local expansion and delivery of tumor-specific T lymphocytes towards enhanced cancer immunotherapies.

    PubMed

    Monette, Anne; Ceccaldi, Caroline; Assaad, Elias; Lerouge, Sophie; Lapointe, Réjean

    2016-01-01

    The success of promising anti-cancer adoptive cell therapies relies on the abilities of the perfused CD8(+) T lymphocytes to gain access to and persist within the tumor microenvironment to carry out their cytotoxic functions. We propose a new method for their local delivery as a living concentrate, which may not only reduce the numbers of cells required for treatment but also enhance their site-specific mobilization. Using combinations of sodium hydrogen carbonate and phosphate buffer as gelling agents, novel injectable chitosan-based biocompatible thermogels (CTGels) having excellent mechanical properties and cytocompatibility have been developed. Three thermogel formulations with acceptable physicochemical properties, such as physiological pH and osmolality, macroporosity, and gelation rates were compared. The CTGel2 formulation outperformed the others by providing an environment suitable for the encapsulation of viable CD8(+) T lymphocytes, supporting their proliferation and gradual release. In addition, the encapsulated T cell phenotypes were influenced by surrounding conditions and by tumor cells, while maintaining their capacity to kill tumor cells. This strongly suggests that cells encapsulated in this formulation retain their anti-cancer functions, and that this locally injectable hydrogel may be further developed to complement a wide variety of existing immunotherapies. PMID:26513416

  14. Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies

    PubMed Central

    Simone, Charles B.; Burri, Stuart H.

    2015-01-01

    Targeted therapies and immunotherapies have quickly become fixtures in the treatment armamentarium for metastatic non-small cell lung cancer (NSCLC). Targeted therapies directed against epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, and ROS-1 rearrangements have demonstrated improved progression free survival (PFS) and, in selected populations, improved overall survival (OS) compared with cytotoxic chemotherapy. Immunotherapies, including checkpoint inhibitor monoclonal antibodies against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), have now also demonstrated improved survival compared with chemotherapy. The use of these novel systemic agents in non-metastatic patient populations and in combination with radiation therapy is not well defined. As radiation therapy has become more effective and more conformal with fewer toxicities, it has increasingly been used in the oligometastatic or oligoprogression setting. This has allowed improvement in PFS and potentially OS, and in the oligoprogressive setting may overcome acquired drug resistance of a specific lesion(s) to allow patients to remain on their targeted therapies. Molecularly targeted therapies and immunotherapies for patients with metastatic NSCLC have demonstrated much success. Advances in radiation therapy and stereotactic body radiotherapy, radiation therapy have led to combination strategies with targeted therapies among patients with lung cancer. Radiation therapy has also been combined with immunotherapies predominantly in the metastatic setting. In the metastatic population, radiation therapy has the ability to provide durable local control and also augment the immune response of systemic agents, which may lead to an abscopal effect of immune-mediated tumor response in disease sites outside of the radiation field in select patients. PMID:26629423

  15. Video Q&A: allergies and allergen immunotherapy--an interview with Alfred William Frankland.

    PubMed

    Frankland, A William

    2014-01-01

    In this video Q&A, we talk to Dr Alfred William Frankland about the highlights of his career, including working alongside Sir Alexander Fleming, co-founding the British Allergy Society, and introducing pollen counts to UK weather forecasts. We also discuss his opinions on why misconceptions about allergies and allergen immunotherapy still exist. Please see related article: http://www.biomedcentral.com/1741-7015/11/255. PMID:24447813

  16. Video Q&A: Allergies and allergen immunotherapy - an interview with Alfred William Frankland

    PubMed Central

    2014-01-01

    In this video Q&A, we talk to Dr Alfred William Frankland about the highlights of his career, including working alongside Sir Alexander Fleming, co-founding the British Allergy Society, and introducing pollen counts to UK weather forecasts. We also discuss his opinions on why misconceptions about allergies and allergen immunotherapy still exist. Please see related article: http://www.biomedcentral.com/1741-7015/11/255. PMID:24447813

  17. Tumor-specific Immunotherapy Targeting the EGFRvIII Mutation in Patients with Malignant Glioma

    PubMed Central

    Sampson, John H.; Archer, Gary E.; Mitchell, Duane A.; Heimberger, Amy B.; Bigner, Darell D.

    2008-01-01

    Conventional therapies for malignant gliomas (MGs) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by non-specific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in MGs and other neoplasms. This mutation encodes a constitutively active tyrosine kinase that enhances tumorgenicity and migration and confers radiation and chemotherapeutic resistance. This in-frame deletion mutation splits a codon resulting in the creation of a novel glycine at the fusion junction between normally distant parts of the molecule and producing a sequence rearrangement which creates a tumor-specific epitope for cellular or humoral immunotherapy in patients with MGs. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction is an efficacious immunotherapy in syngeneic murine models, but patients with MGs have a profound immunosuppression that may inhibit the ability of antigen presenting cells (APCs), even those generated ex vivo, to induce EGFRvIII-specific immune responses. In this report, we summarize our results in humans targeting this mutation in two consecutive and one multi-institutional Phase II immunotherapy trials. These trials demonstrated that vaccines targeting EGFRvIII are capable of inducing potent T- and B-cell immunity in these patients, and an unexpectedly long survival time. Most importantly, vaccines targeting EGFRvIII were universally successful at eliminating tumor cells expressing the targeted antigen without any evidence of symptomatic collateral toxicity. These studies establish the tumor-specific EGFRvIII mutation as a novel target for humoral- and cell-mediated immunotherapy in a variety of cancers. The recurrence of EGFRvIII-negative tumors in our patients, however, highlights the need for targeting a broader repertoire of tumor-specific antigens. PMID:18539480

  18. Efficacy and safety of ??T cell-based tumor immunotherapy: a meta-analysis.

    PubMed

    Buccheri, S; Guggino, G; Caccamo, N; Li Donni, P; Dieli, F

    2014-01-01

    V?9V?2 T cells are important effector cells that may play a role in the anti-tumor immune response. Their capability to exert MHC-nonrestricted lytic activity against different tumor cells in vitro and their detection among tumor infiltrating lymphocytes in a variety of human cancers have supported the development of V?9V?2 T cell-based immunotherapy in the context of novel treatment against cancer. Accordingly, promising reports from recent clinical trials support the use of V ?9V?2 T cells as immunotherapeutic agents, either via adoptive transfer of ex-vivo expanded V ?9V?2 T cells or in vivo activation of V ?9V?2 T cells with compounds such as phosphoantigens or aminobisphosphonates. In this study we have performed a meta-analysis to assess the objective efficacy and safety of V ?9V?2 T cell-based immunotherapy. Database including Pubmed, Web of Science and SCOPUS were investigated to identify relevant studies. Thirteen clinical trials involving patients with advanced or metastatic cancer were selected. In order to estimate the strength of association between V ?9V?2 T cell-based immunotherapy and favorable clinical effect or toxicity grade we used event rate (ER) with 95 percent confidence interval (CI). The total effective rate provided significant results (ER = 0.407; P <0.014) while no correlation was found between serious adverse effects and V?9V?2 T cell-based therapy. This meta-analysis demonstrates that V?9V?2 T cell-based immunotherapy improves overall survival and, in view of its low toxicity grade, provides a proof of principle for its utilization as adjuvant to conventional therapies for resistant/refractory patients care. PMID:24750794

  19. Epicutaneous immunotherapy for food allergy as a novel pathway for oral tolerance induction.

    PubMed

    Mondoulet, Lucie; Dioszeghy, Vincent; Thébault, Claude; Benhamou, Pierre-Henri; Dupont, Christophe

    2015-12-01

    Epicutaneous immunotherapy is a developing technique, aiming at desensitizing patients with food allergy with less risks that oral ingestion or injection could generate. Several clinical trials have been performed and are currently running, in milk and peanut allergy, assessing the safety of the technique and its efficacy. Preclinical models indicate a major role in the mechanisms of desensitization, for example, Tregs and epigenetic modifications. PMID:26584421

  20. Pancreatic cancer: Role of the immune system in cancer progression and vaccine-based immunotherapy

    PubMed Central

    Amedei, Amedeo; Niccolai, Elena; Prisco, Domenico

    2014-01-01

    Pancreatic cancer (PC) is the 5th leading cause of cancer related death in the developed world with more than 260,000 deaths annually worldwide and with a dismal 5-year survival. Surgery is the only potential hope of cure for PC, but, unfortunately, only 20% PC patients is resectable at the time of diagnosis. Therapeutic research efforts have mainly focused on improvements in radio/ chemo treatments and to date, there are only a few chemotherapeutic agents that have shown to be effective against PC, including gemcitabine with or without abraxane as well as a combination of 5-FU, leucovorin, oxaliplatin and irinotecan (the so-called FOLFIRINOX regimen). The survival of patients treated with these regimens is marginal and hence we are in urgent need of novel therapeutic approaches to treat pancreatic cancer. The success of immunotherapeutic strategies in other cancers and various evidences that pancreatic adenocarcinoma elicits antitumor immune responses, suggest that immunotherapies can be a promising alternative treatment modality for this deadly disease. PC immunotherapy treatments include passive immunotherapeutic approaches, such as the use of effector cells generated in vitro, and active immunotherapeutic strategies, which goal is to stimulate an antitumor response in vivo, by means of vaccination. In this review, we describe the immune suppressive mechanisms of pancreatic cancer and discuss recent preclinical and clinical efforts toward PC immunotherapy, including passive approaches, such as the use of antibodies and active strategies (vaccination), with a special mention of most recent treatment with CRS-207 and GVAX. PMID:25483688

  1. Active specific immunotherapy of mouse methylcholanthrene induced tumours with Corynebacterium parvum and irradiated tumour cells.

    PubMed Central

    Bomford, R.

    1975-01-01

    The relative efficiency of active nonspecific or specific immunotherapy of developing methylcholanthrene induced fibrosarcomata with C. parvum was compared. For nonspecific immunotherapy, mice were challenged with tumour cells s.c. or i.v., and 2 days later injected i.v. with dilutions of C. parvum. The only significant effect was a retardation of s.c. tumour growth by the highest concentration of C. parvum (350 mug). However, active specific immunotherapy, using mixtures of C. parvum and irradiated or living tumour cells in the footpads, suppressed tumour growth when given at 2 or 6, but not 10, days after tumour challenge. Successful therapy required: sufficient tumour cells (greater than or equal to 5 X 10(4)); an optimal dose of C. parvum (5-120 mug, increasing with the number of tumour cells); an intact T cell system; the same tumour cells for challenge and treatment. The specificity was confirmed in a protection system in which treatment was given 7 days before tumour challenge. No protective immunity could be achieved with mixtures of C. parvum and foetal cells. Thus in this system C. parvum potentiates protective immunity only to the tumour unique TSTA. PMID:1082344

  2. Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer

    PubMed Central

    2014-01-01

    Knowledge of the basic mechanisms of the immune system as it relates to cancer has been increasing rapidly. These developments have accelerated the translation of these advancements into medical breakthroughs for many cancer patients. The immune system is designed to discriminate between self and non-self, and through genetic recombination there is virtually no limit to the number of antigens it can recognize. Thus, mutational events, translocations, and other genetic abnormalities within cancer cells may be distinguished as “altered-self” and these differences may play an important role in preventing the development or progression of cancer. However, tumors may utilize a variety of mechanisms to evade the immune system as well. Cancer biologists are aiming to both better understand the relationship between tumors and the normal immune system, and to look for ways to alter the playing field for cancer immunotherapy. Summarized in this review are discussions from the 2013 SITC Primer, which focused on reviewing current knowledge and future directions of research related to tumor immunology and cancer immunotherapy, including sessions on innate immunity, adaptive immunity, therapeutic approaches (dendritic cells, adoptive T cell therapy, anti-tumor antibodies, cancer vaccines, and immune checkpoint blockade), challenges to driving an anti-tumor immune response, monitoring immune responses, and the future of immunotherapy clinical trial design. PMID:24883190

  3. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy.

    PubMed

    Amedei, Amedeo; Niccolai, Elena; Prisco, Domenico

    2014-01-01

    Pancreatic cancer (PC) is the 5th leading cause of cancer related death in the developed world with more than 260,000 deaths annually worldwide and with a dismal 5-year survival. Surgery is the only potential hope of cure for PC, but, unfortunately, only 20% PC patients is resectable at the time of diagnosis. Therapeutic research efforts have mainly focused on improvements in radio/ chemo treatments and to date, there are only a few chemotherapeutic agents that have shown to be effective against PC, including gemcitabine with or without abraxane as well as a combination of 5-FU, leucovorin, oxaliplatin and irinotecan (the so-called FOLFIRINOX regimen). The survival of patients treated with these regimens is marginal and hence we are in urgent need of novel therapeutic approaches to treat pancreatic cancer. The success of immunotherapeutic strategies in other cancers and various evidences that pancreatic adenocarcinoma elicits antitumor immune responses, suggest that immunotherapies can be a promising alternative treatment modality for this deadly disease. PC immunotherapy treatments include passive immunotherapeutic approaches, such as the use of effector cells generated in vitro, and active immunotherapeutic strategies, which goal is to stimulate an antitumor response in vivo, by means of vaccination. In this review, we describe the immune suppressive mechanisms of pancreatic cancer and discuss recent preclinical and clinical efforts toward PC immunotherapy, including passive approaches, such as the use of antibodies and active strategies (vaccination), with a special mention of most recent treatment with CRS-207 and GVAX. PMID:25483688

  4. 466?Bee venom Immunotherapy with Standardized Extract, Two Case Comunication and Clinical Progress

    PubMed Central

    Cardona, Aristoteles Alvarez; Nieto, Leticia Hernandez; Melendez, Alvaro Pedroza

    2012-01-01

    Background Bee venom immunotherapy is a safe and effective treatment, indicated in patients with previous history of severe systemic reactions to bee venom, demonstrating succesful desensitization in more than 90% of cases with standardized extract. Currently in Mexico there is no standardized extract commercially available for treatment, despite of having high activity of beekeeping and occupational exposure with at least 17,478 registered stings per year and an annually honey production of nearly 70 tons. Methods We present the clinical progress of 2 patients with history of severe systemic reactions to bee venom and occupational exposure, both with demonstrated sensitization by specific IgE and who underwent specific immunotherapy with standardized extract (Alk-US) reaching a maintenance weekly dose of 100 mcg (PLA2) for the last 4 years. Results Both patients sufered of accidental stings after reached the maintenance dose presenting mild local reactions to stings. Both patients had very different clinical course presenting a wide variety of adverse reactions during desensitization protocol; from mild local to generalized reactions all generally well tolerated allowed to reach the maintenance dose with succesful desensitization proved by accidental exposure without severe systemic reactions. Conclusions Bee venom specific immunotherapy with standardized extract is a well tolerated and efective treatment preventing the development of life threathening reactions in sensitized patients. It is important to promote the use and availability of standardized extract in developing countries with poor safety measures and high occupational exposure.

  5. Immunotherapy Combinations With Checkpoint Inhibitors in Metastatic Melanoma: Current Approaches and Future Directions.

    PubMed

    Atkins, Michael

    2015-12-01

    Based on the complexity of the immune response to cancer and the mechanisms of tumor evasion, it is likely that therapeutic modulation of multiple immune-mediated pathways will be needed to maximally induce tumor regression in patients with advanced melanoma. The rationale of using combination checkpoint inhibitor-based regimens may include the concomitant effects on re-activation of T cells, increased trafficking of tumor reactive lymphocytes into the tumor tissue, and enhanced killing of cancer cells. The administration of nivolumab in combination with ipilimumab demonstrated increased response rates, tumor shrinkage, and median progression-free survival using combined therapy compared with either treatment alone. Although toxicity was also increased, this trial established proof of principle that combination immunotherapy could enhance the efficacy seen with single-agent programmed cell death protein-1 (PD-1) pathway blockade for the unselected patient. Current and future trials are evaluating alternative schedules and other combinations of immunotherapies to determine if they could provide similar efficacy with less toxicity. In addition, efforts are underway to determine how best to integrate combination immunotherapy with other treatment approaches for patients with advanced melanoma. PMID:26598055

  6. The High Molecular Weight Stress Proteins: Identification, Cloning, and Utilization in Cancer Immunotherapy*

    PubMed Central

    Wang, Xiang-Yang; Subjeck, John R.

    2013-01-01

    Although the large stress/heat shock proteins (HSPs), i.e., Hsp110 and Grp170, were identified over 30 years ago, these abundant and highly conserved molecules have received much less attention compared to other conventional HSPs. Large stress proteins act as molecular chaperones with exceptional protein-holding capability and prevent the aggregation of proteins induced by thermal stress. The chaperoning properties of Hsp110 and Grp170 are integral to the ability of these molecules to modulate immune functions and are essential for developing large chaperone complex vaccines for cancer immunotherapy. The potent antitumor activity of the Hsp110/Grp170-tumor protein antigen complexes, demonstrated in preclinical studies, has led to a phase I clinical trial through the National Cancer Institute's RAID Program that is presently underway. Here we review aspects of the structure and function of these large stress proteins, their roles as molecular chaperones in the biology of cell stress, and prospects for their use in immune regulation and cancer immunotherapy. Lastly, we will discuss the recently revealed immunosuppressive activity of scavenger receptor A that binds to Hsp110 and Grp170, as well as the feasibility of targeting this receptor to promote T-cell activation and antitumor immunity induced by large HSP vaccines and other immunotherapies. PMID:23829534

  7. Transcutaneous Peptide Immunotherapy of Japanese Cedar Pollinosis Using Solid-in-Oil Nanodispersion Technology.

    PubMed

    Kitaoka, Momoko; Shin, Yoko; Kamiya, Noriho; Kawabe, Yoshinori; Kamihira, Masamichi; Goto, Masahiro

    2015-12-01

    Peptide immunotherapy is an attractive approach to relieve allergic symptoms such as rhinitis and asthma. Treatment of Japanse cedar pollinosis (Cryptomeria japonica; Cj), from which over one quarter of Japanese population suffer, is becoming a great concern. Recently, oral feeding of a peptide (7crp) consisting of seven immunodominant human T cell epitopes derived from two enzymes present in Cj pollen was demonstrated to have a benefit in treating Cj pollinosis. In this work, we aimed to apply a novel transcutaneous administration system as a simple and easy peptide delivery for an immunotherapy using a T cell epitope peptide. A modified 7crp peptide (7crpR) which contained triarginine linkers between each epitopes was designed to increase water solubility and was encapsulated in a unique solid-in-oil (S/O) nanodispersion. The S/O nanodispersion consists of a nano-sized peptide-surfactant complex dispersed in an oil vehicle. The S/O nanopartilces having an average diameter of 230 nm facilitated the permeation of the peptide 7crpR into the skin and suppressed serum total IgE and antigen-specific IgE levels in a Cj pollinosis mouse model. Transcutaneous administration of the T cell epitope peptide using the S/O nanodispersion system has potential for future simple and easy immunotherapy of Cj pollinosis. PMID:25986596

  8. IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy.

    PubMed

    Pilipow, Karolina; Roberto, Alessandra; Roederer, Mario; Waldmann, Thomas A; Mavilio, Domenico; Lugli, Enrico

    2015-12-15

    Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long-lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8(+) memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T-cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell-based immunotherapy of cancer. Cancer Res; 75(24); 5187-93. ©2015 AACR. PMID:26627006

  9. An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy.

    PubMed

    Tavaré, Richard; Escuin-Ordinas, Helena; Mok, Stephen; McCracken, Melissa N; Zettlitz, Kirstin A; Salazar, Felix B; Witte, Owen N; Ribas, Antoni; Wu, Anna M

    2016-01-01

    The rapidly advancing field of cancer immunotherapy is currently limited by the scarcity of noninvasive and quantitative technologies capable of monitoring the presence and abundance of CD8(+) T cells and other immune cell subsets. In this study, we describe the generation of (89)Zr-desferrioxamine-labeled anti-CD8 cys-diabody ((89)Zr-malDFO-169 cDb) for noninvasive immuno-PET tracking of endogenous CD8(+) T cells. We demonstrate that anti-CD8 immuno-PET is a sensitive tool for detecting changes in systemic and tumor-infiltrating CD8 expression in preclinical syngeneic tumor immunotherapy models including antigen-specific adoptive T-cell transfer, agonistic antibody therapy (anti-CD137/4-1BB), and checkpoint blockade antibody therapy (anti-PD-L1). The ability of anti-CD8 immuno-PET to provide whole body information regarding therapy-induced alterations of this dynamic T-cell population provides new opportunities to evaluate antitumor immune responses of immunotherapies currently being evaluated in the clinic. Cancer Res; 76(1); 73-82. ©2015 AACR. PMID:26573799

  10. Nanoparticle Drug Delivery Systems Designed to Improve Cancer Vaccines and Immunotherapy

    PubMed Central

    Fan, Yuchen; Moon, James J.

    2015-01-01

    Recent studies have demonstrated great therapeutic potential of educating and unleashing our own immune system for cancer treatment. However, there are still major challenges in cancer immunotherapy, including poor immunogenicity of cancer vaccines, off-target side effects of immunotherapeutics, as well as suboptimal outcomes of adoptive T cell transfer-based therapies. Nanomaterials with defined physico-biochemical properties are versatile drug delivery platforms that may address these key technical challenges facing cancer vaccines and immunotherapy. Nanoparticle systems have been shown to improve targeted delivery of tumor antigens and therapeutics against immune checkpoint molecules, amplify immune activation via the use of new stimuli-responsive or immunostimulatory materials, and augment the efficacy of adoptive cell therapies. Here, we review the current state-of-the-art in nanoparticle-based strategies designed to potentiate cancer immunotherapies, including cancer vaccines with subunit antigens (e.g., oncoproteins, mutated neo-antigens, DNA and mRNA antigens) and whole-cell tumor antigens, dendritic cell-based vaccines, artificial antigen-presenting cells, and immunotherapeutics based on immunogenic cell death, immune checkpoint blockade, and adoptive T-cell therapy. PMID:26350600

  11. Conversion of the major birch pollen allergen, Bet v 1, into two nonanaphylactic T cell epitope-containing fragments: candidates for a novel form of specific immunotherapy.

    PubMed Central

    Vrtala, S; Hirtenlehner, K; Vangelista, L; Pastore, A; Eichler, H G; Sperr, W R; Valent, P; Ebner, C; Kraft, D; Valenta, R

    1997-01-01

    A novel approach to reduce the anaphylactic activity of allergens is suggested. The strategy makes use of the presence of conformational immunoglobulin E (IgE) epitopes on one of the most common allergens. The three dimensional structure of the major birch pollen allergen, Bet v 1, was disrupted by expressing two parts of the Bet v 1 cDNA representing amino acids 1-74 and 75-160 in Escherichia coli. In contrast to the complete recombinant Bet v 1, the fragments showed almost no allergenicity and exhibited random coil conformation as analyzed by circular dichroism. Both nonanaphylactic fragments induced proliferation of human Bet v 1-specific T cell clones, indicating that they harbored all dominant T cell epitopes and therefore may be considered as a basis for the development of a safe and specific T cell immunotherapy. PMID:9120011

  12. Minor histocompatibility antigens: allo target molecules for tumor-specific immunotherapy.

    PubMed

    Goulmy, Els

    2004-01-01

    Minor histocompatibility antigens have to be considered as key molecules in the stem cell-based immunotherapy of malignancies. Allogeneic stem cell transplantation (SCT) is a well-established and effective therapy for advanced hematologic malignancies. The apparent powerful graft-versus-leukemia effect of SCT led clinicians to apply SCT for the treatment of metastatic solid tumors. The SCT-based graft-versus-tumor reaction in the allogeneic human leukocyte antigen-matched SCT setting is mediated by allo-immune effectorcells directed against tumor-related target antigens. The target molecules involved in the allo-immune graft-versus-tumor reaction are tumor-specific antigens, tumor-associated antigens, and tissue- and cell-specific minor histocompatibility antigens. The power of the minor histocompatibility antigens in the human leukocyte antigen-identical, stem cell-based immunotherapy for malignancies is their "allo-ness." As opposed to tumor-associated self antigens, the complexes of MHC and allo-target peptide are likely to be more immunogeneic than the major histocompatibility complex and self-target peptide complexes. Moreover, minor histocompatibility allo-antigens are not subject to self tolerance. Earlier minor histocompatibility antigens were seen as alien entities, disturbing the success of the so ideally matched organ and SCT donor-recipient combinations. To date, minor histocompatibility antigens can be set in the favorable light of useful tools for immunotherapy for cancer. The first clinical application of the hematopoietic minor histocompatibility antigens HA-1 and HA-2 is currently being explored in a stem cell-based setting for hematologic malignancies. Because HA-1 is also expressed on carcinoma cells, a stem cell-based vaccination trial for patients with metastatic breast or renal cancer is about to start as well. The immunotherapeutic potential of minor histocompatibility antigens demands serious searches for new minor histocompatibility antigens and analyses of their phenotype frequency, tissue distribution, and functional membrane expression. The minor histocompatibility antigens meeting the prerequisites for specific immunotherapy for malignancies, such as membrane expression and tissue and/or cell specificity, may offer the curative tools for stem cell-based immunotherapy for various hematologic and nonhematologic malignancies. PMID:15000488

  13. Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy.

    PubMed

    Kermer, Vanessa; Hornig, Nora; Harder, Markus; Bondarieva, Anastasiia; Kontermann, Roland E; Müller, Dafne

    2014-01-01

    Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common ?-chain (?c) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15R? chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-? release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy. PMID:24198185

  14. Long-term sublingual immunotherapy for Japanese cedar pollinosis and the levels of IL-17A and complement components 3a and 5a.

    PubMed

    Sakashita, Masafumi; Yamada, Takechiyo; Imoto, Yoshimasa; Hirota, Tomomitsu; Tamari, Mayumi; Ito, Yumi; Kubo, Seita; Osawa, Yoko; Takahashi, Noboru; Fujieda, Shigeharu

    2015-09-01

    Allergen-specific immunotherapy is the only treatment that can alter the natural course of allergic disease. We performed long-term sublingual immunotherapy (SLIT) for patients with seasonal allergic rhinitis caused by Japanese cedar pollen (SAR-JCP), screened molecules as candidate biomarkers, and investigated serum IL-17A and complement components 3a (C3a) and C5a in order to evaluate whether these molecules show changes correlated to symptom scores. In this study, we found that the long-term SLIT reduced the serum levels of IL-17A and C3a and C5a. The levels of C3a in the patients significantly decreased from year 1 compared with those at the baseline, and their levels of IL-17A significantly decreased from year 2 compared with those at baseline. The levels of IL-17A, C3a, and C5a at year 4 of SLIT were significantly lower than not only those at baseline, but also those at year 1. A significant positive correlation was found between the symptom medication scores and the levels of IL-17A at year 4. The symptom medication scores in the group in which IL-17A levels decreased at year 4 were significantly lower than those in the group without such a decrease. The serum level of IL-17A might prove useful as a biological parameter to ascertain the effectiveness of SLIT for patients with SAR-JCP. It is necessary to produce new therapeutics for non-responders in whom serum IL-17A levels are still higher against long-term SLIT. PMID:25934649

  15. Autologous aldrithiol-2-inactivated HIV-1 combined with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose as a vaccine platform for therapeutic dendritic cell immunotherapy.

    PubMed

    Miller, Elizabeth; Spadaccia, Meredith; Sabado, Rachel; Chertova, Elena; Bess, Julian; Trubey, Charles Mac; Holman, Rose Marie; Salazar, Andres; Lifson, Jeffrey; Bhardwaj, Nina

    2015-01-01

    Therapeutic interventions for HIV-1 that successfully augment adaptive immunity to promote killing of infected cells may be a requisite component of strategies to reduce latent cellular reservoirs. Adoptive immunotherapies utilizing autologous monocyte-derived dendritic cells (DCs) that have been activated and antigen loaded ex vivo may serve to circumvent defects in DC function that are present during HIV infection in order to enhance adaptive immune responses. Here we detail the clinical preparation of DCs loaded with autologous aldrithiol-2 (AT-2)-inactivated HIV that have been potently activated with the viral mimic, Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (Poly-ICLC). HIV is first propagated from CD4+ T cells from HIV-infected donors and then rendered non-replicative by chemical inactivation with aldrithiol-2 (AT-2), purified, and quantified. Viral inactivation is confirmed through measurement of Tat-regulated ?-galactosidase reporter gene expression following infection of TZM-bl cells. In-process testing for sterility, mycoplasma, LPS, adventitious agents, and removal of AT-2 is performed on viral preparations. Autologous DCs are generated and pulsed with autologous AT-2-inactivated virus and simultaneously stimulated with Poly-ICLC to constitute the final DC vaccine product. Phenotypic identity, maturation, and induction of HIV-specific adaptive immune responses are confirmed via flow cytometric analysis of DCs and cocultured autologous CD4+ and CD8+ T cells. Lot release criteria for the DC vaccine have been defined in accordance with Good Manufacturing Practice (GMP) guidelines. The demonstrated feasibility of this approach has resulted in approval by the FDA for investigational use in antiretroviral (ART) suppressed individuals. We discuss how this optimized DC formulation may enhance the quality of anti-HIV adaptive responses beyond what has been previously observed during DC immunotherapy trials for HIV infection. PMID:25444812

  16. Efficacy of Sublingual Immunotherapy with Dermatophagoides farinae Extract in Monosensitized and Polysensitized Patients with Allergic Rhinitis: Clinical Observation and Analysis

    PubMed Central

    Xu, Chen-Xia; Zhang, Miao-Lian; Li, Bi-Zhou; He, Ying; Zou, Ze-Hong; Wu, Qiu-Rong; Tao, Ai-Lin; Lai, He; Sun, Jin-Lu

    2015-01-01

    Aim. To investigate differences in the efficacy of sublingual immunotherapy with Dermatophagoides farinae drops in monosensitized and polysensitized allergic rhinitis patients. Methods. The patients enrolled in the study were treated for more than one year by sublingual immunotherapy (SLIT) using Dermatophagoides farinae drops and were divided into a monosensitized group (n = 20) and a polysensitized group (n = 30). Total nasal symptom scores of patients before and after SLIT were analyzed to evaluate the curative effect. The phylogenetic tree of dust mite allergens as well as other allergens that were tested by skin prick test was constructed to help the analysis. Results. There was no significant difference in the efficacy of SLIT between dust mite monosensitized and polysensitized patients. Conclusions. Both dust mite monosensitized and polysensitized patients could be cured by SLIT using Dermatophagoides farinae drops. This study provides a reference for the selection of allergens to be used in immunotherapy for polysensitized AR patients. PMID:26000283

  17. Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: Case study

    PubMed Central

    Heimberger, Amy B.; Sun, Wei; Hussain, S. Farzana; Dey, Mahua; Crutcher, Lamonne; Aldape, Ken; Gilbert, Mark; Hassenbusch, Samuel J.; Sawaya, Raymond; Schmittling, Bob; Archer, Gary E.; Mitchell, Duane A.; Bigner, Darell D.; Sampson, John H.

    2008-01-01

    Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemo-therapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery. PMID:18079360

  18. New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.

    PubMed

    Khawaja, Ayaz M; DeWolfe, Jennifer L; Miller, David W; Szaflarski, Jerzy P

    2015-06-01

    New-onset refractory status epilepticus (NORSE) is defined as a state of persistent seizures with no identifiable etiology in patients without preexisting epilepsy that lasts longer than 24h despite optimal therapy. Management of NORSE is challenging, and the role of immunotherapy (IT) is unclear. We identified patients fulfilling the criteria for NORSE at a single institution. These patients were described, analyzed, and compared with NORSE cases available from the literature. Finally, a pooled analysis of available case series was conducted to compare the outcomes in patients who received IT with those not treated with IT during the course of NORSE in order to generate hypotheses for further research. In our case series, NORSE was diagnosed in 11 patients (9 females) with a mean age of 48 years and a mean duration of 54.4 days. Autoantibodies were identified in 7 patients, of which anti-GAD (glutamic acid decarboxylase) and anti-NMDAR (N-methyl-D-aspartate receptor) were most frequent. Of the 11 patients, 8 were treated with IT (intravenous steroids, immunoglobulins, plasmapheresis, or a combination), and 4 received chemotherapy. Of the 8 patients treated with IT, 6 had favorable outcomes (defined as any outcome other than death, vegetative state, or inability to take care of oneself) compared with 0 out of 3 patients who did not receive IT. Difference in outcomes was significant (p=0.026). Pooled analysis of all identified case series, including ours, showed a statistically significant effect (p=0.022), with favorable outcomes in 42% of the patients who received any IT compared with 20% in those who did not. In all patients with refractory SE and negative comprehensive investigations, a diagnosis of NORSE should be considered. This would aid planning for early immunotherapy. Currently, only Class IV evidence for the use of immunotherapy in NORSE is available. Prospective multicenter studies are necessary to assess the true efficacy of IT in NORSE. PMID:26010959

  19. Cancer immunotherapy utilizing gene-modified T cells: From the bench to the clinic.

    PubMed

    Duong, Connie P M; Yong, Carmen S M; Kershaw, Michael H; Slaney, Clare Y; Darcy, Phillip K

    2015-10-01

    The immune system plays a critical role in the elimination and suppression of pathogens. Although the endogenous immune system is capable of immune surveillance resulting in the elimination of cancer cells, tumor cells have developed a variety of mechanisms to escape immune recognition often resulting in tumor outgrowth. The presence of immune infiltrate in tumors has been correlated with a good prognosis following treatment (Sato et al., 2005; Loi et al., 2013; Clemente et al., 1996; Galon et al., 2006). As such, immune cells such as T cells, have been harnessed in order to target cancer. Tumor reactive lymphocytes, called tumor-infiltrating lymphocytes (TILs) have been isolated and expanded from the tumor and reinfused back into patients for the treatment of melanoma. The promise of adoptive immunotherapy utilizing TILs as a robust treatment for cancer has been highlighted in patients with advanced melanoma with greater than 50% of patients responding to treatment (Dudley et al., 2005). Although TIL therapy has shown promising results in melanoma patients, it has proved difficult to translate this approach to other cancers, given that the numbers of TILs that can be isolated are generally low. To broaden this therapy for other cancers, T cells have been genetically modified to endow them with tumor reactivity using either a T cell receptor (TCR) (Parkhurst et al., 2009, 2011; Chinnasamy et al., 2011) or a chimeric antigen receptor (CAR) (Grupp et al., 2013; Park et al., 2007). This review will outline the origins and development of adoptive immunotherapy utilizing TILs leading to genetic modification strategies to redirect T cells to cancer. Potential hurdles and novel strategies will be discussed for realizing the full potential of adoptive immunotherapy becoming a standard of care treatment for cancer. PMID:25595028

  20. Specific immunotherapy of experimental myasthenia by genetically engineered APCs: the "guided missile" strategy.

    PubMed

    Drachman, D B; Wu, J-M; Miagkov, A; Williams, M A; Adams, R N; Wu, B

    2003-09-01

    Although treatment of MG with general immunosuppressive agents is often effective, it has important drawbacks, including suppression of the immune system as a whole, with the risks of infection and neoplasia, and numerous other adverse side effects. Ideally, treatment of MG should eliminate the specific pathogenic autoimmune response to AChR, without otherwise suppressing the immune system or producing other adverse side effects. Although antibodies to AChR are directly responsible for the loss of AChRs at neuromuscular junctions in MG, the AChR antibody response is T cell-dependent, and immunotherapy directed at T cells can abrogate the autoantibody response, with resulting benefit. As in other autoimmune diseases, the T cell response in MG is highly heterogeneous. The design of specific immunotherapy must take this heterogeneity into account and target the entire repertoire of AChR-specific T cells. We describe our investigation of a novel strategy for specific immunotherapy of MG, involving gene transfer to convert antigen-presenting cells (APCs) to "guided missiles" that target AChR-specific T cells, and that induce apoptosis and elimination of those T cells. This strategy uses the ability of APCs from a given individual to present the entire spectrum of AChR epitopes unique for that individual, and thereby to target the entire repertoire of antigen-specific T cells of the same individual. Using viral vectors, we have genetically engineered the APCs to process and present the most important domain of the AChR molecule, and to express a "warhead" of Fas ligand (FasL) to eliminate the activated AChR-specific T cells with which they interact. Our results show that the APCs express the appropriate gene products, and effectively and specifically eliminate AChR-specific T cells by the Fas/FasL pathway, while sparing T cells of other specificities. PMID:14592923

  1. TH-C-17A-11: Hyperthermia-Driven Immunotherapy Using Non-Invasive Radiowaves

    SciTech Connect

    Serda, R; Savage, D; Corr, S; Curley, S

    2014-06-15

    Purpose: The sad truth is that cancer is blamed for the death of nearly one in four people in the US. Immunotherapy offers hope for stimulating cancer immunity leading to targeted killing of cancer cells and a preventative measure for cancer recurrence. Unfortunately, the clinical efficacy of immunotherapy has not yet been established, however novel approaches are being developed, including combining immunotherapy with traditional chemotherapy, radiotherapy or thermal therapy. Therapeutics such as radiofrequency (RF) ablation and select chemotherapeutics induce mild anticancer immune responses. This project seeks to enhance the immune responses stimulated by these agents by co-delivery of nanoparticle-based chemotherapeutics and immune modulators in the presence of RF induced hyperthermia. Methods: A 4T1 mouse model of breast cancer is used to test the ability of RF waves to enhance accumulation of nanoparticles in tumor tissue by increasing blood flow and extravation of nanoparticles from hyperpermeable vessels. Images of particle and cell trafficking in the tumor are captured using an integrated RF and confocal imaging system, and tumor growth is monitored by tumor bioluminescence and caliper measurements. Results: Here we demonstrate enhanced intratumoral blood flow induced by non-invasive RF waves and an increase in nanoparticle accumulation in the tumor. IL-12 is shown to have powerful anti-tumor effects leading to tumor regression and the release of Th1-biased cytokines. Doxorubicin nanoparticles combined with adjuvant nanoparticles exhibited superior antitumor effects to single agent therapy. Conclusion: RF therapy combined with nanotherapeutics is a promising approach to enhance the delivery of therapeutics to the tumor and to stimulate a tumor microenvironment that supports the development of cancer-specific immune responses. This research was supported by the National Institute of Health grant numbers U54 CA143837 and U54 CA151668, and the Kanzius Foundation.

  2. NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy

    PubMed Central

    Wang, Wei; Erbe, Amy K.; Hank, Jacquelyn A.; Morris, Zachary S.; Sondel, Paul M.

    2015-01-01

    Natural killer (NK) cells play a major role in cancer immunotherapies that involve tumor-antigen targeting by monoclonal antibodies (mAbs). NK cells express a variety of activating and inhibitory receptors that serve to regulate the function and activity of the cells. In the context of targeting cells, NK cells can be “specifically activated” through certain Fc receptors that are expressed on their cell surface. NK cells can express Fc?RIIIA and/or Fc?RIIC, which can bind to the Fc portion of immunoglobulins, transmitting activating signals within NK cells. Once activated through Fc receptors by antibodies bound to target cells, NK cells are able to lyse target cells without priming, and secrete cytokines like interferon gamma to recruit adaptive immune cells. This antibody-dependent cell-mediated cytotoxicity (ADCC) of tumor cells is utilized in the treatment of various cancers overexpressing unique antigens, such as neuroblastoma, breast cancer, B cell lymphoma, and others. NK cells also express a family of receptors called killer immunoglobulin-like receptors (KIRs), which regulate the function and response of NK cells toward target cells through their interaction with their cognate ligands that are expressed on tumor cells. Genetic polymorphisms in KIR and KIR-ligands, as well as Fc?Rs may influence NK cell responsiveness in conjunction with mAb immunotherapies. This review focuses on current therapeutic mAbs, different strategies to augment the anti-tumor efficacy of ADCC, and genotypic factors that may influence patient responses to antibody-dependent immunotherapies. PMID:26284063

  3. Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers

    PubMed Central

    Butterfield, Lisa H.; Palucka, A. Karolina; Britten, Cedrik M.; Dhodapkar, Madhav V.; Håkansson, Leif; Janetzki, Sylvia; Kawakami, Yutaka; Kleen, Thomas-Oliver; Lee, Peter P.; Maccalli, Cristina; Maecker, Holden T.; Maino, Vernon C.; Maio, Michele; Malyguine, Anatoli; Masucci, Giuseppe; Pawelec, Graham; Potter, Douglas M.; Rivoltini, Licia; Salazar, Lupe G.; Schendel, Dolores J.; Slingluff, Craig L.; Song, Wenru; Stroncek, David F.; Tahara, Hideaki; Thurin, Magdalena; Trinchieri, Giorgio; van Der Burg, Sjoerd H.; Whiteside, Theresa L.; Wigginton, Jon M.; Marincola, Francesco; Khleif, Samir; Fox, Bernard A.; Disis, Mary L.

    2011-01-01

    Purpose To facilitate development of innovative immunotherapy approaches, especially for treatment concepts exploiting the potential benefits of personalized therapy, there is a need to develop and validate tools to identify patients who can benefit from immunotherapy. Despite substantial effort, we do not yet know which parameters of anti-tumor immunity to measure and which assays are optimal for those measurements. Experimental Design The iSBTc-SITC, FDA and NCI partnered to address these issues for immunotherapy of cancer. Here, we review the major challenges, give examples of approaches and solutions and present our recommendations. Results and Conclusions While specific immune parameters and assays are not yet validated, we recommend following standardized (accurate, precise and reproducible) protocols and use of functional assays for the primary immunologic readouts of a trial; consideration of central laboratories for immune monitoring of large, multi-institutional trials; and standardized testing of several phenotypic and functional potential potency assays specific to any cellular product. When reporting results, the full QA/QC performed, selected examples of truly representative raw data and assay performance characteristics should be included. Lastly, to promote broader analysis of multiple aspects of immunity, and gather data on variability, we recommend that in addition to cells and serum, that RNA and DNA samples be banked (under standardized conditions) for later testing. We also recommend that sufficient blood be drawn to allow for planned testing of the primary hypothesis being addressed in the trial, and that additional baseline and post-treatment blood is banked for testing novel hypotheses (or generating new hypotheses) that arise in the field. PMID:21558394

  4. Immuno-therapy of Acute Radiation Syndromes : Extracorporeal Immuno-Lympho-Plasmo-Sorption.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava

    Methods Results Summary and conclusions Introduction: Existing Medical Management of the Acute Radiation Syndromes (ARS) does not include methods of specific immunotherapy and active detoxication. Though the Acute Radiation Syndromes were defined as an acute toxic poisonous with development of pathological processes: Systemic Inflammatory Response Syndrome (SIRS), Toxic Multiple Organ Injury (TMOI), Toxic Multiple Organ Dysfunction Syndrome(TMODS), Toxic Multiple Organ Failure (TMOF). Radiation Toxins of SRD Group play an important role as the trigger mechanisms in development of the ARS clinical symptoms. Methods: Immuno-Lympho-Plasmo-Sorption is a type of Immuno-therapy which includes prin-ciples of immunochromato-graphy, plasmopheresis, and hemodialysis. Specific Antiradiation Antitoxic Antibodies are the active pharmacological agents of immunotherapy . Antiradia-tion Antitoxic Antibodies bind selectively to Radiation Neurotoxins, Cytotoxins, Hematotox-ins and neutralize their toxic activity. We have developed the highly sensitive method and system for extracorporeal-immune-lypmh-plasmo-sorption with antigen-specific IgG which is clinically important for treatment of the toxic and immunologic phases of the ARS. The method of extracorporeal-immune-lypmh-plasmo-sorption includes Antiradiation Antitoxic Antibodies (AAA) immobilized on microporous polymeric membranes with a pore size that is capable to provide diffusion of blood-lymph plasma. Plasma of blood or lymph of irradiated mammals contains Radiation Toxins (RT) that have toxic and antigenic properties. Radiation Toxins are Antigen-specific to Antitoxic blocking antibodies (Immunoglobulin G). Plasma diffuses through membranes with immobilized AAA and AA-antibodies bind to the polysaccharide chain of tox-ins molecules and complexes of AAA-RT that are captured on membrane surfaces. RT were removed from plasma. Re-transfusion of plasma of blood and lymph had been provided. We show a statistical significant reduction in postradiation lethality.

  5. FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | Poster

    Cancer.gov

    By Frank Blanchard, Staff Writer The U.S. Food and Drug Administration (FDA) recently approved dinutuximab (ch14.18) as an immunotherapy for neuroblastoma, a rare type of childhood cancer that offers poor prognosis for about half of the children who are affected. The National Cancer Institute’s (NCI) Biopharmaceutical Development Program (BDP) at the Frederick National Laboratory for Cancer Research produced ch14.18 for the NCI-sponsored clinical trials that proved the drug’s effectiveness against the disease.

  6. Highlights of the society for immunotherapy of cancer (SITC) 27th annual meeting

    PubMed Central

    2013-01-01

    The 27th annual meeting of the Society for Immunotherapy of Cancer (SITC) was held on October 26–28, 2012 in North Bethesda, Maryland and the highlights of the meeting are summarized. The topics covered at this meeting included advances in cancer treatment using adoptive cell therapy (ACT), oncolytic viruses, dendritic cells (DCs), immune check point modulators and combination therapies. Advances in immune editing of cancer, immune modulation by cancer and the tumor microenvironment were also discussed as were advances in single cell analysis and the manufacture and potency testing of tumor infiltrating lymphocytes (TIL).

  7. Laser immunotherapy and the tumor-immune system interaction: a mathematical model and analysis

    NASA Astrophysics Data System (ADS)

    Laverty, Sean M.; Dawkins, Bryan A.; Chen, Wei R.

    2014-02-01

    Laser immunotherapy (LIT) is a cancer treatment with promising results in animal models and some `no other option' patients. The therapy elicits an immune response that targets the primary tumor and, perhaps more importantly, otherwise untreatable metastases. We develop and analyze a mathematical model that includes key elements of the host immune response set in motion by LIT. We use Latin Hypercube Sampling (LHS) to EFFICIENTLY sample model parameters from a high-dimensional parameter space and get a broad sense of model dynamics. Depending on a variety of tumor, therapy, and immune parameters, a variety of patient outcomes ranging from tumor clearance to patient death are possible.

  8. CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues

    SciTech Connect

    Fujii, Masakazu; Inoguchi, Toyoshi; Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 ; Batchuluun, Battsetseg; Sugiyama, Naonobu; Kobayashi, Kunihisa; Sonoda, Noriyuki; Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 ; Takayanagi, Ryoichi

    2013-08-16

    Highlights: •CTLA-4Ig completely alleviates HFD-induced insulin resistance. •CTLA-4Ig reduces epididymal and subcutaneous fat tissue weight and adipocyte size. •CTLA-4Ig alters ATM polarization from inflammatory M1 to anti-inflammatory M2. •CTLA-4Ig may lead to a novel anti-obesity/inflammation/insulin resistance agent. •We identified the mechanism of the novel favorable effects of CTLA-4lg. -- Abstract: It has been established that obesity alters the metabolic and endocrine function of adipose tissue and, together with accumulation of adipose tissue macrophages, contributes to insulin resistance. Although numerous studies have reported that shifting the polarization of macrophages from M1 to M2 can alleviate adipose tissue inflammation, manipulation of macrophage polarization has not been considered as a specific therapy. Here, we determined whether cytotoxic T-lymphocyte-associated antigen-4IgG1 (CTLA-4Ig) can ameliorate insulin resistance by induction of macrophages from proinflammatory M1 to anti-inflammatory M2 polarization in the adipose tissues of high fat diet-induced insulin-resistant mice. CTLA4-Ig treatment prevented insulin resistance by changing gene expression to M2 polarization, which increased the levels of arginase 1. Furthermore, flow cytometric analysis confirmed the alteration of polarization from CD11c (M1)- to CD206 (M2)-positive cells. Concomitantly, CTLA-4Ig treatment resulted in weight reductions of epididymal and subcutaneous adipose tissues, which may be closely related to overexpression of apoptosis inhibitors in macrophages. Moreover, proinflammatory cytokine and chemokine levels decreased significantly. In contrast, CCAAT enhancer binding protein ?, peroxisome proliferator-activated receptor ?, and adiponectin expression increased significantly in subcutaneous adipose tissue. This novel mechanism of CTLA-4lg immunotherapy may lead to an ideal anti-obesity/inflammation/insulin resistance agent.

  9. Targeting cancer testis antigens for biomarkers and immunotherapy in colorectal cancer: Current status and challenges.

    PubMed

    Suri, Anil; Jagadish, Nirmala; Saini, Shikha; Gupta, Namita

    2015-12-15

    Colorectal cancer ranks third among the estimated cancer cases and cancer related mortalities in United States in 2014. Early detection and efficient therapy remains a significant clinical challenge for this disease. Therefore, there is a need to identify novel tumor associated molecules to target for biomarker development and immunotherapy. In this regard, cancer testis antigens have emerged as a potential targets for developing novel clinical biomarkers and immunotherapy for various malignancies. These germ cell specific proteins exhibit aberrant expression in cancer cells and contribute in tumorigenesis. Owing to their unique expression profile and immunogenicity in cancer patients, cancer testis antigens are clinically referred as the most promising tumor associated antigens. Several cancer testis antigens have been studied in colorectal cancer but none of them could be used in clinical practice. This review is an attempt to address the promising cancer testis antigens in colorectal cancer and their possible clinical implications as biomarkers and immunotherapeutic targets with particular focus on challenges and future interventions. PMID:26691579

  10. Intralesional antigen immunotherapy for the treatment of warts: current concepts and future prospects.

    PubMed

    Nofal, Ahmad; Salah, Eman; Nofal, Eman; Yosef, Ayman

    2013-08-01

    Many destructive and immunotherapeutic modalities have been used for the management of warts; however, an optimal treatment with high efficacy and absent or low recurrence has not been explored to date. Recently, the use of intralesional immunotherapy with different antigens has shown promising efficacy in the treatment of warts. We review the different aspects of this new modality, including candidates, types of warts treated, dosage, number and interval between treatment sessions, mode of action, efficacy, adverse effects, recurrence rate, advantages, disadvantages, current place and future prospects. A literature review revealed that healthy immune subjects are the best candidates, and a pre-sensitization test is usually done before the start of therapy. The dosage, the number and interval between sessions, and the success rates varied among the different studies. The mode of action is still uncertain, but is essentially mediated through stimulation of T helper-1 cell cytokine response. Adverse effects are mild and generally insignificant, and the recurrence rate is absent or low. Intralesional antigen immunotherapy seems to be a promising, effective and safe treatment modality for viral warts. Future well-designed and controlled studies would help to more clearly define its place in the challenging field of wart therapy. PMID:23813361

  11. Immunoglobulin E-binding epitopes of mite allergens: from characterization to immunotherapy.

    PubMed

    Cui, Yubao

    2014-12-01

    House dust mites and storage mites produce a number of allergens that can induce hypersensitivity reactions in humans and result in allergic diseases like asthma, rhinitis, and dermatitis. Recent advances in identifying and characterizing these allergens--and, in particular, their immunoglobulin E (IgE)-binding epitopes--have produced a wealth of knowledge. Here, methods for identifying IgE-binding epitopes, from immunoassays to in silico approaches, are summarized and placed in context with the identification of epitopes of mite allergens, particularly from the Dermatophagoides spp. major allergen groups 1 and 2. Finally, the transfer of this information to the clinical development and application of new diagnostic and immunotherapeutic approaches is discussed. While progress in recent years has built on the specific immunotherapies established decades ago, much work remains to be done to mitigate mite allergic disease. Future studies should seek to identify epitopes for mite species beyond Dermatophagoides and for minor allergens. Efforts in translational medicine should use the current epitope data to develop modified allergens for immunotherapy. PMID:24218295

  12. NK cell-based cancer immunotherapy: from basic biology to clinical application.

    PubMed

    Li, Yang; Yin, Jie; Li, Ting; Huang, Shan; Yan, Han; Leavenworth, JianMei; Wang, Xi

    2015-12-01

    Natural killer (NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex (MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor (CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell-based approaches may hold great potential for future cancer immunotherapy. PMID:26588912

  13. A New Hope in Immunotherapy for Malignant Gliomas: Adoptive T Cell Transfer Therapy

    PubMed Central

    Chung, Dong-Sup; Shin, Hye-Jin; Hong, Yong-Kil

    2014-01-01

    Immunotherapy emerged as a promising therapeutic approach to highly incurable malignant gliomas due to tumor-specific cytotoxicity, minimal side effect, and a durable antitumor effect by memory T cells. But, antitumor activities of endogenously activated T cells induced by immunotherapy such as vaccination are not sufficient to control tumors because tumor-specific antigens may be self-antigens and tumors have immune evasion mechanisms to avoid immune surveillance system of host. Although recent clinical results from vaccine strategy for malignant gliomas are encouraging, these trials have some limitations, particularly their failure to expand tumor antigen-specific T cells reproducibly and effectively. An alternative strategy to overcome these limitations is adoptive T cell transfer therapy, in which tumor-specific T cells are expanded ex vivo rapidly and then transferred to patients. Moreover, enhanced biologic functions of T cells generated by genetic engineering and modified immunosuppressive microenvironment of host by homeostatic T cell expansion and/or elimination of immunosuppressive cells and molecules can induce more potent antitumor T cell responses and make this strategy hold promise in promoting a patient response for malignant glioma treatment. Here we will review the past and current progresses and discuss a new hope in adoptive T cell therapy for malignant gliomas. PMID:25009822

  14. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy

    PubMed Central

    Leone, Robert D.; Lo, Ying-Chun; Powell, Jonathan D.

    2015-01-01

    The last several years have witnessed exciting progress in the development of immunotherapy for the treatment of cancer. This has been due in great part to the development of so-called checkpoint blockade. That is, antibodies that block inhibitory receptors such as CTLA-4 and PD-1 and thus unleash antigen-specific immune responses against tumors. It is clear that tumors evade the immune response by usurping pathways that play a role in negatively regulating normal immune responses. In this regard, adenosine in the immune microenvironment leading to the activation of the A2a receptor has been shown to represent one such negative feedback loop. Indeed, the tumor microenvironment has relatively high concentrations of adenosine. To this end, blocking A2a receptor activation has the potential to markedly enhance anti-tumor immunity in mouse models. This review will present data demonstrating the ability of A2a receptor blockade to enhance tumor vaccines, checkpoint blockade and adoptive T cell therapy. Also, as several recent studies have demonstrated that under certain conditions A2a receptor blockade can enhance tumor progression, we will also explore the complexities of adenosine signaling in the immune response. Despite important nuances to the A2a receptor pathway that require further elucidation, studies to date strongly support the development of A2a receptor antagonists (some of which have already been tested in phase III clinical trials for Parkinson Disease) as novel modalities in the immunotherapy armamentarium. PMID:25941561

  15. Laser assisted immunotherapy (LIT) for chemotherapy-resistant neoplasms: recent case reports

    NASA Astrophysics Data System (ADS)

    Nordquist, Robert E.; Bahavar, Cody; Zhou, Feifan; Hode, Tomas; Chen, Wei R.; Li, Xiaosong; Naylor, Mark F.

    2014-02-01

    T-cell stimulators such as anti-CTLA-4 antibodies enhance immunologic responses to chemotherapy-resistant solid tumors, such as melanoma, advanced breast cancer, ovarian cancer and pancreatic cancer. The efficacy of these new immunotherapy agents can in theory be enhanced substantially by therapies that stimulate new immunologic (T-cell) responses against the tumor. Laser immunotherapy (LIT) with imiquimod and InCVAX are techniques that produce useful responses in patients with advanced melanoma, the prototypical chemotherapy resistant solid tumor. The mechanism of action of these therapies is thought to be immunological, including the development of new T-cell responses. We have therefore been combining LIT using imiquimod and InCVAX treatment with the new T-cell stimulators (ipilimumab) in cases of stage IV melanoma. While still anecdotal, the use of novel combinations of immunologic therapies should provide much improved responses for chemotherapy-resistant solid tumors (such as melanoma) than was previously possible. Newer T-cell stimulating drugs such as the anti-PD-1 antibodies and anti-PD-L1 antibodies will make this general approach to treating chemoresistant advanced tumors even more effective in the future.

  16. Peptide inhibitors of transforming growth factor-beta enhance the efficacy of antitumor immunotherapy.

    PubMed

    Llopiz, Diana; Dotor, Javier; Casares, Noelia; Bezunartea, Jaione; Díaz-Valdés, Nancy; Ruiz, Marta; Aranda, Fernando; Berraondo, Pedro; Prieto, Jesús; Lasarte, Juan José; Borrás-Cuesta, Francisco; Sarobe, Pablo

    2009-12-01

    Transforming growth factor-beta (TGF-beta) is a cytokine with potent immunosuppressive effects and is overexpressed in many tumors. Therefore, development of molecules able to inhibit TGF-beta is of paramount importance to improve the efficacy of antitumor immunotherapy. TGF-beta inhibitor peptides P144 and P17 were combined with the administration of adjuvant molecules poly(I:C) and agonistic anti-CD40 antibodies, and their effect on the growth of E.G7-OVA established tumors and on antitumor immune response was evaluated. Tumor rejection efficacy of a single administration of adjuvants was enhanced from 15 to 70 % when combined with repeated injections of TGF-beta inhibitor peptides. Simultaneous administration of adjuvants and TGF-beta inhibitor peptides was required for maximal therapeutic efficacy. Although tumor cells produced TGF-beta, it was found that the beneficial effect of peptide administration was mainly due to the inhibition of TGF-beta produced by regulatory CD4(+)CD25(+) T cells rather than by tumor cells. The enhanced antitumor effect was accompanied by a higher activity of dendritic cells, natural killer cells and tumor antigen-specific T cells, as well as by a decrease in the number of myeloid-derived suppressor cells. In conclusion, administration of peptide inhibitors of TGF-beta in therapeutic vaccination enhances the efficacy of immunotherapy by increasing antitumor immune responses. These peptide inhibitors may have important applications for current immunotherapeutic strategies. PMID:19530254

  17. Improving Antigenic Peptide Vaccines for Cancer Immunotherapy Using a Dominant Tumor-specific T Cell Receptor*

    PubMed Central

    Buhrman, Jonathan D.; Jordan, Kimberly R.; Munson, Daniel J.; Moore, Brandon L.; Kappler, John W.; Slansky, Jill E.

    2013-01-01

    Vaccines that incorporate peptide mimics of tumor antigens, or mimotope vaccines, are commonly used in cancer immunotherapy and function by eliciting increased numbers of T cells that cross-react with the native tumor antigen. Unfortunately, they often elicit T cells that do not cross-react with or that have low affinity for the tumor antigen. Using a high affinity tumor-specific T cell clone, we identified a panel of mimotope vaccines for the dominant peptide antigen from a mouse colon tumor that elicits a range of tumor protection following vaccination. The TCR from this high affinity T cell clone was rarely identified in ex vivo evaluation of tumor-specific T cells elicited by mimotope vaccination. Conversely, a low affinity clone found in the tumor and following immunization was frequently identified. Using peptide libraries, we determined if this frequently identified TCR improved the discovery of efficacious mimotopes. We demonstrated that the representative TCR identified more protective mimotopes than the high affinity TCR. These results suggest that targeting a dominant fraction of tumor-specific T cells generates potent immunity and that consideration of the available T cell repertoire is necessary for targeted T cell therapy. These results have important implications when optimizing mimotope vaccines for cancer immunotherapy. PMID:24106273

  18. Targeted depletion of tumour-associated macrophages by an alendronate-glucomannan conjugate for cancer immunotherapy.

    PubMed

    Zhan, Xiudan; Jia, Lixin; Niu, Yiming; Qi, Haixia; Chen, Xiuping; Zhang, Qingwen; Zhang, Junfeng; Wang, Yitao; Dong, Lei; Wang, Chunming

    2014-12-01

    Tumour-associated macrophages (TAMs) are a set of macrophages residing in the tumour microenvironment. They play essential roles in mediating tumour angiogenesis, metastasis and immune evasion. Delivery of therapeutic agents to eliminate TAMs can be a promising strategy for cancer immunotherapy but an efficient vehicle to target these cells is still in pressing need. In this study, we developed a bisphosphonate-glucomannan conjugate that could efficiently target and specifically eliminate TAMs in the tumour microenvironment. We employed the polysaccharide from Bletilla striata (BSP), a glucomannan affinitive for macrophages that express abundant mannose receptors, to conjugate alendronate (ALN), a bisphosphonate compound with in vitro macrophage-inhibiting activities. In both in vitro and in vivo tests, the prepared ALN-BSP conjugate could preferentially accumulate in macrophages and induced them into apoptosis. In the subcutaneous S180 tumour-bearing mice model, the treatment using ALN-BSP effectively eliminated TAMs, remarkably inhibited angiogenesis, recovered local immune surveillance, and eventually suppressed tumour progression, without eliciting any unwanted effect such as systematic immune response. Interestingly, ALN alone failed to exhibit any anti-TAM activity in vivo, probably because this compound was susceptible to the mildly acidic tumour microenvironment. Taken together, these results demonstrate the potential of ALN-BSP as a safe and efficient tool targeted at direct depletion of TAMs for cancer immunotherapy. PMID:25245263

  19. Specific immunotherapy of experimental myasthenia gravis in vitro: the "guided missile" strategy.

    PubMed

    Wu, J M; Wu, B; Miagkov, A; Adams, R N; Drachman, D B

    2001-03-15

    We describe a strategy for specific immunotherapy of myasthenia gravis (MG) based on genetic engineering of antigen presenting cells (APCs) to present the autoantigen acetylcholine receptor (AChR) and express the "warhead" Fas ligand (FasL). For transduction of APCs we prepared recombinant attenuated vaccinia virus vectors carrying the following three gene constructs: (i) AChR fused to LAMP1 to present AChR and target AChR-specific T cells; (ii) FasL to eliminate the targeted T cells; and (iii) truncated FADD to protect APCs from self-destruction by FasL. The engineered APCs effectively expressed the genes of interest and killed AChR-specific T cells in culture by the Fas/FasL pathway. T cells specific for an unrelated antigen were spared. Our in vitro demonstration that engineered APCs target and kill antigen-specific T cells represents a promising novel strategy for specific immunotherapy of MG and other autoimmune diseases. PMID:11333146

  20. The combination of radiotherapy and immunotherapy using glycated chitosan as an immunological stimulant

    NASA Astrophysics Data System (ADS)

    Chang, Chun-Yuan; Leu, Jyh-Der; Wang, Chung-Yi; Chen, Wei R.; Lee, Yi-Jang

    2015-03-01

    Immunotherapy has been reported to effectively treat various cancers. In addition, scientists are dedicated in finding whether the combination of radiotherapy and immunotherapy can efficiently suppress cancer progression and recurrence. Although radiotherapy has been widely used for breast cancer, better strategies to overcome the latestage breast cancer remains explored. The glycated chitosan (GC), a novel immunological stimulant, was demonstrated to trigger local immune response facilitating the enhancement of radiosensitivity. Our previous study also revealed that the cell mortality and invasive ability were decreased under GC treatment, but the underlying mechanism remains unclear. In this study, we used 4T1-3R-L, a derived murine breast cancer cell line from the spontaneous metastasized liver lesion. We combined ionizing radiation with GC to treat 4T1-3R-L and found the expression of DNA damage-related genes such as gamma-H2AX was more than radiation alone In addition, the cell cycle distribution and colony forming assay showed an increased sub-G1 population and decreased cell survival rate after IR combined GC treatment. Taken together, we sought to elucidate the underlying mechanism by the investigation of DNA damage repair process when IR combined with GC, and to explore another advantage of GC to aid other cancer treatments. Based on our most updated results, the GC treatment is able to effectively increase the radiosensitivity through an immune-responsive signaling transduction, indicating that GC could be a valuable therapeutic strategy for treating against advanced breast cancers.

  1. The Fc-alpha receptor is a new target antigen for immunotherapy of myeloid leukemia.

    PubMed

    Mladenov, Radoslav; Hristodorov, Dmitrij; Cremer, Christian; Hein, Lea; Kreutzer, Fabian; Stroisch, Tim; Niesen, Judith; Brehm, Hannes; Blume, Tobias; Brümmendorf, Tim Henrik; Jost, Edgar; Thepen, Theophilus; Fischer, Rainer; Stockmeyer, Bernhard; Barth, Stefan; Stein, Christoph

    2015-12-01

    Antibody-based immunotherapy of leukemia requires the targeting of specific antigens on the surface of blasts. The Fc gamma receptor (CD64) has been investigated in detail, and CD64-targeting immunotherapy has shown promising efficacy in the targeted ablation of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML) and chronic myeloid leukemia cells (CML). Here we investigate for the first time the potential of Fc?RI (CD89) as a new target antigen expressed by different myeloid leukemic cell populations. For specific targeting and killing, we generated a recombinant fusion protein comprising an anti-human CD89 single-chain Fragment variable and the well-characterized truncated version of the potent Pseudomonas aeruginosa exotoxin A (ETA'). Our novel therapeutic approach achieved in vitro EC50 values in range 0.2-3 nM depending on the applied stimuli, that is, interferon gamma or tumor necrosis factor alpha. We also observed a dose-dependent apoptosis-mediated cytotoxicity, which resulted in the elimination of up to 90% of the target cells within 72 hr. These findings were also confirmed ex vivo using leukemic primary cells from peripheral blood samples of three previously untreated patients. We conclude that CD89-specific targeting of leukemia cell lines can be achieved in vitro and that the efficient elimination of leukemic primary cells supports the potential of CD89-ETA' as a potent, novel immunotherapeutic agent. PMID:26041304

  2. Detecting tau in serum of transgenic animal models after tau immunotherapy treatment.

    PubMed

    d'Abramo, Cristina; Acker, Christopher M; Schachter, Joel B; Terracina, Giuseppe; Wang, Xiaohai; Forest, Stefanie K; Davies, Peter

    2016-01-01

    In the attempt to elucidate if the "peripheral sink hypothesis" could be a potential mechanism of action for tau removal in passive immunotherapy experiments, we have examined tau levels in serum of chronically injected JNPL3 and Tg4510 transgenic animals. Measurement of tau in serum of mice treated with tau antibodies is challenging because of the antibody interference in sandwich enzyme-linked immunosorbent assays. To address this issue, we have developed a heat-treatment protocol at acidic pH to remove interfering molecules from serum, with excellent recovery of tau. The present data show that pan-tau and conformational antibodies do increase tau in mouse sera. However, these concentrations in serum do not consistently correlate with reductions of tau pathology in brain, suggesting that large elevations of tau species measured in serum are not predictive of efficacy. Here, we describe a reliable method to detect tau in serum of transgenic animals that have undergone tau immunotherapy. Levels of tau in human serum are less than the sensitivity of current assays, although artifactual signals are common. The method may be useful in similarly treated humans, a situation in which false positive signals are likely. PMID:26508157

  3. Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy

    PubMed Central

    Datta, Jashodeep; Berk, Erik; Cintolo, Jessica A.; Xu, Shuwen; Roses, Robert E.; Czerniecki, Brian J.

    2015-01-01

    Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies. PMID:26082780

  4. Monoclonal antibodies: Principles and applications of immmunodiagnosis and immunotherapy for hepatitis C virus

    PubMed Central

    Tabll, Ashraf; Abbas, Aymn T; El-Kafrawy, Sherif; Wahid, Ahmed

    2015-01-01

    Hepatitis C virus (HCV) is a major health problem worldwide. Early detection of the infection will help better management of the infected cases. The monoclonal antibodies (mAb) of mice are predominantly used for the immunodiagnosis of several viral, bacterial, and parasitic antigens. Serological detection of HCV antigens and antibodies provide simple and rapid methods of detection but lack sensitivity specially in the window phase between the infection and antibody development. Human mAb are used in the immunotherapy of several blood malignancies, such as lymphoma and leukemia, as well as for autoimmune diseases. In this review article, we will discuss methods of mouse and human monoclonal antibody production. We will demonstrate the role of mouse mAb in the detection of HCV antigens as rapid and sensitive immunodiagnostic assays for the detection of HCV, which is a major health problem throughout the world, particularly in Egypt. We will discuss the value of HCV-neutralizing antibodies and their roles in the immunotherapy of HCV infections and in HCV vaccine development. We will also discuss the different mechanisms by which the virus escape the effect of neutralizing mAb. Finally, we will discuss available and new trends to produce antibodies, such as egg yolk-based antibodies (IgY), production in transgenic plants, and the synthetic antibody mimics approach. PMID:26464752

  5. Genetic Manipulation of NK Cells for Cancer Immunotherapy: Techniques and Clinical Implications

    PubMed Central

    Carlsten, Mattias; Childs, Richard W.

    2015-01-01

    Given their rapid and efficient capacity to recognize and kill tumor cells, natural killer (NK) cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Recent advances in viral transduction and electroporation have now allowed detailed characterization of genetically modified NK cells and provided a better understanding for how these cells can be utilized in the clinic to optimize their capacity to induce tumor regression in?vivo. Improving NK cell persistence in?vivo via autocrine IL-2 and IL-15 stimulation, enhancing tumor targeting by silencing inhibitory NK cell receptors such as NKG2A, and redirecting tumor killing via chimeric antigen receptors, all represent approaches that hold promise in preclinical studies. This review focuses on available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors in?vivo, we foresee genetic engineering as an obligatory pathway required to exploit the full potential of NK-cell based immunotherapy in the clinic. PMID:26113846

  6. Strategies and Advancements in Harnessing the Immune System for Gastric Cancer Immunotherapy

    PubMed Central

    Subhash, Vinod Vijay; Yeo, Mei Shi; Tan, Woei Loon; Yong, Wei Peng

    2015-01-01

    In cancer biology, cells and molecules that form the fundamental components of the tumor microenvironment play a major role in tumor initiation, and progression as well as responses to therapy. Therapeutic approaches that would enable and harness the immune system to target tumor cells mark the future of anticancer therapy as it could induce an immunological memory specific to the tumor type and further enhance tumor regression and relapse-free survival in cancer patients. Gastric cancer is one of the leading causes of cancer-related mortalities that has a modest survival benefit from existing treatment options. The advent of immunotherapy presents us with new approaches in gastric cancer treatment where adaptive cell therapies, cancer vaccines, and antibody therapies have all been used with promising outcomes. In this paper, we review the current advances and prospects in the gastric cancer immunotherapy. Special focus is laid on new strategies and clinical trials that attempt to enhance the efficacy of various immunotherapeutic modalities in gastric cancer. PMID:26579545

  7. Topics in chemotherapy, molecular-targeted therapy, and immunotherapy for newly-diagnosed glioblastoma multiforme.

    PubMed

    Okonogi, Noriyuki; Shirai, Katsuyuki; Oike, Takahiro; Murata, Kazutoshi; Noda, Shin-Ei; Suzuki, Yoshiyuki; Nakano, Takashi

    2015-03-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and it is associated with poor survival. The standard therapy for newly-diagnosed GBM is radiotherapy with concurrent temozolomide following maximal surgical resection. To improve the outcome of these patients, combinations of the standard therapy plus molecular-targeted agents have been tested in clinical trials. However, the addition of gefitinib to the standard therapy did not appear to improve clinical outcome, and the standard therapy plus bevacizumab showed no improvement in overall survival, although a 4-month improvement in progression-free survival (PFS) was observed. Phase II data have indicated the potential efficacy of talampanel combined with the standard therapy for patients with newly-diagnosed GBM, and these findings are awaiting validation in phase III trials. In addition, phase II trials have demonstrated that adjuvant immunotherapy is effective and tolerable for treatment of patients with GBM. In this article, we discuss topics in chemotherapy, molecular-targeted therapy, and immunotherapy for patients with newly-diagnosed GBM. PMID:25750269

  8. A Perspective of Immunotherapy for Breast Cancer: Lessons Learned and Forward Directions for All Cancers

    PubMed Central

    Nahas, George R.; Walker, Nykia D.; Bryan, Margarette; Rameshwar, Pranela

    2015-01-01

    Immunotherapy for cancer has been a focus 50 years ago. At the time, this treatment was developed prior to cloning of the cytokines, no knowledge of regulatory T-cells, and very little information that mesenchymal stem cells (MSCs) (originally colony forming unit-fibroblasts [CFU-F]) could be licensed by the inflammatory microenvironment to suppress an immune response. Given the information available at that time, mononuclear cells from the peripheral blood were activated ex vivo and then replaced in the patients with tumor. The intent was to harness these activated immune cells to target the cancer cells. These studies did not lead to long-term responses because the activated cells when reinfused into the patients were an advantage to the resident MSCs, which can home the tumor and then become suppressive in the presence of the immune cells. The immune suppression caused by MSCs would also expand regulatory T-cells, resulting instead in tumor protection. As time progressed, these different fields converged into a new approach to use immunotherapy for cancer. This article discusses these approaches and also reviews chimeric antigen receptor in the context of future treatments for solid tumors, including breast cancer. PMID:26568682

  9. Targeting cancer testis antigens for biomarkers and immunotherapy in colorectal cancer: Current status and challenges

    PubMed Central

    Suri, Anil; Jagadish, Nirmala; Saini, Shikha; Gupta, Namita

    2015-01-01

    Colorectal cancer ranks third among the estimated cancer cases and cancer related mortalities in United States in 2014. Early detection and efficient therapy remains a significant clinical challenge for this disease. Therefore, there is a need to identify novel tumor associated molecules to target for biomarker development and immunotherapy. In this regard, cancer testis antigens have emerged as a potential targets for developing novel clinical biomarkers and immunotherapy for various malignancies. These germ cell specific proteins exhibit aberrant expression in cancer cells and contribute in tumorigenesis. Owing to their unique expression profile and immunogenicity in cancer patients, cancer testis antigens are clinically referred as the most promising tumor associated antigens. Several cancer testis antigens have been studied in colorectal cancer but none of them could be used in clinical practice. This review is an attempt to address the promising cancer testis antigens in colorectal cancer and their possible clinical implications as biomarkers and immunotherapeutic targets with particular focus on challenges and future interventions. PMID:26691579

  10. A prospective highlight on exosomal nanoshuttles and cancer immunotherapy and vaccination

    PubMed Central

    Rafi, Mohammad A.; Omidi, Yadollah

    2015-01-01

    Introduction: Exosomes (EXOs) and ectosomes (ECTOs) are nanoscale membranous extracellular vesicles (EVs) derived from different cells mediating various cellular communications. EXOs are liberated based on the exocytosis of multivesicular bodies, while ECTOs are ubiquitously released from the plasma membranes. Methods: Here, in this paper, we go over the extracellular vesicular machineries and concisely highlight their clinical importance in solid tumors and their possible applications in cancer immunotherapy/vaccination. Results: In various types of cancers, these vesicles play central roles delivering cancer cell messages to the target cells, as a result both of them seem to provide a novel useful means for diagnosis and therapy of malignancies. Dendritic cell-derived exosomes (DEXOs) are able to activate the tumor antigen-specific CD8+ cytotoxic T-lymphocytes (CTLs) and hence induce antitumor responses in vivo. Within the tumor microenvironment (TME), however, tumor cells seem to generate exosomes (the so-called oncosoems) that may act in favor of tumor progression. Conclusions: As complex systems, these vesicular micro-/nano-machines convey important cellular messages dependent upon the cells/tissue setting(s). In addition to their potential in diagnosis of cancers, they have been exploited for cancer immunotherapy/vaccination. However, such treatment strategies need to be carefully designed to attain desired clinical outcomes. PMID:26457248

  11. Radiation meets immunotherapy – a perfect match in the era of combination therapy?

    PubMed Central

    Soukup, Klara

    2015-01-01

    Purpose This review focuses on recent advances in the field of combining radiation with immunotherapy for the treatment of malignant diseases, since various combinatorial cancer therapy approaches have lately proven highly successful. Results With initial case reports and anecdotes progressively converting into solid clinical data, interest in cancer immunotherapy (CIT) has risen steeply. Especially immune checkpoint blockade therapies have recently celebrated tremendous successes in the treatment of severe malignancies resistant to conventional treatment strategies. Nevertheless, the high variability of patient responses to CIT remains a major hurdle, clearly indicating an urgent need for improvement. It has been suggested that successful cancer therapy most probably involves combinatorial treatment approaches. Radiotherapy (RT) has been proposed as a powerful partner for CIT due to its broad spectrum of immune modulatory characteristics. Several preclinical studies, supported by an increasing number of clinical observations, have demonstrated synergistic interactions between RT and CIT resulting in significantly improved therapy outcomes. Conclusions Numerous reports have shown that radiation is capable of tipping the scales from tumor immune evasion to elimination in different tumor types. The next puzzle to be solved is the question of logistics – including types, schedule and dosage of combinatorial RT and CIT strategies. PMID:25630486

  12. Unlocking the Combination: Potentiation of Radiation-Induced Antitumor Responses with Immunotherapy

    PubMed Central

    Wattenberg, Max M.; Fahim, Ahmed; Ahmed, Mansoor M.; Hodge, James W.

    2014-01-01

    There is increasing evidence of the potential for radiation therapy to generate antitumor immune responses. The mechanisms of this immune-activating potential include actions on tumor cells such as immunogenic cell death and phenotypic change. Radiation modulates tumor cell surface expression of cell death receptors, tumor-associated antigens and adhesion molecules. This process of immunomodulation sensitizes tumor cells to immune-mediated killing. Radiation also affects immune compartments, including antigen-presenting cells, cytotoxic T lymphocytes and humoral immunity, leading to specific antitumor immune responses. Recognizing the importance of immunity as a potentiator of response to radiation leads to rational augmentation of antitumor immunity by combining radiation and immunotherapy. Targeted immunotherapy manipulates the immune system in a way that best synergizes with radiation. This article discusses the ability of radiation monotherapy to induce antitumor immunity, with a focus on the effect of radiation on antigen-presenting cells and cytotoxic T lymphocytes. We define two important responses generated by tumor cells, immunogenic cell death and immunomodulation, both of which are radiation dose-dependent. In conclusion, we describe the translation of several combination therapies from the preclinical to the clinical setting and identify opportunities for further exploration. PMID:24960415

  13. The evidence for immunotherapy in dermatomyositis and polymyositis: a systematic review.

    PubMed

    Vermaak, Erin; Tansley, Sarah L; McHugh, Neil J

    2015-12-01

    Dermatomyositis and polymyositis are rare chronic inflammatory disorders with significant associated morbidity and mortality despite treatment. High-dose corticosteroids in addition to other interventions such as immunosuppressants, immunomodulators, and more recently, biologics are commonly used in clinical practice; however, there are no clear guidelines directing their use. Our objective was to systematically review the evidence for immunotherapy in the treatment of dermatomyositis and polymyositis. Relevant studies were identified through Embase and PubMed database searches. Trials were selected using pre-determined selection criteria and then assessed for quality. Randomized controlled trials and experimental studies without true randomization and including adult patients with definite or probable dermatomyositis or polymyositis were evaluated. Any type of immunotherapy was considered. Clinical improvement, judged by assessment of muscle strength after 6 months, was the primary outcome. Secondary outcomes included IMACS definition of improvement, improvements in patient and physician global scores, physical function, and muscle enzymes. Twelve studies met eligibility criteria. Differences in trial design, quality, and variable reporting of baseline characteristics and outcomes made direct comparison impossible. Although no treatment can be recommended on the basis of this review, improved outcomes were demonstrated with a number of agents including methotrexate, azathioprine, ciclosporin, rituximab, and intravenous immunoglobulin. Plasmapheresis and leukapheresis were of no apparent benefit. More high-quality randomized controlled trials are needed to establish the role of immunosuppressive agents in the treatment of these conditions and the clinical context in which they are most likely to be beneficial. PMID:26299472

  14. Molecular Pathways: Targeting the Stimulator of Interferon Genes (STING) in the Immunotherapy of Cancer.

    PubMed

    Corrales, Leticia; Gajewski, Thomas F

    2015-11-01

    Novel immunotherapy approaches are transforming the treatment of cancer, yet many patients remain refractory to these agents. One hypothesis is that immunotherapy fails because of a tumor microenvironment that fails to support recruitment of immune cells, including CD8(+) T cells. Therefore, new approaches designed to initiate a de novo antitumor immune response from within the tumor microenvironment are being pursued. Recent evidence has indicated that spontaneous activation of the Stimulator of Interferon Genes (STING) pathway within tumor-resident dendritic cells leads to type I IFN production and adaptive immune responses against tumors. This pathway is activated in the presence of cytosolic DNA that is detected by the sensor cyclic GMP-AMP synthase (cGAS) and generates cyclic GMP-AMP (cGAMP), which binds and activates STING. As a therapeutic approach, intratumoral injection of STING agonists has demonstrated profound therapeutic effects in multiple mouse tumor models, including melanoma, colon, breast, prostate, and fibrosarcoma. Better characterization of the STING pathway in human tumor recognition, and the development of new pharmacologic approaches to engage this pathway within the tumor microenvironment in patients, are important areas for clinical translation. Clin Cancer Res; 21(21); 4774-9. ©2015 AACR. PMID:26373573

  15. Prostate Cancer Immunotherapy with Sipuleucel-T: Current Standards and Future Directions.

    PubMed

    Wei, Xiao X; Fong, Lawrence; Small, Eric J

    2015-12-01

    The management of advanced prostate cancer, specifically metastatic castrate-resistant prostate cancer (mCRPC), remains a therapeutic challenge. Sipuleucel-T (Provenge; APC8015) was approved by the FDA in 2010 for the treatment of asymptomatic or minimally symptomatic mCRPC patients, and it remains the only FDA-approved immunotherapy for prostate cancer of any indication to date. Given the continued need to improve therapeutics in patients with advanced prostate cancer, as well as recent enthusiasm for cancer immunotherapy, there is a wide range of ongoing trials evaluating combinations of sipuleucel-T with other therapeutics. Additional trials are aiming to expand the application of sipuleucel-T to prostate cancer patients beyond the mCRPC setting. Ongoing challenges include understanding the full mechanism of action of sipuleucel-T, optimizing the sequence of sipuleucel-T in relation to other therapies for mCRPC in clinical practice, and the identification of surrogate markers to predict survival benefit in clinical trials. PMID:26488270

  16. SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery

    PubMed Central

    2011-01-01

    Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies. PMID:21929757

  17. Requirement for Innate Immunity and CD90+ NK1.1? Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy

    PubMed Central

    Moskalenko, Marina; Pan, Michael; Fu, Yichun; de Moll, Ellen H.; Hashimoto, Daigo; Mortha, Arthur; Leboeuf, Marylene; Jayaraman, Padmini; Bernardo, Sebastian; Sikora, Andrew G.; Wolchok, Jedd; Bhardwaj, Nina; Merad, Miriam; Saenger, Yvonne

    2015-01-01

    We sought to define cellular immune mechanisms of synergy between tumor-antigen–targeted monoclonal antibodies and chemotherapy. Established B16 melanoma in mice was treated with cytotoxic doses of cyclophosphamide in combination with an antibody targeting tyrosinase-related protein 1 (?TRP1), a native melanoma differentiation antigen. We find that Fc? receptors are required for efficacy, showing that antitumor activity of combination therapy is immune mediated. Rag1?/? mice deficient in adaptive immunity are able to clear tumors, and thus innate immunity is sufficient for efficacy. Furthermore, previously treated wild-type mice are not significantly protected against tumor reinduction, as compared with mice inoculated with irradiated B16 alone, consistent with a primarily innate immune mechanism of action of chemo-immunotherapy. In contrast, mice deficient in both classical natural killer (NK) lymphocytes and nonclassical innate lymphocytes (ILC) due to deletion of the IL2 receptor common gamma chain IL2?c?/?) are refractory to chemo-immunotherapy. Classical NK lymphocytes are not critical for treatment, as depletion of NK1.1+ cells does not impair antitumor effect. Depletion of CD90+NK1.1? lymphocytes, however, both diminishes therapeutic benefit and decreases accumulation of macrophages within the tumor. Tumor clearance during combination chemo-immunotherapy with monoclonal antibodies against native antigen is mediated by the innate immune system. We highlight a novel potential role for CD90+NK1.1? ILCs in chemo-immunotherapy. PMID:25600438

  18. [Intralymphatic administration of adoptive (LAK) immunotherapy in the treatment of patients with metastatic cancer resistant to conventional therapies].

    PubMed

    Simo Camps, E; Piñas Forcadell, I; García Llorente, F; Vich Pascuchi, J M; Ribera del Pueyo, M; Claret Godo, A

    1992-05-01

    Between January, 1990 and May, 1991, we administered LAK immunotherapy using the intralymphatic route to 25 patients with metastatic cancer resistant to conventional therapies. In the preparation of the immunotherapy, we followed the technique described by Pizza G. et al. The age of our patients ranged between 50 and 75 years and their Karnofsky's indexes were above 70%. The histological type of the metastasis were determined by Rx, ECO and/or CAT before and after the administration of the immunotherapy. In the intralymphatic administration, we followed the technique described by Pizza G. et al. The immunological therapy was administered on days 1, 21, 90 and 111 and the clinical response was assessed by RC, RP, EE and F. The immunological behaviour of the host was assessed through the determination of lymphoid populations (CD2, CD4, CD5 and CD8) and cytolytic cells were studied with monoclonal antibodies CD and CD16. Such immunological study was carried out before the administration of each immunotherapy series. In 7 out of 25 patients (28%), we were able to administer the four LAK series. Such patients were subsequently studied, observing that, although tumoral lesions did not increase in size, they did not disappear and, thus, they were classified as clinically stable. Clinical and analytical toxicity was null. The immunological study did not show any statistically significant changes and the activity of cytotoxic cells (NK) was not modified. PMID:1504202

  19. Enhancing Cancer Immunotherapy by Intracellular Delivery of Cell-Penetrating Peptides and Stimulation of Pattern-Recognition Receptor Signaling

    PubMed Central

    Wang, Helen Y.; Wang, Rong-Fu

    2013-01-01

    The importance of T-cell-mediated antitumor immunity has been demonstrated in both animal models and human cancer immunotherapy. In the past 30 years, T-cell-based immunotherapy has been improved with an objective clinical response rate of up to 72%. Identification of MHC class I- and II-restricted tumor antigens recognized by tumor-reactive T cells has generated a resurgence of interest in cancer vaccines. Although clinical trials with cancer peptide/protein vaccines have only met a limited success, several phase II/III clinical trials are either completed or ongoing with encouraging results. Recent advances in immunotherapy have led to the approval of two anticancer drugs (sipuleucel-T vaccine and anti-CTLA-4 antibody) by the US FDA for the treatment of meta-static castration-resistant prostate cancer and melanoma, respectively. Intracellular delivery of antigenic peptides into dendritic cells (DCs) prolongs antigen presentation of antigen-presenting cells to T cells, thus further improving clinical efficacy of peptide/protein cancer vaccines. Because innate immune responses are critically important to provide sensing and initiating of adaptive immunity, combined use of cell-penetrating peptide vaccines with stimulation of innate immune signaling may produce potent anti-tumor immune responses. We will discuss the recent progress and novel strategies in cancer immunotherapy. PMID:22449781

  20. Adverse Events During Immunotherapy Against Grass Pollen-Induced Allergic Rhinitis - Differences Between Subcutaneous and Sublingual Treatment.

    PubMed

    Aasbjerg, Kristian; Dalhoff, Kim Peder; Backer, Vibeke

    2015-08-01

    Allergic rhinitis (AR) triggered by grass pollen is a common disease, affecting millions of people worldwide. Treatment consists of symptom-alleviating drugs, such as topical corticosteroids or antihistamines. Another option is potentially curative immunotherapy, currently available as sublingual and subcutaneous treatment. We investigated the potential differences in the prevalence and severity of adverse events related to subcutaneous and sublingual immunotherapy (SLIT) against grass pollen-induced AR. A thorough literature search was performed with PubMed and EMBASE. The findings were compared with the available summaries of product characteristics (SPC) and with commercial pharmacology databases (Micromedex). The majority of available safety data originate from registered products of standardized allergens. A surprisingly large percentage of drugs, especially those used in the United States, have no systematically collected safety data. No sufficiently powered randomized trials comparing sublingual and subcutaneous immunotherapy (SCIT) were available, but general safety assessments indicate that sublingual tablet treatment is safer than subcutaneous treatment. Not all commonly used immunotherapy drugs are officially registered, and not all have systematically collected safety data. This is especially true for older drugs used in the United States. In contrast, newer drugs that have undergone extensive clinical testing have better documentation, but unified collection of safety data is still lacking. Considering the evidence available, most drugs elicit similar side effects from the same organ systems, and symptoms from the sublingual drug classes are probably less severe. However, a head-to-head comparison of safety and efficacy is lacking. PMID:25968654

  1. EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy

    PubMed Central

    Kumai, T; Matsuda, Y; Oikawa, K; Aoki, N; Kimura, S; Harabuchi, Y; Celis, E; Kobayashi, H

    2013-01-01

    Background: Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy. Methods: We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition. Results: Among several predicted peptide epitopes, EGFR875–889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR875–889 epitope could be detected in the blood of HNSCC patients. EGFR875–889-reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR875–889-reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells. Conclusion: We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR875–889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy. PMID:24045666

  2. Dynamic Contrast Enhanced MRI Detects Early Response to Adoptive NK Cellular Immunotherapy Targeting the NG2 Proteoglycan in a Rat Model of Glioblastoma

    PubMed Central

    Thuen, Marte; Gras Navarro, Andrea; Huuse, Else Marie; Thorsen, Frits; Poli, Aurelie; Zimmer, Jacques; Haraldseth, Olav; Lie, Stein Atle; Enger, Per Øyvind; Chekenya, Martha

    2014-01-01

    There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI) of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/CSPG4 with mAb9.2.27 combined with natural killer (NK) cells. Contrast enhanced conventional T1-weighted MRI at 7±1 and 17±2 days post-treatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (ve), was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p?=?0.002 and p?=?0.017 respectively) in cohort 1 animals treated with 1 million NK cells. ve was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p<0.0001), indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p<0.0001) and untreated controls (p?=?0.014) in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC) of water and ve in combination NK+mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced ve in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other groups. In conclusion, ve was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy. PMID:25268630

  3. Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy

    PubMed Central

    Flingai, Seleeke; Plummer, Emily M.; Patel, Ami; Shresta, Sujan; Mendoza, Janess M.; Broderick, Kate E.; Sardesai, Niranjan Y.; Muthumani, Kar; Weiner, David B.

    2015-01-01

    Dengue virus (DENV) is the most important mosquito-borne viral infection in humans. In recent years, the number of cases and outbreaks has dramatically increased worldwide. While vaccines are being developed, none are currently available that provide balanced protection against all DENV serotypes. Advances in human antibody isolation have uncovered DENV neutralizing antibodies (nAbs) that are capable of preventing infection from multiple serotypes. Yet delivering monoclonal antibodies using conventional methods is impractical due to high costs. Engineering novel methods of delivering monoclonal antibodies could tip the scale in the fight against DENV. Here we demonstrate that simple intramuscular delivery by electroporation of synthetic DNA plasmids engineered to express modified human nAbs against multiple DENV serotypes confers protection against DENV disease and prevents antibody-dependent enhancement (ADE) of disease in mice. This synthetic nucleic acid antibody prophylaxis/immunotherapy approach may have important applications in the fight against infectious disease. PMID:26220099

  4. CAR T-cell immunotherapy: The path from the by-road to the freeway?

    PubMed

    Whilding, Lynsey M; Maher, John

    2015-12-01

    Chimeric antigen receptors are genetically encoded artificial fusion molecules that can re-program the specificity of peripheral blood polyclonal T-cells against a selected cell surface target. Unparallelled clinical efficacy has recently been demonstrated using this approach to treat patients with refractory B-cell malignancy. However, the approach is technically challenging and can elicit severe toxicity in patients. Moreover, solid tumours have largely proven refractory to this approach. In this review, we describe the important structural features of CARs and how this may influence function. Emerging clinical experience is summarized in both solid tumours and haematological malignancies. Finally, we consider the particular challenges imposed by solid tumours to the successful development of CAR T-cell immunotherapy, together with a number of innovative strategies that have been developed in an effort to reverse the balance in favour of therapeutic benefit. PMID:26563646

  5. Human Cancer Immunotherapy with PD-1/PD-L1 Blockade

    PubMed Central

    Zheng, Peilin; Zhou, Zhiguang

    2015-01-01

    The ligation of programmed cell death-1 (PD-1) to its ligands PD-L1 and PD-L2 counteracts T-cell activation, which is critical in immune tolerance. The persistent high expression of PD-1 and PD-L1 are also observed on tumor-infiltrating lymphocytes and various tumor cells, maintaining the highly suppressive microenvironment in tumor sites and promoting tumor malignancies. The blockade of PD-1 axis with PD-L2 fusion protein or monoclonal antibodies against either PD-1 or PD-L1 has been clinically evaluated in various tumor types. This short review summarizes the progress of PD-1 axis blockade in clinical trials to evaluate its effectiveness in the antitumor immunotherapy. PMID:26448693

  6. The role of peptide and DNA vaccines in myeloid leukemia immunotherapy

    PubMed Central

    2013-01-01

    While chemotherapy and targeted therapy are successful in inducing the remission of myeloid leukemia as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), the disease remains largely incurable. This observation is likely due to the drug resistance of leukemic cells, which are responsible for disease relapse. Myeloid leukemia vaccines may most likely be beneficial for eradicating minimal residual disease after treatment with chemotherapy or targeted therapy. Several targeted immunotherapies using leukemia vaccines have been heavily investigated in clinical and preclinical trials. This review will focus on peptides and DNA vaccines in the context of myeloid leukemias, and optimal strategies for enhancing the efficacy of vaccines based on myeloid leukemia immunization are also summarized. PMID:23394714

  7. Laser immunotherapy for the treatment of human breast cancer: one-year follow up results

    NASA Astrophysics Data System (ADS)

    Hode, Tomas; Adalsteinsson, Orn; Ferrel, Gabriela L.; Lunn, John A.; Guerra, Maria C.; Li, Xiaosong; Nordquist, Robert E.; Chen, Wei R.

    2011-03-01

    The immediate goal of the trial was to determine the breast cancer patient tolerance and the toxicity of Laser immunotherapy (LIT), the optimal dose for the alteration of the course of the disease, and the reduction of the tumor burden. Ten stage III and IV cancer patients were treated, all of which were considered to be out of all other options. No toxicity or significant adverse reactions were observed and the treatment was well tolerated by all patients. Almost all the treated patients have had positive responses: A majority of patients experienced large-scale reduction of primary breast tumors, and all the stage IV patients experienced either complete or significant reductions in distant metastases in the lungs, liver, bone, and the brain, indicating a strong systemic effect of the treatment. We also report two cases of triple negative breast cancer patients that showed limited or no response to LIT.

  8. Precision Medicine for Molecularly Targeted Agents and Immunotherapies in Early-Phase Clinical Trials

    PubMed Central

    Lopez, Juanita; Harris, Sam; Roda, Desam; Yap, Timothy A

    2015-01-01

    Precision medicine in oncology promises the matching of genomic, molecular, and clinical data with underlying mechanisms of a range of novel anticancer therapeutics to develop more rational and effective antitumor strategies in a timely manner. However, despite the remarkable progress made in the understanding of novel drivers of different oncogenic processes, success rates for the approval of oncology drugs remain low with substantial fiscal consequences. In this article, we focus on how recent rapid innovations in technology have brought greater clarity to the biological and clinical complexities of different cancers and advanced the development of molecularly targeted agents and immunotherapies in clinical trials. We discuss the key challenges of identifying and validating predictive biomarkers of response and resistance using both tumor and surrogate tissues, as well as the hurdles associated with intratumor heterogeneity. Finally, we outline evolving strategies employed in early-phase trial designs that incorporate omics-based technologies. PMID:26609214

  9. Genetics and immunotherapy: using the genetic landscape of gliomas to inform management strategies.

    PubMed

    Wang, Joanna Y; Bettegowda, Chetan

    2015-07-01

    Recent work in genetics has identified essential driver mutations in gliomas and has profoundly changed our understanding of tumorigenesis. New insights into the molecular basis of glioma has informed the development of therapies demonstrating considerable potential, including immunotherapeutic approaches such as peptide and dendritic cell vaccines against EGFRvIII. However, the selective targeting of one component of a dysregulated pathway may be inadequate for a durable clinical response, given the intratumoral heterogeneity of glioblastoma (GBM) and hypermutated profiles displayed by tumor recurrences. Immune checkpoint blockade with anti-cytotoxic T lymphocyte antigen-4 (CTLA) and anti-programmed cell death 1 (PD-1) have demonstrated encouraging results in clinical trials with other solid tumors, and recent data suggest that this type of therapy may be particularly useful for tumors with high mutational burdens. Although the survival for patients with GBM has remains grim, the use of immunotherapy may finally change patient outcomes. PMID:25697584

  10. A Safe Bacterial Microsyringe for In Vivo Antigen Delivery and Immunotherapy

    PubMed Central

    Le Gouëllec, Audrey; Chauchet, Xavier; Laurin, David; Aspord, Caroline; Verove, Julien; Wang, Yan; Genestet, Charlotte; Trocme, Candice; Ahmadi, Mitra; Martin, Sandrine; Broisat, Alexis; Cretin, François; Ghezzi, Catherine; Polack, Benoit; Plumas, Joël; Toussaint, Bertrand

    2013-01-01

    The industrial development of active immunotherapy based on live-attenuated bacterial vectors has matured. We developed a microsyringe for antigen delivery based on the type III secretion system (T3SS) of P. aeruginosa. We applied the “killed but metabolically active” (KBMA) attenuation strategy to make this bacterial vector suitable for human use. We demonstrate that attenuated P. aeruginosa has the potential to deliver antigens to human antigen-presenting cells in vitro via T3SS with considerable attenuated cytotoxicity as compared with the wild-type vector. In a mouse model of cancer, we demonstrate that this KBMA strain, which cannot replicate in its host, efficiently disseminates into lymphoid organs and delivers its heterologous antigen. The attenuated strain effectively induces a cellular immune response to the cancerous cells while lowering the systemic inflammatory response. Hence, a KBMA P. aeruginosa microsyringe is an efficient and safe tool for in vivo antigen delivery. PMID:23531551

  11. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps

    PubMed Central

    Sharma, Padmanee; Wagner, Klaus; Wolchok, Jedd D.; Allison, James P.

    2012-01-01

    The US Food and Drug Administration (FDA) recently approved two novel immunotherapy agents, sipuleucel-T and ipilimumab, which showed a survival benefit for patients with metastatic prostate cancer and melanoma, respectively. The mechanisms by which these agents provide clinical benefit are not completely understood. However, knowledge of these mechanisms will be crucial for probing human immune responses and tumour biology in order to understand what distinguishes responders from non-responders. The following next steps are necessary: first, the development of immune-monitoring strategies for the identification of relevant biomarkers; second, the establishment of guidelines for the assessment of clinical end points; and third, the evaluation of combination therapy strategies to improve clinical benefit. PMID:22020206

  12. The immune response in cancer: from immunology to pathology to immunotherapy.

    PubMed

    Giraldo, Nicolas A; Becht, Etienne; Vano, Yann; Sautès-Fridman, Catherine; Fridman, Wolf H

    2015-08-01

    In the recent years, breakthrough advances in the characterization of the tumor-infiltrating immune cells and in the understanding of their influence on tumor invasion and metastasis have been accomplished. These studies have allowed the development of assays quantifying immune infiltrates to predict patient's clinical outcome. Increasing evidence supports their utility as prognostic and potentially teragnostic markers. The in-depth characterization of the tumor's immune profile and the standard histopathological criteria are becoming the optimal method of tumor classification in the era of personalized medicine. This review describes the major concepts in the anti-tumor immunity field, with particular focus on the tumor immune microenvironment and the delicate balance between inflammatory and anti-tumor immune responses, its importance as a prognostic tool, and its utility as a teragnostic marker for patients receiving new-generation immunotherapies. PMID:26077464

  13. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.

    PubMed

    Vétizou, Marie; Pitt, Jonathan M; Daillère, Romain; Lepage, Patricia; Waldschmitt, Nadine; Flament, Caroline; Rusakiewicz, Sylvie; Routy, Bertrand; Roberti, Maria P; Duong, Connie P M; Poirier-Colame, Vichnou; Roux, Antoine; Becharef, Sonia; Formenti, Silvia; Golden, Encouse; Cording, Sascha; Eberl, Gerard; Schlitzer, Andreas; Ginhoux, Florent; Mani, Sridhar; Yamazaki, Takahiro; Jacquelot, Nicolas; Enot, David P; Bérard, Marion; Nigou, Jérôme; Opolon, Paule; Eggermont, Alexander; Woerther, Paul-Louis; Chachaty, Elisabeth; Chaput, Nathalie; Robert, Caroline; Mateus, Christina; Kroemer, Guido; Raoult, Didier; Boneca, Ivo Gomperts; Carbonnel, Franck; Chamaillard, Mathias; Zitvogel, Laurence

    2015-11-27

    Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade. PMID:26541610

  14. Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy

    PubMed Central

    2013-01-01

    Summary Adoptive cellular immunotherapy (ACT) is a potentially curative therapy for patients with advanced cancer. Eradication of tumor in mouse models and humans correlates with both a high dose of adoptively transferred cells and cells with a minimally differentiated phenotype that maintain replicative capacity and multipotency. We speculate that response to ACT not only requires transfer of cells with immediate cytolytic effector function to kill the bulk of fast-growing tumor, but also transfer of tumor-specific cells that maintain an ability for self-renewal and the capacity to produce a continual supply of cytolytic effector progeny until all malignant cells are eliminated. Current in vitro methods to expand cells to sufficient numbers and still maintain a minimally differentiated phenotype are hindered by the biological coupling of clonal expansion and effector differentiation. Therefore, a better understanding of the physiologic mechanism that couples cell expansion and differentiation in CD8+ T cells may improve the efficacy of ACT. PMID:24329803

  15. Role of Common-Gamma Chain Cytokines in NK Cell Development and Function: Perspectives for Immunotherapy

    PubMed Central

    Meazza, Raffaella; Azzarone, Bruno; Orengo, Anna Maria; Ferrini, Silvano

    2011-01-01

    NK cells are components of the innate immunity system and play an important role as a first-line defense mechanism against viral infections and in tumor immune surveillance. Their development and their functional activities are controlled by several factors among which cytokines sharing the usage of the common cytokine-receptor gamma chain play a pivotal role. In particular, IL-2, IL-7, IL-15, and IL-21 are the members of this family predominantly involved in NK cell biology. In this paper, we will address their role in NK cell ontogeny, regulation of functional activities, development of specialized cell subsets, and acquisition of memory-like functions. Finally, the potential application of these cytokines as recombinant molecules to NK cell-based immunotherapy approaches will be discussed. PMID:21716670

  16. Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy.

    PubMed

    Flingai, Seleeke; Plummer, Emily M; Patel, Ami; Shresta, Sujan; Mendoza, Janess M; Broderick, Kate E; Sardesai, Niranjan Y; Muthumani, Kar; Weiner, David B

    2015-01-01

    Dengue virus (DENV) is the most important mosquito-borne viral infection in humans. In recent years, the number of cases and outbreaks has dramatically increased worldwide. While vaccines are being developed, none are currently available that provide balanced protection against all DENV serotypes. Advances in human antibody isolation have uncovered DENV neutralizing antibodies (nAbs) that are capable of preventing infection from multiple serotypes. Yet delivering monoclonal antibodies using conventional methods is impractical due to high costs. Engineering novel methods of delivering monoclonal antibodies could tip the scale in the fight against DENV. Here we demonstrate that simple intramuscular delivery by electroporation of synthetic DNA plasmids engineered to express modified human nAbs against multiple DENV serotypes confers protection against DENV disease and prevents antibody-dependent enhancement (ADE) of disease in mice. This synthetic nucleic acid antibody prophylaxis/immunotherapy approach may have important applications in the fight against infectious disease. PMID:26220099

  17. Targeting of the Tumor Necrosis Factor Receptor Superfamily for Cancer Immunotherapy

    PubMed Central

    2013-01-01

    The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy. PMID:23840967

  18. Inhibition of IL-2 induced IL-10 production as a principle of phase-specific immunotherapy.

    PubMed

    Bodas, Manish; Jain, Nitya; Awasthi, Amit; Martin, Sunil; Penke Loka, Raghu Kumar; Dandekar, Dineshkumar; Mitra, Debashis; Saha, Bhaskar

    2006-10-01

    Leishmania donovani, a protozoan parasite, inflicts a fatal disease, visceral leishmaniasis. The suppression of antileishmanial T cell responses that characterizes the disease was proposed to be due to deficiency of a T cell growth factor, IL-2. We demonstrate that during the first week after L. donovani infection, IL-2 induces IL-10 that suppresses the host-protective functions of T cells 14 days after infection. The observed suppression is concurrent with increased CD4+ glucocorticoid-induced TNF receptor+ T cells and Foxp3 expression in BALB/c mice, implicating IL-2-dependent regulatory T cell control of antileishmanial immune responses. Indeed, IL-2 and IL-10 neutralization at different time points after the infection demonstrates their distinct roles at the priming and effector phases, respectively, and establishes kinetic modulation of ongoing immune responses as a principle of a rational, phase-specific immunotherapy. PMID:16982902

  19. Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations

    PubMed Central

    Lesterhuis, W. Joost; Rinaldi, Catherine; Jones, Anya; Rozali, Esdy N.; Dick, Ian M.; Khong, Andrea; Boon, Louis; Robinson, Bruce W.; Nowak, Anna K.; Bosco, Anthony; Lake, Richard A.

    2015-01-01

    Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs, and define contextually relevant novel therapeutic targets. PMID:26193793

  20. Immunotherapy and Immunochemotherapy in Visceral Leishmaniasis: Promising Treatments for this Neglected Disease

    PubMed Central

    Roatt, Bruno Mendes; Aguiar-Soares, Rodrigo Dian de Oliveira; Coura-Vital, Wendel; Ker, Henrique Gama; Moreira, Nádia das Dores; Vitoriano-Souza, Juliana; Giunchetti, Rodolfo Cordeiro; Carneiro, Cláudia Martins; Reis, Alexandre Barbosa

    2014-01-01

    Leishmaniasis has several clinical forms: self-healing or chronic cutaneous leishmaniasis or post-kala-azar dermal leishmaniasis; mucosal leishmaniasis; visceral leishmaniasis (VL), which is fatal if left untreated. The epidemiology and clinical features of VL vary greatly due to the interaction of multiple factors including parasite strains, vectors, host genetics, and the environment. Human immunodeficiency virus infection augments the severity of VL increasing the risk of developing active disease by 100–2320 times. An effective vaccine for humans is not yet available. Resistance to chemotherapy is a growing problem in many regions, and the costs associated with drug identification and development, make commercial production for leishmaniasis, unattractive. The toxicity of currently drugs, their long treatment course, and limited efficacy are significant concerns. For cutaneous disease, many studies have shown promising results with immunotherapy/immunochemotherapy, aimed to modulate and activate the immune response to obtain a therapeutic cure. Nowadays, the focus of many groups centers on treating canine VL by using vaccines and immunomodulators with or without chemotherapy. In human disease, the use of cytokines like interferon-? associated with pentavalent antimonials demonstrated promising results in patients that did not respond to conventional treatment. In mice, immunomodulation based on monoclonal antibodies to remove endogenous immunosuppressive cytokines (interleukin-10) or block their receptors, antigen-pulsed syngeneic dendritic cells, or biological products like Pam3Cys (TLR ligand) has already been shown as a prospective treatment of the disease. This review addresses VL treatment, particularly immunotherapy and/or immunochemotherapy as an alternative to conventional drug treatment in experimental models, canine VL, and human disease. PMID:24982655

  1. Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy

    PubMed Central

    Mehraj, Vikram; Jenabian, Mohammad-Ali; Vyboh, Kishanda; Routy, Jean-Pierre

    2014-01-01

    Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication. PMID:25624956

  2. Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging.

    PubMed

    Maute, Roy L; Gordon, Sydney R; Mayer, Aaron T; McCracken, Melissa N; Natarajan, Arutselvan; Ring, Nan Guo; Kimura, Richard; Tsai, Jonathan M; Manglik, Aashish; Kruse, Andrew C; Gambhir, Sanjiv S; Weissman, Irving L; Ring, Aaron M

    2015-11-24

    Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1-directed immunotherapy could be improved with smaller, nonantibody therapeutics, we used directed evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high-affinity PD-1 was effective in treating both small (50 mm(3)) and large tumors (150 mm(3)), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, we found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, nonantibody therapeutics for enhanced cancer immunotherapy and immune diagnostics. PMID:26604307

  3. Chimeric Antigen Receptors for T cell Immunotherapy: Current Understanding and Future Direction

    PubMed Central

    Curran, Kevin J.; Pegram, Hollie J.; Brentjens, Renier J.

    2015-01-01

    Background The genetic engineering of T cells through the introduction of a chimeric antigen receptor (CAR) allows for generation of tumor targeted T cells. Once expressed by T cells, CARs combine antigen-specificity with T cell activation in a single fusion molecule. Most CARs are comprised of an antigen binding domain, an extracellular spacer/hinge region, a trans-membrane domain, and an intracellular signaling domain resulting in T cell activation following antigen binding. Methods The authors performed a search of the literature regarding tumor immunotherapy using CAR modified T cells to provide a concise review of this topic. Results This review will focus on the elements of CAR design required for successful application of this technology in cancer immunotherapy. Most notably, proper target antigen selection, co-stimulatory signaling, and the ability of CAR modified T cells to traffic, persist, and retained function following adoptive transfer are required for optimal tumor eradication. Furthermore, recent clinical trials have demonstrated tumor burden and chemotherapy conditioning prior to adoptive transfer as critically important for this therapy. Future research into counteracting the suppressive tumor microenvironment and the ability to activate an endogenous anti-tumor response by CAR modified T cells may enhance the therapeutic potential of this treatment. Conclusion In conclusion CAR modified T cell therapy is a highly promising treatment for cancer having already demonstrated both promising pre-clinical and clinical results. However, further modification and additional clinical trials will need to be conducted to ultimately optimize the anti-tumor efficacy of this approach. PMID:22262649

  4. The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy.

    PubMed

    Zhai, Lijie; Dey, Mahua; Lauing, Kristen L; Gritsina, Galina; Kaur, Rajwant; Lukas, Rimas V; Nicholas, M Kelly; Rademaker, Alfred W; Dostal, Carlos R; McCusker, Robert H; Raizer, Jeffrey J; Parsa, Andrew T; Bloch, Orin; Wainwright, Derek A

    2015-12-01

    We hypothesized that peripheral tryptophan (Trp) and/or kynurenine (Kyn) levels would provide prognostic value for physicians planning to enroll glioblastoma multiforme (GBM) patients in immunotherapy. GBM is the most common form of malignant glioma in adults. Despite aggressive surgical resection, irradiation and chemotherapy, patients with GBM have a median survival of only 14.6months after diagnosis. This poor outcome has led to the search for more effective treatments, including immunotherapy. However, the identification of parameters that proactively stratify GBM patients who have the potential for therapeutic benefit has been challenging. Given recent observations demonstrating high indoleamine 2,3 dioxygenase 1 (IDO1) expression in GBM, the immunosuppressive impact of IDO1-mediated Trp catabolism, as well as active transport of Trp and the IDO1-downstream Trp catabolite, Kyn, across the blood brain barrier, we hypothesized that peripheral blood analysis of this pathway would provide diagnostic utility. When comparing individuals without tumors to GBM patients prior to surgical resection, or at the 48hour (48h) and ?10week (10w+) postoperative time points, Trp levels were significantly decreased (p<0.0002). Similarly, Kyn levels were decreased in the pre- and 48h postoperative GBM patients (p<0.0001), while there was no difference between individuals without tumors and 10w+ GBM patients. Interestingly, those 10w+ patients with a high Kyn/Trp ratio (?9.5) had a mean overall survival (OS) of 23.6±a standard error of 6.8months, compared to an OS of 38.7±4.9months for patients with lower Kyn/Trp values. Since the 10w+ blood draw and analyses occurred prior to patient enrollment in the heat shock protein peptide complex-96 clinical trial, these novel data suggest that the late Kyn/Trp index may be a relevant clinical benchmark, providing prognostic value for GBM patients who are enrolled in immunotherapeutic regimens. PMID:26279502

  5. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia

    NASA Astrophysics Data System (ADS)

    Shingai, Masashi; Nishimura, Yoshiaki; Klein, Florian; Mouquet, Hugo; Donau, Olivia K.; Plishka, Ronald; Buckler-White, Alicia; Seaman, Michael; Piatak, Michael; Lifson, Jeffrey D.; Dimitrov, Dimiter; Nussenzweig, Michel C.; Martin, Malcolm A.

    2013-11-01

    Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS. However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals. These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9, 10, 11, 12, 13, 14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian-human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques. Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4-7days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3-5weeks in some long-term chronically SHIV-infected animals with low CD4+ T-cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected individuals experiencing immune dysfunction.

  6. Doxil Synergizes with Cancer Immunotherapies to Enhance Antitumor Responses in Syngeneic Mouse Models

    PubMed Central

    Rios-Doria, Jonathan; Durham, Nicholas; Wetzel, Leslie; Rothstein, Raymond; Chesebrough, Jon; Holoweckyj, Nicholas; Zhao, Wei; Leow, Ching Ching; Hollingsworth, Robert

    2015-01-01

    Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8+ T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity. PMID:26408258

  7. Combining Immunotherapy with Oncogene-Targeted Therapy: A New Road for Melanoma Treatment

    PubMed Central

    Aris, Mariana; Barrio, María Marcela

    2015-01-01

    Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50?years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF-inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field. PMID:25709607

  8. Repeated infusions of infliximab, a chimeric anti-TNF? monoclonal antibody, in patients with active spondyloarthropathy: one year follow up

    PubMed Central

    Kruithof, E; Van den Bosch, F; Baeten, D; Herssens, A; De Keyser, F; Mielants, H; Veys, E

    2002-01-01

    Background: In a pilot study, the anti-tumour necrosis factor ? monoclonal antibody, infliximab, induced a rapid and significant improvement in global, peripheral, and axial disease manifestations of patients with active spondyloarthropathy. Objective: To determine whether repeated infusions of infliximab would effectively and safely maintain the observed effect. Methods: Safety and efficacy of a maintenance regimen (5 mg/kg infliximab every 14 weeks) was evaluated using the measurements reported in the pilot study. Of the 21 patients, 19 completed the one year follow up for efficacy; two patients changed to another dosing regimen after week 12 owing to partial lack of efficacy. However, they are still being followed up for safety analysis. Results: After each re-treatment a sustained significant decrease of all disease manifestations was observed. Before re-treatment, symptoms recurred in 3/19 (16%) at week 20, in 13/19 (68%) at week 34, and in 15/19 (79%) at week 48. No withdrawals due to adverse events occurred. Twelve minor infectious episodes were observed. Twelve patients (57%) developed antinuclear antibodies; in four of them (19%) anti-dsDNA antibodies were detected. However, no lupus-like symptoms occurred. Conclusion: In this open study of infliximab in patients with active spondyloarthropathy, the significant improvement of all disease manifestations was maintained over a one year follow up period without major adverse events. Although recurrence of symptoms was noted in a rising number of patients before each re-treatment, no loss of efficacy was observed after re-treatment. PMID:11830424

  9. Golimumab as the first monthly subcutaneous fully human anti-TNF-alpha antibody in the treatment of inflammatory arthropathies.

    PubMed

    Hutas, Gabor

    2010-07-01

    Golimumab (Simponi, Centocor Ortho Biotech Inc., PA, USA) is the first transgenic human monoclonal antibody against TNF-alpha that has been approved in the treatment of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Golimumab is synthesized using conventional hybridoma technique after immunizing transgenic mice containing human immunoglobulin genes. The constant region of golimumab is identical to that of infliximab, but the variable regions of golimumab have fully human sequences. In this article, we present the pharmacodynamic and pharmacokinetic properties as well as the clinical efficacy and tolerability of golimumab. PMID:20635999

  10. Adoptive immunotherapy of human pancreatic cancer with lymphokine-activated killer cells and interleukin-2 in a nude mouse model

    SciTech Connect

    Marincola, F.M.; Da Pozzo, L.F.; Drucker, B.J.; Holder, W.D. Jr. )

    1990-11-01

    A pancreatic cancer cell line was grown in orthotopic and heterotopic positions in young Swiss/NIH nude mice, which were tested with adoptive immunotherapy. Mice were injected with 1 x 10(7) human cancer cells in the subcutaneous tissue and duodenal lobe of the pancreas. The mice were randomly divided into four groups: group IA (LAK + IL-2) (N = 25) received 2 X 10(7) human lymphokine-activated killer (LAK) cells from normal donors by tail vein injection followed by 10,000 units of human recombinant interleukin-2 (IL-2) given intraperitoneally every 12 hours for 28 days; group IB (IL-2) (N = 27) was given the same dose of IL-2 alone; group IC (RPMI-1640) (N = 18) received a placebo consisting of 1 ml of RPMI-1640 intraperitoneally every 12 hours; and group ID (LAK) (N = 14) received 2 X 10(7) LAK cells but no IL-2. Toxicity was significantly higher in group IB, with a mortality rate of 45.5% (10/22 animals) versus a 0% mortality (0/25) in group IA. None of the group IA or IB animals died of pancreatic cancer during the experiment. The animals that did not receive IL-2 died before 28 days in 14.2% of group IC and in 16.7% of group ID. The area under the growth curve of subcutaneous tumors during the course of treatment and the pancreatic tumor weight at the end of treatment were compared in each group. Subcutaneous tumors had a reduced rate of growth in group IA animals compared to all the other treatments. Pancreatic tumor growth was slowed in group IA. The animals treated with IL-2 alone (group IB) showed some slowing of tumor growth that was intermediate between group IA, group IC, and group ID. A similar experiment was done with irradiated (375 rad) mice. Nine nude mice with tumors were treated with LAK + IL-2 (group IIA), eight received IL-2 alone (group IIB), and seven received placebo (group IIC).

  11. Immunogenicity without Efficacy of an Adenoviral Tuberculosis Vaccine in a Stringent Mouse Model for Immunotherapy during Treatment

    PubMed Central

    Alyahya, S. Anisah; Nolan, Scott T.; Smith, Cara M. R.; Bishai, William R.; Sadoff, Jerald; Lamichhane, Gyanu

    2015-01-01

    To investigate if bacterial persistence during TB drug treatment could be overcome by modulation of host immunity, we adapted a clinically-relevant model developed for the evaluation of new drugs and examined if immunotherapy with two adenoviral vaccines, Ad35-TBS (AERAS-402) and Ad26-TBS, could shorten therapy in mice. Even though immunotherapy resulted in strong splenic IFN-? responses, no effect on bacterial replication in the lungs was seen. Multiplex assay analysis of lung samples revealed the absence of cytokine augmentation such as IFN-?, TNF-? and IL-2, suggesting that immunization failed to induce immunity in the lungs. In this model, we show that IFN-? levels were not associated with protection against disease relapse. The results obtained from our study raise questions regarding the traits of protective TB immunity that are relevant for the development of future immunotherapeutic and post-exposure vaccination strategies. PMID:25996375

  12. Challenges and Opportunities for Quantitative Clinical Pharmacology in Cancer Immunotherapy: Something Old, Something New, Something Borrowed, and Something Blue.

    PubMed

    Stroh, M; Carlile, D J; Li, C-C; Wagg, J; Ribba, B; Ramanujan, S; Jin, J; Xu, J; Charoin, J-E; Xhu, Z-X; Morcos, P N; Davis, J D; Phipps, A

    2015-09-01

    Cancer immunotherapy (CIT) initiates or enhances the host immune response against cancer. Following decades of development, patients with previously few therapeutic options may now benefit from CIT. Although the quantitative clinical pharmacology (qCP) of previous classes of anticancer drugs has matured during this time, application to CIT may not be straightforward since CIT acts via the immune system. Here we discuss where qCP approaches might best borrow or start anew for CIT. PMID:26451328

  13. Challenges and Opportunities for Quantitative Clinical Pharmacology in Cancer Immunotherapy: Something Old, Something New, Something Borrowed, and Something Blue

    PubMed Central

    Stroh, M; Carlile, DJ; Li, C-C; Wagg, J; Ribba, B; Ramanujan, S; Jin, J; Xu, J; Charoin, J-E; Xhu, Z-X; Morcos, PN; Davis, JD; Phipps, A

    2015-01-01

    Cancer immunotherapy (CIT) initiates or enhances the host immune response against cancer. Following decades of development, patients with previously few therapeutic options may now benefit from CIT. Although the quantitative clinical pharmacology (qCP) of previous classes of anticancer drugs has matured during this time, application to CIT may not be straightforward since CIT acts via the immune system. Here we discuss where qCP approaches might best borrow or start anew for CIT. PMID:26451328

  14. Potential utility of the pan-Bcl-2 inhibitor GX15–070 (obatoclax) in cancer immunotherapy

    PubMed Central

    Kim, Peter S; Schlom, Jeffrey

    2014-01-01

    An exploration of the immunotherapeutic potential of the pan-Bcl-2 inhibitor GX15–070 (GX15) has revealed that early-activated T cells derived from human peripheral blood are more sensitive to GX15 than are prolonged-activated T cells. Furthermore, non-memory and regulatory T cells also exhibit higher sensitivity to GX15. The implication of these prior findings suggests that GX15 may enhance the efficacy of immunotherapies in clinical settings. PMID:25083341

  15. Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions.

    PubMed

    Mineharu, Yohei; Kamran, Neha; Lowenstein, Pedro R; Castro, Maria G

    2014-12-01

    The success of immunotherapeutic approaches targeting glioblastoma multiforme (GBM) demands a robust antiglioma T-cell cytotoxic and memory response. Recent evidence suggests that rapamycin regulates T-cell differentiation. Herein, we tested whether administration of rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and thymidine kinase/ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of rapamycin with Ad-Flt3L + Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of antitumor CD8(+) T cells. Rats treated with rapamycin + Ad-Flt3L + Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L + Ad-TK/GCV-treated GL26 tumor-bearing mice, associated with an increase in the frequency of tumor-specific and IFN?(+) CD8(+) T cells. More importantly, rapamycin administration, even for a short interval, elicited a potent long-lasting central memory CD8(+) T-cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8(+) T cells within the tumor and IFN? release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data, therefore, point to rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a phase I clinical trial for GBM. PMID:25256739

  16. Immunotherapy and radiation therapy: considerations for successfully combining radiation into the paradigm of immuno-oncology drug development.

    PubMed

    Sharon, Elad; Polley, Mei-Yin; Bernstein, Michael B; Ahmed, Mansoor

    2014-08-01

    As the immunotherapy of cancer comes of age, adding immunotherapeutic agents to radiation therapy has the potential to improve the outcomes for patients with a wide variety of malignancies. Despite the enormous potential of such combination therapy, laboratory data has been lacking and there is little guidance for pursuing novel treatment strategies. Animal models have significant limitation in combining radiation therapy with immunotherapy and some of the limitations of preclinical models are discussed in this article. In addition to the preclinical challenges, radiation therapy and immunotherapy combinations may have overlapping toxicities, and for both types of therapy, early and late manifestations of toxicity are possible. Given these risks, special attention should be given to the design of the specific Phase I clinical trial that is chosen. In this article, we describe several Phase I design possibilities that may be employed, including the 3 + 3 design (also known as the cohort of 3 design), the continual reassessment method (CRM), and the time-to-event continual reassessment method (TITE-CRM). Efficacy end points for further development of combination therapy must be based on multiple factors, including disease type, stage of disease, the setting of therapy and the goal of therapy. While the designs for future clinical trials will vary, it is clear that these two successful modalities of therapy can and should be combined for the benefit of cancer patients. PMID:25003314

  17. The expanding horizon of immunotherapy in the treatment of malignant disorders: allogeneic hematopoietic stem cell transplantation and beyond.

    PubMed

    Tsirigotis, Panagiotis; Shimoni, Avichai; Nagler, Arnon

    2014-09-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a very effective therapeutic modality with curative potential in patients with hematological malignancies. The therapeutic efficacy is mainly based on the alloreactive reaction of donor lymphocytes against malignant cells of the recipient named as 'graft-versus-leukemia' or 'graft-versus-tumor' (GVL, GVT) effect. However, besides the beneficial GVL effect, alloreactive reaction attacks normal cells and provokes the deleterious 'graft-versus-host disease' (GVHD) which represents the major limitation of allo-SCT. Current trials have focused on a dual goal: augmentation of GVL and complete abolishment of GVHD. From a theoretical point of view complete dissociation of GVL from GVHD can occur by selecting antigenic targets present on malignant and absent from normal cells. Hematopoietic tissue-restricted minor histocompatibility antigens and leukemia or tumor-associated antigens are ideal candidates for tumor-targeted immunotherapy. Other options for inducing anti-tumor immunity in the absence of GVHD are natural killer (NK) cell immunotherapy, amplification of immune responses by using monoclonal antibodies, and bispecific T and NK-cell engagers. Genetically modified immune effectors such as T-cells armed with chimeric antigen receptors (CAR) or transduced with T-cell receptors with anti-tumor specificity are another exciting field of immunotherapy against malignancies. PMID:24888385

  18. Thermoreversible Poly(ethylene glycol)-g-Chitosan Hydrogel as a Therapeutic T Lymphocyte Depot for Localized Glioblastoma Immunotherapy

    PubMed Central

    2015-01-01

    The outcome for glioblastoma patients remains dismal for its invariably recrudesces within 2 cm of the resection cavity. Local immunotherapy has the potential to eradicate the residual infiltrative component of these tumors. Here, we report the development of a biodegradable hydrogel containing therapeutic T lymphocytes for localized delivery to glioblastoma cells for brain tumor immunotherapy. Thermoreversible poly(ethylene glycol)-g-chitosan hydrogels (PCgels) were optimized for steady T lymphocyte release. Nuclear magnetic resonance spectroscopy confirmed the chemical structure of poly(ethylene glycol)-g-chitosan, and rheological studies revealed that the sol-to-gel transition of the PCgel occurred around ?32 °C. T lymphocyte invasion through the PCgel and subsequent cytotoxicity to glioblastoma were assessed in vitro. The PCgel was shown to be cellular compatible with T lymphocytes, and the T lymphocytes retain their anti-glioblastoma activity after being encapsulated in the PCgel. T lymphocytes in the PCgel were shown to be more effective in killing glioblastoma than those in the Matrigel control. This may be attributed to the optimal pore size of the PCgel allowing better invasion of T lymphocytes. Our study suggests that this unique PCgel depot may offer a viable approach for localized immunotherapy for glioblastoma. PMID:24890220

  19. Adjuvant Immunotherapy of Melanoma, and Development of New Approaches Using the Neo- Adjuvant Approach in Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad

    2013-01-01

    Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. While early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death–the latter approaching 70% or more at 5 years. In patients at high-risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse free and overall survival. Neo-adjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFN?. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neo-adjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neo-adjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFN?, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab [BMS], and BRAF inhibitor vemurafenib [Genentech]) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 [BMS, Merck, Curetech] and anti-PDL-1[Genentech]) as well as other molecularly targeted agents such as the BRAF inhibitor dabrafenibin[GSK] and the MEK inhibitors trametinib [GSK] selumetinib [AZ] and MEK162 [Novartis] in the near future. Evaluation of the clinical role of these agents as adjuvant therapy will take years to accomplish to ascertain the relapse-free survival benefits and overall survival benefits of these agents, but neo-adjuvant exploration may provide early critical evidence of the therapeutic benefits, as well as clarifying the mechanisms of these agents alone and in combination. PMID:23608443

  20. [Current Cancer Immunotherapy Using Activated Lymphocytes - Do Lymphocytes Actually Recognize Cancer Cells ?].

    PubMed

    Yamaguchi, Yoshiyuki; Katata, Yousuke; Okawaki, Makoto; Yamamura, Masahiro; Sawaki, Akira

    2015-09-01

    Molecular cloning of interleukin-2(IL-2)has enabled adoptive cell therapy(ACT)to be established by using autologous activated lymphocytes. The low of regenerative medicine will promote the active development of ACT for public use, and ACTs that utilize tumor-infiltrating lymphocytes(TIL), in vitro tumor-sensitized lymphocytes, natural killer T cells, and gammadelta T cells are being evaluated as advanced medical treatments in Japan. In addition, chimeric antigen receptor genemodified T(CAR-T)cells and T cell receptor gene-modified T(TCR-T)cells are available for investigational clinical use. CART and TCR-T cells have been associated with serious adverse events as well as drastic clinical efficacies, indicating the importance of choosing the antigens to be targeted. Presently, it is accurate to state that lymphocytes do recognize cancer cells. Clinical ACT research focusing on TIL and mutated cancer antigens will be initiated for the development of personalized immunotherapy for cancer in the future. PMID:26469157

  1. Quality controls in cellular immunotherapies: rapid assessment of clinical grade dendritic cells by gene expression profiling.

    PubMed

    Castiello, Luciano; Sabatino, Marianna; Zhao, Yingdong; Tumaini, Barbara; Ren, Jiaqiang; Ping, Jin; Wang, Ena; Wood, Lauren V; Marincola, Francesco M; Puri, Raj K; Stroncek, David F

    2013-02-01

    Cell-based immunotherapies are among the most promising approaches for developing effective and targeted immune response. However, their clinical usefulness and the evaluation of their efficacy rely heavily on complex quality control assessment. Therefore, rapid systematic methods are urgently needed for the in-depth characterization of relevant factors affecting newly developed cell product consistency and the identification of reliable markers for quality control. Using dendritic cells (DCs) as a model, we present a strategy to comprehensively characterize manufactured cellular products in order to define factors affecting their variability, quality and function. After generating clinical grade human monocyte-derived mature DCs (mDCs), we tested by gene expression profiling the degrees of product consistency related to the manufacturing process and variability due to intra- and interdonor factors, and how each factor affects single gene variation. Then, by calculating for each gene an index of variation we selected candidate markers for identity testing, and defined a set of genes that may be useful comparability and potency markers. Subsequently, we confirmed the observed gene index of variation in a larger clinical data set. In conclusion, using high-throughput technology we developed a method for the characterization of cellular therapies and the discovery of novel candidate quality assurance markers. PMID:23147403

  2. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy

    PubMed Central

    Sun, Cheng; Sun, Hao-yu; Xiao, Wei-hua; Zhang, Cai; Tian, Zhi-gang

    2015-01-01

    The mechanisms linking hepatitis B virus (HBV) and hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) remain largely unknown. Natural killer (NK) cells account for 25%–50% of the total number of liver lymphocytes, suggesting that NK cells play an important role in liver immunity. The number of NK cells in the blood and tumor tissues of HCC patients is positively correlated with their survival and prognosis. Furthermore, a group of NK cell-associated genes in HCC tissues is positively associated with the prolonged survival. These facts suggest that NK cells and HCC progression are strongly associated. In this review, we describe the abnormal NK cells and their functional impairment in patients with chronic HBV and HCV infection, which contribute to the progression of HCC. Then, we summarize the association of NK cells with HCC based on the abnormalities in the numbers and phenotypes of blood and liver NK cells in HCC patients. In particular, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may serve as a predictor for the occurrence of HCC. Finally, we present the current achievements in NK cell immunotherapy conducted in mouse models of liver cancer and in clinical trials, highlighting how chemoimmunotherapy, NK cell transfer, gene therapy, cytokine therapy and mAb therapy improve NK cell function in HCC treatment. It is conceivable that NK cell-based anti-HCC therapeutic strategies alone or in combination with other therapies will be great promise for HCC treatment. PMID:26073325

  3. Mechanisms of allergen specific immunotherapy--T-cell tolerance and more.

    PubMed

    Jutel, M; Akdis, M; Blaser, K; Akdis, C A

    2006-07-01

    Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen-specific T-regulatory (Treg) cells and T helper 2 cells appears to be decisive in the development of allergic and healthy immune response against allergens. Treg cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen-specific T helper 2 cells in allergic individuals. A decrease in interleukin (IL)-4, IL-5 and IL-13 production by allergen-specific CD4+ T cells due to the induction of peripheral T cell tolerance is the most essential step in allergen-specific immunotherapy (SIT). Suppressed proliferative and cytokine responses against the major allergens are induced by multiple suppressor factors, such as cytokines like IL-10 and transforming growth factor (TGF)-beta and cell surface molecules like cytotoxic T lymphocyte antigen-4, programmed death-1 and histamine receptor 2. There is considerable rationale for targeting T cells to increase efficacy of SIT. Such novel approaches include the use of modified allergens produced using recombinant DNA technology and adjuvants or additional drugs, which may increase the generation of allergen-specific peripheral tolerance. By the application of the recent knowledge in Treg cells and related mechanisms of peripheral tolerance, more rational and safer approaches are awaiting for the future of prevention and cure of allergic diseases. PMID:16792576

  4. Discovery of Mesothelin and Exploiting it as a Target for Immunotherapy

    PubMed Central

    Pastan, Ira; Hassan, Raffit

    2014-01-01

    We have recently reported that an immunotoxin targeting mesothelin produced durable major tumor regressions in patients with extensive treatment refractory mesothelioma. These unprecedented tumor responses have prompted us to review how mesothelin was discovered and the advances that led to these tumor responses. This review is not comprehensive but focuses on major developments over the past 20 years since mesothelin was first identified in our laboratory. Mesothelin is a cell-surface glycoprotein whose expression in normal human tissues is restricted to mesothelial cells. Because it is highly expressed by many solid tumors it is an attractive immunotherapy target. Antibody based therapies currently in clinical trials include an immunotoxin, a chimeric monoclonal antibody and an antibody drug conjugate. In addition, a mesothelin tumor vaccine and a mesothelin-CAR are being evaluated in the clinic. SS1P, an anti-mesothelin immunotoxin was the first mesothelin directed therapy to enter the clinic and its use showed that mesothelin targeted therapy was safe in patients. More importantly our recent work has shown that SS1P in combination with pentostatin and cyclophosphamide can result in durable tumor regression in patients with advanced mesothelioma and opens up the possibility that such an approach can benefit patients with many common cancers. PMID:24824231

  5. Chemokine Receptor-Specific Antibodies in Cancer Immunotherapy: Achievements and Challenges

    PubMed Central

    Vela, Maria; Aris, Mariana; Llorente, Mercedes; Garcia-Sanz, Jose A.; Kremer, Leonor

    2015-01-01

    The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications. PMID:25688243

  6. Stem cell-derived exosomes: roles in stromal remodeling, tumor progression, and cancer immunotherapy.

    PubMed

    Fatima, Farah; Nawaz, Muhammad

    2015-03-01

    Stem cells are known to maintain stemness at least in part through secreted factors that promote stem-like phenotypes in resident cells. Accumulating evidence has clarified that stem cells release nano-vesicles, known as exosomes, which may serve as mediators of cell-to-cell communication and may potentially transmit stem cell phenotypes to recipient cells, facilitating stem cell maintenance, differentiation, self-renewal, and repair. It has become apparent that stem cell-derived exosomes mediate interactions among stromal elements, promote genetic instability in recipient cells, and induce malignant transformation. This review will therefore discuss the potential of stem cell-derived exosomes in the context of stromal remodeling and their ability to generate cancer-initiating cells in a tumor niche by inducing morphologic and functional differentiation of fibroblasts into tumor-initiating fibroblasts. In addition, the immunosuppressive potential of stem cell-derived exosomes in cancer immunotherapy and their prospective applications in cell-free therapies in future translational medicine is discussed. PMID:26369565

  7. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy.

    PubMed

    Meng, Xiangjiao; Huang, Zhaoqin; Teng, Feifei; Xing, Ligang; Yu, Jinming

    2015-12-01

    Checkpoint blockades turn on a new paradigm shift in immunotherapy for cancer. Remarkable clinical efficacy, durable response and low toxicity of programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockades have been observed in various malignancies. However, a lot of cancer patients failed to respond to the PD-1/PD-L1 checkpoint blockades. It is crucial to identify a biomarker to predict the response to checkpoint blockades. The overexpression of PD-L1 is an important and widely-explored predictive biomarker for the response to PD-1/PD-L1 antibodies. However PD-L1 staining cannot be used to accurately select patients for PD-1/PD-L1 pathway blockade due to the low prediction accuracy and dynamic changes. Tumor-infiltrating immune cells and molecules in the tumor microenvironment, or along with PD-L1 expression, may be important in predicting clinical benefits of PD-1/PD-L1 checkpoint blockades. Gene analysis has proven to be new approach for judging the potential clinical benefit of immune checkpoint inhibitors, such as mutational landscape and mismatch-repair deficiency. Further preclinical and clinical studies are necessary to carry out before its application in clinical practice. Challenges should be overcome to identify patients accurately who will benefit from PD-1/PD-L1 checkpoint blockades. In this review, we focus on the predictive biomarkers for checkpoint blockades of PD-1/PD-L1 pathway. PMID:26589760

  8. Immunotherapy for B-Cell Neoplasms using T Cells expressing Chimeric Antigen Receptors

    PubMed Central

    Boulassel, Mohamed-Rachid; Galal, Ahmed

    2012-01-01

    Immunotherapy with T cells expressing chimeric antigen receptors (CAR) is being evaluated as a potential treatment for B-cell neoplasms. In recent clinical trials it has shown promising results. As the number of potential candidate antigens expands, the choice of suitable target antigens becomes more challenging to design studies and to assess optimal efficacy of CAR. Careful evaluation of candidate target antigens is required to ensure that T cells expressing CAR will preferentially kill malignant cells with a minimal toxicity against normal tissues. B cells express specific surface antigens that can theoretically act as targets for CAR design. Although many of these antigens can stimulate effective cellular immune responses in vivo, their implementation in clinical settings remains a challenge. Only targeted B-cell antigens CD19 and CD20 have been tested in clinical trials. This article reviews exploitable B cell surface antigens for CAR design and examines obstacles that could interfere with the identification of potentially useful cellular targets. PMID:23269948

  9. Cancer immunotherapy for pancreatic cancer utilizing ?-gal epitope/natural anti-Gal antibody reaction

    PubMed Central

    Tanemura, Masahiro; Miyoshi, Eiji; Nagano, Hiroaki; Eguchi, Hidetoshi; Matsunami, Katsuyoshi; Taniyama, Kiyomi; Hatanaka, Nobutaka; Akamatsu, Hiroki; Mori, Masaki; Doki, Yuichiro

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis of all malignancies and is largely resistant to standard therapy. Novel treatments against PDAC are desperately needed. Anti-Gal is the most abundant natural antibody in humans, comprising about 1% of immunoglobulins and is also naturally produced in apes and Old World monkeys. The anti-Gal ligand is a carbohydrate antigen called “?-gal epitopes” with the structure Gal?1-3Gal?1-4GlcNAc-R. These epitopes are expressed as major carbohydrate antigens in non-primate mammals, prosimians, and New World monkeys. Anti-Gal is exploited in cancer vaccines to increase the immunogenicity of antigen-presenting cells (APCs). Cancer cells or PDAC tumor lysates are processed to express ?-gal epitopes. Vaccination with these components results in in vivo opsonization by anti-Gal IgG in PDAC patients. The Fc portion of the vaccine-bound anti-Gal interacts with Fc? receptors of APCs, inducing uptake of the vaccine components, transport of the vaccine tumor membranes to draining lymph nodes, and processing and presentation of tumor-associated antigens (TAAs). Cancer vaccines expressing ?-gal epitopes elicit strong antibody production against multiple TAAs contained in PDAC cells and induce activation of multiple tumor-specific T cells. Here, we review new areas of clinical importance related to the ?-gal epitope/anti-Gal antibody reaction and the advantages in immunotherapy against PDAC. PMID:26523105

  10. Cancer immunotherapy for pancreatic cancer utilizing ?-gal epitope/natural anti-Gal antibody reaction.

    PubMed

    Tanemura, Masahiro; Miyoshi, Eiji; Nagano, Hiroaki; Eguchi, Hidetoshi; Matsunami, Katsuyoshi; Taniyama, Kiyomi; Hatanaka, Nobutaka; Akamatsu, Hiroki; Mori, Masaki; Doki, Yuichiro

    2015-10-28

    Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis of all malignancies and is largely resistant to standard therapy. Novel treatments against PDAC are desperately needed. Anti-Gal is the most abundant natural antibody in humans, comprising about 1% of immunoglobulins and is also naturally produced in apes and Old World monkeys. The anti-Gal ligand is a carbohydrate antigen called "?-gal epitopes" with the structure Gal?1-3Gal?1-4GlcNAc-R. These epitopes are expressed as major carbohydrate antigens in non-primate mammals, prosimians, and New World monkeys. Anti-Gal is exploited in cancer vaccines to increase the immunogenicity of antigen-presenting cells (APCs). Cancer cells or PDAC tumor lysates are processed to express ?-gal epitopes. Vaccination with these components results in in vivo opsonization by anti-Gal IgG in PDAC patients. The Fc portion of the vaccine-bound anti-Gal interacts with Fc? receptors of APCs, inducing uptake of the vaccine components, transport of the vaccine tumor membranes to draining lymph nodes, and processing and presentation of tumor-associated antigens (TAAs). Cancer vaccines expressing ?-gal epitopes elicit strong antibody production against multiple TAAs contained in PDAC cells and induce activation of multiple tumor-specific T cells. Here, we review new areas of clinical importance related to the ?-gal epitope/anti-Gal antibody reaction and the advantages in immunotherapy against PDAC. PMID:26523105

  11. A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy.

    PubMed

    Valton, Julien; Guyot, Valérie; Marechal, Alan; Filhol, Jean-Marie; Juillerat, Alexandre; Duclert, Aymeric; Duchateau, Philippe; Poirot, Laurent

    2015-09-01

    The adoptive transfer of chimeric antigen receptor (CAR) T cell represents a highly promising strategy to fight against multiple cancers. The clinical outcome of such therapies is intimately linked to the ability of effector cells to engraft, proliferate, and specifically kill tumor cells within patients. When allogeneic CAR T-cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome. This work proposes to address these three requirements through the development of multidrug-resistant T cell receptor ??-deficient CAR T cells. We demonstrate that these engineered T cells displayed efficient antitumor activity and proliferated in the presence of purine and pyrimidine nucleoside analogues, currently used in clinic as preconditioning lymphodepleting regimens. The absence of TCR?? at their cell surface along with their purine nucleotide analogues-resistance properties could prevent their alloreactivity and enable them to resist to lymphodepleting regimens that may be required to avoid their ablation via HvG reaction. By providing a basic framework to develop a universal T cell compatible with allogeneic adoptive transfer, this work is laying the foundation stone of the large-scale utilization of CAR T-cell immunotherapies. PMID:26061646

  12. Perspectives in Molecular Imaging Using Staging Biomarkers and Immunotherapies in Alzheimer's Disease

    PubMed Central

    Leclerc, Benoît; Abulrob, Abedelnasser

    2013-01-01

    Sporadic Alzheimer's disease (AD) is an emerging chronic illness characterized by a progressive pleiotropic pathophysiological mode of actions triggered during the senescence process and affecting the elderly worldwide. The complex molecular mechanisms of AD not only are supported by cholinergic, beta-amyloid, and tau theories but also have a genetic basis that accounts for the difference in symptomatology processes activation among human population which will evolve into divergent neuropathological features underlying cognitive and behaviour alterations. Distinct immune system tolerance could also influence divergent responses among AD patients treated by immunotherapy. The complexity in nature increases when taken together the genetic/immune tolerance with the patient's brain reserve and with neuropathological evolution from early till advance AD clinical stages. The most promising diagnostic strategies in today's world would consist in performing high diagnostic accuracy of combined modality imaging technologies using beta-amyloid 42 peptide-cerebrospinal fluid (CSF) positron emission tomography (PET), Pittsburgh compound B-PET, fluorodeoxyglucose-PET, total and phosphorylated tau-CSF, and volumetric magnetic resonance imaging hippocampus biomarkers for criteria evaluation and validation. Early diagnosis is the challenge task that needs to look first at plausible mechanisms of actions behind therapies, and combining them would allow for the development of efficient AD treatment in a near future. PMID:23476143

  13. Personalized cell-mediated immunotherapy and vaccination: combating detrimental uprisings of malignancies

    PubMed Central

    Barar, Jaleh; Omidi, Yadollah

    2015-01-01

    A large number of researchers worldwide have conducted various investigations to advance the cell-based immunotherapies and to examine their clinical benefits as an ultimate prevention and/or treatment modalities against life-threatening malignancies. This dominion needs integration of science and technology to change the face of treatment of diseases towards much more personalized medicines. It is now plausible to reprogram the human cells for the prevention and treatment of diseases through various mechanisms such as modulation of immune system, nonetheless we should understand the complexity of biological functions of the cells in a holistic way to be able to manipulate the central dogma of the life to prevent any inadvertent mistake. We should, if not must, comprehend the interrelations of the cellular components (e.g., transport machineries) in the developmental processes of diseases. Still, we do not have a complete image of life, perhaps as expressive barcodes, and many pieces are missing. While completing this puzzle to picture the whole image and examine new treatment modalities, we should take extra caution upon unknown/little-known biological phenomena because trifling modulation/ alteration in the complex systems of the life may result in tremendous impacts. In short, it seems we need to consider malignancies as complex systems and treat them in a holistic manner by targeting its hallmarks. Taken all, the immune system reinforcement would be one of the main foundations in combating detrimental malignancy uprising. PMID:26191499

  14. A RANKL mutant used as an inter-species vaccine for efficient immunotherapy of osteoporosis

    PubMed Central

    Liu, Changzhen; Zhao, Yunfeng; He, Wen; Wang, Wei; Chen, Yuan; Zhang, Shiqian; Ma, Yijing; Gohda, Jin; Ishida, Takaomi; Walter, Thomas S.; Owens, Raymond J.; Stuart, David I.; Ren, Jingshan; Gao, Bin

    2015-01-01

    Anti-cytokine therapeutic antibodies have been demonstrated to be effective in the treatment of several auto-immune disorders. However, The problems in antibody manufacture and the immunogenicity caused by multiple doses of antibodies inspire people to use auto-cytokine as immunogen to induce anti-cytokine antibodies. Nevertheless, the tolerance for inducing immune response against self-antigen has hindered the wide application of the strategy. To overcome the tolerance, here we proposed a strategy using the inter-species cytokine as immunogen for active immunization (TISCAI) to induce anti-cytokine antibody. As a proof of concept, an inter-species cytokine RANKL was successfully used as immunogen to induce anti-RANKL immune response. Furthermore, to prevent undesirable side-effects, the human RANKL was mutated based on the crystal structure of the complex of human RANKL and its rodent counterpart receptor RANK. We found, the antibodies produced blocked the osteoclast development in vitro and osteoporosis in OVX rat models. The results demonstrated this strategy adopted is very useful for general anti-cytokine immunotherapy for different diseases settings. PMID:26412210

  15. Allergen-Specific Immunotherapy with Monomeric Allergoid in a Mouse Model of Atopic Dermatitis

    PubMed Central

    Babakhin, Alexander; Andreev, Sergey; Nikonova, Alexandra; Shilovsky, Igor; Buzuk, Andrey; Elisyutina, Olga; Fedenko, Elena; Khaitov, Musa

    2015-01-01

    Atopic dermatitis (AD) is a widespread and difficult to treat allergic skin disease and is a tough challenge for healthcare. In this study, we investigated whether allergen-specific immunotherapy (ASIT) with a monomeric allergoid obtained by succinylation of ovalbumin (sOVA) is effective in a mouse model of atopic dermatitis. An experimental model of AD was reproduced by epicutaneous sensitization with ovalbumin (OVA). ASIT was performed with subcutaneous (SC) administration of increasing doses of OVA or sOVA. The levels of anti-OVA antibodies, as well as cytokines, were detected by ELISA. Skin samples from patch areas were taken for histologic examination. ASIT with either OVA or sOVA resulted in a reduction of both the anti-OVA IgE level and the IgG1/IgG2a ratio. Moreover, ASIT with sOVA increased the IFN-? level in supernatants after splenocyte stimulation with OVA. Histologic analysis of skin samples from the sites of allergen application showed that ASIT improved the histologic picture by decreasing allergic inflammation in comparison with untreated mice. These data suggest that ASIT with a succinylated allergen represents promising approach for the treatment of AD. PMID:26275152

  16. Specific immunotherapy in combination with Clostridium butyricum inhibits allergic inflammation in the mouse intestine.

    PubMed

    Shi, Yanhong; Xu, Ling-Zhi; Peng, Kangsheng; Wu, Wei; Wu, Ruijin; Liu, Zhi-Qiang; Yang, Gui; Geng, Xiao-Rui; Liu, Jun; Liu, Zhi-Gang; Liu, Zhanju; Yang, Ping-Chang

    2015-01-01

    The current therapy on allergic inflammation is unsatisfactory. Probiotics improve the immunity in the body. This study aims to test a hypothesis that administration with Clostridium butyricum (C. butyricum) enforces the effect of specific immunotherapy (SIT) on intestinal allergic inflammation. In this study, an ovalbumin (OVA) specific allergic inflammation mouse model was created. The mice were treated with SIT or/and C. butyricum. The results showed that the intestinal allergic inflammation was only moderately alleviated by SIT, which was significantly enforced by a combination with C. butyricum; treating with C. butyricum alone did not show much inhibitory efficacy. The increase in the frequency of the interleukin (IL)-10-producing OVA-specific B cell (OVAsBC) was observed in mice in parallel to the inhibitory effect on the intestinal allergic inflammation. The in vitro treatment of the OVAsBCs with OVA increased the histone deacetylase-1 (HDAC1) phosphorylation, modulated the transcription of the Bcl6 gene, and triggered the OVAsBCs to differentiate to the IgE-producing plasma cells. Exposure to both OVA and butyrate sodium in the culture increased the expression of IL-10 in OVAsBCs. In conclusion, administration with C. butyricum enforces the inhibitory effect of SIT on allergic inflammation in the mouse intestine. PMID:26627845

  17. Specific immunotherapy in combination with Clostridium butyricum inhibits allergic inflammation in the mouse intestine

    PubMed Central

    Shi, Yanhong; Xu, Ling-Zhi; Peng, Kangsheng; Wu, Wei; Wu, Ruijin; Liu, Zhi-Qiang; Yang, Gui; Geng, Xiao-Rui; Liu, Jun; Liu, Zhi-Gang; Liu, Zhanju; Yang, Ping-Chang

    2015-01-01

    The current therapy on allergic inflammation is unsatisfactory. Probiotics improve the immunity in the body. This study aims to test a hypothesis that administration with Clostridium butyricum (C. butyricum) enforces the effect of specific immunotherapy (SIT) on intestinal allergic inflammation. In this study, an ovalbumin (OVA) specific allergic inflammation mouse model was created. The mice were treated with SIT or/and C. butyricum. The results showed that the intestinal allergic inflammation was only moderately alleviated by SIT, which was significantly enforced by a combination with C. butyricum; treating with C. butyricum alone did not show much inhibitory efficacy. The increase in the frequency of the interleukin (IL)-10-producing OVA-specific B cell (OVAsBC) was observed in mice in parallel to the inhibitory effect on the intestinal allergic inflammation. The in vitro treatment of the OVAsBCs with OVA increased the histone deacetylase-1 (HDAC1) phosphorylation, modulated the transcription of the Bcl6 gene, and triggered the OVAsBCs to differentiate to the IgE-producing plasma cells. Exposure to both OVA and butyrate sodium in the culture increased the expression of IL-10 in OVAsBCs. In conclusion, administration with C. butyricum enforces the inhibitory effect of SIT on allergic inflammation in the mouse intestine. PMID:26627845

  18. Immune checkpoint blockade opens an avenue of cancer immunotherapy with a potent clinical efficacy.

    PubMed

    Adachi, Keishi; Tamada, Koji

    2015-08-01

    Recent progress in tumor immunology has revealed that tumors generate immunologically restrained milieu during the process of their growth, which facilitates the escape of tumors from host immune systems. Immune checkpoint molecules, which transduce co-inhibitory signals to immuno-competent cells, are one of the most important components conferring the immunosuppressive capacity in the tumor microenvironment. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) are typical immune checkpoint molecules intimately involved in the suppression of anti-tumor immunity. Antibodies against those molecules have been developed, such as ipilimumab (anti-CTLA-4 antibody), nivolumab and pembrolizumab (anti-PD-1 antibody), and have been approved by regulatory agencies and used in some countries. Treatment with these antibodies demonstrates previously unobserved clinical efficacies superior to the conventional therapies. In this review, we first discuss the escape mechanisms of cancer from host immune systems, and then focus on the recent advances in immune checkpoint blockade therapy and on the new findings of related immune reactions, aiming to provide a better understanding of the novel cancer immunotherapies. PMID:25981182

  19. Immunotherapy of tumors with human telomerase reverse transcriptase immortalized human umbilical vein endothelial cells.

    PubMed

    Mu, Xiyan; Sang, Yaxiong; Fang, Chunju; Shao, Bin; Yang, Lu; Yao, Kui; Zhao, Xitong; Gou, Jinhai; Wei, Yuquan; Yi, Tao; Wu, Yang; Zhao, Xia

    2015-11-01

    Human umbilical endothelial cells (HUVECs) have been proven to be effective in tumor anti-angiogenesis but the mechanism remained to be further demonstrated. The restricted ability of HUVECs to proliferate in vitro also limits their application on a large scale. In the present study, we immortalized HUVECs with hTERT genes by lentiviral infection and explored the antitumor immunity of hTERT-expressing HUVECs (HUVEC-TERTs). Results showed that HUVEC-TERTs maintained high telomere activity and expressed CD31, VEGFR-II and integrin ?5. Passage-30 HUVEC-TERTs were able to form vascular tubes in vitro without showing signs of senescence. In vivo HUVEC-TERTs elicited antitumor immunity in mouse LL2 and CT26 models protectively and therapeutically. Both humoral and cellular immunity participated in the tumor anti-angiogenesis as HUVEC-neutralizing sera antibodies and HUVEC-specific CTL were detected. The subsets of activated spleen T lymphocytes included both CD4+ T cells and CD8+ T cells. Moreover, MDSCs and Tregs were decreased while T lymphocytes were aggregated in the tumor microenvironment. Collectively, the present study is the first to confirm the antitumor immunity of hTERT-immortalized HUVECs. Both anti-angiogenesis and tumor microenvironmental regulation participated in the antitumor activity. Transducing hTERT genes might be a new strategy to allow HUVECs to be applied on a large scale in cancer immunotherapy. PMID:26398907

  20. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies.

    PubMed

    Pellegrini, Marc; Calzascia, Thomas; Elford, Alisha R; Shahinian, Arda; Lin, Amy E; Dissanayake, Dilan; Dhanji, Salim; Nguyen, Linh T; Gronski, Matthew A; Morre, Michel; Assouline, Brigitte; Lahl, Katharina; Sparwasser, Tim; Ohashi, Pamela S; Mak, Tak W

    2009-05-01

    Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-beta signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors. PMID:19396174

  1. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    NASA Astrophysics Data System (ADS)

    Li, Xiaosong; Hode, Tomas; Guerra, Maria C.; Ferrel, Gabriela L.; Nordquist, Robert E.; Chen, Wei R.

    2011-02-01

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  2. New combinations and immunotherapies for melanoma: latest evidence and clinical utility

    PubMed Central

    Menzies, Alexander M.

    2013-01-01

    Until recently there was no effective systemic therapy for metastatic melanoma. Increased understanding of tumor biology and immune regulation has led to the development of drugs targeting the mitogen-activated protein kinase (MAPK) pathway (BRAF inhibitors and MEK inhibitors) and T-cell regulation (CTLA4 antibodies). These drugs are the new standard of care, however barriers to better patient outcomes include limited responses and significant toxicities (CTLA4 antibodies) and lack of durability in the majority of cases (BRAF and MEK inhibitors). This review discusses the next stages of development of treatments in melanoma, including immune checkpoint blocking drugs targeting the PD-1/PD-L1 axis, and the use of BRAF and MEK inhibitors in combination. Both approaches lead to a higher proportion of durable responses coupled with less toxicity. In an effort to improve outcomes even further, clinical trials of combinations of MAPK inhibitors, immunotherapies and other signal pathway inhibitors are underway. Adjuvant studies of many of these drugs have commenced, with the hope of also improving outcomes in patients with early-stage melanoma. PMID:23997828

  3. Interstitial Laser Irradiation of Solid Tumors in Laser Assisted Cancer Immunotherapy

    NASA Astrophysics Data System (ADS)

    Evans, Lindsay; Bandyopadhyay, Pradip

    2006-03-01

    Laser Assisted Cancer Immunotherapy (LACI) is an experimental therapeutic approach in cancer treatment. Current experiments in our laboratory begin with growing superficial tumors 5 to 7 mm in diameter in BALB/C mice using the CRL-2539 cell line. Tumor sizes were measured with a vernier caliper prior to injection of light absorbing dye (Indocyanine Green, ICG) and immunoadjuvant (Glycated Chitosan, GC). These measurements were continued during the post-therapy period. After injection with the ICG and GC, the mice underwent interstitial irradiation of the tumor with a diode laser operating at 804 nm. Microthermocouples were inserted into the tumor and the laser power was varied in order to monitor the temperature and keep it within in the desired range. Tumors were irradiated at 55^o C, 65^oC, and 75^oC to find out at which temperature the maximum amount of tumor necrosis and strong immune response could be elicited. The growth of the tumors after the LACI treatment will be plotted to show the affect of the therapy at different temperatures. The data suggest that the growth rate of the tumors is slowed down considerably using this approach. * This work is supported by a grant from The National Institutes of Health.

  4. A combination of local inflammation and central memory T cells potentiates immunotherapy in the skin

    PubMed Central

    Fiorenza, Salvatore; Kenna, Tony J.; Comerford, Iain; McColl, Shaun; Steptoe, Raymond J.; Leggatt, Graham R.; Frazer, Ian H.

    2012-01-01

    Adoptive T cell therapy utilises the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. Here, we utilise a murine model of immunotherapy to optimise cell-mediated immunity in the skin. We show that in vitro derived central but not effector memory-like T cells bring about rapid regression of skin expressing cognate antigen as a transgene in keratinocytes. Local inflammation induced by the TLR7 receptor agonist, imiquimod, subtly yet reproducibly decreases time to skin graft rejection elicited by central but not effector memory T cells in an immunodeficient mouse model. Local CCL4, a chemokine liberated by TLR7 agonism, similarly enhances central memory T cell function. In this model, IL-2 facilitates the development of in vivo of effector function from central memory but not effector memory T cells. In a model of T cell tolerogenesis, we further show that adoptively transferred central but not effector memory T cells can give rise to successful cutaneous immunity that is dependent on a local inflammatory cue in the target tissue at the time of adoptive T cell transfer. Thus, adoptive T cell therapy efficacy can be enhanced if CD8+ T cells with a central memory T cell phenotype are transferred and IL-2 is present with contemporaneous local inflammation. PMID:23144496

  5. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

    PubMed Central

    Fuller, Michael J.; Callendret, Benoit; Zhu, Baogong; Freeman, Gordon J.; Hasselschwert, Dana L.; Satterfield, William; Sharpe, Arlene H.; Dustin, Lynn B.; Rice, Charles M.; Grakoui, Arash; Ahmed, Rafi; Walker, Christopher M.

    2013-01-01

    Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti–PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti–PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited. PMID:23980172

  6. Antitumor and Adjuvant Activity of ?-carrageenan by Stimulating Immune Response in Cancer Immunotherapy.

    PubMed

    Luo, Min; Shao, Bin; Nie, Wen; Wei, Xia-Wei; Li, Yu-Li; Wang, Bi-Lan; He, Zhi-Yao; Liang, Xiao; Ye, Ting-Hong; Wei, Yu-Quan

    2015-01-01

    ?-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of ?-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of ?-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4(+)CD8(+) T lymphocytes in spleen. In addition, ?-carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-? in tumor, most of which was secreted by infiltrating macrophages. Moreover, ?-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that ?-carrageenan was with a good safety profile. Thus, ?-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy. PMID:26098663

  7. The promise of ?? T cells and the ?? T cell receptor for cancer immunotherapy.

    PubMed

    Legut, Mateusz; Cole, David K; Sewell, Andrew K

    2015-11-01

    ?? T cells form an important part of adaptive immune responses against infections and malignant transformation. The molecular targets of human ?? T cell receptors (TCRs) remain largely unknown, but recent studies have confirmed the recognition of phosphorylated prenyl metabolites, lipids in complex with CD1 molecules and markers of cellular stress. All of these molecules are upregulated on various cancer types, highlighting the potential importance of the ?? T cell compartment in cancer immunosurveillance and paving the way for the use of ?? TCRs in cancer therapy. Ligand recognition by the ?? TCR often requires accessory/co-stimulatory stress molecules on both T cells and target cells; this cellular stress context therefore provides a failsafe against harmful self-reactivity. Unlike ?? T cells, ?? T cells recognise their targets irrespective of HLA haplotype and therefore offer exciting possibilities for off-the-shelf, pan-population cancer immunotherapies. Here, we present a review of known ligands of human ?? T cells and discuss the promise of harnessing these cells for cancer treatment. PMID:25864915

  8. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.

    PubMed

    Peng, Dongjun; Kryczek, Ilona; Nagarsheth, Nisha; Zhao, Lili; Wei, Shuang; Wang, Weimin; Sun, Yuqing; Zhao, Ende; Vatan, Linda; Szeliga, Wojciech; Kotarski, Jan; Tarkowski, Rafa?; Dou, Yali; Cho, Kathleen; Hensley-Alford, Sharon; Munkarah, Adnan; Liu, Rebecca; Zou, Weiping

    2015-11-12

    Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy. PMID:26503055

  9. CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer.

    PubMed

    Paret, Claudia; Simon, Petra; Vormbrock, Kirsten; Bender, Christian; Kölsch, Anne; Breitkreuz, Andrea; Yildiz, Özlem; Omokoko, Tana; Hubich-Rau, Stefanie; Hartmann, Christoph; Häcker, Sabine; Wagner, Meike; Roldan, Diana Barea; Selmi, Abderaouf; Türeci, Özlem; Sahin, Ugur

    2015-09-22

    Triple-negative breast cancer (TNBC) is a high medical need disease with limited treatment options. CD8+ T cell-mediated immunotherapy may represent an attractive approach to address TNBC. The objectives of this study were to assess the expression of CXorf61 in TNBCs and healthy tissues and to evaluate its capability to induce T cell responses. We show by transcriptional profiling of a broad comprehensive set of normal human tissue that CXorf61 expression is strictly restricted to testis. 53% of TNBC patients express this antigen in at least 30% of their tumor cells. In CXorf61-negative breast cancer cell lines CXorf61 expression is activated by treatment with the hypomethylating agent 5-aza-2'-deoxycytidine. By vaccination of HLA-A*02-transgenic mice with CXorf61 encoding RNA we obtained high frequencies of CXorf61-specific T cells. Cloning and characterization of T cell receptors (TCRs) from responding T cells resulted in the identification of the two HLA-A*0201-restricted T cell epitopes CXorf6166-74 and CXorf6179-87. Furthermore, by in vitro priming of human CD8+ T cells derived from a healthy donor recognizing CXorf6166-74 we were able to induce a strong antigen-specific immune response and clone a human TCR recognizing this epitope. In summary, our data confirms this antigen as promising target for T cell based therapies. PMID:26327325

  10. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series

    PubMed Central

    2014-01-01

    Background Invasive fungal infections are very severe infections associated with high mortality rates, despite the availability of new classes of antifungal agents. Based on pathophysiological mechanisms and limited pre-clinical and clinical data, adjunctive immune-stimulatory therapy with interferon-gamma (IFN-?) may represent a promising candidate to improve outcome of invasive fungal infections by enhancing host defence mechanisms. Methods In this open-label, prospective case series, we describe eight patients with invasive Candida and/or Aspergillus infections who were treated with recombinant IFN-? (rIFN-?, 100 ?g s.c., thrice a week) for 2 weeks in addition to standard antifungal therapy. Results Recombinant IFN-? treatment in patients with invasive Candida and/or Aspergillus infections partially restored immune function, as characterized by an increased HLA-DR expression in those patients with a baseline expression below 50%, and an enhanced capacity of leukocytes from treated patients to produce proinflammatory cytokines involved in antifungal defence. Conclusions The present study provides evidence that adjunctive immunotherapy with IFN-? can restore immune function in fungal sepsis patients, warranting future clinical studies to assess its potential clinical benefit. Trial registration ClinicalTrials.gov - NCT01270490 PMID:24669841

  11. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy.

    PubMed

    Klebanoff, Christopher A; Scott, Christopher D; Leonardi, Anthony J; Yamamoto, Tori N; Cruz, Anthony C; Ouyang, Claudia; Ramaswamy, Madhu; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L; Sukumar, Madhusudhanan; Crompton, Joseph G; Palmer, Douglas C; Borman, Zachary A; Clever, David; Thomas, Stacy K; Patel, Shashankkumar; Yu, Zhiya; Muranski, Pawel; Liu, Hui; Wang, Ena; Marincola, Francesco M; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A; Siegel, Richard M; Restifo, Nicholas P

    2016-01-01

    Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies. PMID:26657860

  12. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

    PubMed

    Fuller, Michael J; Callendret, Benoit; Zhu, Baogong; Freeman, Gordon J; Hasselschwert, Dana L; Satterfield, William; Sharpe, Arlene H; Dustin, Lynn B; Rice, Charles M; Grakoui, Arash; Ahmed, Rafi; Walker, Christopher M

    2013-09-10

    Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited. PMID:23980172

  13. Immunohistochemical analysis of immune response in breast cancer and melanoma patients after laser immunotherapy

    NASA Astrophysics Data System (ADS)

    Nordquist, Robert E.; Bishop, Shelly L.; Ferguson, Halie; Vaughan, Melville B.; Jose, Jessnie; Kastl, Katherine; Nguyen, Long; Li, Xiaosong; Liu, Hong; Chen, Wei R.

    2011-03-01

    Laser immunotherapy (LIT) has shown great promise in pre-clinical studies and preliminary clinical trials. It could not only eradicate treated local tumors but also cause regression and elimination of untreated metastases at distant sites. Combining a selective photothermal therapy with an active immunological stimulation, LIT can induce systemic anti-tumor immune responses. Imiquimod (IMQ), a toll-like receptor agonist, was used for the treatment of late-stage melanoma patients and glycated chitosan (GC), a biological immunological modulator, was used for the treatment of late-stage breast cancer patients, in combination of irradiation of a near-infrared laser light. To observe the immunological changes before and after LIT treatment, the pathological tissues of melanoma and breast cancer patients were processed for immunohistochemical analysis. Our results show that LIT changed the expressions of several crucial T cell types. Specifically, we observed significant decreases of CD3+ T-cells and a significant increase of CD4+,CD8+, and CD68+ T-cells in the tumor samples after LIT treatment. While not conclusive, our study could shed light on one the possible mechanisms of anti-tumor immune responses induced by LIT. Further studies will be conducted to identify immunological biomarkers associated with LIT-induced clinical response.

  14. Antitumor and Adjuvant Activity of ?-carrageenan by Stimulating Immune Response in Cancer Immunotherapy

    PubMed Central

    Luo, Min; Shao, Bin; Nie, Wen; Wei, Xia-Wei; Li, Yu-Li; Wang, Bi-Lan; He, Zhi-Yao; Liang, Xiao; Ye, Ting-Hong

    2015-01-01

    ?-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of ?-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of ?-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4+CD8+ T lymphocytes in spleen. In addition, ?-carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-? in tumor, most of which was secreted by infiltrating macrophages. Moreover, ?-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that ?-carrageenan was with a good safety profile. Thus, ?-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy. PMID:26098663

  15. Monitoring Circulating ?? T Cells in Cancer Patients to Optimize ?? T Cell-Based Immunotherapy

    PubMed Central

    Oberg, Hans-Heinrich; Kellner, Christian; Peipp, Matthias; Sebens, Susanne; Adam-Klages, Sabine; Gramatzki, Martin; Kabelitz, Dieter; Wesch, Daniela

    2014-01-01

    The success of ?? T cell-based immunotherapy, where the cytotoxic activity of circulating ?? T lymphocytes is activated by nitrogen-containing bisphosphonates (n-BP), or possibly by bispecific antibodies or the combination of both, requires a profound knowledge of patients’ ?? T cells. A possible influence of radio- or chemotherapy on ?? T cells as well as their reported exhaustion after repetitive treatment with n-BP or their lack of response to various cancers can be easily determined by the monitoring assays described in this perspective article. Monitoring the absolute cell numbers of circulating ?? T cell subpopulations in small volumes of whole blood from cancer patients and determining ?? T cell cytotoxicity using the Real-Time Cell Analyzer can give a more comprehensive assessment of a personalized tumor treatment. Possible future directions such as the combined usage of n-BP or phosphorylated antigens together with bispecific antibodies that selectively target ?? T cells to tumor-associated antigens, will be discussed. Such strategies induce expansion and enhance ?? T cell cytotoxicity and might possibly avoid their exhaustion and overcome the immunosuppressive tumor microenvironment. PMID:25566256

  16. Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy

    PubMed Central

    Guven-Maiorov, Emine; Acuner-Ozbabacan, Saliha Ece; Keskin, Ozlem; Gursoy, Attila; Nussinov, Ruth

    2014-01-01

    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-?. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching—PRISM). PMID:24670367

  17. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype.

    PubMed

    Irani, Sarosh R; Stagg, Charlotte J; Schott, Jonathan M; Rosenthal, Clive R; Schneider, Susanne A; Pettingill, Philippa; Pettingill, Rosemary; Waters, Patrick; Thomas, Adam; Voets, Natalie L; Cardoso, Manuel J; Cash, David M; Manning, Emily N; Lang, Bethan; Smith, Shelagh J M; Vincent, Angela; Johnson, Michael R

    2013-10-01

    Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346-4515 pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11-200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immunotherapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross-sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n = 13) (P < 0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenotype. Immunotherapy is associated with excellent control of the frequently anti-epileptic drug refractory seizures, hastens time to recovery, and may prevent the subsequent development of cognitive impairment observed in this study. PMID:24014519

  18. Anti-A? Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer's Disease and Cerebral Amyloid Angiopathy.

    PubMed

    DiFrancesco, Jacopo C; Longoni, Martina; Piazza, Fabrizio

    2015-01-01

    Amyloid-related imaging abnormalities (ARIA) represent the major severe side effect of amyloid-beta (A?) immunotherapy for Alzheimer's disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-A? autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy-related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-A? autoantibody as a promising candidate biomarker for ARIA in clinical trials. PMID:26441825

  19. Anti-A? Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer’s Disease and Cerebral Amyloid Angiopathy

    PubMed Central

    DiFrancesco, Jacopo C.; Longoni, Martina; Piazza, Fabrizio

    2015-01-01

    Amyloid-related imaging abnormalities (ARIA) represent the major severe side effect of amyloid-beta (A?) immunotherapy for Alzheimer’s disease (AD). Early biomarkers of ARIA represent an important challenge to ensure safe and beneficial effects of immunotherapies, given that different promising clinical trials in prodromal and subjects at risk for AD are underway. The recent demonstration that cerebrospinal fluid (CSF) anti-A? autoantibodies play a key role in the development of the ARIA-like events characterizing cerebral amyloid angiopathy-related inflammation generated great interest in the field of immunotherapy. Herein, we critically review the growing body of evidence supporting the monitoring of CSF anti-A? autoantibody as a promising candidate biomarker for ARIA in clinical trials. PMID:26441825

  20. Anti-programmed death receptor 1 immunotherapy in melanoma: rationale, evidence and clinical potential

    PubMed Central

    Freeman-Keller, Morganna

    2015-01-01

    Malignant melanoma is a significant public health problem; according to 2013 Surveillance, Epidemiology, and End Results data, its average incidence rate rose 2.6% each year for the last decade, and it is now the fifth most common cancer diagnosis in the United States. The rising incidence and historical poor response to chemotherapy have led to intense investigation of novel treatments for melanoma, including therapies to improve the immune-mediated destruction of cancer cells. Among the hallmarks of malignancy is the ability to evade this process: while early stages of tumor growth can induce functional CD8+ T-cell responses, cancer cells become increasingly embedded in an immune-suppressive tumor stroma. In the tumor microenvironment, T-cell proliferation and effector function are impaired due to engagement of T-cell programmed death receptor 1 (PD-1) with programmed death receptor ligand (PD-L1) expressed by cancer cells and antigen-presenting cells, which blocks T-cell-mediated cytotoxicity. This receptor-ligand engagement thereby inhibits immunity, allows the tumor to continue to grow, and contributes to the phenomenon of ‘T-cell exhaustion’. One immunotherapy strategy currently under investigation is inhibition of the interaction between PD-L1 and PD-1, thereby overcoming a critical immune checkpoint to facilitate destruction of cancer cells. In this review we discuss the preclinical rationale for PD-1 pathway inhibition in cancer, recent results of clinical trials targeting PD-1 and PD-L1, and evaluate its potential as a future anticancer therapy. PMID:25553080