Background Chemerin is a specific chemoattractant for macrophages and dendritic cells (DC). In addition, it can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules and is able to activate fibroblast-like synoviocytes (FLS), suggesting a role in the pathogenesis of rheumatoid arthritis (RA). Chemerin is also an adipocytokine that has been related to the inflammatory state of endothelial cells and as such could be involved in the changes in endothelial cells in RA and perhaps increased cardiovascular morbidity. We investigated whether anti-Tumor Necrosis Factor (TNF) treatment affects chemerin levels. Materials and Methods 49 patients with active RA (disease activity score evaluated in 28 joints (DAS28) ?3.2) were started on adalimumab therapy. Blood was drawn from patients while fasting at baseline and 16 weeks after initiation of treatment. Chemerin serum levels were measured by ELISA and related to disease activity, mediators of inflammation and known risk factors for cardiovascular disease. Results Adalimumab therapy reduced chemerin serum levels, which was correlated with the reduction in DAS28 (r?=?0.37, p?=?0.009). In addition, the decrease in chemerin serum levels after anti-TNF treatment was associated with the decrease in serum levels of IL-6 (r?=?0.39, p?=?0.033) and macrophage migration inhibitory factor (MIF) (r?=?0.31, p?=?0.049). Baseline chemerin serum levels were not related to traditional risk factors for atherosclerosis, except perhaps for smoking (p?=?0.07). Conclusions This exploratory study shows that adalimumab therapy lowers chemerin levels, which is associated with the reduction in disease activity parameters, and inflammatory mediators IL-6 and MIF. This suggests a possible involvement of chemerin in the migration/retention of macrophages in the synovium. Trial Registration Nederlands Trial Register NTR 857
Herenius, Marieke M. J.; Oliveira, Ana S. F.; Wijbrandts, Carla A.; Gerlag, Danielle M.; Tak, Paul P.; Lebre, Maria C.
Tumor necrosis factor-? (TNF-?), a proinflammatory cytokine, plays a key role in the pathogenesis of many inflammatory diseases, including arthritis. Neutralization of this cytokine by anti-TNF-? antibodies has shown its efficacy in rheumatoid arthritis (RA) and is now widely used. Nevertheless, some patients currently treated with anti-TNF-? remain refractory or become nonresponder to these treatments. In this context, there is a need for new or complementary therapeutic strategies. In this study, we investigated in vitro and in vivo anti-inflammatory potentialities of an anti-TNF-? triplex-forming oligonucleotide (TFO), as judged from effects on two rat arthritis models. The inhibitory activity of this TFO on articular cells (synoviocytes and chondrocytes) was verified and compared to that of small interfering RNA (siRNA) in vitro. The use of the anti-TNF-? TFO as a preventive and local treatment in both acute and chronic arthritis models significantly reduced disease development. Furthermore, the TFO efficiently blocked synovitis and cartilage and bone destruction in the joints. The results presented here provide the first evidence that gene targeting by anti-TNF-? TFO modulates arthritis in vivo, thus providing proof-of-concept that it could be used as therapeutic tool for TNF-?-dependent inflammatory disorders.
Paquet, Joseph; Henrionnet, Christel; Pinzano, Astrid; Vincourt, Jean-Baptiste; Gillet, Pierre; Netter, Patrick; Chary-Valckenaere, Isabelle; Loeuille, Damien; Pourel, Jacques; Grossin, Laurent
The aetiology of breathing difficulties in patients with inflammatory arthritis being treated with anti-TNF agents can be multi-factorial. Exacerbation of fibrosing alveolitis in patients recently commencing Infliximab has been previously described. Bronchospasm, although reported in some study patients, has not been formally investigated so far. The objective of this study is to define the incidence of bronchospasm in patients treated with anti-TNF agents and investigate details of their respiratory problems. We retrospectively reviewed the notes for 421 patients with inflammatory arthritis being treated with anti-TNF agents at our centre to identify patients who had developed respiratory symptoms during the course of this treatment (cardiac or pleural disease, thromboembolic phenomena or infection were excluded). We identified 7 patients where bronchospasm was thought to be due to treatment with anti-TNF drugs (1.7%). Four of these had to discontinue anti-TNF treatment; two of these needed oral corticosteroid therapy. Two patients were stabilised with increased inhaled beta-2 agonist and steroid, while one patient did not need treatment. All patients had significant exposure to smoking. Bronchospasm is not an uncommon side-effect of anti-TNF treatment. The aetiology of this is probably multi-factorial, but current or previous smoking appears to be a predisposing factor. The frequency and severity of bronchospasm appears to be greater than previously anticipated, all three anti-TNF agents appear to be implicated. PMID:19340514
Dubey, S; Kerrigan, N; Mills, K; Scott, D G
Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Overexpression of tumor necrosis factor-? (TNF-?) occurs in the AD brain. Recent clinical studies have shown that the anti-TNF-? therapy improves cognition function of AD patients rapidly. However, the underlying mechanism remains elusive. The present study investigates the effects of intracerebroventricular injection of the monoclonal TNF-? antibody, Infliximab,
Jian-Quan Shi; Wei Shen; Jun Chen; Bian-Rong Wang; Ling-Ling Zhong; Yin-Wei Zhu; Hai-Qing Zhu; Qiao-Quan Zhang; Ying-Dong Zhang; Jun Xu
AIM: To evaluate whether combination therapy with anti-tumour necrosis factor ? (TNF?) antibody and Zn acetate is beneficial in dextran sodium sulphate (DSS) colitis. METHODS: Colitis was induced in CD1-Swiss mice with 5% DSS for 7 d. The experimental mice were then randomised into the following subgroups: standard diet + DSS treated (induced colitis group); standard diet + DSS + subcutaneous 25 ?g anti-TNF? treated group; Zn acetate treated group + DSS + subcutaneous 25 ?g anti-TNF?; standard diet + DSS + subcutaneous 6.25 ?g anti-TNF? treated group and Zn acetate treated group + DSS + subcutaneous 6.25 ?g anti-TNF?. Each group of mice was matched with a similar group of sham control animals. Macroscopic and histological features were scored blindly. Homogenates of the colonic mucosa were assessed for myeloperoxidase activity as a biochemical marker of inflammation and DNA adducts (8OH-dG) as a measure of oxidative damage. RESULTS: DSS produced submucosal erosions, ulcers, inflammatory cell infiltration and cryptic abscesses which were reduced in both groups of mice receiving either anti-TNF? alone or combined with zinc. The effect was more pronounced in the latter group (vs Zn diet, P < 0.02). Myeloperoxidase activity (vs controls, P < 0.02) and DNA adducts, greatly elevated in the DSS fed colitis group (vs controls, P < 0.05), were significantly reduced in the treated groups, with a more remarkable effect in the group receiving combined therapy (vs standard diet, P < 0.04). CONCLUSION: DSS induces colonic inflammation which is modulated by the administration of anti-TNF?. Combining anti-TNF? with Zn acetate offers marginal benefit in colitis severity.
Barollo, Michela; Medici, Valentina; D'Inca, Renata; Banerjee, Antara; Ingravallo, Giuseppe; Scarpa, Marco; Patak, Surajit; Ruffolo, Cesare; Cardin, Romilda; Sturniolo, Giacomo Carlo
Autoimmune hepatitis (AIH) is occasionally triggered by drug treatments. Recently, as biological agents are becoming widely used for autoimmune disorders, there have been a growing number of reports of the development of autoimmune processes related to these agents. A 52-year-old Japanese woman with psoriasis developed liver damage two months after initiation of anti-TNF-? therapy with adalimumab. Liver histological findings were compatible with AIH, and positive conversions of ANAs were detected. The patient was treated with prednisolone and had a good response. While some cases of AIH triggered by anti-TNF-? therapies have been reported, the pathogenesis remains unspecified. When elevation of liver enzymes is observed with high IgG levels and seropositivity of ANA during the course of anti-TNF-? therapy, liver biopsy findings may be essential and important to make definitive diagnosis of AIH.
Rheumatoid arthritis (RA) is a chronic systemic disease that leads to increases in health system economic burden through direct and indirect costs, including chronic treatment, reduced productivity and premature mortality. Anti-TNF agents have represented a major advance in the treatment of RA. The most commonly used (adalimumab, etanercept and infliximab) have demonstrated their cost-effectiveness at label doses. However, physicians may need to adapt the treatment by increasing the dose when a drug is not effective enough or by reducing it when there is a sustained effectiveness. In a cross-sectional study conducted in our hospital in which information from RA patients treated with anti-TNF drugs under conventional and modified doses were collected, the authors analyzed the costs of the medication in order to estimate the mean patient-year cost, the annual costs related to clinical efficacy and the cost per responder patient to anti-TNF treatment when dosage modification is undertaken in daily clinical practice. PMID:23763534
de la Torre, Inmaculada; Valor, Lara; Nieto, Juan Carlos; Hernandez, Diana; Martinez, Lina; Gonzalez, Carlos M; Monteagudo, Indalecio; Longo, Javier Lopez; Montoro, Maria; Carreño, Luis
BACKGROUND: Inhibition of tumour necrosis factor (TNF) is an effective way of reducing synovitis and preventing joint damage in rheumatoid arthritis (RA), yet very little is known about its specific effect on foot pain and disability. The aim of this study was to evaluate whether anti-TNF therapy alters the presence of forefoot pathology and\\/or reduces foot pain and disability. METHODS:
Catherine J Bowen; Christopher J Edwards; Lindsey Hooper; Keith Dewbury; Madeleine Sampson; Sally Sawyer; Jane Burridge; Nigel K Arden
Background: We wondered whether short-term coseasonal sublingual immunotherapy (SLIT) can reduce the development of asthma in children with hay fever in an open randomized study. Objective: We sought to determine whether SLIT is as effective as subcutaneous immunotherapy in reducing hay fever symptoms and the development of asthma in children with hay fever. Methods: One hundred thirteen children aged 5
Elio Novembre; Elena Galli; Fabiola Landi; Carlo Caffarelli; Massimo Pifferi; Emanuela De Marco; Samuele E. Burastero; Giliola Calori; Luca Benetti; Paolo Bonazza; Paola Puccinelli; Silvano Parmiani; Roberto Bernardini; Alberto Vierucci
Several cases of sarcoidosis with pulmonary, neurological or ophthalmological involvement occurring during a treatment by anti-TNF? have been reported in the literature. We report a 66-year-old man who presented with renal failure and hypercalcaemia, associated with fatigue, shortness of breath and dry cough. He was receiving infliximab since 2004 for psoriatic arthritis. The diagnosis of sarcoidosis was obtained with biopsy sampling
A. Olivier; B. Gilson; S. Lafontaine; J.-X. Pautot; P. Bindi
For patients with active ankylosing spondylitis (AS), medical therapy with TNF-blockers such as infliximab is increasingly considered the standard of care. This is especially true for patients who continue to have symptoms of active inflammation despite medication with nonsteroidal antiinflammatory drugs at the maximum possible dose. Insufficient control of disease activity as indicated by pain, stiffness and decrease of function is the most common clinical reason for starting anti-TNF therapy. The most recent follow-up data show that anti-TNF therapy with infliximab is clinically efficacious and safe, not only on a short- but also on a long-term basis in AS. Furthermore, there is evidence that infliximab also works in other spondyloarthritides (SpA) such as SpA associated with psoriasis, undifferentiated (early axial) SpA and in SpA associated with chronic inflammatory bowel diseases. Its benefit has even been reported in cases of reactive SpA. Withdrawal of long-term therapy in AS patients usually leads to flares and relapses after several weeks to months, but single cases of lasting remission have been reported. Only limited data are available regarding the optimal dosage of infliximab in SpA. In clinical practice, selected patients might not need doses of infliximab higher than 3 mg/kg but most patients will need doses of 5 mg/kg. A definite influence on radiographic progression after long-term continuous treatment with infliximab compared with conventional therapy has not been proven so far. This is in contrast to function and mobility, which even slightly improve over time in the patients who are still on therapy after 5 or more years (slightly over 50% of the initially treated patients in clinical trials). Antibody formation may lead to loss of efficacy (secondary nonresponse). Serious adverse events on anti-TNF therapy have remained rare as these can be largely prevented by appropriate screening. The large benefits of anti-TNF therapy in AS seem to outweigh the few shortcomings of this treatment. PMID:20383886
Baraliakos, Xenofon; Braun, Juergen
Abstract Background Substantial progress has been made in the medical management of rheumatoid arthritis (RA) over the past decade with the introduction of biologic therapies, including anti-tumour necrosis factor alpha (anti-TNF?) therapy medications. However, individuals with RA taking anti-TNF? medication continue to experience physical, psychological and functional consequences, which could potentially benefit from rehabilitation. There is evidence that therapeutic exercise should be included as an intervention for people with RA, but to date there is little evidence of the benefits of therapeutic exercise for people with RA on anti-TNF? therapy medication. A protocol for a multicentre randomised controlled three-armed study which aims to examine the effect of dynamic group exercise therapy on land or in water for people with RA taking anti-TNF? therapy medication is described. Methods/Design Six hundred and eighteen individuals with RA, on anti-TNF? therapy medication, will be randomised into one of 3 groups: a land-based exercise group; a water-based exercise group or a control group. The land and water-based groups will exercise for one hour, twice a week for eight weeks. The control group will receive no intervention and will be asked not to alter their exercise habits for the duration of the study. The primary outcome measure, the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) which measures functional ability, and secondary measures of pain, fatigue and quality of life, will be assessed at baseline, eight and 24 weeks by an independent assessor unaware of group allocation. Changes in outcome from 0 to 8 weeks and 0 to 24 weeks in the 'land-based exercise group versus control group' and the 'water-based exercise group versus control group' will be examined. Analysis will be conducted on an intention to treat basis. Discussion This trial will evaluate the effectiveness of group exercise therapy on land or in water, for people with RA taking anti-TNF? therapy medication. If these exercise groups are found to be beneficial, they could be conducted in local community facilities thus making these forms of exercise more easily accessible for individuals and potentially reduce the burden on health services. Trial Registration This trial is registered with ClinicalTrials.gov (a service of the United States National Institutes of Health) identifier: NCT00855322.
Controlled trials and meta-analyses have shown that immunosuppressants are effective in steroid-dependent Crohn's disease (CD) and, although less well demonstrated, ulcerative colitis (UC). It has also been demonstrated that anti-TNF are effective in steroid-dependent and steroid-refractory CD and UC. Anti-TNF can also decrease hospitalization rate and the need for surgery. This seems also to be the case for immunosuppressants. The early use of anti-TNF seems more effective than later use, and early mucosal healing is associated with decreased rate of surgery. On the contrary, early use of purine analogues does not seem to improve outcome in CD. Anti-TNF therapies have been shown superior to immunosuppressants and combination therapy superior to anti-TNF monotherapy in inducing steroid-free remission and mucosal healing. The main strategic questions which remain at this stage include: When to start immunosuppressants or anti-TNF? Is there still a place for immunosuppressant monotherapy? How to optimize anti-TNF? Is it possible to stop anti-TNF? The main justification of immunosuppressant monotherapy is the low cost of this treatment and the possibility of achieving a very stable and long-standing remission in a subset of patients. According to this and provided there is no rapid need for more effective therapy, this treatment could be tried in any inflammatory bowel disease patient not correctly maintained after a course of steroids and 5-aminosalicylic acid. However, the failure to respond to this treatment should be recognized early and a step up to anti-TNF considered. An anti-TNF treatment should be considered early in patients at risk of rapid evolution towards tissue damage and complications. The benefit/risk of the immunosuppressant + anti-TNF combination therapy should be assessed on a case-by-case basis. Anti-TNF treatment should always be fully optimized by adapting dosage and potentially adding an immunosuppressant before considering treatment failure. Treatment de-escalation should only be considered when a long-standing stable remission has been achieved both clinically and biologically. The cost sparing and theoretical decrease in complication risk should be put in perspective with the risk of relapse and disease progression. © 2013 S. Karger AG, Basel. PMID:24030227
Background Although enzyme replacement therapy (ERT) is available for several lysosomal storage disorders, the benefit of this treatment to the skeletal system is very limited. Our previous work has shown the importance of the Toll-like receptor 4/TNF-alpha inflammatory pathway in the skeletal pathology of the mucopolysaccharidoses (MPS), and we therefore undertook a study to examine the additive benefit of combining anti-TNF-alpha therapy with ERT in a rat model of MPS type VI. Methodology/Principal Findings MPS VI rats were treated for 8 months with Naglazyme® (recombinant human N-acetyl-galactosamine-4-sulfatase), or by a combined protocol using Naglazyme® and the rat-specific anti-TNF-alpha drug, CNTO1081. Both protocols led to markedly reduced serum levels of TNF-alpha and RANKL, although only the combined treatment reduced TNF-alpha in the articular cartilage. Analysis of cultured articular chondrocytes showed that the combination therapy also restored collagen IIA1 expression, and reduced expression of the apoptotic marker, PARP. Motor activity and mobility were improved by ERT, and these were significantly enhanced by combination treatment. Tracheal deformities in the MPS VI animals were only improved by combination therapy, and there was a modest improvement in bone length. Ceramide levels in the trachea also were markedly reduced. MicroCT analysis did not demonstrate any significant positive effects on bone microarchitecture from either treatment, nor was there histological improvement in the bone growth plates. Conclusions/Significance The results demonstrate that combining ERT with anti-TNF- alpha therapy improved the treatment outcome and led to significant clinical benefit. They also further validate the usefulness of TNF-alpha, RANKL and other inflammatory molecules as biomarkers for the MPS disorders. Further evaluation of this combination approach in other MPS animal models and patients is warranted.
Eliyahu, Efrat; Wolfson, Theodore; Ge, Yi; Jepsen, Karl J.; Schuchman, Edward H.; Simonaro, Calogera M.
By employing modified Cornell model, we have evaluated the potential of adjunctive immunotherapy with DNA vaccines to shorten the tuberculosis chemotherapy period and reduce disease reactivation. We demonstrate that ?-crystallin based DNA vaccine (DNAacr) significantly reduced the chemotherapy period from 12 weeks to 8 weeks when compared with the chemotherapy alone. Immunotherapy with SodA based DNA vaccine (DNAsod) reduced the pulmonary bacilli only as much as DNAvec. Both DNAacr and DNAsod, although significantly delayed the reactivation in comparison to the chemotherapy alone, this delay was associated with the immunostimulatory sequences present in the vector backbone and was not antigen specific. Both DNA vaccines resulted in the production of significantly higher number of TEM cells than the chemotherapy alone, however, only in the case of DNAsod, this enhancement was significant over the DNAvec treatment. Overall, our findings emphasize the immunotherapeutic potential of DNAacr in shortening the duration of TB chemotherapy.
Chauhan, Priyanka; Jain, Ruchi; Dey, Bappaditya; Tyagi, Anil K.
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.
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.
Objective. The primary objective of this retrospective study was to investigate the possibility of achieving partial remission (PR) in AS patients treated with anti-TNF-? antagonists, such as adalimumab (ADA), etanercept (ETA) and infliximab (INF), in a real clinical practice setting. Predictors of PR were also evaluated. Methods. A retrospective study was conducted in patients with AS treated with ADA, ETA and INF from 2000 to 2012. Kaplan-Meier survival curves were plotted to determine the rates of PR during the treatment with anti-TNF-? drugs. Results. A total of 283 patients with AS were treated with ADA (18.7%), ETA (26.8%) and INF (54.4%) as first anti-TNF-? drugs, with a PR rate of 57.6%. The probability of obtaining PR with ADA, ETA or INF was not significantly different among all anti-TNF-? patients. AS patients treated with a second anti-TNF-? drug had a PR rate of 40.5%, but after switching for lack of response, the probability of obtaining PR with a second anti-TNF-? drug was significantly lower from that of the first anti-TNF-? drug (P = 0.0039). The probability of obtaining PR in patients with enthesitis (P = 0.04) or psoriasis (P = 0.0016) or low levels of CRP (P = 0.0225) was significantly lower compared with that of patients without these manifestations at baseline. Conclusion. Our real-life study on PR confirmed the effectiveness of ADA, ETA or INF as first or second anti-TNF-? drugs. The presence at baseline of enthesitis or psoriasis or low CRP values yielded a lower probability of obtaining PR. PMID:23878312
Spadaro, Antonio; Lubrano, Ennio; Marchesoni, Antonio; D'Angelo, Salvatore; Ramonda, Roberta; Addimanda, Olga; Perrotta, Fabio Massimo; Olivieri, Ignazio; Punzi, Leonardo; Salvarani, Carlo
Dermatophagoides pteronyssinus and D. farinae are the most common house dust mites and are among the most common sources of indoor allergens worldwide. These species are very common in humid regions, where most allergic individuals are sensitized to house dust mites. Specific immunotherapy with mite extracts has demonstrated clinical benefits in several double-blind, placebo-controlled trials that are included in recent reviews of subcutaneous immunotherapy, including pediatric and adult patients with rhinoconjunctivitis and or asthma. Most successful studies of mite immunotherapy have used native allergen extracts adsorbed onto aluminum hydroxide, or chemically modified mite-allergen extracts. Several studies have also shown efficacy using sublingual immunotherapy in pediatric and adult patients with asthma and/or rhinitis. Additionally, the efficacy of subcutaneous immunotherapy has been demonstrated in patients with atopic dermatitis, although more double-blind, placebo-controlled studies are needed. Based on several studies, it cannot be concluded that mite immunotherapy is more dangerous or safer than immunotherapy with grasses, epithelia, or animal epithelia. Because the delivery of high doses of allergen carries with it the risk for immunoglobulin E (IgE)-mediated events, several methods have been developed to reduce specific IgE binding to mite-allergen extracts. An important challenge for future mite immunotherapy modalities is the delivery of relatively high doses without a significant risk for severe reactions. PMID:16899204
Fernández-Caldas, Enrique; Iraola, Victor; Boquete, Manuel; Nieto, Antonio; Casanovas, Miguel
Background: Refractory asthma represents an important condition, with considerable morbidity and mortality. Tumor necrosis factor ? (TNF-?) is a potential target for treatment of severe asthma. However, controlled studies have shown controversial results and the risk-benefit profile of TNF-blocking agents is still debated. Objectives: To describe the effect of infliximab on asthma control in patients with severe, uncontrolled, steroid-dependent asthma. Methods: From 2007 to 2010, 7 patients received infliximab in our center. All had severe refractory asthma, with frequent severe exacerbations and hospitalizations in the intensive care unit despite maximal inhaled treatment, daily oral steroids and omalizumab treatment. Results: Asthma control improved in the 6 patients who received infliximab for at least 3 months. Oral steroids could be stopped in 4 and the frequency of exacerbations and hospitalizations was greatly reduced, especially for the 3 patients with brittle asthma. Two patients showed severe adverse effects (bacterial pneumonia and extension of spreading melanoma). Three patients have received infliximab for more than 2 years, with good tolerance. Conclusion: This case series suggests that anti-TNF-? drugs may improve the condition of a subgroup of patients with severe steroid-refractory asthma, with a favourable risk-benefit profile for most, considering asthma severity, occurrence of life-threatening exacerbations and complications of long-term oral steroids. Specific controlled trials of this subgroup are warranted.
Taille, Camille; Poulet, Claire; Marchand-Adam, Sylvain; Borie, Raphael; Dombret, Marie-Christine; Crestani, Bruno; Aubier, Michel
TNF is an important mediator of inflammation, which can have deleterious effects when produced inappropriately. We have described a recombinant inhibitor of TNF, termed TNFR-IgG, or TNFR immunoadhesin, composed of the extracellular portion of the type 1 (p55) TNF receptor (TNFR) linked to the hinge and Fc regions of IgG heavy chain. This bivalent, Ab-like molecule is a potent inhibitor of TNF, exhibiting significantly higher affinity for the cytokine than soluble TNFR. Here, we compare the TNF-neutralizing capacity of TNFR-IgG to that of an anti-TNF mAb. In vitro, TNFR-IgG was 10- to 50-fold more potent than anti-TNF mAb at blocking the cytotoxic effect of exogenous TNF on actinomycin D-treated murine L-M cells. In vivo, the plasma half-life of TNFR-IgG in mice was approximately 6 days, similar to that reported for the anti-TNF mAb. However, the immunoadhesin was approximately 10-fold more effective than the Ab at neutralizing the activity of endogenous TNF, as assessed in a model for murine listeriosis. These results demonstrate a markedly greater potency of the TNFR immunoadhesin compared with the anti-TNF mAb at inhibiting TNF activity in vitro and in vivo. PMID:8301136
Haak-Frendscho, M; Marsters, S A; Mordenti, J; Brady, S; Gillett, N A; Chen, S A; Ashkenazi, A
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
Nordgaard-Lassen, Inge; Dahlerup, Jens Frederik; Belard, Erika; Gerstoft, Jan; Kjeldsen, Jens; Kragballe, Knud; Ravn, Pernille; Sørensen, Inge Juul; Theede, Klaus; Tjellesen, Lone
Idiopathic recurrent pericarditis (IRP) is defined by 2 or more episodes of acute pericarditis of unknown etiology. Either auto-immune or auto-inflammatory diseases are suspected. Usually, non-steroidal anti-inflammatory drugs, colchicine or low dose steroid treatments are effective, however, side effects and/or non-response patients are frequent. We report on three paedriatic patients with IRP from our paediatric rheumatology unit. The patients were non-responders to standard therapy and were treated with tumour necrosis factor alpha blocking agents (anti-TNF-?) and showed significant improvement. In two patients, the treatment was tapered and then stopped following several years of therapy. Symptoms flared in the last patient when therapy was tapered more quickly. We conclude that anti-TNF-? can be useful in selected cases of IRP. PMID:23711245
Nieto González, Juan Carlos; Monteagudo Saez, Indalecio; López-Longo, Francisco Javier; Serrano, Belén; Mata Martínez, Carmen; Carreño Pérez, Luis
Purpose of the review TNF inhibitors are effective for achieving disease control in several inflammatory diseases. Although anti-TNF agents can inhibit bone loss in vitro, their role in the prevention of clinically relevant outcomes such as osteoporosis and fractures has not been clearly established. Recent findings There are many studies of the effects of TNF inhibitors on markers of bone turnover; however few have measured bone mineral density (BMD) or fractures. Most of these studies have small sample sizes and a minority had a placebo control group. Overall these studies suggest that the anti-resorptive effects of anti-TNF therapy are related to control of disease activity. Summary The antiresorptive effects of TNF inhibitors are likely related to their anti-inflammatory properties. Studies to date have not demonstrated any advantages of TNF inhibitors over traditional non biologic therapies in the prevention of bone loss and fractures.
Kawai, Vivian K.; Stein, C. Michael; Perrien, Daniel S.; Griffin, Marie R.
Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease that dramatically impairs quality of life. A number of compounds are available to treat RA, but they vary in effectiveness. Thus, no optimal treatment strategy has been defined. Currently, disease-modifying anti-rheumatic drugs (DMARDs) and anti-tumor necrosis factor-alpha (anti-TNF-?) agents are considered the treatments of choice. For patients with inadequate responses to
Juan Jin; Yan Chang; Wei Wei
Cytokines such as tumor necrosis factor (TNF) are expressed at high levels in rheumatoid joint tissue, where they contribute significantly to inflammation and articular destruction. TNF was the first cytokine to be fully validated as a therapeutic target for rheumatoid arthritis (RA). In nearly a decade since anti-TNF agents—such as infliximab, etanercept and adalimumab—were launched as the first biologic therapies
Marc Feldmann; Peter C. Taylor
Sleep disturbances and problems are increased in ankylosing spondylitis (AS). But much is not known in a quantitative way about sleep problems and effect of treatments on AS. This study is aimed first, to investigate sleep disturbances in AS and secondly, to evaluate the effects of anti-TNF treatment on SD in AS. One hundred seventy-one (Female/male: 90/81) AS patients fulfilling modified New York criteria and 86 (F/M: 56/30) age- and gender-matched controls without inflammatory diseases were included into the study. Demographic data and disease activity and treatments were recorded using The Bath Ankylosing Spondylitis Functional Index (BASFI) and The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The Medical Outcomes Study (MOS) Sleep Questionnaire was used for evaluating sleep and problems of sleep. AS patients had higher sleep disturbance scale (SDS) and sleep problem index (SPI) II scores. Group A (patients using NSAID and/or DMARD, 53.2% of patients) had higher BASDAI and BASFI compared with Group B (Patients using anti-TNF treatments) (4.29 ± 2.38 vs. 2.46 ± 2.32, p < 0.001; 1.95 ± 2.15 vs. 0.93 ± 1.31, p < 0.001, respectively). Whereas Group A had higher scores of SDS, awaken short of breath or headache, somnolence, and SPI-II than controls, none of the sleep parameters were statistically different between patients on anti-TNF treatments and controls. BASDAI was positively correlated with SPI-I, SPI-II, SDS, and somnolence scale. AS patients had increased sleep problems and disturbances compared with controls. Anti-TNF agents improve significantly these problems. Sleep problems are significantly correlated with the disease activity. PMID:21448640
Karada?, Omer; Nakas, Dilek; Kalyoncu, Umut; Akdo?an, Ali; Kiraz, Sedat; Ertenli, Ihsan
La terapia occupazionale nell'artrite reumatoide: studio prospettico a breve termine in pazienti in trattamento con farmaci anti-TNF-alfa Occupational therapy in rheumatoid arthritis: short term prospective study in patients treated with anti-TNF-alpha drugs
SUMMARY Objective: to assess the effect of occupational therapy (OT) in rheumatoid arthritis (RA) patients treated with anti- TNF-alpha drugs in a short-term open controlled prospective study. Methods: 31 RA subjects ((M\\/F=5\\/26; mean age= 56 (range=28-73) years; mean disease duration= 165 (range =15- 432) months), treated with anti- TNF-alpha drugs, were allocated to OT (n=15) or control (n=16) group. We
F. Pasqui; L. Mastrodonato; F. Ceccarelli; R. Scrivo; L. Magrini; V. Riccieri; M. Di Franco; M. Gentili; G. Valesini; A. Spadaro
The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections’ development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don’t reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence.
Benucci, M; Saviola, G; Baiardi, P; Manfredi, M; Sarzi Puttini, P; Atzeni, Fabiola
BACKGROUND: Substantial progress has been made in the medical management of rheumatoid arthritis (RA) over the past decade with the introduction of biologic therapies, including anti-tumour necrosis factor alpha (anti-TNF?) therapy medications. However, individuals with RA taking anti-TNF? medication continue to experience physical, psychological and functional consequences, which could potentially benefit from rehabilitation. There is evidence that therapeutic exercise should
Angela Reid; Audrey Brady; Catherine Blake; Anne-Barbara Mongey; Douglas J Veale; Oliver FitzGerald; Tara Cusack
Anemia is one of the extra-articular findings of ankylosing spondylitis (AS), and anti-TNF therapy has been shown benefit in patients with anemia associated AS. In this study, we aimed to evaluate and compare the effects of biological and non-biological agents on hemoglobin levels in AS patients. One hundred consecutive patients who fulfilled ASAS criteria for AS were included in the study. Fifty-four of the patients treated with anti-TNF agents (20 patients treated with infliximab, 20 patients with adalimumab, and 14 patients with etanercept), and 46 patients treated with non-steroidal anti-inflammatory drugs and/or other disease modifying anti-rheumatic drugs. The C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), hemoglobin (HGB), hematocrit (HCT) counts, and BASDAI scores were compared before starting therapy and at 52 weeks. There was no statistically significant difference between patients about demographical data (age, sex) and disease age (p > 0.05 for all). Significant difference was determined between HGB, HCT, CRP, ESR, and BASDAI values before and after therapy (for infliximab p: 0.001; 0.000; 0.000; 0.000; 0.000, respectively, and for adalimumab p: 0.017; 0.03; 0.001; 0.002; 0.000, respectively). In etanercept group, there was no significant difference in HGB values, when compared with before starting therapy and at 52 weeks (p > 0.05). In the group of treated with non-biological agents, ESR values and BASDA? scores showed distinctive improvement after 52 weeks of therapy, but was not a significant difference in hemoglobin and hematocrit values. Conclusion: Anti-TNF-alpha therapy with monoclonal antibodies (adalimumab and infliximab) did not only suppress disease activity but also provided a significant improvement in HGB levels. In the groups of treated with a TNF-alpha receptor antagonist (ETA) and non-biological agents, disease activity was suppressed, but there was not founded significant improvement in HGB levels after 52 weeks. Different outcomes of anti-TNF agents may be associated with their different effect mechanisms. PMID:23143665
Bes, Cemal; Yazici, Ayten; Soy, Mehmet
INTRODUCTION: Rat adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) feature bone loss and systemic increases in TNF?, IL-1?, and receptor activator of NF-?B ligand (RANKL). Anti-IL-1 or anti-TNF? therapies consistently reduce inflammation in these models, but systemic bone loss often persists. RANKL inhibition consistently prevents bone loss in both models without reducing joint inflammation. Effects of these therapies on systemic
Marina Stolina; Georg Schett; Denise Dwyer; Steven Vonderfecht; Scot Middleton; Diane Duryea; Efrain Pacheco; Gwyneth Van; Brad Bolon; Ulrich Feige; Debra Zack; Paul Kostenuik
Aim. In Crohn's disease (CD), anti-TNF-? treatment is a potent medication. We aimed to characterize the effect of anti-TNF-? treatment on T effector and regulatory cells. Material and Methods. We studied T-effector and regulatory cells on cellular and mRNA levels in intestinal biopsy samples from 13 Crohn's disease patient. Biopsies were obtained at baseline and 3 months after anti-TNF-? treatment, and from 14 inflammation-free control subjects. Results. Patients had higher numbers of ileal IL-17+ and forkhead box P3 (FOXP3)+ cells than did control subjects, both before ( P ? 0.001 and P ? 0.05, resp.) and after the anti-TNF-? treatment (P ? 0.01, P ? 0.01). Intestinal interferon-? and IL-17 mRNA expression was higher in Crohn's disease and remained elevated after anti-TNF-? treatment. The ratio of IL-17+ cells to CD4+ cells decreased (P ? 0.05) and compared to baseline the ratio of IL-17+ cells to FOXP3+ was lower after treatment (P ? 0.05). Conclusions. TNF-?-blocking agents improved intestinal balance between IL-17+ T-effector and regulatory T cells, although intestinal IL-17 upregulation remained elevated.
Holtta, Veera; Sipponen, Taina; Westerholm-Ormio, Mia; Salo, Harri M.; Kolho, Kaija-Leena; Farkkila, Martti; Savilahti, Erkki; Vaarala, Outi; Klemetti, Paula
Anecdotal reports have shown that tumour necrosis factor (TNF)-? inhibition may cause unchecked superficial infection with the microorganisms responsible for pityriasis versicolor (PV). We observed several cases of PV, which is frequently resistant to topical therapies, in psoriatic patients undergoing anti-TNF-? monoclonal antibody therapy. To evaluate the incidence and the therapeutic management of PV in this group of individuals, between 1 January and 27 December 2010, we examined 153 psoriatic patients for the hypopigmented/hyperpigmented macular and scaling lesions associated with PV. All patients positive for PV were given topical therapy with miconazole nitrate cream twice daily for 28 days, after which they were re-evaluated. In patients non-responsive to topical therapy, we started systemic therapy with fluconazole, 300 mg week(-1) for 3 weeks. We diagnosed seven cases of PV. At the end of topical treatment, complete healing of lesions was observed in only one patient. In the other six patients, systemic treatment led to complete resolution of the infection. Although the onset of PV during anti-TNF-? therapy is seldom reported, it is not likely to be rare, but rather under-reported because of its limited pathological significance. In our opinion, the therapeutic management of this condition deserves greater consideration, as the use of topical treatments alone is largely ineffective compared with systemic treatment. PMID:22283428
Balestri, Riccardo; Rech, Giulia; Piraccini, Bianca Maria; Antonucci, Angela; Ismaili, Alma; Patrizi, Annalisa; Bardazzi, Federico
Background. Allergy to cat dander is a common form of allergic disease. Allergen immunotherapy has been demonstrated to be effective in decreasing allergic symptoms. Objectives. To examine outcomes in allergic asthmatic patients on cat immunotherapy (CIT) compared to allergic asthmatics on traditional immunotherapy (IT) without cat sensitivity. Methods. A retrospective review identified allergic asthmatics on CIT for at least three years. An equal number of allergic asthmatics on IT were identified for comparison. Outcomes investigated include measurements of risk of asthma exacerbation. Results. Thirty-five patients were identified in each group. There were no differences in the CIT group versus the comparison group regarding total number of prednisone tapers (18 tapers versus 14 tapers, resp.), number of patients requiring prednisone tapers (10 patients versus 10 patients, resp.), total number of acute visits (29 visits versus 38 visits, resp.), and number of patients requiring acute visits (15 patients versus 21 patients, resp.). When stratified by concomitant ICS use, patients on CIT were less likely to require an acute visit (46% versus 78%, resp.). Conclusions. Allergic asthmatics with cat sensitivity on CIT with close dander exposure have similar risk of asthma exacerbation compared to allergic asthmatics without cat sensitivity on immunotherapy.
Williams, Aerik A.; Cohn, John R.; Fung, Shirley M.; Padams, Patricia
BackgroundAnti-tumour necrosis factor (TNF) therapy may be associated with opportunistic infections (OIs).ObjectiveTo describe the spectrum of non-tuberculosis OIs associated with anti-TNF therapy and identify their risk factors.MethodsA 3-year national French registry (RATIO) collected all cases of OI in patients receiving anti-TNF treatment for any indication in France. A case–control study was performed with three controls treated with anti-TNF agents per
D Salmon-Ceron; F Tubach; O Lortholary; O Chosidow; S Bretagne; N Nicolas; E Cuillerier; B Fautrel; C Michelet; J Morel; X Puéchal; D Wendling; M Lemann; P Ravaud; X Mariette
Listeria monocytogenes is an aerobic gram positive intracellular bacillus, predominantly affecting pregnant women, immunocompromised patients and old individuals. Invasive listeriosis, meningitis and meningoencephalitis, bacteraemia with or without joint, eye or heart focalization are clinical manifestations of the disease. Anti-TNF-? drugs blocking the host's response against various microorganisms, particularly intracellular agents like Listeria monocytogenes, increase the risk of disease. We report two cases of L. monocytogenes meningitis in ulcerative colitis patients under infliximab plus steroids. One patient is HIV-1 infected. A review of reported invasive listeriosis cases under anti-TNF drugs is also showed. PMID:22626505
Abreu, Cândida; Magro, Fernando; Vilas-Boas, Filipe; Lopes, Susana; Macedo, Guilherme; Sarmento, António
Inflammatory bowel disease affects women in their peak reproductive years. Increased disease activity during pregnancy has been associated with adverse outcomes. Thus, it is recommended that immunosuppressant medications be continued during pregnancy. However, data regarding the safety of these medications during pregnancy are sparse and often conflicting. The study by Casanova et al. (1) adds to the growing evidence that the use of thiopurines and anti-TNF? agents during pregnancy does not increase the risk of birth defects. Results from prospective studies with longer follow-up are needed to fully understand the impact of thiopurines and anti-TNF? agents on child development and maturation of the immune system. PMID:23459048
Sheibani, Sarah; Mahadevan, Uma
Objectives: Our aim was to compare an AntiCD20 therapy (rituximab) for rheumatoid arthritis in two patient populations (Group 1), anti-TNF? naïve patients and inadequate responders to Anti-TNF? therapy (Group 2). Methods: We analyzed the efficacy of the drug Rituximab (RTX) in RA patients who failed methotrexate (MTX) or had a relative or absolute contraindication to receive anti-TNF? therapy. Results: 25 patients were identified according to the above criteria and followed up for a mean period of 6 months. Thirteen patients were biologic naïve and twelve patients had already failed anti-TNF? therapy. Group 1 used 2> DMARDs (32% vs 20%, p<0.005), group 2 had more years of disease progression (5±1.89 v s4.10±3.92, p<0.001). The remission as measured by the DAS28 reached faster in group 1 (1.25±0.12 vs 2.15±1.64, p<0,001). Severe infections especially by herpes viruses were more frequent in group 2. Conclusions: Comparing clinical improvement in both groups the decrease of acute phase reactants and the clinical remission measured by DAS28 was reached in both groups, however it was reached more belatedly in group 2 (at 6 months), this is due to the fact that they have more years of the disease evolution and a higher HAQ.
Gutierrez-Gonzalez, Luis Arturo; Gudino, Marco Antonio Rivera; Ceija, Ibell Oropeza; Leonet, Marialina Marin; Noguera, Zair Tovar
Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It is usually chronic and challenging to treat. Some antidepressants are first-line pharmacological treatments for neuropathic pain. The noradrenaline that is recruited by the action of the antidepressants on reuptake transporters has been proposed to act through ?2-adrenoceptors (?2-ARs) to lead to the observed therapeutic effect. However, the complex downstream mechanism mediating this action remained to be identified. In this study, we demonstrate in a mouse model of neuropathic pain that an antidepressant's effect on neuropathic allodynia involves the peripheral nervous system and the inhibition of cytokine tumor necrosis factor ? (TNF?) production. The antiallodynic action of nortriptyline is indeed lost after peripheral sympathectomy, but not after lesion of central descending noradrenergic pathways. More particularly, we report that antidepressant-recruited noradrenaline acts, within dorsal root ganglia, on ?2-ARs expressed by non-neuronal satellite cells. This stimulation of ?2-ARs decreases the neuropathy-induced production of membrane-bound TNF?, resulting in relief of neuropathic allodynia. This indirect anti-TNF? action was observed with the tricyclic antidepressant nortriptyline, the selective serotonin and noradrenaline reuptake inhibitor venlafaxine and the ?2-AR agonist terbutaline. Our data revealed an original therapeutic mechanism that may open novel research avenues for the management of painful peripheral neuropathies. PMID:23978467
Bohren, Yohann; Tessier, Luc-Henri; Megat, Salim; Petitjean, Hugues; Hugel, Sylvain; Daniel, Dorothée; Kremer, Mélanie; Fournel, Sylvie; Hein, Lutz; Schlichter, Rémy; Freund-Mercier, Marie-José; Yalcin, Ipek; Barrot, Michel
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
Guidi, Luisa; Felice, Carla; Procoli, Annabella; Bonanno, Giuseppina; Martinelli, Enrica; Marzo, Manuela; Mocci, Giammarco; Pugliese, Daniela; Andrisani, Gianluca; Danese, Silvio; De Vitis, Italo; Papa, Alfredo; Armuzzi, Alessandro; Rutella, Sergio
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.
Procoli, Annabella; Bonanno, Giuseppina; Martinelli, Enrica; Danese, Silvio; De Vitis, Italo; Papa, Alfredo; Armuzzi, Alessandro; Rutella, Sergio
La presenza del fattore reumatoide, la disabilità ed il numero di precedenti anti-TNF? falliti predicono la risposta clinica a rituximab nell'artrite reumatoide* Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF? agents failed are associated with response to rituximab in rheumatoid arthritis
SUMMARY Objective: Predictors of response to biologics in rheumatoid arthritis (RA) is an important issue in the current era. Rituximab (RTX) has been demonstrated effective and safe in active RA, resistant to traditional or biologic DMARDs. Methods: Fifty-seven patients with active longstanding RA were treated with RTX after traditional DMARD or anti- TNF alpha therapy failure. Results: Number of anti-TNF
L. Quartuccio; S. Salvin; M. Saracco; S. Lombardi; M. Fabris; E. Mansutti; M. Maset; S. Pellerito; S. De Vita
Introduction. –Current slow-acting anti-rheumatic drugs available for rheumatoid arthritis can fail for certain severe cases; some are used empirically. Improvements in our knowledge of its pathogenesis and advances in molecular biology have made it possible to develop partially selective immunotherapy approaches.Current knowledge and key points. –Tumor necrosis factor- ? (TNF-?) is a critical inflammatory mediator in rheumatoid arthritis and may
B. Mugnier; G. Bouvenot
Objectives To compare the risk of keratinoctye skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) in patients treated for rheumatoid arthritis (RA) compared with the general population, and to determine whether anti-tumour necrosis factor (TNF) therapy exacerbates this risk. Methods Patients with RA enrolled in the British Society for Rheumatology Biologics Register, a prospective national cohort established in 2001 to monitor the safety of anti-TNF, were followed until 2008. 11 881 patients treated with anti-TNF were compared with 3629 patients receiving non-biological disease-modifying antirheumatic drugs (nbDMARD). Standardised incidence ratios (SIR) were calculated for each cohort and rates between cohorts were compared using Cox proportional HR, adjusted using inverse probability of treatment weighting. Results SIR for skin cancer was increased in both cohorts compared with the English population: SIR 1.72 (95% CI 1.43 to 2.04) anti-TNF; 1.83 (95% CI 1.30 to 2.50) nbDMARD only. In patients without previous skin cancer, BCC incidence per 100 000 patient-years was 342 (95% CI 290 to 402) after anti-TNF and 407 (95% CI 288 to 558) after nbDMARD. HR after anti-TNF adjusted for treatment weighting was 0.95 (95% CI 0.53 to 1.71). SCC incidence per 100 000 patient-years: anti-TNF 53 (95% CI 33 to 79); nbDMARD 43 (95% CI 12 to 110); adjusted HR 1.16 (95% CI 0.35 to 3.84). Conclusions Skin cancers were increased among treated patients with RA. No evidence was found that anti-TNF therapy exacerbates the risk of BCC or SCC but this cannot be excluded. Patients with RA should use sun protection and be monitored for skin cancer.
Mercer, Louise K; Green, Adele C; Galloway, James B; Davies, Rebecca; Lunt, Mark; Dixon, William G; Watson, Kath D; Symmons, Deborah PM; Hyrich, Kimme L
The therapeutic use of (a) radiation-inactivated tumor cells, (b) Bacillus Calmette-Guérin (BCG), and (c) heparinized plasma from normal mice to reduce radiation-induced impairment of existing antitumor resistance was investigated in female C3H\\/He hosts of syngeneic mammary carcinoma implants. The mice, which had been moderately presensitized 50 days before challenge, were given 300 rad whole-body irradiation at various times up to
Multiple myeloma is still a fatal disease. Despite advances in high-dose chemotherapy, stem cell transplantation, and the development of novel therapeutics, relapse of the underlying disease remains the primary cause of treatment failure. Strategies for post-transplantation immunomodulation are desirable for eradication of remaining tumor cells. To this end, immunotherapy aimed at inducing myeloma-specific immunity in patients has been explored. Idiotype protein, secreted by myeloma cells, has been the primary target for immunotherapy as it is the best defined tumor-specific antigen. This chapter focuses on novel immunotherapies that are being developed to treat patients with myeloma. I will discuss potential myeloma antigens, antigen-specific T cells and their function on myeloma tumor cells, and T-cell-based and antibody-based immunotherapies for myeloma. Furthermore, clinical studies of T-cell-based immunotherapy in the form of vaccination, allogeneic stem cell transplantation and donor lymphocyte infusions, with or without donor vaccination using patient-derived idiotype, and future application of donor-derived or patient-derived, antigen-specific T-cell infusion in this disease are also discussed. Based on the specificity of the immune effector molecules and cells, immunotherapies with specific T cells or therapeutic antibodies may represent novel strategies for the treatment of multiple myeloma in the near future.
Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent fever, peritonitis/pleuritis, or arthritis attacks. Patients may have FMF-associated mutations of pyrin. The role of biologics such as anti-tumor necrosis factor (TNF) agents (infliximab, etanercept, adalimumab, golimumab) and anakinra, canakinumab, or rilonacept in the treatment of FMF needs to be clarified. Herein we present reports of three patients (all were positive for HLA B27) with typical spondylitis associated with FMF who were successfully managed with anti-TNF agents, along with a literature review. The patients were a 37-year-old man with concomitant Crohn's disease and amyloidosis who was treated with infliximab (INF, 5 mg/kg for 3 years) and switched to adalimumab (ADA), and two female patients (a 24-year-old and a 31-year-old) with FMF who developed severe spondylitis and who were also treated with ADA. Anti-TNF agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF-associated amyloidosis and spondylitis. PMID:21567247
Ozgocmen, Salih; Akgul, Ozgur
Drug-induced lupus erythematosus (DILE) is a lupus-like syndrome temporally related to continuous drug exposure which resolves upon drug discontinuation. There are currently no standard diagnostic criteria for DILE. Findings include skin manifestations, arthritis, serositis, anti-nuclear and anti-histone antibodies positivity. Similarly to idiopathic lupus erythematosus, DILE can be divided into systemic (SLE), subacute cutaneous (SCLE) and chronic cutaneous lupus (CCLE). Systemic DILE presents as a milder version of idiopathic SLE, and the drugs most frequently implicated are hydralazine, procainamide and quinidine. Anti-TNF? therapies are the latest class of medications found to be associated, although rarely, with a "lupus-like" syndrome, which is however clinically distinct from classical DILE. Drug-induced SCLE is the most common form of DILE. It is very similar to idiopathic SCLE in terms of clinical and serologic characteristics. The most commonly implicated drugs are antihypertensive drugs and terbinafine, but in recent years also proton pump inhibitors and chemotherapeutic agents have been associated. Drug-induced CCLE is very rare and usually caused by fluorouracil agents and NSAIDS, but some cases have induced by pantoprazole and anti-TNF? agents. PMID:22937775
Dalle Vedove, Camilla; Simon, Jan C; Girolomoni, Giampiero
Drug-induced lupus erythematosus (DILE) is a lupus-like syndrome temporally related to continuous drug exposure which resolves upon drug discontinuation. There are currently no standard diagnostic criteria for DILE. Findings include skin manifestations, arthritis, serositis, anti-nuclear and anti-histone antibodies positivity. Similarly to idiopathic lupus erythematosus, DILE can be divided into systemic (SLE), subacute cutaneous (SCLE) and chronic cutaneous lupus (CCLE). Systemic DILE presents as a milder version of idiopathic SLE, and the drugs most frequently implicated are hydralazine, procainamide and quinidine. Anti-TNF? therapies are the latest class of medications found to be associated, although rarely, with a “lupus-like” syndrome, which is however clinically distinct from classical DILE. Drug-induced SCLE is the most common form of DILE. It is very similar to idiopathic SCLE in terms of clinical and serologic characteristics. The most commonly implicated drugs are antihypertensive drugs and terbinafine, but in recent years also proton pump inhibitors and chemotherapeutic agents have been associated. Drug-induced CCLE is very rare and usually caused by fluorouracil agents and NSAIDS, but some cases have induced by pantoprazole and anti-TNF? agents.
Dalle Vedove, Camilla; Simon, Jan C; Girolomoni, Giampiero
The objectives of this study are to evaluate the effect of anti-drug antibodies on the clinical efficacy and withdrawal rate of the anti-TNF? biologics in patients with rheumatic diseases. Consecutive patients with rheumatic diseases recently commenced on anti-TNF? biologics were recruited. Serum samples were collected for assay of drug level and antibody titer against the corresponding biologics. Comparison of the clinical efficacy and drug retention rate was performed between patients with and without anti-drug antibodies. Fifty-eight Chinese patients were studied (64 % women; age 47.8?±?12.9 years; disease duration 6.7?±?6.4 years). The proportion of patients using infliximab (IFX), adalimumab (ADA), and etanercept (ETN) was 41, 28, and 31 %, respectively. Antibodies against IFX, ADA, and ETN were demonstrated in 12(50 %), 5(31 %) and 0(0 %) patients, respectively. Patients who developed anti-drug antibodies had significantly lower levels of the corresponding drugs (IFX level: 0.004?±?0.01 vs 3.81?±?3.49 ?g/ml; p?=?0.002; ADA level: 0.0 vs 7.6?±?8.3 ?g/ml; p?=?0.008). Anti-drug antibody-positive patients had a significantly higher cumulative drug withdrawal rate due to inefficacy (64.7 and 71.8 % vs 10.3 and 10.3 % at month 12 and month 24, respectively; p?0.001). In rheumatoid arthritis and psoriatic arthritis, non-responders was significantly more frequent in antibody-positive patients (54 vs 13 %; p?=?0.01). In spondyloarthritis, the improvement in ankylosing spondylitis disease activity score was significant in patients without antibodies (3.89?±?0.82 to 2.22?±?0.86; p?=?0.01) but not in those with anti-drug antibodies (3.40?±?1.67 to 3.23?±?1.40; p?=?0.73). We concluded that the presence of neutralizing antibodies is associated with lower serum levels of the anti-TNF? biologics, leading to lower efficacy and higher withdrawal rate. PMID:23887439
Mok, C C; van der Kleij, D; Wolbink, G J
Objective. A prospective study was conducted in order to establish whether AS patients, who are defined as non-responders after 3 months of anti-TNF therapy, show improvement on performance-based tests of physical functioning. Methods. At baseline and 3 months after the start of anti-TNF therapy, AS patients completed seven performance-based tests of physical functioning, questionnaires on self-reported physical functioning (BASFI) and disease activity (BASDAI), and a pain and a global patient assessment. The concordance between ?20% intra-individual improvement on the performance-based test of physical functioning and (i) response to anti-TNF therapy [Assessment of SpondyloArthritis International Society 20% (ASAS20) response] and (ii) ?20% intra-individual improvement on self-reported physical functioning (BASFI) was assessed. Results. One hundred AS patients were included, of which 82 patients completed all tests at both time points. After 3 months of anti-TNF therapy, 27 (32.9%) patients were categorized as non-responders according to the ASAS20 response criteria. Improvement in performance-based physical functioning was seen in 13 of the 27 non-responders (48.1%) (i.e. n = 13/82 = 15.9% of the total group). Furthermore, 30 (36.6%) patients showed no improvement on self-reported physical functioning (BASFI). However, 17 of the 30 (56.7%) patients did improve on the performance-based tests of physical functioning (i.e. n = 17/82 = 20.7% of the total group). Conclusion. After 3 months of anti-TNF therapy, performance-based tests of physical functioning showed improvement in 48.1% of the ASAS20 non-responders. With these performance-based tests, new information on outcome after anti-TNF therapy can be generated. Using performance-based tests alongside the BASFI could have additional value in the evaluation of outcomes for patients receiving anti-TNF therapy. PMID:23864170
van Weely, Salima F E; van Denderen, J Christiaan; Steultjens, Martijn P M; Nurmohamed, Michael T; Dijkmans, Ben A C; Dekker, Joost; van der Horst-Bruinsma, Irene E
Juvenile idiopathic arthritis (JIA) is an inflammatory disease associated with bone loss and low bone mineral density (BMD). The treatment involves disease-modifying antirheumatic drugs, glucocorticoids (GCs) and biological agents. The aim of this study was to evaluate effects of 12-month therapy with the anti-tumor necrosis factor alpha (anti-TNF?) preparations on bone mineral density (BMD) and biochemical turnover markers (BTM) in adult patients with JIA who were previously either treated or not treated with glucocorticoids (GC) and to assess effects of the discontinuation of GCs on their bone status. Nineteen adult patients (12 women, 7 men) aged 18-33 years with active JIA were prospectively enrolled to receive the anti-TNF? therapy (infliximab, etanercept or adalimumab). BMD and BTMs were determined at baseline and 1-year follow-up. The anti-TNF? therapy resulted in a significant reduction in disease activity score 28 (DAS28) and C-reactive protein (CRP) and a significant increase in BMD at the lumbar spine and total body and in serum N-terminal propeptide of type I procollagen (PINP, marker of bone formation). No significant changes in serum beta C-terminal telopeptide of type I collagen (?CTX, marker of osteoclastic bone resorption) and osteocalcin (marker of bone remodeling) were found. A significant negative correlation was observed between the change in the DAS28, CRP and serum PINP. The change in serum PINP concentrations positively correlated with the change in lumbar spine BMD. A significant increase in serum PINP was observed only in patients discontinuing GCs during the anti-TNF? treatment. After the initiation of the anti-TNF? therapy in young adults with JIA, the increase in new bone formation can be explained by discontinuation of GCs administration as the patients with the largest reduction in DAS28 and CRP probably are the ones most likely to stop GC. PMID:23370856
Brabnikova Maresova, Kristyna; Jarosova, Katerina; Pavelka, Karel; Stepan, Jan J
Melanoma immunotherapy has been an area of intense research for decades, and this work is now yielding more tangible results for patients. Work has focused on 4 main areas: cytokine therapy, administration of immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Cytokine therapy is an established treatment for advanced melanoma, and immune-modulating antibodies have recently emerged as an exciting new area of drug development with efficacy now established in a phase III trial. Adoptive T-cell therapy provides the proof of principle that T cells can attack and eliminate tumors. It has been challenging, however, to adapt this treatment for widespread use. Vaccines have generally yielded poor results, but intratumor pathogen-based strategies have shown encouraging results in recent trials, perhaps due to stronger immune stimulation. A review of the field of melanoma immunotherapy is provided here, with emphasis on those agents that have reached clinical testing. Novel strategies to induce the immune system to attack melanomas are reviewed. In the future, it is envisioned that immunotherapy will have further application in combination with cytotoxic and targeted therapies. PMID:21105125
Sivendran, Shanthi; Glodny, Bradley; Pan, Michael; Merad, Miriam; Saenger, Yvonne
Allergen-specific immunotherapy has been carried out for almost a century and remains one of the few antigen-specific treatments for inflammatory diseases. The mechanisms by which allergen-specific immunotherapy exerts its effects include the modulation of both T-cell and B-cell responses to allergen. There is a strong rationale for improving the efficacy of allergen-specific immunotherapy by reducing the incidence and severity of
Cezmi A. Akdis; Rudolf Valenta; Mark Larché
Background Nonetheless biologic modifier therapies are available treatment strategies for sight-threatening uveitis in children, the lack of evidence from head-to-head randomized controlled studies limits our understanding of timing of therapy when to commence therapy, which agent to choose and how long to continue treatment, and, in case of failure, if switching to another anti-TNF-? strategy might be eventually an option. Our aim was to compare the efficacy of Adalimumab when used as first anti-TNF? therapy versus Adalimumab used after the failure of a previous anti-TNF? (Infliximab) in an open-label, comparative, multi-center, cohort study of childhood chronic uveitis. Methods 26 patients (14 F, 12 M; median age: 8.6 years) with refractory, non-infectious active uveitis were enrolled. Due to the refractory course of uveitis to previous DMARD treatment, Group 1 received Adalimumab (24 mg/sq mt, every 2 weeks), as first anti-TNF? choice; Group 2 received Adalimumab, as second anti-TNF? drug, due to the loss of efficacy of Infliximab, administered after a period of at least 1 year. Both groups received Adalimumab for at least 1 year of treatment. Primary outcome was, once remission was achieved, the time to a first relapse. Results 14 children (10 with JIA, 3 with idiopathic uveitis, 1 with Behçet’s disease) were recruited in Group 1; 12 children (7 with JIA, 3 with idiopathic uveitis, 1 with early-onset sarcoidosis, 1 with Behçet’s disease) in Group 2. Group 2 showed a lower probability to steroid discontinuation during the first 12 months of treatment (Mantel-Cox ?24.12, p<0.04). In long-term follow-up, Group 1 had higher probability of uveitis remission during the time of treatment on Adalimumab (median ±SE: 18 ±1.1 vs 4 ±0.6 months, CI 95%: 15.6-27.5 vs 2.7-5.2, Mantel-Cox ?210.12, p<0.002). Conclusions Even if limited to a relatively small group, our study suggests a better efficacy of Adalimumab when used as first anti-TNF? treatment in childhood chronic uveitis.
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.
Marant, Claire; Arnould, Benoit; Marrel, Alexia; Spizak, Cederic; Colombel, Jean-Frederic; Faure, Patrick; Hagege, Herve; Lemann, Marc; Nahon, Stephane; Tucat, Gilbert; Vandromme, Luc; Thibout, Emmanuel; Goldfarb, Gerard
Alzheimer’s disease (AD) is a growing health care epidemic. It is the most common cause of dementia and its incidence is rising. Age, which influences the oxidative and inflammatory states of the brain, is the most important risk factor. Currently there is no disease modifying treatments available for this irreversible, progressive debilitating disease. Immunotherapy represents an emerging, potentially disease modifying strategy aimed at reducing the pathological lesions of AD and facilitating cognitive improvement. Many clinical trials are currently underway. This literature review highlights current knowledge regarding the physiology of aging and how it relates to the pathogenesis of AD. In addition, immunotherapy is discussed in the context of its mechanism, current studies and future goals.
Madeo, Jennifer; Frieri, Marianne
The remarkable specificity of the immune system through antigen recognition has long attracted investigators to the possibility of immune-based therapy for cancer. Previous cancer immunotherapeutics had been restricted to non-specific immunomodulatory agents, such as the cytokines IL-2 or IFN-?. However, the molecular definition of cancer-associated antigens introduced the possibility of specific vaccines and adoptive T cell approaches aiming to target the tumor cells more specifically. The recent introduction of total exome sequencing has enabled the identification of patient tumor-specific epitopes generated through somatic point mutations, raising the possibility of targeting tumor antigens in individual patients which are even more tumor-specific. Transcriptional profiling and immunohistochemistry analyses have revealed a subset of patients with a pre-existing T cell-inflamed tumor microenvironment. This phenotype may be predictive of clinical outcome to immunotherapies and offers the possibility of a predictive biomarker. Further analysis of these tumors has identified a set of defined immune suppressive factors which themselves are being targeted with new immunotherapeutics, already with interesting early phase clinical trial results. Understanding not only the expression of tumor antigens but also the dynamic between a growing tumor and the host immune response is thus generating a rich set of opportunities for the specific immunotherapy of cancer.
Gajewski, Thomas F.
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.
Braun, J; Davis, J; Dougados, M; Sieper, J; van der Linden, S; van der Heijde, D
The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. CD4+ T cells comprise a large proportion of the inflammatory cells that invade the synovial tissue and may therefore be a cell type of pathogenic importance. Both methotrexate and infliximab are effective in the treatment of inflammatory arthritis; however, the biological effects triggered by these treatments and the biochemical mechanisms underlining the cell response are still not fully understood. Thus, in this study the global metabolic changes associated with methotrexate or infliximab treatment of isolated human CD4+ T cells were examined using gas chromatography/mass spectrometry or liquid chromatography/mass spectrometry. In total 148 metabolites involved in selective pathways were found to be significantly altered. Overall, the changes observed are likely to reflect the effort of CD4+ cells to increase the production of cellular reducing power to offset the cellular stress exerted by treatment. Importantly, analysis of the global metabolic changes associated with MTX or infliximab treatment of isolated human CD4+ T cells suggested that the toxicity associated with these agents is minimal when used at clinically relevant concentrations. PMID:23974102
Chimenti, Maria Sole; Tucci, Paola; Candi, Eleonora; Perricone, Roberto; Melino, Gerry; Willis, Anne E
Objective: To develop and compare candidate improvement criteria for anti-TNF? treatment in ankylosing spondylitis with optimal discriminating capacity between treatment and placebo. Methods: Data from two randomised controlled trials which included 99 patients treated with infliximab or etanercept were used to evaluate 50 candidate improvement criteria. These were developed on the basis of pain, patient's global assessment, function, morning stiffness, spinal mobility, and C reactive protein. Different levels of improvement in each domain (20–60%) were used to define Boolean type criteria. These criteria were compared with different percentages of improvement on the BASDAI and with modified ASAS improvement criteria. Bootstrap methods were applied to calculate 95% confidence intervals (CI) of the ?2 test values to select the best candidate improvement criteria. Results: The best performing improvement criteria were "20% improvement in five of six domains" (?2 = 31.9 (95% CI, 18.0 to 46.9)) with a low placebo response of 2.9% and a high response to infliximab of 67.7%; and "ASAS 40% improvement" (?2 = 26.5 (13.3 to 41.1)), with response to placebo of 5.7% and response to infliximab of 64.7%. The good discriminating capacity of the two improvement criteria was confirmed by the combined dataset of the infliximab and etanercept trial. Conclusions: The "five of six" improvement criterion has the advantage of including the objective domains spinal mobility and acute phase reactants, but requires only 20% improvement. The ASAS 40% improvement criterion has the advantage of setting a high threshold, but only in patient reported outcomes. The choice between these improvement criteria needs to be based on further validation from upcoming trials.
Brandt, J; Listing, J; Sieper, J; Rudwaleit, M; van der Heijde, D; Braun, J
Background Inflammatory bowel disease (IBD) and resultant colitis occurring prior to puberty are frequently associated with delayed puberty and losses of growth and bone mineralization. Some of this delay may be due to colonic inflammation and associated systemic inflamma- tion. To date no treatments for IBD have been shown to normalize the timing of puberty. Our objective in this study was to determine whether there is a normalization of the timing of puberty during treatment of colitis using mono- clonal antibodies (abs) to tumor necrosis factor (TNF)-?. Methods We induced colitis in 23-day-old C57Bl6 female mice using 3% dextran sodium sulfate (DSS) for 7 days, followed by removal of DSS for an additional 3 days, resulting in 10 days of worsening colitis. DSS- treated mice received either TNF-? ab or Control ab on days 4 and 8 of colitis, while non-colitic Control mice received injections of TNF-? ab (Control + TNF-? ab). All groups were followed for the timing of vaginal opening until day of life 33, when they were euthanized for serum and colon collection. Results The DSS + TNF-? ab group had lower levels of systemic interleukin (IL)-6 and a partial normalization of the timing of vaginal opening compared to the DSS + Control ab group. There were no differences in weight gain, growth, or colon histological inflammatory scores between the DSS + TNFa ab and DSS + Control ab groups over the course of the experiment. Conclusions We conclude that anti-TNF-? ab treatment causes a partial normalization of pubertal timing coincident with decreased systemic inflammation in DSS colitis. These data may have implications regarding growth and bone mineralization outcomes in pediatric IBD.
DeBoer, Mark Daniel; Steinman, Jeremy; Li, Yongli
Purpose With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage. Methods Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated. Results Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ?HA and ?C2C/CPII from baseline to week 54 correlated significantly with not only ?CRP, but also ?DAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ?HA to ?DAS28 disappeared, whereas correlations of ?C2C/CPII to ?DAS28, ?JNS, and ?HAQ remained significant. These results suggest a role of ?C2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation. Conclusion The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ?C2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3.
Niki, Yasuo; Takeuchi, Tsutomu; Nakayama, Masanori; Nagasawa, Hayato; Kurasawa, Takahiko; Yamada, Harumoto; Toyama, Yoshiaki; Miyamoto, Takeshi
The idea of exploiting the immune system to treat tumors (cancer immunotherapy) is at least a century old. Immunotherapy is generally classified into two functional approaches: Passive immunotherapy administers preformed elements of the immune system (tumor-reactive antibodies, antitumor cytokines, or tumoricidal effector\\u000a cells) to patients with the intent that these agents will directly attack the cancer cells. Active immunotherapy (including
Denise R. Shaw; Albert F. LoBuglio
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
Bendtzen, Klaus; Geborek, Pierre; Svenson, Morten; Larsson, Lotta; Kapetanovic, Meliha C; Saxne, Tore
Specific allergen injection immunotherapy is highly effective in selected patients with IgE-mediated disease, including respiratory allergy and venom anaphylaxis. Research in this area provides insight into the immunologic basis of allergic disease and may assist in the development of more highly targeted treatment. Immunotherapy reduces immediate allergen-induced symptoms and concentrations of inflammatory mediators, including histamine and prostaglandin D2, in ragweed-sensitive
Stephen R. Durham; Stephen J. Till
The therapeutic effects of the combination of chemotherapy (cyclophosphamide and actinomycin D) and immunotherapy (TNF-? and macrophages) were evaluated on L1210 leukemia in mice. When given as single agents, both cyclophosphamide (CY), administered intraperitoneally 2 days after subcutaneous inoculation of leukemic cells, and actinomycin D (Act D), injected intratumorally (i.t.) 4 days following injection of leukemic cells, exerted therapeutic effects
Witold Lasek; Magdalena Sora; Anna Wa?kowicz; Marek Jakóbisiak
Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) are major components of the immune suppressive cells that potentially limit the effectiveness of an immunotherapy-based treatment. Both of these suppressive cell types have been shown to expand in tumor models and promote T-cell dysfunction that in turn favors tumor progression. This study demonstrates that Listeria monocytogenes (Lm)-LLO immunotherapies effect on the suppressive ability of MDSC and Treg in the tumor microenvironment (TME), resulting in a loss in the ability of these cells to suppress T cells. This alteration of immunosuppression in the TME was an inherent property of all Lm-LLO immunotherapies tested and was independent of the tumor model. The virtually total loss in the suppressive ability of these cells in the TME was linked to the reduction in the expression of arginase I in MDSC and IL-10 in Treg. The results presented here provide insight into a novel mechanism of Lm-LLO immunotherapies that potentially contributes to therapeutic antitumor responses. PMID:24145358
Wallecha, Anu; Singh, Reshma; Malinina, Inga
Active immunotherapy products (widely known as “cancer vaccines”) are products intended to stimulate an immune response to mediate tumor destruction or reduce the progression of disease in patients where cancer has been diagnosed. Some quality attributes of these products are very difficult to characterize or present a high variability (especially if they are for autologous use), further complicating the interpretation of some of the clinical data. Furthermore, questions arise in the evaluation of efficacy and safety data in comparison with current chemical or biological treatments for the same indications. Some of these aspects are discussed in this paper in relationship with the regulatory requirements in the European Union and as applied to two recently assessed medicinal products, Oncophage and Provenge, both considered therapeutic “cancer vaccines” for renal cell carcinoma and prostate cancer, respectively.
Camarero, Jorge; Ruiz, Sol
The efficacy of allergen immunotherapy for the treatment of allergic rhinoconjunctivitis with or without seasonal bronchial asthma and anaphylaxis caused by the sting of the hymenoptera class of insects has been clearly demonstrated in numerous well-designed, placebo-controlled trials. Immunotherapy whether by subcutaneous injection of allergen extract or by oral/sublingual routes modifies peripheral and mucosal TH2 responses in favour of TH1 responses and augments IL-10 synthesis by TRegs both locally and by peripheral T cells. Recent researches into the cellular and molecular basis of allergic reactions have advanced our understanding of the mechanisms involved in allergic diseases. They have also helped the development of innovative approaches that are likely to further improve the control of allergic responses in the future. Novel approaches to immunotherapy that are currently being explored include the use of peptide-based allergen preparations, which do not bind IgE and therefore do not activate mast cells, but reduce both Th1 and Th2-cytokine synthesis, while increasing levels of IL-10. Alternative strategies include the use of adjuvants, such as nucleotide immunostimulatory sequences derived from bacteria CpG or monophosphoryl lipid A that potentiate Th1 responses. Blocking the effects of IgE using anti-IgE such as omalizumab, a recombinant humanized monoclonal antibody that selectively binds to IgE, has been shown to be a useful strategy in the treatment of allergic asthma and rhinitis. The combination of anti-IgE-monoclonal antibody omalizumab with allergen immunotherapy has proved beneficial for the treatment of allergic diseases, offering improved efficacy, limited adverse effects, and potential immune-modifying effects. This combination may also accelerate the rapidity by which immunotherapy induces TReg cells. If allergic diseases are due to a lack of allergen-specific TReg cells, then effective therapies should target the induction and the development of TReg cells producing cytokines such as IL-10. PMID:18319521
Nouri-Aria, Kayhan T
A single-dose cynomolgus monkey pharmacokinetic study was performed comparing two monoclonal anti-TNF antibodies (mAbs), GNExTNFvF and Humira. Normal pharmacokinetic profiles were observed over the first week of the study, followed by a rapid drop in serum mAb levels after day 8. In order to determine whether an anti-therapeutic antibody (ATA) response led to the abnormal clearance of antibody in this study, ATA assays were developed using two electrochemiluminescent technologies, BioVeris and Meso Scale Discovery (MSD). Characterization of the assays demonstrated that the two platforms gave similar sensitivities and tolerance to the presence of therapeutic antibody. Analysis of the cynomolgus monkey serum samples revealed that all animals developed significant ATA titers with log titer values of 2-4, with the BioVeris and MSD technologies giving very similar results. Immunodepletion studies confirmed the CDR-specificity of the ATA response for the GNExTNFvF-dosed cynos, although the Humira-dosed cynos showed both CDR-specific and human IgG1 framework-specific ATAs. To further characterize the ATA response, neutralizing antibody (NAb) assays were developed using two different approaches, flow cytometry and MSD. Flow cytometry and MSD cell-binding assays used Jurkat cells transfected with noncleavable TNF (huTNF(NC)). Neutralizing activity was assessed by the ability of ATA-positive serum samples to block the binding of biotinylated anti-TNF to huTNF(NC) Jurkat cells, showing that all but one animal developed neutralizing antibodies. Although both technologies displayed similar trends, the MSD approach showed greater differentiation between samples and could detect a broader range of neutralizing activities. PMID:19345224
Loyet, Kelly M; Deng, Rong; Liang, Wei-Ching; Wu, Yan; Lowman, Henry B; DeForge, Laura E
Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. Here, we review the major immunotherapeutic approaches currently under investigation for colorectal cancer, including cancer vaccines and adoptive cell therapy. Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval, and mainstream adoption of colorectal cancer immunotherapeutics. PMID:23725603
Xiang, Bo; Snook, Adam E; Magee, Michael S; Waldman, Scott A
T lymphocytes require signaling by the T cell receptor and by nonclonotypic cosignaling receptors. The costimulatory and inhibitory signals profoundly influence the course of immune responses by amplifying or reducing the transcriptional effects of T cell receptor triggering. The inhibitory receptors such as CTLA-4, PD-1, and BTLA have recently drawn much attention as potential targets for immunotherapies. This review focuses on the progress that has been made with the mentioned receptors in the field of immunotherapies for autoimmune diseases, malignancies, infectious diseases, and transplantation.
Wu, Yan-Ling; Liang, Jing; Zhang, Wen; Tanaka, Yoshimasa; Sugiyama, Hiroshi
In the past decade, we have witnessed important gains in the treatment of ovarian cancer; however, additional advances are required to reduce mortality. With compelling evidence that ovarian cancers are immunogenic tumors, immunotherapy should be further pursued and optimized. The dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory antibodies, create new opportunities in ovarian cancer therapeutics. Herein, we review current progress and future prospects in vaccine and adoptive T-cell therapy development as well as immunomodulatory therapy tools available for immediate clinical testing.
Kandalaft, Lana E.; Powell, Daniel J.; Singh, Nathan; Coukos, George
T lymphocytes require signaling by the T cell receptor and by nonclonotypic cosignaling receptors. The costimulatory and inhibitory signals profoundly influence the course of immune responses by amplifying or reducing the transcriptional effects of T cell receptor triggering. The inhibitory receptors such as CTLA-4, PD-1, and BTLA have recently drawn much attention as potential targets for immunotherapies. This review focuses on the progress that has been made with the mentioned receptors in the field of immunotherapies for autoimmune diseases, malignancies, infectious diseases, and transplantation. PMID:23197939
Wu, Yan-Ling; Liang, Jing; Zhang, Wen; Tanaka, Yoshimasa; Sugiyama, Hiroshi
Clinical trials employing immunotherapy frequently involve patients with many different types of cancer. Accordingly, this Cancergram focuses on the immunotherapy employed rather than the disease diagnosis. Adoptive, active specific, and active non-specif...
Clinical trials employing immunotherapy frequently involve patients with many different types of cancer. Accordingly, this Cancergram focuses on the immunotherapy employed rather than the disease diagnosis. Adoptive, active specific, and active nonspecifi...
Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4–6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor response in vivo.
Niccolai, Elena; Prisco, Domenico; D'Elios, Mario Milco; Amedei, Amedeo
Objectives:(1) To show that a single-chain Fv antibody (scFv) against tumour necrosis factor ? (TNF?) (ESBA105) has efficacy comparable to a full length anti-TNF? IgG (infliximab); (2) to evaluate whether ESBA105 has all the properties required for the local treatment of arthritis; and (3) to investigate its discriminative tissue penetration properties.Methods:In vivo efficacy was measured in arthritis of the knee
D M Urech; U Feige; S Ewert; V Schlosser; M Ottiger; K Polzer; G Schett; P Lichtlen
While bone marrow edema (BME) is diagnostic of spondyloarthropathy, its nature remains poorly understood. In contrast, BME in ankylosing spondylitis is caused by TNF-induced vascular and cellular changes. To investigate the relationship between chronic compression and TNF signaling in compression induced BME we utilized a tail vertebrae compression model with WT, TNF-Tg and TNFR1&2?/? mice to evaluate: 1) healing following release of chronic compression, 2) induction of BME in the absence of TNFR, and 3) efficacy of anti-TNF therapy. Compression-induced normalized marrow contrast enhancement (NMCE) in WT was significantly decreased 3-fold (p<0.01) within 2 weeks of release, while the NMCE values in TNF-Tg vertebrae remained elevated, but had a significant decrease (p<0.05) by 6 weeks after the release of compression. TNFR1&2?/? mice were resistant to compression-induced BME. Anti-TNF therapy did not affect NMCE vs. placebo. Histological examination revealed that NMCE values significantly correlated with marrow vascularity and cellularity (p<0.05), which account for 76% of the variability of NMCE. Collectively, these data demonstrate a critical role for TNF in the induction of chronic compression-induced BME, but not in its maintenance. Amelioration of BME is achieved through biomechanical stability, but is not affected by anti-TNF therapy.
Papuga, M. Owen; Kwok, Edmund; You, Zhigang; Rubery, Paul T.; Dougherty, Paul E.; Pryhuber, Gloria; Beck, Christopher A.; Hilton, Matthew J.; Awad, Hani A.; Schwarz, Edward M.
Anti-TNF-Alpha-Adalimumab Therapy Is Associated with Persistent Improvement of Endothelial Function without Progression of Carotid Intima-Media Wall Thickness in Patients with Rheumatoid Arthritis Refractory to Conventional Therapy
To determine whether treatment with the anti-TNF-alpha blocker adalimumab yields persistent improvement of endothelial function and prevents from morphological progression of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) refractory to conventional therapy, a series of 34 consecutive RA patients, attending hospital outpatient clinics and who were switched from disease modifying antirheumatic drug therapy to anti-TNF-alpha-adalimumab treatment because of severe disease, were assessed by ultrasonography techniques before the onset of adalimumab therapy (at day 0) and then at day 14 and at month 12. Values of flow-mediated endothelium-dependent vasodilatation at day 14 and at month 12 were significantly higher (mean ± standard deviation (SD): 6.1 ± 3.9%; median: 5.7% at day 14, and mean ± SD: 7.4 ± 2.8%; median: 6.9% at month 12) than those obtained at day 0 (mean: 4.5 ± 4.0%; median: 3.6%; P = 0.03 and P < 0.001, resp.). Endothelium-independent vasodilatation results did not significantly change compared with those obtained at day 0. No significant differences were observed when carotid artery intima-media wall thickness values obtained at month 12 (mean ± SD: 0.69 ± 0.21?mm) were compared with those found at day 0 (0.65 ± 0.16?mm) (P = 0.3). In conclusion, anti-TNF-alpha-adalimumab therapy has beneficial effects on the development of the subclinical atherosclerosis disease in RA.
Gonzalez-Juanatey, Carlos; Vazquez-Rodriguez, Tomas R.; Miranda-Filloy, Jose A.; Gomez-Acebo, Ines; Testa, Ana; Garcia-Porrua, Carlos; Sanchez-Andrade, Amalia; Llorca, Javier; Gonzalez-Gay, Miguel A.
While bone marrow edema (BME) is diagnostic of spondyloarthropathy, its nature remains poorly understood. In contrast, BME in ankylosing spondylitis is caused by tumor necrosis factor (TNF)-induced vascular and cellular changes. To investigate the relationship between chronic compression and TNF signaling in compression-induced BME we utilized a tail vertebrae compression model with WT, TNF-Tg, and TNFR1&2-/- mice to evaluate: (i) healing following release of chronic compression, (ii) induction of BME in the absence of TNFR, and (iii) efficacy of anti-TNF therapy. Compression-induced normalized marrow contrast enhancement (NMCE) in WT was significantly decreased threefold (p?0.01) within 2 weeks of release, while the NMCE values in TNF-Tg vertebrae remained elevated, but had a significant decrease (p?0.05) by 6 weeks after the release of compression. TNFR1&2-/- mice were resistant to compression-induced BME. Anti-TNF therapy did not affect NMCE versus placebo. Histological examination revealed that NMCE values significantly correlated with marrow vascularity and cellularity (p?0.05), which account for 76% of the variability of NMCE. Collectively, these data demonstrate a critical role for TNF in the induction of chronic compression-induced BME, but not in its maintenance. Amelioration of BME is achieved through biomechanical stability, but is not affected by anti-TNF therapy. PMID:21445993
Papuga, M Owen; Kwok, Edmund; You, Zhigang; Rubery, Paul T; Dougherty, Paul E; Pryhuber, Gloria; Beck, Christopher A; Hilton, Matthew J; Awad, Hani A; Schwarz, Edward M
Allergen specific immunotherapy, together with drugs and allergen avoidance, is a cornerstone in the management of respiratory allergy. The traditional subcutaneous route is burdened with the risk of severe adverse events; therefore, safer routes of administration (noninjection or local routes) have been investigated and developed. Controlled trials failed to demonstrate the clinical efficacy and the safety of oral and bronchial
Giorgio Walter Canonica; Giovanni Passalacqua
Conclusion The future certainly holds promise for the treatment of food allergies. Generally, future treatments can be divided into immunological\\u000a manipulation of the food-allergic subject (mucosal vaccines, new immunotherapies, cytokine level alterations) or manipulation\\u000a of the food through genetic engineering to diminish or abolish its allergenic activity.
Samuel B. Lehrer; Laurianne G. Wild; Kenneth L. Bost; Ricardo U. Sorensen
Anticancer immunotherapy holds great promises, as long-term responses to interleukin-2 have been observed in metastatic melanoma and renal cell carcinoma patients. However, improving the relative low rates of such responses has constituted a great challenge. In our experience, high-dose radiation combined with interleukin-2 provided encouraging results that are worth exploring further.
Seung, Steven K.; Curti, Brendan; Crittenden, Marka; Urba, Walter
In the year 2003, subcutaneous allergen immunotherapy continues to be the gold standard in the etiological treatment of allergic diseases affecting the respiratory tract because (1) it acts simultaneously on all the affected parts of this system, (2) it is effective over a long term after it has been stopped, (3) it can alter the natural course of the allergic
E Alvarez-Cuesta; A Beristain
Current management of food allergy involves strict avoidance, education on recognizing and managing allergic reactions, and carrying an adrenaline autoinjector. This approach is burdensome and associated with reduced quality of life. Patients with food allergy would benefit greatly from a treatment that could achieve desensitization or long-term tolerance. Recent studies have shown that oral immunotherapy (OIT) can induce desensitization and modulate allergen-specific immune responses; however, it remains uncertain whether OIT can induce long-term tolerance. Nevertheless, successful desensitization provides a major advance in management by reducing the risk of reaction to low amounts of allergen. Allergic reactions during OIT are common, although severe reactions are less common. Therefore, OIT should be performed in specialist centers under close medical supervision and would ideally be conducted as part of ongoing research studies. OIT holds promise as a novel approach to managing food allergy. PMID:19063824
Tang, Mimi L K
This article summarizes and provides commentary regarding guidelines on the administration of immunotherapy (IT) for allergic airway disease. Recent investigations have provided important insights into the immunologic mechanism of IT and the prominent role of interleukin-10-producing regulatory T lymphocytes. The most important aspect of successful IT is the administration of an appropriate dose of an extract containing a sufficient concentration of the relevant allergen. This is largely possible now only with standardized extracts. When the major allergen content of successful IT extracts was quantified, efficacy was demonstrated across a surprisingly narrow concentration range (approximately 5-24 ?g per injection), irrespective of the extract. This presumably reflects the concentration of an antigen that drives an immune response toward tolerance. It may be predicted that as major allergen content is quantified in currently nonstandardized extracts, effective IT will also be achieved by administering a dose in this range, in contrast to current practices involving fairly arbitrary dosing decisions. With the availability of nonsedating antihistamines, intranasal corticosteroids, and the leukotriene modifiers, inadequate pharmacologic response or intolerable side effects are less commonly the major indications for starting IT for allergic rhinitis (AR). However, with the recognition that a relatively short course (3-5 years) of IT can provide long-term immunomodulation and clinical benefit, a desire to avoid long-term pharmacotherapy and the associated high costs may be the primary indication for IT in AR cases. While evidence overwhelmingly supports the beneficial influences of IT in asthma cases, the positioning of IT for this disorder is not established. The observed prevention of asthma in children who have AR is intriguing, but further studies are required to assess the extent to which the prevalence and severity of chronic asthma will be reduced when these children reach adulthood. Similarly, safety issues overwhelmingly suggest that uncontrolled asthma is the greatest risk factor for mortality associated with IT and that IT therefore may be contraindicated for most patients who have inadequate pharmacologic responses or are unable to tolerate useful pharmacologic agents. Paradoxically, these are the patients for whom a response to IT may be most desirable.
Food allergies are caused by immune responses to food proteins and represent a breakdown of oral tolerance. They can range from mild pruritis to life-threatening anaphylaxis. The only current consensus for treatment is food avoidance, which is fraught with compliance issues. For this reason, there has been recent interest in immunotherapy, which may induce desensitization and possibly even tolerance. Through these effects, immunotherapy may decrease the potential for adverse serious reactions with accidental ingestions while potentially leading to an overall health benefit. In this review, we discuss the mechanisms of food allergy and give an overview of the various immunotherapeutic options and current supporting evidence, as well as look towards the future of potential novel therapeutic modalities.
Kamdar, Toral; Bryce, Paul J
Allergen-specific immunotherapy in the treatment of allergic rhinitis has a well-documented clinical efficacy that indicates\\u000a a statistically significant and clinically relevant reduction in symptom scores and the need for pharmacotherapy. The clinical\\u000a efficacy of recently published studies is equivalent to or superior to the effect of standard antiallergic drugs. Additional\\u000a advantages are related to a downregulation of the allergic phenotype
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.
Kirkwood, John M.; Butterfield, Lisa H.; Tarhini, Ahmad A.; Zarour, Hassane; Kalinski, Pawel; Ferrone, Soldano
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 immunotherapy Updating national healthcare policies to support allergen specific immunotherapy Prioritising funding for allergen specific immunotherapy research Monitoring the macroeconomic and health economic parameters of allergy Reinforcing allergy teaching in medical disciplines and specialties The effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade.
Our immune system is characterized by remarkable specificity, potency, and memory -- the ability of a single vaccine treatment to provide life-long protection. No pharmacologic treatment for any indication can provide the same level of safety, efficacy, and long-lasting effect that a vaccine can. Thus, researchers and clinicians alike have sought to apply these characteristics to the treatment of cancer. Yet, for the last 125 years, the field has failed to realize this potential. Here, we will review some of the most promising cancer immunotherapeutic approaches in development today, as recent clinical successes signal the beginning of cancer immuno-therapy's transition from experimental to established therapy. PMID:23449114
Snook, Adam E; Waldman, Scott A
Most cancer patients are treated with some combination of surgery, radiation, and chemotherapy. Despite recent advances in local therapy with curative intent, chemotherapeutic treatments for metastatic disease often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore, the evaluation of novel therapeutic options is of great interest. Conventional, along with newer treatment strategies target the immune system that suppresses genitourinary (GU) malignancies. Metastatic renal cell carcinoma and non-muscle-invasive bladder caner represent the most immune-responsive types of all human cancer. This review examines the rationale and emerging evidence supporting the anticancer activity of immunotherapy, against GU malignancies.
Inamoto, Teruo; Azuma, Haruhito
Therapeutic cancer vaccination, e.g. by using tumour antigen-presenting dendritic cells (DCs) that 'educate' the immune system to recognise and attack tumour cells, represents a new concept of treatment in oncology. DCbased immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DCs emerge as a feasible and effective strategy to control residual disease in acute myeloid leukaemia (AML), in particular as a post-remission treatment to prevent full relapse. This innovative approach takes advantage of the intrinsic potential of the immune system to eradicate malignant disease. PMID:23340144
Van De Velde, A L R; Anguille, S; Berneman, Z N
Over the past several decades, rheumatology has directed its focus to understanding and countering the immune dysregulation underlying autoimmune diseases with rheumatologic manifestations. Older therapies, effective though poorly understood, are being scrutinized anew and are yielding the immune-modulating mechanisms behind their efficacy. New therapies, the "biologics," are drugs tailored to address specific immune defects and imbalances. This article discusses the current standard and biologic immunotherapies of the rheumatic diseases, correlating our current understanding of their mechanisms with dysfunctions believed to be present in the major autoimmune syndromes, especially rheumatoid arthritis and systemic lupus erythematosus. PMID:22703852
Miller, Anne V; Ranatunga, Sriya K M
The immune system plays a significant role in Alzheimer disease (AD). ?-Amyloid deposition in the cortex is thought to be an initiating event in AD and the widely believed amyloid hypothesis proposes removal of amyloid may delay disease progression. Human trials of active or passive immune agents have failed to show benefit and increased adverse events of vasogenic edema and microhemorrhages. Evidence suggests the illness may be too advanced by the time patients are symptomatic with dementia. Future directions include better understanding of how and where immunotherapies should be targeted and treating patients at earlier stages of the illness. PMID:23896510
Farlow, Martin R; Brosch, Jared R
Lung cancer is the leading cause of cancer-related deaths worldwide. Although treatment methods in surgery, irradiation, and chemotherapy have improved, prognosis remains unsatisfactory and developing new therapeutic strategies is still an urgent demand. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumor cells by recognition of tumor-associated antigens without damage to normal cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and phase III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumor antigens work in only a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumor cells because tumor cells escape from host immune scrutiny. Understanding of the mechanism of immune evasion regulated by tumor cells is required for the development of more effective immunotherapeutic approaches against lung cancer. This paper discusses the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer.
Ho, Ming-Yi; Tang, Shye-Jye; Sun, Kuang-Hui; Yang, Winnie
The broad applicability of allergen-specific immunotherapy for the treatment and eventually prevention of IgE-mediated allergy is limited by the poor quality and allergenic activity of natural allergen extracts that are used for the production of current allergy vaccines. Today, the genetic code of the most important allergens has been deciphered; recombinant allergens equalling their natural counterparts have been produced for diagnosis and immunotherapy, and a large panel of genetically modified allergens with reduced allergenic activity has been characterized to improve safety of immunotherapy and explore allergen-specific prevention strategies. Successful immunotherapy studies have been performed with recombinant allergens and hypoallergenic allergen derivatives and will lead to the registration of the first recombinant allergen-based vaccines in the near future. There is no doubt that recombinant allergen-based vaccination strategies will be generally applicable to most allergen sources, including respiratory, food and venom allergens and allow to produce safe allergy vaccines for the treatment of the most common forms of IgE-mediated allergies. PMID:21352238
Valenta, Rudolf; Linhart, B; Swoboda, I; Niederberger, V
Background\\/Objectives: Active and passive immunization methodologies against amyloid-? (A?) are employed to clear and reduce cerebral A?towards treatment of Alzheimer’s disease (AD) patients. The therapeutic potential of these antibodies in AD patients is limited because of adverse inflammatory reactions and cerebral hemorrhage, which are associated with the treatment. We propose a novel approach to inhibit A? production via antibodies against
Idan Rakover; Michal Arbel; Beka Solomon
Background: Grass pollen immunotherapy significantly reduces hay fever symptoms and medication requirements. Effects on seasonal asthma are less clear, and concerns over safety persist. Objective: The goal of this study was to assess the effects of grass pollen immunotherapy on symptoms, bronchial hyperresponsiveness, and quality of life in seasonal rhinitis and asthma. Methods: Forty-four patients with severe summer hay fever
Samantha M. Walker; Giovanni B. Pajno; Marcia Torres Lima; Duncan R. Wilson; Stephen R. Durham
Allergen specific immunotherapy (SIT) is the practice of administering gradually increasing doses of the specific causative allergen to reduce the clinical reactivity of allergic subjects, and is the only treatment targeting the causes of hypersensitivity and not only the symptoms, as done by drugs. The traditional, subcutaneous immunotherapy (SCIT) was burdened by the problem of systemic reactions which may be sometimes severe and - though very rarely - even fatal. This was the background to develop non injections routes for SIT and particularly sublingual immunotherapy (SLIT), that emerged as a real treatment option for respiratory allergy. A number of studies was conducted to evaluate efficacy and safety of SLIT, the first meta-analysis - including 22 placebo-controlled trials - concluded for positive results in both issues, but the number of studies on children was too low to draw definite conclusions. Since then, many other studies became available and make possible to analyze SLIT in children in its well defined aspects as well as in sides still requiring more solid data.
Marseglia, Gian Luigi; Incorvaia, Cristoforo; La Rosa, Mario; Frati, Franco; Marcucci, Francesco
Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients.
Pardee, Angela D.; Butterfield, Lisa H.
Major advances have been made in the field of immunology in the past two decades. A better understanding of the molecular and cellular mechanisms controlling the immune system, has opened the door to many innovative and promising new cancer therapies that manipulate the immune response. For instance, toll-like receptor agonists have been shown to boost immune responses toward tumors. Also, a wide array of cell-based immunotherapies utilizing T cells, NK cells, and dendritic cells have been established. Furthermore, a rapidly expanding repertoire of monoclonal antibodies is being developed to treat tumors, and many of the available antibodies have demonstrated impressive clinical responses. Here, we examine some of these immunotherapeutic approaches currently in use or testing to treat cancer, and we examine available evidence with regards to mechanism and efficacy of these treatments.
Borghaei, Hossein; Smith, Mitchell R.; Campbell, Kerry S.
This is the sixth edition of the Compendium of Tumor Immunotherapy Protocols, a publication sponsored by the International Cancer Research Data Bank, National Cancer Institute, and published on an annual basis by the International Registry of Tumor Immuno...
Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with
Jacques Banchereau; Karolina Palucka
The term 'immunotherapy' refers to treating diseases by inducing, enhancing or suppressing immune responses. As allergy is an excessive, detrimental immune reaction to otherwise harmless environmental substances, immunotherapy of allergic disease is aimed at the induction of tolerance toward sensitizing antigens. This article focuses on the historical developments, present state and future outlook for immunotherapy with haptens as a therapeutic modality for allergic contact dermatitis. Inspired by the effectiveness of immunotherapy in respiratory allergies, attempts were undertaken at curing allergic contact dermatitis by means of controlled administration of the sensitizing haptens. Animal and human experiments confirmed that tolerance to haptens can be induced most effectively when the induction of tolerance precedes attempted sensitization. In real life, however, therapy is sought by people who are already sensitized and an effective reversal of hypersensitivity seems more difficult to achieve. Decades of research on Rhus hypersensitivity led to a conclusion that immunotherapy can suppress Rhus dermatitis, however, only to a limited degree, for a short period of time, and at a high risk of side effects, which makes this method therapeutically unprofitable. Methodological problems with most available studies of immunotherapy of contact allergy to nickel make any definite conclusions impossible at this stage. PMID:21843085
Background Ovarian cancer is frequently diagnosed at an advanced stage, and although initially responsive to surgery and chemotherapy, has a high rate of recurrence and mortality. Cellular immunotherapy may offer the prospect of treatment to prevent or delay recurrent metastatic disease. Objective To provide an overview of current innovations in cellular immunotherapy for ovarian cancer, with an emphasis on dendritic cell vaccination and adoptive T cell immunotherapy. Methods Three key areas are explored in this review. First, an appraisal of the current state of the art of cellular immunotherapy for treatment of ovarian cancer. Second, a discussion of the immunological defenses erected by ovarian cancer to prevent immunological attack, with an emphasis on the role of tumor-associated regulatory T cells. Third, an exploration of innovative techniques that may enhance the ability of cellular immunotherapy to overcome ovarian tumor-associated immune suppression. Results/conclusion Ovarian cancer is recognized as a paradigm for tumor-associated immune suppression. Innovative approaches for antagonism of tumor-associated regulatory T cell infiltration and redirection of self antigen-driven regulatory T cell activation may provide the key to development of future strategies for cellular immunotherapy against ovarian cancer.
Cannon, Martin J; O'Brien, Timothy J
The use of tumour necrosis factor (TNF) antagonists (infliximab [IFN], etanercept [ETN], adalimumab [ADA]) has changed the course of many rheumatic diseases, including rheumatoid arthritis (RA). However, some questions concerning their safety have emerged since their approval because they can trigger immunisation, induce rare type I and III hypersensitivity, and cause acute and delayed reactions. The aim of this study was to evaluate the correlations between hypersensitivity reactions to biological agents, disease activity and the development of class-specific IgA and IgM antibodies against the three anti-TNF agents in patients with RA. This longitudinal observational study involved consecutive outpatients with active RA who started treatment with IFN (n=30), ETN (n=41) or ADA (n=28). Clinical data and systemic and local side effects were collected prospectively at baseline and after six months of anti-TNF treatment. Serum samples were taken at the same time points in order to measure antibodies against the TNF blockers, anti-nuclear (ANA) and anti-dsDNA antibodies. The IgA and IgM antibodies specific to all three anti-TNF-? agents were analysed using ImmunoCaP Phadia- Thermofisher especially developed in collaboration with the laboratory of Immunology and Allergy, San Giovanni di Dio, Florence. The mean age of the 99 patients (86% females) was 54.6±12.4 years, and the median disease duration was 11.2±.3.2 years (range 3-14.3). The three treatment groups were comparable in terms of age, gender, rheumatoid factor and anti-citrullinated peptide (CCP) antibody positivity, and baseline C-reactive protein levels, erythrocyte sedimentation rate, 28-joint disease activity scores, and concomitant medications. Twelve patients treated with INF (40%) had anti-IFN IgM, and two (6%) anti-IFN IgA; 19 patients treated with ADA (68%) had anti-ADA IgM, and four (6%) anti-ADA IgA; and 27 patients treated with ETN (66%) had anti-ETN IgM, and 24 (58%) anti-ETN IgA. There were five systemic reactions in the IFN group, and seven adverse local reactions in both the ADA and the ETN group. There was no correlation between drug-specific IgA and IgM antibodies (p=0.65). There was also no correlation between the antibodies and disease activity after six months of treatment (r=0.189;p=0.32). Our findings show that the development of antibodies against IFN, ADA or ETN of IgA and IgM class are not related to any decrease in efficacy or early discontinuation of anti-TNF treatment in RA patients, nor to systemic and local reactions. Further studies of larger series of RA patients are needed to confirm the relationships between the development of drug-specific antibodies, serum TNF blocker levels, and disease activity. PMID:24115967
Benucci, Maurizio; Saviola, Gianantonio; Meacci, Francesca; Manfredi, Mariangela; Infantino, Maria; Campi, Paolo; Severino, Maurizio; Iorno, Miriam; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola
The use of tumour necrosis factor (TNF) antagonists (infliximab [IFN], etanercept [ETN], adalimumab [ADA]) has changed the course of many rheumatic diseases, including rheumatoid arthritis (RA). However, some questions concerning their safety have emerged since their approval because they can trigger immunisation, induce rare type I and III hypersensitivity, and cause acute and delayed reactions. The aim of this study was to evaluate the correlations between hypersensitivity reactions to biological agents, disease activity and the development of class-specific IgA and IgM antibodies against the three anti-TNF agents in patients with RA. This longitudinal observational study involved consecutive outpatients with active RA who started treatment with IFN (n=30), ETN (n=41) or ADA (n=28). Clinical data and systemic and local side effects were collected prospectively at baseline and after six months of anti-TNF treatment. Serum samples were taken at the same time points in order to measure antibodies against the TNF blockers, anti-nuclear (ANA) and anti-dsDNA antibodies. The IgA and IgM antibodies specific to all three anti-TNF-? agents were analysed using ImmunoCaP Phadia- Thermofisher especially developed in collaboration with the laboratory of Immunology and Allergy, San Giovanni di Dio, Florence. The mean age of the 99 patients (86% females) was 54.6±12.4 years, and the median disease duration was 11.2±.3.2 years (range 3-14.3). The three treatment groups were comparable in terms of age, gender, rheumatoid factor and anti-citrullinated peptide (CCP) antibody positivity, and baseline C-reactive protein levels, erythrocyte sedimentation rate, 28-joint disease activity scores, and concomitant medications. Twelve patients treated with INF (40%) had anti-IFN IgM, and two (6%) anti-IFN IgA; 19 patients treated with ADA (68%) had anti-ADA IgM, and four (6%) anti-ADA IgA; and 27 patients treated with ETN (66%) had anti-ETN IgM, and 24 (58%) anti-ETN IgA. There were five systemic reactions in the IFN group, and seven adverse local reactions in both the ADA and the ETN group. There was no correlation between drug-specific IgA and IgM antibodies (p=0.65). There was also no correlation between the antibodies and disease activity after six months of treatment (r=0.189;p=0.32). Our findings show that the development of antibodies against IFN, ADA or ETN of IgA and IgM class are not related to any decrease in efficacy or early discontinuation of anti-TNF treatment in RA patients, nor to systemic and local reactions. Further studies of larger series of RA patients are needed to confirm the relationships between the development of drug-specific antibodies, serum TNF blocker levels, and disease activity.
Benucci, Maurizio; Saviola, Gianantonio; Meacci, Francesca; Manfredi, Mariangela; Infantino, Maria; Campi, Paolo; Severino, Maurizio; Iorno, Miriam; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola
IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review.
Johansen, Pal; von Moos, Seraina; Mohanan, Deepa; Kundig, Thomas M.; Senti, Gabriela
The formulation of therapeutic strategies to enhance immune-mediated tumor destruction is a central goal of cancer immunology. Substantive progress toward delineating the mechanisms involved in innate and adaptive tumor immunity has improved the prospects for crafting efficacious treatments. Schemes under active clinical evaluation include cancer vaccines, monoclonal antibodies, recombinant cytokines, and adoptive cellular infusions. While these manipulations increase tumor immunity in many patients, the majority still succumbs to progressive disease. Detailed analysis of subjects on experimental protocols together with informative studies of murine tumor models have begun to clarify the parameters that determine therapeutic activity and resistance. These investigations have highlighted efficient dendritic cell activation and inhibition of negative immune regulation as central pathways for intervention. This review discusses the development of genetically modified whole tumor cell vaccines and antibody-blockade of cytotoxic T lymphocyte associated antigen-4 (CTLA-4) as immunotherapies targeting these key control points. Early-stage clinical testing raises the possibility that combinatorial approaches that augment dendritic cell-mediated tumor antigen presentation and antagonize negative immune regulation may accomplish significant tumor destruction without the induction of serious autoimmune disease. PMID:16730268
Hodi, F Stephen; Dranoff, Glenn
Dendritic cells (DC) are the most potent antigen-presenting cells that initiate T cell-mediated immune responses against cancer. It has been almost a decade since the first trial of DC-based cancer immunotherapy was published. Despite the many clinical trials conducted since, few solid conclusions have been reached, and no specific-immunotherapy has routinely demonstrated meaningful anti-tumour responses. Clinical-grade DC can be obtained from three distinct cell populations in the blood - monocytes, CD34(+) progenitors or direct isolation of circulating blood DC. This review discusses the science behind DC-based cancer immunotherapy, with a particular emphasis on the use of monocyte-derived DC in melanoma clinical trials, and the various potential avenues for improvement of patient clinical response rates. PMID:18473960
Peng, Judy C; Thomas, Ranjeny; Dredge, Keith
European Academy of Allergology and Clinical Immunology - World Allergy Organization World Allergy and Asthma Congress, Milan, Italy, 22-26 June 2013 The only method aiming to permanently cure allergic disorders is allergen immunotherapy. Over the last 20 years there has been great progress in understanding the mechanisms that govern allergen immunotherapy in order to meet three basic prerequisites: safety, effectiveness and compliance. In the present summary report from the European Academy of Allergology and Clinical Immunology-World Allergy Organization Congress held last June in Milan, we review key points concerning the main axes as diagnosis, novel modalities, routes and protocols, as well as two important immunotherapy fields: food and insect venom allergy. PMID:24088073
Mitsias, Dimitris I; Kalogiros, Lampros A; Papadopoulos, Nikolaos G
Background. The aim of this study was to compare the efficacy of epicutaneous immunotherapy (EPIT) to sublingual immunotherapy (SLIT) in a model of mice sensitized to Phleum pratense pollen. Methods. BALB/c mice were sensitized by sub-cutaneous route to pollen protein extract mixed treated for 8 weeks, using sham, EPIT, or SLIT. Measurements involved the serological response and cytokine profile from reactivated splenocytes, plethysmography after aerosol challenge to pollen, cell, and cytokine contents in the bronchoalveolar lavages (BALs). Results. After immunotherapy, sIgE was significantly decreased in the treated groups compared to sham (P < 0.001), whereas sIgG2a increased with EPIT and SLIT (P < 0.001 and P < 0.005 versus sham). Reactivated splenocytes secreted higher levels of Th2 cytokines with sham (P < 0.01). Penh values were higher in sham than EPIT and SLIT. Eosinophil recruitment in BAL was significantly reduced only by EPIT (P < 0.01). Conclusion. In this model of mice sensitized to pollen, EPIT was at least as efficient as SLIT.
Mondoulet, Lucie; Dioszeghy, Vincent; Ligouis, Melanie; Dhelft, Veronique; Puteaux, Emilie; Dupont, Christophe; Benhamou, Pierre-Henri
Introduction: Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system. Some immunotherapies broadly activate the immune system while others precisely target distinct tumor antigens. Because of this heterogeneity, the side effects associated with immunotherapy can be mild and localized or more severe and systemic. Areas covered: Cytokines, adoptive cellular therapies and vaccines are the most commonly used immunotherapies for the treatment of a number of malignancies and have been used for many decades. Checkpoint blockade has recently emerged as a promising immunotherapy. The biggest benefits of immunotherapy have been demonstrated in melanoma, renal cell carcinoma and hematologic malignancies. Emerging data are highlighting the potential for broad applicability of immunotherapy in a number of solid and hematologic malignancies. Expert opinion: Immunotherapies are slowly becoming integrated into the standard of care in cancer treatment. Promising results using immunotherapy have been reported demonstrating complete remissions and cures in many patients with aggressive malignancies. The complexity and cost of engineering and administering of some forms of immunotherapy limit their use to distinct patient populations. High-throughput and cost-effective techniques are being used to broaden the applications of immunotherapy to treat cancer patients. PMID:23668362
Alatrash, Gheath; Jakher, Haroon; Stafford, Patricia D; Mittendorf, Elizabeth A
Cancer immunotherapy comprises a variety of treatment approaches, incorporating the tremendous specificity of the adaptive immune system (T cells and antibodies) as well as the diverse and potent cytotoxic weaponry of both adaptive and innate immunity. Immunotherapy strategies include antitumor monoclonal antibodies, cancer vaccines, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate immune cells or block immune inhibitory pathways (so-called immune checkpoints). Although clear clinical efficacy has been demonstrated with antitumor antibodies since the late 1990s, other immunotherapies had not been shown to be effective until recently, when a spate of successes established the broad potential of this therapeutic modality. These successes are based on fundamental scientific advances demonstrating the toleragenic nature of cancer and the pivotal role of the tumor immune microenvironment in suppressing antitumor immunity. New therapies based on a sophisticated knowledge of immune-suppressive cells, soluble factors, and signaling pathways are designed to break tolerance and reactivate antitumor immunity to induce potent, long-lasting responses. Preclinical models indicate the importance of a complex integrated immune response in eliminating established tumors and validate the exploration of combinatorial treatment regimens, which are anticipated to be far more effective than monotherapies. Unlike conventional cancer therapies, most immunotherapies are active and dynamic, capable of inducing immune memory to propagate a successful rebalancing of the equilibrium between tumor and host.
Topalian, Suzanne L.; Weiner, George J.; Pardoll, Drew M.
Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta
Marc E Weksler
Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations.
Weksler, Marc E
Specific immunotherapy (SIT) represents the only curative treatment of allergy and is, therefore, of particular interest for immunological and pharmacological research. The current understanding of immunological mechanisms underlying SIT focuses on regulatory T cells (T regs), which balance Th1 and Th2 effector functions. This ensures that allergens are recognized, but tolerated by the immune system. There is clear evidence that
Carsten B. Schmidt-Weber; Kurt Blaser
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.
De Souza Reboucas, Juliana; Esparza, Irene; Ferrer, Marta; Sanz, Maria Luisa; Irache, Juan Manuel; Gamazo, Carlos
The chemo-immunotherapy (CIT) and chemo-adoptive immunotherapy (CAIT) regimens tested in the past decade are summarized. From them we have learned a great deal about the interactions between various chemotherapeutic agents, immune modulating agents and effector cells. The most commonly reported result in multi-modality experiments with CAIT has been a synergistic enhancement in antitumor activity. Clinical trials usually demonstrated improvement in patient quality of life, an extension of survival time, and occasional complete regression of tumor. In many animal models, this enhancement often meant the complete regression and apparent cure of tumor in the animal. One mechanism by which this synergistic enhancement takes place appears to be a suppression of tumor-associated suppressor T cell activity by the chemotherapeutic agents, thereby inducing enhanced cytolytic activity against tumor by the adoptively transferred, activated effector cells. In CAIT the most commonly used drug has been cyclophosphamide. In CIT a wide variety of chemotherapy agents have been used but none of the clinical trials made use of cyclophosphamide. Thus, direct comparisons are not possible. Suggestive of the intricate regulatory processes involved, many CIT studies indicate a synergy only when specific doses of chemotherapy and immunotherapy agents are given, and in a specific sequence. CIT has become less toxic, is being handled on a cost-effective outpatient basis, while maintaining similar objective response rates to earlier inpatient treatments. In the future, CAIT and CIT will probably have an increasing role in the management of patients with specific cancers. PMID:11908930
Gomez, G G; Hutchison, R B; Kruse, C A
Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called ‘nature’s adjuvants’ and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.
Palucka, Karolina; Banchereau, Jacques
\\u000a While a majority of patients with acute lymphocytic leukemia (ALL) demonstrate response following treatment with standard\\u000a chemotherapy, subsequent progression due to the emergence of resistant disease is often encountered. The failure to eradicate\\u000a disease is most commonly observed in adult patients particularly with high-risk features such as adverse cytogenetics. In\\u000a contrast, immunotherapy may be successful in targeting chemotherapy-resistant clones. The
Jacalyn Rosenblatt; David Avigan
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.
Orentas, Rimas J.; Lee, Daniel W.; Mackall, Crystal
Introduction: Amyloid deposit and hyperphosphorylated Tau protein contribute to pathological changes seen in Alzheimer's disease (AD) and imply that removal may reverse the cognitive decline. Immunotherapy is a potential way of reducing the load of amyloid or Tau in the brain. Areas covered: This review summarizes recent clinical trials that have investigated immunotherapy to treat AD and its potential mechanisms. In addition, the potential opportunities as well as challenges of immunotherapy for AD in clinical trials are also discussed. Expert opinion: Amyloid-based immunotherapy for AD is a novel method with potential; however, some clinical trials were terminated because of the adverse effects. Further studies need to determine the following questions: (i) which is better, passive, or active immunotherapy; (ii) which could be used for the vaccine, amyloid or Tau; (iii) which is better, short- or long-antigen vaccine; and (iv) the route of delivery for antigen or antibody. PMID:24053611
Li, Yun; Liu, Yahong; Wang, Zhaojun; Jiang, Yongjun
Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-?-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment.
BACKGROUND: We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor ? (TNF-?) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). DESIGN: Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab. RESULTS: Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn's disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-?-secreting Th1 cells and IFN-?-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. CONCLUSIONS: New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions. PMID:23468464
Tillack, Cornelia; Ehmann, Laura Maximiliane; Friedrich, Matthias; Laubender, Rüdiger P; Papay, Pavol; Vogelsang, Harald; Stallhofer, Johannes; Beigel, Florian; Bedynek, Andrea; Wetzke, Martin; Maier, Harald; Koburger, Maria; Wagner, Johanna; Glas, Jürgen; Diegelmann, Julia; Koglin, Sarah; Dombrowski, Yvonne; Schauber, Jürgen; Wollenberg, Andreas; Brand, Stephan
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
Antony, S; Kuttan, R; Kuttan, G
For a long time, cancer immunotherapy has focused on the induction of tumor-specific T cell-mediated immune responses. Now, a mounting body of evidence indicates that efficient anticancer immune responses also rely on innate immunity. Tietze et al. have recently elucidated an antigen-nonspecific role for memory CD8+ T cells in cytokine-based cancer immunotherapy.
Sckisel, Gail D.; Murphy, William J.
The functioning of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Unregulated activities of these mediators can lead to the development of serious inflammatory diseases. In particular, enhanced tumour-necrosis factor-? (TNF-?) synthesis is associated with the development of rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Inhibiting TNF-? activities in these diseases
Frances Rena Bahjat; Emmanuel A. Theodorakis; Lyle L. Moldawer; Michael A. Palladino
Basic disease-modifying treatment for relapsing forms of active multiple sclerosis (MS) is now available in many countries with high prevalence rates, for this chronic inflammatory disease of the central nervous system. Several lines of evidence support early immunomodulatory treatment with either recombinant interferon-beta or glatiramer acetate, and positive results from phase III trials encourage start of treatment even in patients with clinically isolated syndromes (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for effective escalating strategies. Patients with suboptimal treatment response to basic therapy have been treated with combination therapies, cytotoxic drugs (such as mitoxantrone and cyclophosphamide) or autologous hematopoietic stem cell transplantation. Recently, the monoclonal antibody, natalizumab, was added to this armamentarium. None of these strategies have been vigorously evaluated in large randomized, controlled phase III trials with patients who failed basic therapy. Therefore, the decision to escalate immunotherapy is still based on limited evidence. This article will review potential candidates for intensified immunosuppression and call for innovative study designs to better evaluate escalating immunotherapy in MS.
Traboulsee, Anthony; Devonshire, Virginia; Oger, Joel
OBJECTIVE: Compare the radiographic progression of ankylosing spondylitis (AS) patients treated with infliximab (INF) versus historical controls (Herne cohort, HC) never treated with tumour necrosis factor (TNF)-blockers over 8 years. METHODS: Patients were selected based on the availability of lateral cervical and lumbar radiographs at baseline (BL) and after 8 years. Radiographs were scored by two blinded readers using modified Stokes AS spinal score (mSASSS). Mixed linear models were applied to compare radiographic progression between cohorts after adjustment for baseline status. RESULTS: Patients in INF (n=22) and HC (n=34) did not differ in the mSASSS status: 13.2±17.6 in INF versus 14.2±13.8 in HC (p=0.254). Both showed progression at 8 years: mean mSASSS 20.2±21.4 in INF and 25.9±17.8 in HC. After adjustment for baseline damage the mean mSASSS (SEM) at 8 years was 21.0 (1.4) in INF and 25.5 (1.1) HC (p=0.047). The mean mSASSS difference was similar in the groups between baseline and 4 years but was more pronounced in HC between 4 and 8 years (p=0.03 between groups). The mean number of syndesmophytes, although similar at baseline, differed significantly at 8 years: 1.0±0.6 new syndesmophytes/patient in INF versus 2.7±0.8 in HC (p=0.007). Adjustment for age, symptom duration, HLA-B27, Bath AS disease activity index and Bath AS function index at baseline had no influence. CONCLUSIONS: Despite limitations of patient numbers and retrospective study design, these data show increase in new bone formation in both patients treated with anti-TNF and those who did not. However, since there was even less bone formation in the INF treated group after 8 years, these data argue against a major role for the TNF-brake hypothesis. PMID:23505240
Baraliakos, Xenofon; Haibel, Hildrun; Listing, Joachim; Sieper, Joachim; Braun, Jürgen
BACKGROUND: Nonetheless biologic modifier therapies are available treatment strategies for sight-threatening uveitis in children, the lack of evidence from head-to-head randomized controlled studies limits our understanding of timing of therapy when to commence therapy, which agent to choose and how long to continue treatment, and, in case of failure, if switching to another anti-TNF-alpha strategy might be eventually an option. Our aim was to compare the efficacy of Adalimumab when used as first anti-TNFalpha therapy versus Adalimumab used after the failure of a previous anti-TNFalpha (Infliximab) in an open-label, comparative, multi-center, cohort study of childhood chronic uveitis. METHODS: 26 patients (14 F, 12 M; median age: 8.6 years) with refractory, non-infectious active uveitis were enrolled. Due to the refractory course of uveitis to previous DMARD treatment, Group 1 received Adalimumab (24 mg/sq mt, every 2 weeks), as first anti-TNFalpha choice; Group 2 received Adalimumab, as second anti-TNFalpha drug, due to the loss of efficacy of Infliximab, administered after a period of at least 1 year. Both groups received Adalimumab for at least 1 year of treatment. Primary outcome was, once remission was achieved, the time to a first relapse. RESULTS: 14 children (10 with JIA, 3 with idiopathic uveitis, 1 with Behcet's disease) were recruited in Group 1; 12 children (7 with JIA, 3 with idiopathic uveitis, 1 with early-onset sarcoidosis, 1 with Behcet's disease) in Group 2. Group 2 showed a lower probability to steroid discontinuation during the first 12 months of treatment (Mantel-Cox chi24.12, p<0.04). In long-term follow-up, Group 1 had higher probability of uveitis remission during the time of treatment on Adalimumab (median +/-SE: 18 +/-1.1 vs 4 +/-0.6 months, CI 95%: 15.6-27.5 vs 2.7-5.2, Mantel-Cox chi210.12, p<0.002). CONCLUSIONS: Even if limited to a relatively small group, our study suggests a better efficacy of Adalimumab when used as first anti-TNFalpha treatment in childhood chronic uveitis. PMID:23587261
Simonini, Gabriele; Taddio, Andrea; Cattalini, Marco; Caputo, Roberto; de Libero, Cinzia; Parentin, Fulvio; Pagnini, Ilaria; Lepore, Loredana; Cimaz, Rolando
Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease. Specific immunotherapy involves administering protein allergen to tolerise allergen reactive CD4+ T cells, thought key in driving allergic responses. Yet specific immunotherapy risks allergic reactions including anaphylaxis as a consequence of preformed allergen-specific IgE antibodies binding to the protein, subsequent cross-linking and mast cell degranulation. CD4+ T cells direct their responses to short "immunodominant" peptides within the allergen. Such peptides can be given therapeutically to induce T cell tolerance without facilitating IgE cross-linking. Peptide immunotherapy (PIT) offers attractive treatment potential for allergic disease. However, PIT has not yet been shown to be effective in children. This review discusses the immunological mechanisms implicated in PIT and briefly covers outcomes from adult PIT trials. This provides a context for discussion of the challenges for the application of PIT, both generally and more specifically in relation to children.
Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease. Specific immunotherapy involves administering protein allergen to tolerise allergen reactive CD4+ T cells, thought key in driving allergic responses. Yet specific immunotherapy risks allergic reactions including anaphylaxis as a consequence of preformed allergen-specific IgE antibodies binding to the protein, subsequent cross-linking and mast cell degranulation. CD4+ T cells direct their responses to short "immunodominant" peptides within the allergen. Such peptides can be given therapeutically to induce T cell tolerance without facilitating IgE cross-linking. Peptide immunotherapy (PIT) offers attractive treatment potential for allergic disease. However, PIT has not yet been shown to be effective in children. This review discusses the immunological mechanisms implicated in PIT and briefly covers outcomes from adult PIT trials. This provides a context for discussion of the challenges for the application of PIT, both generally and more specifically in relation to children. PMID:22409934
Mackenzie, Karen J; Anderton, Stephen M; Schwarze, Jürgen
Sublingual immunotherapy has been shown in some clinical studies to modulate allergen-specific antibody responses [with a decrease in the immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and activation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen-specific T-cell responses in atopic patients from a T helper (Th)2 to Th1 profile, there is currently a growing interest in eliciting regulatory T cells, capable of downregulating both Th1 and Th2 responses through the production of interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We discuss herein immune mechanisms involved during allergen-specific sublingual immunotherapy (SLIT), in comparison with subcutaneous immunotherapy. During SLIT, the allergen is captured within the oral mucosa by Langerhans-like dendritic cells expressing high-affinity IgE receptors, producing IL-10 and TGF-beta, and upregulating indoleamine dioxygenase (IDO), suggesting that such cells are prone to induce tolerance. The oral mucosa contains limited number of proinflammatory cells, such as mast cells, thereby explaining the well-established safety profile of SLIT. In this context, second-generation vaccines based on recombinant allergens in a native conformation formulated with adjuvants are designed to target Langerhans-like cells in the sublingual mucosa, with the aim to induce allergen-specific regulatory T cells. Importantly, such recombinant vaccines should facilitate the identification of biological markers of SLIT efficacy in humans. PMID:16409190
Moingeon, P; Batard, T; Fadel, R; Frati, F; Sieber, J; Van Overtvelt, L
Alopecia Areata (AA) is a common non-scarring alopecia directed against the anagenic hair follicle. Various treatment modalities have been used for the treatment of severe AA. Topical immunotherapy is the best documented treatment so far for severe and refractory AA. Dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphencyprone (DPCP) are the contact allergens used for this purpose. DNCB has been found to be mutagenic by the Ames test and is largely replaced by DPCP and SADBE. DPCP and SADBE are both known to be non-mutagenic compounds and have comparable efficacy results and relapse rates. SADBE requires special solvents and additives to maintain its potency and is more expensive than the rest. DPCP has a response rate varying from 60% in severe Alopecia Areata to 17% in patients with alopecia totalis or universalis, and shows about 88 to 100% high response rate in patients with patchy Alopecia Areata.
Singh, Gurcharan; Lavanya, MS
Manipulation of cell renewal pathways creates T memory stem cells that can generate a sustained and targeted immune response. These findings have broad implications for vaccine development and immunotherapy.
Koehn, Brent H; Schoenberger, Stephen P
Allergen specific immunotherapy involves the repeated administration of allergen products in order to induce clinical and immunologic tolerance to the offending allergen. Immunotherapy is the only etiology-based treatment that has the potential for disease modification, as reflected by longterm remission following its discontinuation and possibly prevention of disease progression and onset of new allergic sensitizations. Whereas subcutaneous immunotherapy is of proven value in allergic rhinitis and asthma there is a risk of untoward side effects including rarely anaphylaxis. Recently the sublingual route has emerged as an effective and safer alternative. Whereas the efficacy of SLIT in seasonal allergy is now well-documented in adults and children, the available data for perennial allergies and asthma is less reliable and particularly lacking in children. This review evaluates the efficacy, safety and longterm benefits of SCIT and SLIT and highlights new findings regarding mechanisms, potential biomarkers and recent novel approaches for allergen immunotherapy.
Cappella, Antonio; Durham, Stephen R.
... not yet available outside of clinical trials . Anti-PD-1 Drug Studies RESOURCES: Immunotherapy for melanoma skin ... Drug s Melanoma cells often have a protein called PD-L1 on their surface that helps them avoid ...
Cancer immunotherapy attempts to harness the exquisite power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is clearly capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for immunotherapy is to use advances in cellular and molecular immunology to develop strategies that effectively and safely augment antitumor responses.
Blattman, Joseph N.; Greenberg, Philip D.
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.
Animal models have clearly shown that tumor cells may be amenable to molecular manipulation which can result in immune activation and rejection of unmodified cells (Chapters 4 and 5). The challenge now is to design clinical trials which have a realistic chance of success, (although the definition of 'success' is itself an important issue [see Chapter 9]. How should such a strategy be formulated? A review of the previous fifteen years since the first (immune) gene transfer studies were reported, encompasses a great wealth of data. Unfortunately, far from crystallising a set of unifying principles, these diverse reports shroud us in a fog of uncertainty as to how best to proceed. However, if this technology is to have practical, widespread application in the treatment of cancer patients, it is necessary to identify certain critical immunological goals which any protocols should achieve. Clear elucidation of these goals, by unifying the huge amount of disparate experimental data, must eventually be accomplished. In this chapter, we have reviewed the literature covering the era of molecular immunotherapy. We propose four general goals around which widely applicable clinical protocols, not necessarily dependent upon tumour type or experimental bias, might be based and suggest how they may be achieved in the context of gene transfer. PMID:9034596
Vile, R G; Chong, H
Fungal infections still represent relevant human illnesses worldwide and some are accompanied by unacceptably high mortality rates. The limited current availability of effective and safe antifungal agents makes the development of new drugs and approaches of antifungal vaccination/immunotherapy every day more needed. Among them, small antibody(Ab)-derived peptides are arousing great expectations as new potential antifungal agents. In this topic, the search path from the study of the yeast killer phenomenon to the production of Ab-derived peptides characterized by in vitro and in vivo fungicidal activity will be focused. In particular, Abs that mimic the antimicrobial activity of a killer toxin (“antibiobodies”) and antifungal peptides derived from antibiobodies (killer peptide) and other unrelated Abs [complementarity determining regions (CDR)-based and constant region (Fc)-based synthetic peptides] are described. Mycological implications in terms of reevaluation of the yeast killer phenomenon, roles of antibiobodies in antifungal immunity, of ?-glucans as antifungal targets and vaccines, and of Abs as sources of an unlimited number of sequences potentially active as new immunotherapeutic tools against fungal agents and related mycoses, are discussed.
Magliani, Walter; Conti, Stefania; Giovati, Laura; Zanello, Pier Paolo; Sperinde, Martina; Ciociola, Tecla; Polonelli, Luciano
Immunotherapeutic strategies have become part of standard cancer treatment. Chimeric and humanized antibodies have demonstrated activity against a variety of tumors. Although the humanized anti-CD33 antibody HuM195 has only modest activity against overt acute myeloid leukemia (AML), it can eliminate minimal residual disease in acute promyelocytic leukemia. High-dose radioimmunotherapy with b-particle-emitting isotopes targeting CD33, CD45, and CD66 can potentially allow intensification of antileukemic therapy before hematopoietic stem cell transplantation. Conversely, a-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumor cell kill while sparing surrounding normal tissues. Targeted chemotherapy with the anti-CD33- calicheamicin construct gemtuzumab ozogamicin has produced remissions in relapsed AML and appears promising when used in combination with standard chemotherapy for newly diagnosed AML. T-cell recognition of peptide antigens presented on the cell surface in combination with major histocompatibility complex antigen provides another potentially promising approach for the treatment of AML. PMID:16091194
Jurcic, Joseph G
Occupational allergy to components of wheat flour is the main cause of rhinitis and asthma of workers in bakeries and similar activities. An immunological mechanism IgE-mediated is involved and the sensitising properties of some proteins of wheat where assessed. Nowadays it is possible to have an extract to be used for specific immunotherapy. The aim of this treatment should be a reduction of individual immunological reactivity and the possibility of going on the particular activity of allergic bakers, pastry makers or pizza makers. An observational crossectional retrospective study was performed on 41 sensitised workers that were diagnosed in the same occupational health unit. All underwent a subcutaneous specific immunotherapy (SCIT) with the same schedule and the same extract (Lofarma Allergeni, Milan) for 4 or more years, without avoiding their work activity. The outcome was investigated after five or ten years. Data were collected by a questionnaire. 34 subjects on 41 are still at work with an acceptable quality of life and a normal working efficiency, mainly in their small enterprises. In the "old" subgroup (19 cases), treated in the past, several bakers still at work stopped SCIT even from 4-10 years. In the "new" subgroup (15 cases), still in treatment, symptoms and drug use during the work activity resulted to be reduced or absent in the majority of cases. According to results of other immunotherapies by allergenic vaccines (pollens, mites) also for wheat flour occupational allergy a specific treatment seems to be possible and SCIT may be an useful tool to reduce and control the biological individual effects of allergy. By the occupational point of view wheat flour SCIT allows a relocation in many of cases and may be associated to other intervention of environmental prevention at workplaces, improving the relocation of occupational allergic subjects when requested. PMID:18409768
Cirla, A M; Lorenzini, R A; Cirla, P E
The protective activity of rosmarinic acid from Perilla frutescens on liver injury induced by LPS in d-GalN-sensitized mice was examined. We also investigated the effects of antitumor necrosis factor-? antibody (anti-TNF), superoxide dismutase (SOD), and aminoguanidine (AG) on this model in order to elucidate the mechanism of rosmarinic acid protection. Perilla extract (PE) and rosmarinic acid (RA) treatments significantly reduced
Naomi Osakabe; Akiko Yasuda; Midori Natsume; Chiaki Sanbongi; Yoji Kato; Toshihiko Osawa; Toshikazu Yoshikawa
Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT) was introduced as an option to subcutaneous immunotherapy (SCIT), the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5%
Cristoforo Incorvaia; Simonetta Masieri; Patrizia Berto; Silvia Scurati; Franco Frati
Over most of the 20th century, immunotherapy for cancer was based on empiricism. Interesting phenomena were observed in the areas of cancer, infectious diseases, or transplantation. Inferences were made and extrapolated into new approaches for the treatment of cancer. If tumors regressed, the treatment approaches could be refined further. However, until the appropriate tools and reagents were available, investigators were unable to understand the biology underlying these observations. In the early 1990s, the first human tumor T cell antigens were defined and dendritic cells were discovered to play a pivotal role in antigen presentation. The current era of cancer immunotherapy is one of translational research based on known biology and rationally designed interventions and has led to a rapid expansion of the field. The beginning of the 21st century brings the possibility of a new era of effective cancer immunotherapy, combining rational, immunological treatments with conventional therapies to improve the outcome for patients with cancer. PMID:12525559
Davis, Ian D; Jefford, Michael; Parente, Phillip; Cebon, Jonathan
Asthma is the most common chronic disease of childhood. Specific immunotherapy is widely used in several countries for managing allergic asthma. Many clinical trials and a meta-analysis of several studies support its efficacy to reduce the symptoms and medical requirements. The purpose of this study was to clarify the efficacy of subcutaneous immunotherapy (SCIT) in improving the symptoms and reducing medication requirements in primary school children with asthma in comparison with pharmacotherapy. A single-blind, drug-controlled clinical trial was performed. A total of 242 primary school children with allergic asthma were included in the study. The patients were recruited from subjects attending the Allergic Center in Mosul City. Their age range was 7-12 years with mean age of 10 +/- 2 years. From the total only 197 children (81%) completed the study and were eligible for analysis, of those, 85 children were managed with SCIT and 112 children were managed with pharmacotherapies only. The follow-up after 1 year indicated that the children treated with SCIT show a marked reduction in the clinical symptoms, medication requirements, and the level of serum-specific IgE when compared with children treated with conventional drugs. SCIT was effective treatment and can prevent or decrease the onset of new sensitization to the offending allergen and maintain its beneficial effect for years after discontinuation. PMID:20819323
Alzakar, Riyadh H; Alsamarai, Abdulghani Mohamad
The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8+ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8+ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of integrative cancer immunotherapies that sculpt the tumor microenvironment to promote definitive tumor rejection.
An emerging problem in chronic phase CML is molecular persistence. It is mainly due to the quiescent stem cell population that are completely insensitive to Imitinib therapy. We have developed a novel immunotherapy against CML. We have screened One-Bead-O...
P. R. Kumaresan
Food allergy is a growing health concern in the westernized world with approx. 6% of children suffering from it. A lack of approved treatment has led to strict avoidance of the culprit food proteins being the only standard of care. Nowadays in-depth research is conducted to evaluate the possible use of allergen-specific immunotherapy (SIT) as an active therapeutic option for food allergy. Various routes of administration for the immunotherapy are investigated, including subcutaneous, oral, sublingual, and epicutaneous, and some appear to be successful in inducing a temporary tolerant state. Most research has been conducted with oral immunotherapy due to its efficacious and relatively safe profile. Increasing interest is dedicated to safer and more convenient approaches, such as sublingual and epicutaneous SIT; however, doubts exist about their possible capacity to induce temporary tolerant state and permanent oral tolerance. The high frequency of allergic adverse reactions of the various approaches and the inability to achieve permanent oral tolerance have highlighted the need of refinements in the strategies. A promising strategy for preventing IgE cross-linking and thus enhancing safety of SIT, while still activating T cells, is the use of tolerogenic peptides. The implementation of such an immunotherapy approach has the potential of not only increasing the chance of achieving a permanent state of tolerance, but also improving the safety and tolerability of the therapy. Immunotherapy for food allergy is still not ready for the clinic, but current and upcoming studies are dedicated to collect enough evidence for the possible implementation of allergen-SIT as a standard treatment for food allergy. PMID:24112425
Kostadinova, Atanaska I; Willemsen, Linette E M; Knippels, Léon M J; Garssen, Johan
Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.
Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.
Immunotherapy is the generic name for treatment modalities aiming to reinforce the immune system against diseases in which the immune system plays a role. The design of an optimal immunotherapeutic treatment against chronic viruses and associated diseases requires a detailed understanding of the interactions between the target virus and its host, in order to define the specific strategies that may have the best chance to deliver success at each stage of disease. Recently, a first series of successes was reported for the immunotherapy of Human Papilloma Virus (HPV)-induced premalignant diseases but there is definitely room for improvement. Here I discuss a number of topics that in my opinion require more study as the answers to these questions allows us to better understand the underlying mechanisms of disease and as such to tailor treatment.
van der Burg, Sjoerd H
Diverse immunotherapy approaches have achieved success in controlling individual aspects of immune responses in animal models. Transfer of such immunotherapies to clinical trials has obtained some success in patients, with clinical responses observed or effective antigen specific immune responses achieved, but has had limited impact on patient survival. Key elements required to generate de novo cell-mediated antitumour immune responses in vivo include recruitment of antigen-presenting cells to the tumour site, loading these cells with antigen, and their migration and maturation to full antigen-presenting function. In addition, it is essential for antigen-specific T cells to locate the tumour to mediate cytotoxicity, emphasizing the need for local inflammation to target effector cell recruitment. We review those therapies that involve the tumour site as a target and source of antigen for the initiation of immune responses, and discuss strategies to generate and co-ordinate an optimal cell-mediated immune response to control tumours locally.
Crittenden, Marka R; Thanarajasingam, Uma; Vile, Richard G; Gough, Michael J
Factors influencing the host immune response to central nervous system (CNS) tumors are not yet well understood. This review will outline what is known about anti-tumor immune responses against CNS tumors and describe how advances in our knowledge of basic immunology may be applied to brain tumor immunotherapy. We will first focus on cellular immune system interactions involved in peripheral anti-tumor immune responses. Then, we will discuss characteristics of tumors arising within the confines of the CNS that distinguish them from peripheral neoplasms, emphasizing immune defects that seem to limit or curtail specific anti-tumor immunity against brain tumors. Finally, the current state of immune-based treatment paradigms and future directions will be discussed, paying particular attention to adoptive cellular immunotherapy and tumor vaccine approaches for the treatment of malignant gliomas. PMID:15353342
Prins, Robert M; Liau, Linda M
Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, we describe both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, supporting the concept that immune modulation of the tumor microenvironment represents a useful approach in cancer immunotherapy. PMID:23589109
Vonderheide, Robert H; Bajor, David L; Winograd, Rafael; Evans, Rebecca A; Bayne, Lauren J; Beatty, Gregory L
Immunotherapy for treatment of solid cancer mostly is an experimental treatment. In contrast, intravesical immunotherapy of superficial bladder cancer with bacille Calmette-Guérin (BCG) is clinically well established and accepted worldwide because of better results compared to topical chemotherapy. BCG is currently regarded as the most successful immunotherapy of cancer. Unfortunately the mechanism of action has not yet been fully clarified. This article gives an overview on the complex research on the mechanisms of actionhighly successful therapy. PMID:16710680
Böhle, A; Suttmann, H; Brandau, S
Specific allergen immunotherapy represents the only curative treatment of allergy. No studies have evaluated its efficacy in feline allergic asthma. We hypothesized that an abbreviated course of immunotherapy (rush immunotherapy, RIT) would blunt eosinophilic airways inflammation in experimental feline asthma induced with Bermuda grass allergen (BGA).The 6-month study included asthmatic-RIT treated cats; asthmatic-no RIT treated cats; and non-asthmatic cats. RIT
Carol R. Reinero; Jenni R. Byerly; Roy D. Berghaus; Londa J. Berghaus; Edward S. Schelegle; Dallas M. Hyde; Laurel J. Gershwin
Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment
Imatinib revolutionized gastrointestinal stromal tumor (GIST) treatment but median-progression-free-survival of unresectable/metastatic disease is < 2 y. B-RAFV600-mutated-melanoma responds to vemurafenib dramatically but median-progression-free-survival is < 9 mo. Combining imatinib with immunotherapy (peginterferon ?-2b) in GIST showed significant induction of antitumor immunity and highly promising clinical outcomes. This strategy warrants further testing in other malignancies.
Chen, Lei L.; Gouw, Launce; Sabripour, Mahyar; Hwu, Wen-Jen; Benjamin, Robert S.
Cancer immunotherapy aims to establish immune-mediated control of tumor growth by priming T-cell responses to target tumor-associated antigens. Three signals are required for T-cell activation: (i) presentation of cognate antigen in self MHC molecules; (ii) costimulation by membrane-bound receptor-ligand pairs; and (iii) soluble factors to direct polarization of the ensuing immune response. The ability of dendritic cells (DCs) to provide
Jeanette E Boudreau; Aude Bonehill; Kris Thielemans; Yonghong Wan
Both innate and adaptive immunity underpin cancer immunosurveillance. To stimulate both these arms of the immune system, we used allogeneic cells loaded with natural killer T (NKT) cell ligands and expressing tumor-associated antigens, resulting in NKT cell activation, dendritic-cell maturation and ultimately in the elicitation of adaptive T-cell responses. This approach holds great promise for the development of novel anticancer immunotherapies.
Fujii, Shin-ichiro; Shimizu, Kanako
Recent mechanistic insights obtained from preclinical studies and the approval of the first immunotherapies has motivated increasing number of academic investigators and pharmaceutical/biotech companies to further elucidate the role of immunity in tumor pathogenesis and to reconsider the role of immunotherapy. Additionally, technological advances (e.g., next-generation sequencing) are providing unprecedented opportunities to draw a comprehensive picture of the tumor genomics landscape and ultimately enable individualized treatment. However, the increasing complexity of the generated data and the plethora of bioinformatics methods and tools pose considerable challenges to both tumor immunologists and clinical oncologists. In this review, we describe current concepts and future challenges for the management and analysis of data for cancer immunology and immunotherapy. We first highlight publicly available databases with specific focus on cancer immunology including databases for somatic mutations and epitope databases. We then give an overview of the bioinformatics methods for the analysis of next-generation sequencing data (whole-genome and exome sequencing), epitope prediction tools as well as methods for integrative data analysis and network modeling. Mathematical models are powerful tools that can predict and explain important patterns in the genetic and clinical progression of cancer. Therefore, a survey of mathematical models for tumor evolution and tumor-immune cell interaction is included. Finally, we discuss future challenges for individualized immunotherapy and suggest how a combined computational/experimental approaches can lead to new insights into the molecular mechanisms of cancer, improved diagnosis, and prognosis of the disease and pinpoint novel therapeutic targets. PMID:22986455
Charoentong, Pornpimol; Angelova, Mihaela; Efremova, Mirjana; Gallasch, Ralf; Hackl, Hubert; Galon, Jerome; Trajanoski, Zlatko
Active immunotherapy products (widely known as "cancer vaccines") are products intended to stimulate an immune response to mediate tumor destruction or reduce the progression of disease in patients where cancer has been diagnosed. Some quality attributes of these products are very difficult to characterize or present a high variability (especially if they are for autologous use), further complicating the interpretation of some of the clinical data. Furthermore, questions arise in the evaluation of efficacy and safety data in comparison with current chemical or biological treatments for the same indications. Some of these aspects are discussed in this paper in relationship with the regulatory requirements in the European Union and as applied to two recently assessed medicinal products, Oncophage and Provenge, both considered therapeutic "cancer vaccines" for renal cell carcinoma and prostate cancer, respectively. PMID:22863755
Camarero, Jorge; Ruiz, Sol
The promising results of several multicenter studies during the last few years have improved the immunomodulatory treatment of multiple sclerosis (MS). The different compounds tested were shown to reduce the number of relapses and to modulate the course of disease to various extents. The transition of the results obtained in therapeutic trials into daily clinical practice is often delayed or
P. Rieckmann; K. V. Toyka
Amyloid-? (A?) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimer's disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of A? clearance on the development of tau pathology. Here we show that A? immunotherapy reduces not only extracellular A? plaques but also intracellular A? accumulation and
Salvatore Oddo; Lauren Billings; J. Patrick Kesslak; David H. Cribbs; Frank M. LaFerla
Guillain-Barré syndrome (GBS) is an acute inflammatory disorder of the peripheral nervous system thought to be due to autoimmunity for which immunotherapy is usually prescribed. To provide the best evidence on which to base clinical practice, we systematically reviewed the results of randomized trials of immunotherapy for GBS. We searched the Cochrane Library, MEDLINE and EMBASE in July 2006 and
R. A. C. Hughes; A. V. Swan; J.-C. Raphaël; D. Annane; R. van Koningsveld; Doorn van P. A
Cancer is the second most common cause of death in the world. Treatment of cancer is very challenging and immunotherapy has been developed as a potential way to fight cancer. The main obstacle with immunotherapy is that cancer cells evolve from healthy body cells in response to an accumulation of genetic mutations. As a consequence, the immune system struggles to
Patrizia Stoitzner; Florian Sparber; Christoph H Tripp
The "Cochrane Corner" is a quarterly section in the Journal that highlights systematic reviews relevant to otolaryngology-head and neck surgery, with invited commentary to aid clinical decision making. This installment features an updated Cochrane Review titled "Sublingual Immunotherapy for Allergic Rhinitis," which strengthens conclusions of the original 2003 review that sublingual immunotherapy is a safe and effective treatment strategy. PMID:21493409
Burton, Martin J; Krouse, John H; Rosenfeld, Richard M
In this review we discuss existing as well as new approaches to immunotherapy directed against infected or cancerous cells. These approaches traditionally exploit either natural components of immune system (such as cytokines, chemokines, co-stimulatory molecules and adjuvants), or monoclonal antibodies designed to target foreign agents and/or diseased cells through their molecular markers. Additional strategies in development include therapeutic vaccines, oncolytic viruses and T-cell therapies. In addition, we briefly describe a novel strategy called ReDIT (Re-Directed ImmunoTherapy), based on re-orienting the existing long-lasting immune responses (e.g. induced by measles vaccination or natural infection) towards new target molecules on the surface of infected or malignant cells. This can be principally achieved by using bi-functional protein constructs that contain an antigen carrier component and a re-directing component. The antigen carrier component can consist of the ectodomain of the measles hemagglutinin that can be recognized by antibodies and memory cells generated during previous infection or vaccination. The re-directing component consists of the specific virus- or tumor antigen-binding molecule. The fusion constructs are expected to boost existing anti-measles immunity and re-direct it against a new target, engaging the existing anti-measles immunity as an effector mechanism. Thus, ReDIT is a promising novel approach that may represent a valuable addition to immunotherapy of difficult to treat infections and tumors, as it exploits a mechanism distinct from other available therapies. PMID:23237083
Trnková, K; Pastoreková, S; Petrik, J
The aim of this study was the immunological characterization of glioblastoma cells. Glioblastoma cell lines were cultured in serum and serum-free neurobasal (NBE) medium conditions. These cell lines were characterized by flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), western blot and natural killer (NK) cell-cytotoxicity assays. A previously described NK cell expansion method that uses K562 cells expressing interleukin (IL)-15 and 4-1 BB Ligand (BBL) (K562-mb15-41BBL) was used. RT-PCR and western blots for the expression of tumor-associated antigens (TAAs), were carried out in 32 glioblastoma and seven normal brain tissues. U87 and U343 tumor cell lines showed increased expression for major histocompatibility complex (MHC)-I and -II molecules. No significant differences in the levels of CD133, MHC class I/II, MHC class I-related chain A (MICA), MICB, UL16 binding protein 1-3 (ULBP 1-3) expression in these cell lines and in NK cell cytotoxicity were observed between serum and NBE conditions. Regardless of culture conditions, U87 and U343 cell lines were sensitive to expanded NK cells, with median cytotoxicities at 4:1 effector/target ratio of 43.2% and 46.5%, respectively. In RT-PCR, U343 and U87 showed the expression of most TAAs at a high ratio compared with U251. Western blots demonstrated positive expression for BIRC5, CD99 and ERBB2 in U251, U87 and U343 cell lines and tissues. These highly-expressed TAAs such as BIRC5, CD99 and ERBB2 in glioblastoma tissue could be the targets for immunotherapy. U87 and U343 cell lines could be useful for studying the efficacy of immunotherapy related to various TAAs and NK cell immunotherapy. PMID:23749904
Jung, Tae-Young; Choi, Yoo-Duk; Kim, Young-Hee; Lee, Je-Jung; Kim, Hyung-Seok; Kim, Ju-Sun; Kim, Sang-Ki; Jung, Shin; Cho, Duck
Tumors express antigens that should induce immune-mediated rejection, but spontaneous rejection of established tumors is rare. Recent work demonstrates that one reason for the lack of tumor rejection is that tumors actively defeat host immunity. This concept forces us to rethink current approaches to harnessing potent, specific host immunity to battle cancer, most of which are based on the paradigm that inducing more antitumor immune cells alone is therapeutic. However, as I discuss in this Personal Perspective, a newer paradigm predicts that reducing tumor-driven immune suppression will be clinically beneficial. CD4+CD25+ Tregs are one mechanism of tumor-driven immune evasion that provide prototypical targets for testing novel anticancer treatment strategies within the newer paradigm.
Curiel, Tyler J.
IFN-?-adsorbed DMSA-coated magnetite nanoparticles can be used as an efficient in vivo drug delivery system for tumor immunotherapy. Magnetic nanoparticles, with adsorbed interferon-?, were targeted to the tumor site by application of an external magnetic field. A relevant therapeutic dosage of interferon in the tumor was detected and led to a notable reduction in tumor size. In general, only 10% of the total injected nanoparticles after multiple exposures were found in tissues by AC susceptibility measurements of the corresponding resected tissues. Magnetic nanoparticle biodistribution is affected by the application of an external magnetic field.
Gutiérrez, L.; Mejías, R.; Barber, D. F.; Veintemillas-Verdaguer, S.; Serna, C. J.; Lázaro, F. J.; Morales, M. P.
Warm autoimmune hemolytic anemia (WAIHA) is one of four clinical types of autoimmune hemolytic anemia (AIHA), with the characteristics of autoantibodies maximally active at body temperature. It produces a variable anemia—sometimes mild and sometimes severe. With respect to the absence or presence of an underlying condition, WAIHA is either idiopathic (primary) or secondary, which determines the treatment strategies in practice. Conventional treatments include immune suppression with corticosteroids and, in some cases, splenectomy. In recent years, the number of clinical studies with monoclonal antibodies and immunosuppressants in the treatment of WAIHA increased as the knowledge of autoimmunity mechanisms extended. This thread of developing new tools of treating WAIHA is well exemplified with the success in using anti-CD20 monoclonal antibody, Rituximab. Following this success, other treatment methods based on the immune mechanisms of WAIHA have emerged. We reviewed these newly developed immunotherapy treatments here in order to provide the clinicians with more options in selecting the best therapy for patients with WAIHA, hoping to stimulate researchers to find more novel immunotherapy strategies.
Laser immunotherapy is a special cancer treatment modality using an intratumor injection of a special formulation consisting of a novel immunoadjuvant and a laser-absorbing dye, followed by a non-invasive near-IR laser irradiation. Our early experiments using a metastatic mammary rat tumor model showed that laser immunotherapy could cause acute selective photothermal tumor destruction and induce a systemic, long-term specific anti-tumor immunity. In the current study, laser immunotherapy was used to treat metastatic prostate tumors in Copenhagen male rats. The transplantable tumors metastasize mainly to the lung and the lung cancer is usually the cause of death. Two experimental were performed in our study. The first was to study the effect of laser immunotherapy on the tumor burdens, both the primary and the metastasis in the lung. The second was to study the effect of laser immunotherapy on the long-term survival of the tumor-bearing rats. For comparison, some rat tumors were also treated by the laser-dye combination to study the photothermal effect. Tour results showed that both the photothermal effect and the laser immunotherapy could slow the growth of primary tumors and the metastatic tumors. The laser-dye-immunoadjuvant treatment resulted in more than 20 percent long-term survival rate in tumor-bearing rats. Our experimental results indicate that the laser immunotherapy has a great potential in treating metastatic tumors.
Chen, Wei R.; Ritchey, Jerry W.; Bartles, Kenneth E.; Lucroy, Michael D.; Liu, Hong; Nordquist, Robert E.
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.
Heimberger, Amy B.; Sampson, John H.
Immunotherapy involves the specific treatment of IgE-mediated allergic diseases, indicated for allergic rhinitis and conjunctivitis, allergic asthma, insect sting (bee and wasp) allergy, and food allergy (especially cow's milk, egg and wheat). Subcutaneous injection immunotherapy with pollens (both trees and grass), animal danders, insect venoms and house dust mite preparations for allergic rhinitis and asthma is effective for both adults and children. Sublingual immunotherapy indicated for allergic rhinitis caused by grass pollens (especially timothy), is effective and appears to be a safe route of administration. Specific oral tolerance induction is used in children over five years of age with severe food allergy. PMID:22312833
Valovirta, Erkka; Korhonen, Krista; Kuitunen, Mikael; Kukkonen-Harjula, Katriina; Lammintausta, Kaija; Pallasaho, Paula; Ralli, Pia; Savolainen, Johannes; Toskala, Elina; Virtanen, Tuomas
Grazax is a lyophilisate of an extract of Timothy-grass pollen (Phleum pratense) administered by the sublingual route to induce desensitization (or hyposensitization) to grass pollen in subjects with hay fever. Since allergen avoidance measures are limited in hay fever sufferers, present treatment, at least in the United Kingdom, is almost always by symptomatic medication. The effectiveness of symptomatic treatment in hay fever is variable and depends on patient compliance and the judicious prescribing of antihistamines and anti-inflammatory preparations either alone or in combination. Desensitization (hyposensitization or specific immunotherapy) by subcutaneous injection has been shown to be very efficacious and is used for patients who do not adequately respond to drug treatment. A rare side effect of desensitizing injections is anaphylaxis, and so use is limited to specialized centers. For these reasons there has been considerable interest in specific immunotherapy by the sublingual route. Grazax has recently been approved in the United Kingdom. It is commenced at least four months prior to the expected start of the grass pollen season and in line with injection immunotherapy treatment will be recommended for a period of three years with annual reviews to assess patient outcomes. Grazax grass allergen tablets are well tolerated in patients with grass pollen allergy with most adverse events being mild local reactions. There have been no instances of anaphylaxis. In randomized double-blind placebo controlled trials Grazax reduces symptoms and medication scores in adults with hay fever. The long-term effects of Grazax are currently being investigated. PMID:18174969
Kay, A B
Although cancer tends to affect the elderly, most preclinical studies are performed in young subjects. In this study, we developed a melanoma-specific cancer immunotherapy that shows efficacy in aged but not young hosts by mitigating age-specific tumor-associated immune dysfunction. Both young and aged CD4+CD25hi regulatory T cells (Tregs) exhibited equivalent in vitro T cell suppression and tumor-associated augmentation in numbers. However denileukin diftitox (DT)-mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. DT-mediated Treg depletion significantly increased myeloid-derived suppressor cell (MDSC) numbers in aged but not young mice, and MDSC depletion improved tumor-specific immunity and reduced tumor growth in aged mice. Combining Treg depletion with anti-Gr-1 antibody was immunologically and clinically more efficacious than anti-Gr-1 antibody alone in aged B16-bearing mice, similar to Treg depletion alone in young mice. In contrast, DT increased MDSC in young and aged mice following MC-38 tumor challenge, although effects were greater in aged mice. Anti-Gr1 boosted DT effects in young but not aged mice. Aged anti-tumor immune effector cells are therefore competent to combat tumor when underlying tumor-associated immune dysfunction is appropriately mitigated, but this dysfunction varies with tumor, thus also varying responses to immunotherapy. By tailoring immunotherapy to account for age-related tumor-associated immune dysfunctions, cancer immunotherapy for aged patients with specific tumors can be remarkably improved.
Hurez, Vincent; Daniel, Benjamin J.; Sun, Lishi; Liu, Ai-Jie; Ludwig, Sara M.; Kious, Mark J.; Thibodeaux, Suzanne R.; Pandeswara, Srilakshmi; Murthy, Kruthi; Livi, Carolina B.; Wall, Shawna; Brumlik, Michael J.; Shin, Tahiro; Zhang, Bin; Curiel, Tyler J.
Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy
Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.
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
Gonzales, Michael; Fratianni, Carmel; Mamillapali, Chaitanya; Khardori, Romesh
The purpose of this article is to examine the use of myeloid dendritic cells (DCs) as immunotherapy in the treatment of cancer. DCs can be stimulated either from circulating blood or bone marrow progenitor cells using cytokines, particularly granulocyte macrophage-colony-stimulating factor (GM-CSF) (e.g., sargramostim, Leukine). GM-CSF has been shown to promote maturation, mobilization, and antigen presentation of DCs in vivo or ex vivo as a therapeutic cancer vaccine. Once stimulated, DCs can present tumor antigen to naive T cells to initiate an immune response. In addition to myeloid-related DC stimulation, antitumor properties of GM-CSF include direct cytotoxicity, antiangiogenesis properties, and potential upregulation of antibody-dependent cellular cytotoxicity. Oncology nurses need to be knowledgeable regarding new therapies. Using knowledge gained through reading professional journals and self-education, nurses can inform patients of new therapies, which may increase patients' hope. PMID:17063617
Buchsel, Patricia C; DeMeyer, Elaine S
Bacterial toxins share the ability to enter host cells to target various intracellular proteins and to modulate host immune responses. Over the last 20 years, toxins and their mutated variants, as well as live attenuated bacteria, have been exploited for vaccination and immunotherapy of various infectious, malignant and autoimmune diseases. The ability of Bordetella pertussis adenylate cyclase toxin to translocate its adenylate cyclase domain across the host cell membrane, as well as the pathways of intracellular trafficking of Bacillus anthracis lethal and edema toxins, Shigella dysenteriae shiga toxin or Escherichia coli shiga-like toxin, have been repeatedly exploited for the delivery of antigenic epitopes into host cells and for stimulation of antigen-specific T cell responses. Similarly, E. coli ?-hemolysin, or effector proteins of Yersinia and Salmonella secreted by the type III secretion systems, were used to facilitate the delivery of fused heterologous proteins or peptides for antigenic presentation. Vibrio cholerae cholera toxin, E. coli heat-labile enterotoxin, B. pertussis pertussis toxin or the Cry1A protein of Bacillus thuringiensis have shown a great potential to act as adjuvants and to stimulate mucosal as well as systemic immune responses. The immunotherapeutic potential of some toxins, like Clostridium perfringens perfringolysin O, Streptococcus intermedius intermedilysin, or Streptococcus pneumoniae pneumolysin needs to be evaluated further. The Bordetella adenylate cyclase toxoid used as a vaccine delivery tool, or Corynebacterium diphtheriae diphtheria toxin and Pseudomonas aeruginosa exotoxin A-based immunotoxins, are currently in various phases of clinical trials for cancer immunotherapy, as are some antigen-delivering Salmonella and Listeria monocytogenes strains. PMID:22339216
Adkins, Irena; Holubova, Jana; Kosova, Martina; Sadilkova, Lenka
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite intensive treatment, the prognosis for patients with GBM remains grim with a median survival of only 14.6 months. Immunotherapy has emerged as a promising approach for treating many cancers and affords the advantages of cellular-level specificity and the potential to generate durable immune surveillance. The complexity of the tumor microenvironment poses a significant challenge to the development of immunotherapy for GBM, as multiple signaling pathways, cytokines, and cell types are intricately coordinated to generate an immunosuppressive milieu. The development of new immunotherapy approaches frequently uncovers new mechanisms of tumor-mediated immunosuppression. In this review, we discuss many of the current approaches to immunotherapy and focus on the challenges presented by the tumor microenvironment.
Jackson, Christopher; Ruzevick, Jacob; Phallen, Jillian; Belcaid, Zineb; Lim, Michael
Molecular identification of tumor antigens has made possible to develop tumor-specific immunotherapy. Provenge was approved by FDA as a first therapeutic drug for cancer in 2010. A line of drug candidates is in late phase clinical trials as therapeutic vaccine for patients with solid tumors. Adoptive immunotherapy with tumor-specific T cells demonstrated clinical effectiveness in patients with advanced malignancy such as metastatic melanoma and synovial cell sarcoma. Genetically engineered T cells were administrated to cancer patients with promising results and may extend the application of adoptive immunotherapy of tumor. Although recent findings in tumor biology and immunity suggest the integrated immune response against tumor with special emphasis on inhibitory mechanism, we are unmistakably witnessing the moment that immunotherapy of cancer becomes a medical option. PMID:23259373
Ikeda, Hiroaki; Shiku, Hiroshi
Here, we propose to harness the immune system by immunotherapy (IT) alongside conventional radiotherapy (RT) to improve the treatment of men with advanced or recurrent prostate cancer. The overall aim is to determine whether local irradiation of prostate ...
Prostate cancer remains a significant health problem for men in the Western world. Although treatment modalities are available, these do not confer long-term benefit and are accompanied by deleterious side effects. Immunotherapy represents a valuable alternative to conventional treatments by inducing tumour-specific immune responses that control the growth of cancer cells. Sipuleucel-T is approved by the FDA as an immunotherapeutic agent for the treatment of patients with asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC). Although this approval has raised cost-versus-benefit issues, it has provided proof of concept for the therapeutic potential of active immunotherapy approaches for metastatic CRPC. Numerous clinical studies have demonstrated clinical benefit using immunotherapy compared to traditional chemotherapy and several active immunotherapy approaches (at various developmental stages)have demonstrated the potential to change the face of prostate cancer treatment. PMID:22641164
Karan, Dev; Holzbeierlein, Jeffrey M; Van Veldhuizen, Peter; Thrasher, J Brantley
In order to improve the prognosis for patients with head and neck squamous cell cancer (HNSCC) the introduction of new therapeutic strategies is necessary. The concept of immunotherapy has been applied and improved for several years and recent studies have used tumor-specific antigens which facilitates targeted oncologic therapy. However, immunotherapy is hampered by the fact that immunosuppressive mechanisms are pronounced and relevant effector cells are suppressed, especially in patients with HNSCC. Successful immunotherapy could induce an antitumor immune response by restitution of these cell populations. Current anti-tumor immunotherapy includes unspecific immune stimulation, genetic modification of tumor and immune cells, the use of monoclonal antibodies, e.g. cetuximab, adoptive cell transfer and tumor vaccination. In the future, these biologic therapies alone or in combination with conventional therapeutic regimens could present a valuable therapeutic option for HNSCC patients. PMID:23247754
Schuler, P J; Hoffmann, T K; Gauler, T C; Bergmann, C; Brandau, S; Lang, S
Response to systemic antifungal therapy alone remains disproportionately less satisfactory in immunosuppressed transplant and oncology patients. As insight in fungal immunopathogenesis forges ahead, interventions for boosting immune functions along with antimicrobial drugs has shown promise in preclinical experiments. The clinical experience with immunotherapy for invasive mold disease is limited. Most studies have involved small numbers of patients at a single institution or data collected retrospectively. An overview of various facts of immune modulatory drug intervention is presented, including major considerations in antifungal immunotherapy in immunosuppressed patients. Patients in whom immunotherapy is being considered must be critically evaluated to identify the underlying immune defects, including treatment-induced immunosuppression. Antifungal immunotherapy is appealing; however, before routine clinical use is recommended, well-designed prospective comparative clinical trials are urgently needed. PMID:23532473
OBJECTIVE: To define the diagnostic characteristics and predictors of treatment response in patients with suspected autoimmune dementia. PATIENTS AND METHODS: Between January 1, 2002, and January 1, 2009, 72 consecutive patients received immunotherapy for suspected autoimmune dementia. Their baseline clinical, radiologic, and serologic characteristics were reviewed and compared between patients who were responsive to immunotherapy and those who were not. Patients were classified as responders if the treating physician had reported improvement after immunotherapy (documented in 80% by the Kokmen Short Test of Mental Status, neuropsychological testing, or both). RESULTS: Initial immunotherapeutic regimens included methylprednisolone in 56 patients (78%), prednisone in 12 patients (17%), dexamethasone in 2 patients (3%), intravenous immune globulin in 1 patient (1%), and plasma exchange in 1 patient (1%). Forty-six patients (64%) improved, most in the first week of treatment. Thirty-five percent of these immunotherapy responders were initially diagnosed as having a neurodegenerative or prion disorder. Pretreatment and posttreatment neuropsychological score comparisons revealed improvement in almost all cognitive domains, most notably learning and memory. Radiologic or electroencephalographic improvements were reported in 22 (56%) of 39 patients. Immunotherapy responsiveness was predicted by a subacute onset (P<.001), fluctuating course (P<.001), tremor (P=.007), shorter delay to treatment (P=.005), seropositivity for a cation channel complex autoantibody (P=.01; neuronal voltage-gated potassium channel more than calcium channel or neuronal acetylcholine receptor), and elevated cerebrospinal fluid protein (>100 mg/dL) or pleocytosis (P=.02). Of 26 immunotherapy-responsive patients followed up for more than 1 year, 20 (77%) relapsed after discontinuing immunotherapy. CONCLUSION: Identification of clinical and serologic clues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance if needed, thus favoring an optimal outcome.
Flanagan, Eoin P.; McKeon, Andrew; Lennon, Vanda A.; Boeve, Bradley F.; Trenerry, Max R.; Tan, K. Meng; Drubach, Daniel A.; Josephs, Keith A.; Britton, Jeffrey W.; Mandrekar, Jayawant N.; Lowe, Val; Parisi, Joseph E.; Pittock, Sean J.
The main aims of the international meeting “Immunotherapy of Cancer: Challenges and Needs” were to review the state of the\\u000a art of cancer immunotherapy and to identify critical issues which deserve special attention for promoting progress of research\\u000a in this field, with a particular focus on the perspectives of clinical research. Novel concepts and strategies for identifying,\\u000a monitoring and predicting
Maria Ferrantini; Imerio Capone; Francesco M. Marincola; Giorgio Parmiani; Filippo Belardelli
Bee venom (BV) allergy is potentially dangerous for allergic individuals because a single bee sting may induce an anaphylactic reaction, eventually leading to death. Currently, venom immunotherapy (VIT) is the only treatment with long-lasting effect for this kind of allergy and its efficiency has been recognized worldwide. This therapy consists of subcutaneous injections of gradually increasing doses of the allergen. This causes patient lack of compliance due to a long time of treatment with a total of 30-80 injections administered over years. In this article we deal with the characterization of different MS-PLGA formulations containing BV proteins for VIT. The PLGA microspheres containing BV represent a strategy to replace the multiple injections, because they can control the solute release. Physical and biochemical methods were used to analyze and characterize their preparation. Microspheres with encapsulation efficiencies of 49-75% were obtained with a BV triphasic release profile. Among them, the MS-PLGA 34kDa-COOH showed to be best for VIT because they presented a low initial burst (20%) and a slow BV release during lag phase. Furthermore, few conformational changes were observed in the released BV. Above all, the BV remained immunologically recognizable, which means that they could continuously stimulate the immune system. Those microspheres containing BV could replace sequential injections of traditional VIT with the remarkable advantage of reduced number of injections. PMID:21356289
Trindade, Reginaldo A; Kiyohara, Pedro K; de Araujo, Pedro S; Bueno da Costa, Maria H
The effectiveness of immunotherapy using a streptococcal preparation, OK-432, was evaluated for cervical cancer. The 382 eligible patients were stratified by presence/absence of surgical operation and clinical stage, and then, in each stratum, were randomly divided into two groups: an OK-432 treatment group and a control treatment group. The 3-year recurrence-free rates of 221 patients in the OK-432 group and 161 patients in the control group were 71.9% and 58.6%, respectively. The intergroup difference was statistically significant (P less than 0.05). Delayed skin reactions to phytohemagglutinin (PHA) and Su-polysaccharide extracted from Streptococcus pyogenes Su-strain (Su-PS) and peripheral lymphocyte counts were reduced within two months after the initiation of therapy in both groups. The observed immunological changes were apparently reversed by 3 months after the start of the therapy in the OK-432 group, but this took at least one year in the control group, with significant intergroup differences at 6 and 12 months of the therapy (P less than 0.01). These results indicate that OK-432 can be considered as one of the most effective and useful immunotherapeutic agents for cervical cancer. PMID:2889522
HARRIS et. al. isolated somatic hybrid cells (A9/SEWA) between polyoma-induced tumor and mouse fibroblast cell lines. Although these hybrid cells were no longer tumorigenic, we found that their immunogenicity was conserved. It therefore seemed to us that these antigenic, non transplantable, living cells would be an ideal tool for immunotherapy experiments. In our first experiments we assessed the immunoprotection afforded by A9/SEWA cells in both the SEWA tumor/A.SW mouse and C3HPy/C3H mouse systems. However, the efficiency of immunization with hybrid cells is dependent on the stability of the cells, especially in respect to the expression of the TATA. So we also tried to evaluate the immunogenicity as a function of the number of subcultures undergone by the hybrid line. In both systems, the immunogenicity was very good in the early subcultures but, in the C3HPy tumor/C3H mouse system, a loss of immunogenicity was observed as the number of subcultures increased. Thus any clinical application or immunization by hybrid cells would necessitate the verification of the presence of the tumor-associated antigens at each subculture. We are at present experimenting with various in vitro techniques for detection of the expression of these antigens. PMID:197461
Favre, R; Carcassonne, Y; Meyer, G
Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory Tcells (Treg) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as “sinks” for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression.
Paulos, Chrystal M.; Kaiser, Andrew; Wrzesinski, Claudia; Hinrichs, Christian S.; Cassard, Lydie; Boni, Andrea; Muranski, Pawel; Sanchez-Perez, Luis; Palmer, Douglas C.; Yu, Zhiya; Antony, Paul A.; Gattinoni, Luca; Rosenberg, Steven A.; Restifo, Nicholas P.
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.
Piccoli, B.; Castiglione, F.
TADG-12 and CA125 are two proteins expressed with high specificity in ovarian cancer tumors. They thus would be potential antigens for immunotherapy in ovarian cancer. The invention is based on the discovery of peptides in TADG-12 and CA125 that can be used to induce an autologous T cell response that lyses ovarian cancer cells expressing TADG-12 or CA125. The peptides are contacted with dendritic cells in vitro to generate peptide-loaded dendritic cells. The peptide-loaded dendritic cells are contacted with T cells in vitro to amplify CD8+ T cells that recognize the peptide. At least one CA125 peptide and at least one TADG-12 peptide were found that amplified CD8+ T cells, even from cancer patients, that lysed autologous CA125-expressing or TADG-12-expressing tumor cells. The peptide-loaded dendritic cells can be administered to a cancer patient to amplify CD8+ T cells in vivo that attack the cancer cells. Alternatively, autologous CD8+ T cells can be amplified ex vivo and then infused into the cancer patient.
Introduction Brain tumors are a unique class of cancers since they are anatomically shielded from normal immunosurveillance by the blood brain barrier, lack a normal lymphatic drainage system and reside in a potently immunosuppressive environment. Of the primary brain cancers, glioblastoma multiforme (GBM) is the most common and aggressive in adults. Although treatment options include surgery, radiation and chemotherapy, the average lifespan of GBM patients remains at only 14.6 months post-diagnosis. Areas covered A review of key cellular and molecular immune system mediators in the context of brain tumors including TGF-?, cytotoxic T cells, Tregs, CTLA-4, PD-1, and IDO, is discussed. In addition, prognostic factors, currently utilized immunotherapeutic strategies, on-going clinical trials, and a discussion of new or potential immunotherapies for brain tumor patients are considered. Expert opinion Current drugs that improve the quality of life and overall survival in patients with brain tumors, especially for GBM, are poorly effective. This disease requires a re-analysis of currently accepted treatment strategies, as well as newly designed approaches. Here, we review the fundamental aspects of immunosuppression in brain tumors, new and promising immunotherapeutic drugs, as well as combinatorial strategies that focus on the simultaneous inhibition of immunosuppressive hubs, both in immune- and brain tumor-cells, which is critical to consider for achieving future success for the treatment of this devastating disease.
Wainwright, Derek; Nigam, Pragati; Thaci, Bart; Dey, Mahua
The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:23725878
Gogas, Helen; Polyzos, Aristidis; Kirkwood, John
Cancer immunotherapy aims to establish immune-mediated control of tumor growth by priming T-cell responses to target tumor-associated antigens. Three signals are required for T-cell activation: (i) presentation of cognate antigen in self MHC molecules; (ii) costimulation by membrane-bound receptor-ligand pairs; and (iii) soluble factors to direct polarization of the ensuing immune response. The ability of dendritic cells (DCs) to provide all three signals required for T-cell activation makes them an ideal cancer vaccine platform. Several strategies have been developed to enhance and control antigen presentation, costimulation, and cytokine production. In this review, we discuss progress toward developing DC-based cancer vaccines by genetic modification using RNA, DNA, and recombinant viruses. Furthermore, the ability of DC-based vaccines to activate natural killer (NK) and B-cells, and the impact of gene modification strategies on these populations is described. Clinical trials using gene-modified DCs have shown modest results, therefore, further considerations for DC manipulation to enhance their clinical efficacy are also discussed.
Boudreau, Jeanette E; Bonehill, Aude; Thielemans, Kris; Wan, Yonghong
The induction of allergen-specific anergy in peripheral T cells represents a key step in specific immunotherapy (SIT). Here we demonstrate that the anergic state results from increased IL-10 production. In bee venom (BV)-SIT the specific proliferative and cytokine responses against the main allergen, the phospholipase A2 (PLA), and T cell epitope-containing PLA peptides were significantly suppressed after 7 d of treatment. Simultaneously, the production of IL-10 increased during BV-SIT. After 28 d of BV-SIT the anergic state was established. Intracytoplasmic cytokine staining of PBMC combined with surface marker detection revealed that IL-10 was produced initially by activated CD4(+)CD25(+), allergen-specific T cells, and followed by B cells and monocytes. Neutralization of IL-10 in PBMC fully reconstituted the specific proliferative and cytokine responses. A similar state of IL-10-associated T cell anergy, as induced in BV-SIT, was found in hyperimmune individuals who recently had received multiple bee stings. The addition of IL-10 to soluble CD40 ligand IL-4-stimulated PBMC or purified B cells inhibited the PLA-specific and total IgE and enhanced the IgG4 formation. Accordingly, increased IL-10 production by SIT causes specific anergy in peripheral T cells, and regulates specific IgE and IgG4 production toward normal IgG4-related immunity.
Akdis, C A; Blesken, T; Akdis, M; Wuthrich, B; Blaser, K
After several decades of controversies, allergen specific immunotherapy (SIT) was recognized as an effective treatment for respiratory and hymenoptera allergy by the World Health Organization in 1998. SIT involves the administration (usually subcutaneous) of increasing doses of allergen in order to achieve a hyposensitization. Moreover, SIT is the only allergen-specific treatment capable of modifying the natural history of the disease. During the last 25 years, there was an impressive development of basic and clinical research in the field of SIT, with the goal of improving the safety, the efficacy and ameliorating the knowledge on the mechanisms of action. In this regard, the sublingual route (SLIT) was extensively studied and, recently, validated. SLIT can be considered a milestone in the history of SIT, since it is expected to change the clinical practice. In parallel, the growing detailed knowledge of the immunological mechanisms of SIT has provided the opportunity to explore new forms of specific hyposensitization, such as the use of adjuvants (bacterial and DNA-based), recombinant and engineered allergens, allergenic peptides and chimeric molecules. The last frontier seems to be the manipulation of genoma with replicons and allergen-encoding plasmids. PMID:19909232
Passalacqua, Giovanni; Compalati, Enrico; Canonica, Giorgio Walter
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.
Demaria, Sandra [Department of Pathology, New York University School of Medicine, New York, NY (United States); Bhardwaj, Nina [Department of Medicine, New York University School of Medicine, New York, NY (United States); McBride, William H. [Department of Radiation Oncology, Experimental Division, University of California at Los Angeles School of Medicine, Los Angeles, CA (United States); Formenti, Silvia C. [Department of Radiation Oncology NYU Cancer Institute, New York University School of Medicine, New York, NY (United States)]. E-mail: firstname.lastname@example.org
Prevalence rates of food allergy have increased rapidly in recent decades. Of concern, rates of increase are greatest among children under 5 yrs of age and for those food allergies that persist into adulthood such as peanut or tree nut allergy and shellfish allergy. Given these trends, the overall prevalence of food allergy will compound over time as the number of children affected by food allergy soars and a greater proportion of food-allergic children are left with persistent disease into adulthood. It is therefore vital to identify novel curative treatment approaches for food allergy. Acquisition of oral tolerance to the diverse array of ingested food antigens and intestinal microbiota is an active immunologic process that is successfully established in the majority of individuals. In subjects who develop food allergy, there is a failure or loss of oral tolerance acquisition to a limited number of food allergens. Oral immunotherapy (OIT) offers a promising approach to induce specific oral tolerance to selected food allergens and represents a potential strategy for long-term curative treatment of food allergy. This review will summarize the current understanding of oral tolerance and clinical trials of OIT for the treatment of food allergy. PMID:23905867
Tang, M L K; Martino, D J
Laser immunotherapy using laser photothermal therapy and immunological stimulation could achieve tumor-specific immune responses, as indicated by our previous pre-clinical and preliminary clinical studies. To further study the effect of laser immunotherapy, we conducted an investigation combining laser immunotherapy and surgery. After laser immunotherapy, treated tumors were surgically removed at different time points. The survival rates of treated mice were compared among different groups. Furthermore, the cured mice were rechallenged to test the immunity induced by laser immunotherapy. Our results showed that the mice treated with surgical removal one week after laser immunotherapy had the highest survival rate (77%). When the tumors were removed immediately after laser immunotherapy treatment, the survival rate was 57%. Most cured mice withstood tumor rechallenges, indicating an induction of tumor immunity by laser immunotherapy. The differentiations between different surgery groups indicate that the treated tumors have contributed to the immunological responses of the hosts.
Chen, Vivian A.; Le, Henry; Li, Xiaosong; Wolf, Roman F.; Ferguson, Halie; Sarkar, Akhee; Liu, Hong; Nordquist, Robert E.; Chen, Wei R.
Encasings for mattresses, blankets and pillows in combination with mite allergen reduction on the floor have proved effective\\u000a in reducing bronchial hyperreactivity of mite-allergic children. We studied the effect of combining the use of encasings with\\u000a specific immunotherapy in comparison to the use of encasings alone (control group). Twenty mite-allergic children (Skin Prick\\u000a Test, RAST, mean age 10 years) with
K. Paul; U. Klettke; U. Wahn
Nasal allergies are prevalent affecting a large percentage of the population. Not only the upper respiratory tract but the whole body is involved. Allergies produce morbidity (and even occasional mortality) as they can lead to asthma development, and increased number of accidents. Immunotherapy results can be evaluated by following symptom scores, medication use, and objective measurements. Using a Peak Flow Meter (PFM) to evaluate immunotherapy results, it became evident that patients with and without asthma exhibited an improvement in the Peak Flow (PF) value, suggesting that lower airway involvement in allergic patients could be more prevalent than assumed. A consecutive chart review was performed including patients of any age with nasal allergies (with or without asthma) treated with immunotherapy for at least 6 months that had at least 2 complete evaluations. When immunotherapy was successful, most patients exhibited an increase in the PF value regardless of asthma status. A very significant finding was that most allergy sufferers may have lower airway inflammation. The use of the PF value to assess immunotherapy results and the potential failure to diagnose asthma in allergy sufferers are discussed. A better diagnosis of lower airway inflammation could be substantial in the management of these patients.
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
Clifton, Guy T; Sears, Alan K; Clive, Kevin S; Holmes, Jarrod P; Mittendorf, Elizabeth A; Ioannides, Constantine G; Ponniah, Sathibalan; Peoples, George E
Evaluation of: van den Eertwegh AJ, Versluis J, van den Berg HP et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a Phase 1 dose-escalation trial. Lancet Oncol. 13(5), 509 – 517 (2012). A significant interest in the development of therapeutic cancer vaccines over the last decade has led to an improvement in overall survival of cancer patients in several clinical trials. As a result, two active immunotherapy agents, sipuleucel-T and ipilimumab, have been approved by the US FDA for the treatment of prostate cancer and melanoma, respectively. GVAX(®) cellular vaccine (Cell Genesysis, Inc., CA, USA) is another active immunotherapy agent targeting prostate cancer and it has been well studied in various clinical trials. The current publication, by van den Eertwegh et al., demonstrated a combination of two active immunotherapy approaches, using GVAX and ipilimumab for the treatment of metastatic castration-resistant prostate cancer. While GVAX is designed to amplify the antitumor response specific to prostate cancer cells, ipilimumab contributes to T-cell activation. Thus, the authors presented the possibility of augmenting antitumor T-cell activity in two different ways. They successfully demonstrated a tolerable dose and safety profile of ipilimumab in combination with GVAX for patients with metastatic castration-resistant prostate cancer. However, further studies of such immunotherapy combinations and detailed analysis of their immunological effects are needed to observe clinical benefit. PMID:22788125
Karan, Dev; Van Veldhuizen, Peter
Purpose Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane Chondroitin Sulphate Proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)-based immunotherapy of MM. Experimental Design We assayed adhesion, motility, invasiveness, wound-healing, apoptosis and anchorage-independent growth of MM cells on cell cultures. CSPG4 expression and signaling was studied by immunoblotting. The growth of MM SCID mice xenografts induced by PPM-Mill cells, engineered to express the luciferase reporter gene, was monitored by imaging, upon treatment with CSPG4 mAb TP41.2. Animal toxicity and survival were assayed in both tumor inhibition and therapeutic experiments. Results CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of extracellular matrix components (ECM). Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of FAK and AKT, reduced expression of cyclin D1 and apoptosis. Moreover, TP41.2 significantly reduced MM cell motility, migration and invasiveness, and inhibited MM growth in soft agar. In vivo, treatment with mAb TP41.2 prevented or inhibited the growth of MM xenografts in SCID mice, with a significant increase in animal survival. Conclusion These results establish the safety of CSPG4 mAb-based immunotherapy and suggest that CSPG4 mAb-based immunotherapy may represent a novel approach for the treatment of MM.
Rivera, Zeyana; Ferrone, Soldano; Wang, Xinhui; Jube, Sandro; Yang, Haining; Pass, Harvey; Kanodia, Shreya; Gaudino, Giovanni; Carbone, Michele
Prions are infectious proteins responsible for a group of fatal neurodegenerative diseases called TSEs (transmissible spongiform encephalopathies) or prion diseases. In mammals, prions reproduce themselves by recruiting the normal cellular protein PrP(C) and inducing its conversion into the disease-causing isoform denominated PrP(Sc). Recently, anti-prion antibodies have been shown to permanently cure prion-infected cells. However, the inability of full-length antibodies and proteins to cross the BBB (blood-brain barrier) hampers their use in the therapy of TSEs in vivo. Alternatively, brain delivery of prion-specific scFv (single-chain variable fragment) by AAV (adeno-associated virus) transfer delays the onset of the disease in infected mice, although protection is not complete. We investigated the anti-prion effects of a recombinant anti-PrP (D18) scFv by direct addition to scrapie-infected cell cultures or by infection with both lentivirus and AAV-transducing vectors. We show that recombinant anti-PrP scFv is able to reduce proteinase K-resistant PrP content in infected cells. In addition, we demonstrate that lentiviruses are more efficient than AAV in gene transfer of the anti-PrP scFv gene and in reducing PrP(Sc) content in infected neuronal cell lines. Finally, we have used a bioinformatic approach to construct a structural model of the D18scFv-PrP(C) complex. Interestingly, according to the docking results, Arg(PrP)(151) (Arg(151) from prion protein) is the key residue for the interactions with D18scFv, anchoring the PrP(C) to the cavity of the antibody. Taken together, these results indicate that combined passive and active immunotherapy targeting PrP might be promising strategies for therapeutic intervention in prion diseases. PMID:19000036
Campana, Vincenza; Zentilin, Lorena; Mirabile, Ilaria; Kranjc, Agata; Casanova, Philippe; Giacca, Mauro; Prusiner, Stanley B; Legname, Giuseppe; Zurzolo, Chiara
Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context.
Drake, Charles G.
There is much promise in the use of immunotherapy for the treatment of cancer. Approaches such as those using antibodies or adoptive cell transfer can mediate complete tumor regression in a proportion of patients. However, the tumor microenvironment can inhibit immune responses leading to ineffective or suboptimal responses of tumors to immunotherapy in the majority of cases. As our knowledge of the tumor microenvironment increases, many strategies are emerging for changing the immunosuppressive nature of the tumor toward a microenvironment able to support immunity. These strategies aim to enhance the ability of immunotherapies to initiate effective immune responses able to destroy tumors. In this article, we review approaches that use immunomodulators specifically to modify the tumor microenvironment, and their use in combination with other immune-based strategies for cancer therapy.
Devaud, Christel; John, Liza B; Westwood, Jennifer A; Darcy, Phillip K; Kershaw, Michael H
Hematopoietic stem cell transplantation (HSCT) is a particularly important treatment for hematologic malignancies. Unfortunately, following allogeneic HSCT, graft-versus-host disease, immunosuppression and susceptibility to opportunistic infections remain among the most substantial problems restricting the efficacy and use of this procedure, particularly for cancer. Adoptive immunotherapy and/or manipulation of the graft offer ways to attack residual cancer as well as other transplant-related complications. Recent exciting discoveries have demonstrated that HSCT could be expanded to solid tissue cancers with profound effects on the effectiveness of adoptive immunotherapy. This review will provide a background regarding HSCT, discuss the complications that make it such a complex treatment procedure following up with current immunotherapeutic strategies and discuss emerging approaches in applying immunotherapy in HSCT for cancer.
Bouchlaka, Myriam N; Redelman, Doug; Murphy, William J
Non-Muscle-Invasive-Bladder-Cancer represents 75-85% of the new bladder cancer cases per year. Trans-uretral vesical resection is the milestone for diagnosis and therapy. After primary treatment, recurrence is frequent depending on the presence of several established risk factors: multiplicity, T dimension, prior recurrence. In some patients disease progress to an advanced stage. Adjuvant chemo-immunotherapy has been widely used depending on the risk category assigned on the basis of the risk factors for recurrence. In low risk categories a one shot treatment with chemotherapy is considered the standard treatment without any maintenance therapy. In intermediate risk patients, adjuvant induction therapy and maintenance chemotherapy or immunotherapy for at least one year is recommended. In high risk patients adjuvant induction and maintenance immunotherapy until 3 years is considered the best strategy. In this review data on the different drugs used in this setting will be discussed. PMID:23893180
Leopardo, D; Cecere, S C; Di Napoli, M; Cavaliere, C; Pisano, C; Striano, S; Marra, L; Menna, L; Claudio, L; Perdonà, S; Setola, S; Berretta, M; Franco, R; Tambaro, R; Pignata, S; Facchini, G
Recent advancements have made radiation and chemotherapy the standard of care for newly diagnosed glioblastomas. The use of these therapies has resulted in an increased diagnosis of pseudoprogression and radiation-induced necrosis. Standard MRI techniques are inadequate in differentiating tumor recurrence from posttreatment effects. Diagnosis of a posttreatment lesion as glioma recurrence rather than radiochemotherapy or immunotherapy treatment effect is critical. This increase in accuracy plays a role as newer immunotherapies incurring posttreatment effects on MRI emerge. Advancements with magnetic resonance spectroscopy, diffusion-weighted imaging, and functional positron emission tomography scans have shown promising capabilities. Further investigations are necessary to assess the imaging algorithms and accuracy of these modalities to differentiate true glioma recurrence from radiotherapy or immunotherapy treatment effect. PMID:19944976
Yang, Isaac; Huh, Nancy G; Smith, Zachary A; Han, Seunggu J; Parsa, Andrew T
Recently, the combining of different drugs has greatly improved response and survival rates in gynecological malignancies. Results are however far from being satisfactory. Treatments used in case of advanced or recurrent disease offer limited results in terms of long-term responses. The urgent need for new and more effective treatments has prompted researchers to investigate and propose new therapeutic strategies. One of the most interesting approaches that are being explored is constituted by immunotherapy. Currently, immunotherapeutic strategies include vaccination with peptide, viral vectors, carbohydrates and antiidiotypic antibodies. In addition, cell based immunotherapy has been adopted in vitro activated lymphocytes and dendritic cells. Most experience has been acquired in ovarian cancer and cervical cancer. Little has been investigated in endometrial and rare gynecologic neoplasms.The clinical experiences and results achieved with immunotherapy in this setting of patients have been reviewed and the future avenues that are currently being explored have also been discussed. PMID:22934850
Bellati, F; Napoletano, C; Ruscito, I; Visconti, V; Antonilli, M; Gasparri, M L; Zizzari, I G; Rahimi, H; Palaia, I; Rughetti, A; Benedetti Panici, P; Nuti, M
Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8+ T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules.
Kitamura, Hiroshi; Tsukamoto, Taiji
Immunotherapy is a novel approach for the treatment of systemic malignancies. Passive and adaptive immunotherapy have been applied to the treatment of a wide variety of solid tumors such as malignant melanoma (1), renal cell carcinoma (2) and ovarian cancer (3). Several early clinical trials of immune based therapy for both non-small (NSCLC) and small cell lung cancer (SCLC) have demonstrated limited or no success (3),(4) but recent trials of antigen-specific cancer immunotherapy have shown early therapeutic potential and are now being rigorously evaluated on a larger scale (5). In this communication we briefly review the historic aspects of immune based therapy for solid cancer, describe therapeutic strategies aimed at targeting lung cancer, and discuss limitations of current therapy and future directions of this field.
Murala, Sanjay; Alli, Vamsi; Kreisel, Daniel; Gelman, Andrew E; Krupnick, Alexander S
Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context. PMID:20651745
Drake, Charles G
To foster the success of clinical trials in radio-immunotherapy (RIT), one needs to determine (i) the quantity and spatial distribution of the administered radionuclide carrier in the patient over time, (ii) the absorbed dose in the tumour sites and critical organs based on this distribution and (iii) the volume of tumour mass(es) and normal organs from computerized tomography or magnetic resonance imaging and appropriately correlated with nuclear medicine imaging techniques (such as planar, single-photon emission computerized tomography or positron-emission tomography). Treatment planning for RIT has become an important tool in predicting the relative benefit of therapy based on individualized dosimetry as derived from diagnostic, pre-therapy administration of the radiolabelled antibody. This allows the investigator to pre-select those patients who have `favourable' dosimetry characteristics (high time-averaged target: non-target ratios) so that the chances for treatment success may be more accurately quantified before placing the patient at risk for treatment-related organ toxicities. The future prospects for RIT treatment planning may yield a more accurate correlation of response and critical organ toxicity with computed absorbed dose, and the compilation of dose - volume histogram information for tumour(s) and normal organ(s) such that computing tumour control probabilities and normal tissue complication probabilities becomes possible for heterogeneous distributions of the radiolabelled antibody. Additionally, radiobiological consequences of depositing absorbed doses from exponentially decaying sources must be factored into the interpretation when trying to compute the effects of standard external beam isodose display patterns combined with those associated with RIT.
Erdi, Alev K.; Erdi, Yusuf E.; Yorke, Ellen D.; Wessels, Barry W.
Interleukin-2 (IL-2) has been used extensively in cellular immunotherapy trials as a systemic activator of the immune system as well as an ex vivo stimulant for lymphoid cell function. Despite the measurement of several in vitro and in vivo immunologic parameters related to cellular immunotherapy, determinants of successful cellular immunotherapy remain unknown. To further delineate the consequences of exposing peripheral blood lymphocytes to high concentrations of IL-2, we assessed the supernatants of IL-2-activated peripheral blood lymphocytes for production of tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma). Exposure of normal monocyte-depleted peripheral blood mononuclear cells (PBMC) to IL-2 caused a dose-dependent increase in secretion of TNF and IFN-gamma which increased linearly after 48 h in culture. Analysis of positively selected, highly purified PBMC subpopulations exposed to IL-2 revealed that TNF-alpha and TNF-beta were produced by both CD3+ and CD16+ subpopulations but not by CD22+ cells. These studies were extended to supernatants obtained from PBMC cultures used in the adoptive cellular immunotherapy of patients with advanced cancer. Patients treated with lymphokine-activated killer (LAK) cell immunotherapy were classified as responders (N = 14) or non-responders (N = 17) to therapy. We found no significant difference in the production of TNF between responders and nonresponders (22 +/- 9 U ml-1 vs. 20 +/- 6 U ml-1), P > 0.05. However, LAK cell supernatants harvested from non-responders contained a significantly higher level of IFN-gamma (232 +/- 94 U ml-1) compared with responders (42 +/- 14), P < 0.05. Furthermore, the linear association between IFN-gamma and TNF-alpha production was different between these two response groups (rs = -0.19 for non-responders and rs = 0.48 for responders). These results suggest that secondary cytokine production by adoptively transferred lymphocytesmay play an important role in the host response to cellular immunotherapy. PMID:1341247
Schoof, D D; Hunt, P; Obando, J A; Cusack, J C; Andrews, V; Terashima, Y; Eberlein, T J
Allergy immunotherapy tablets (AIT) have expanded the treatment options for patients suffering from respiratory allergies. Efficacy is established in adults and children for two different commercially available grass AITs. The ALK grass AIT has an efficacy comparable to subcutaneous immunotherapy (SCIT), with a proven disease-modifying effect after treatment completion. Safety profiles favour AIT over SCIT. Studies suggest that tablets in all aspects are superior to sublingual drops. AITs for other allergies including house dust mite and birch and ragweed pollen are in development. PMID:21668858
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.
The preparation of chemically modified allergens, with a reduced IgE binding capacity (responsible for side effects with traditional immunotherapy) but with the same or greater immunogenic activity, is one of the paths followed to obtain better results with specific immunotherapy (IT). The aim of the study was to evaluate the tolerability and effects of extracts of Phleum pratense, modified with glutaraldehyde and absorbed on aluminium hydroxide, in controlling the seasonal symptomatology induced by grass pollen in a group of 10 monosensitized patients, compared to a group of 10 similar patients not treated with specific IT but with drugs alone. The monitoring parameters were: 1) Clinical: a) symptomatology after specific conjuctival provocation test (pre and post seasonal) and during the natural exposure to the allergen b) drug consumption. 2) Immunological (peripheral blood eosinophils, total and specific IgE, total specific IgG). 3) Cytological, before, during and after the pollen season. Conclusions: in subjects treated with specific IT a) both the overall symptomatology and the drug consumption resulted significantly reduced compared to the controls (p = 0.045); b) the phlogistic infiltrate showed a tendency to decrease during the pollen season; c) the peripheral blood eosinophils, total and specific IgE and IgG did not show any significant variation compared to the controls; d) no systemic reactions occurred and there were only two slight local reactions. PMID:9010561
Vittorio, R; Giorgio, C; Giampaola, G; Annamaria, R; Paola, V; Silvia, P; Walter, C G
Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts-including physicians, nurses, and patient advocates-to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-?2b, pegylated-interferon-?2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted. PMID:23982524
Kaufman, Howard L; Kirkwood, John M; Hodi, F Stephen; Agarwala, Sanjiv; Amatruda, Thomas; Bines, Steven D; Clark, Joseph I; Curti, Brendan; Ernstoff, Marc S; Gajewski, Thomas; Gonzalez, Rene; Hyde, Laura Jane; Lawson, David; Lotze, Michael; Lutzky, Jose; Margolin, Kim; McDermott, David F; Morton, Donald; Pavlick, Anna; Richards, Jon M; Sharfman, William; Sondak, Vernon K; Sosman, Jeffrey; Steel, Susan; Tarhini, Ahmad; Thompson, John A; Titze, Jill; Urba, Walter; White, Richard; Atkins, Michael B
Background To examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC) from allergic patients undergoing rush immunotherapy (RIT) that might be manifest within the first few months of treatment. Methods For this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI) expression and T-regulatory cell frequency as detected by expression of CD3+CD4+CD25bright cells at each timepoint using flow cytometry. Results In comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ?1.5-fold expression change (p less than or equal to 0.05, BH-FDR), we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR), we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1?, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints. Conclusions We observed significant changes in gene expression early in peripheral blood samples from allergic patients undergoing RIT. Moreover, serum levels for allergen specific IgG4 also increased over the course of treatment. These studies suggest that RIT induces rapid and dynamic alterations in both innate and adaptive immunity which can be observed in the periphery of allergic patients. These alterations could be directly related to the therapeutic shift in the allergen-specific class of immunoglobulin.
Malignant melanoma is a tumor of the melanocytes of the skin with different types, that can metastasize to many organs including the brain at the advanced stages. Metastasis to brain is most dreadful complication, and at times untreatable as it's noted in the late stages. Therefore, tremendous effort has been made in the past decades to treat metastatic melanoma patients more efficiently. Although chemotherapy is one of the treatment options, it also interferes with all rapidly dividing cells including the non-cancerous cells; therefore one should consider the side effects. As there is lot of evidence that melanoma is immunogenic, a concept of immunotherapy has risen. Immunotherapy uses molecules of the body's own immune system and disrupts the growth of cancer cells has gained a lot of attention in the past two decades. Adoptive cell therapies (ACT), vaccines, viruses, and cytokine administration in immunotherapy stimulate T cells to recognize and destroy the cancer cells. This article is a brief review of various molecules and strategies that are currently used in immunotherapy against malignant melanoma. These include the anti-Cytotoxic T-lymphocyte antigen-4 (CTLA4) antibody, cytokine administration, vaccine therapy, oncolytic viruses, adoptive cell therapy, and inhibitor of STAT3 activation. PMID:22697295
Allen, Timothy; Gundrajakuppam, Lavanya
In the United States, prostate cancer is the most frequent malignancy in men and ranks second in terms of mortality. Although recurrent or metastatic disease can be managed initially with androgen ablation, most patients eventually develop castration-resistant disease within a number of years, for which conventional treatments (eg, chemotherapy) provide only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer, and this field is evolving rapidly. Encouragingly, the US Food and Drug Administration (FDA) has recently approved two novel immunotherapy agents for patients with advanced cancer: the antigen presenting cell-based product sipuleucel-T and the anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody ipilimumab, based on improvements in overall survival in patients with castration-resistant prostate cancer and metastatic melanoma, respectively. Currently, a number of trials are investigating the role of various immunological approaches for the treatment of prostate cancer, many of them with early indications of success. As immunotherapy for prostate cancer enters its golden age, the challenge of the future will be to design rational combinations of immunotherapy agents with each other or with other standard prostate cancer treatments in an effort to improve patient outcomes further.
Boikos, Sosipatros A.; Antonarakis, Emmanuel S.
The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction. PMID:22778760
Zhou, Gang; Levitsky, Hyam
Advances in our understanding of autoimmunity and tumour immunity have led to improvements in immunotherapy for these diseases. Ironically, effective tumour immunity requires the induction of the same responses that underlie autoimmunity, whereas autoimmunity is driven by dysregulation of the same mechanisms that are involved in host defence and immune surveillance. Therefore, as we manipulate the immune system to treat
Rachel R. Caspi
The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this reinvigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included in order to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors.
Mitchell, Duane A.; Sampson, John H.
The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.
Zhou, Gang; Levitsky, Hyam
Report of a gastrointestinal stromal tumor in an 11-year-old girl who presented with a large lump in the upper abdomen. After complete surgical excision and histopathology, postoperative immunotherapy with imatinib led to an excellent outcome and a tumor-free survival of 3 years.
Bhatnagar, Sushmita N.
The goal of this research is to logically integrate immunotherapy (IT) with conventional radiotherapy (RT) to improve the treatment of men with advanced or recurrent prostate cancer. The initial aim is to determine whether local RT of prostate tumors in a...
This is the second annual report on the grant 'Rescuing high avidity T cells for prostate cancer immunotherapy'. The purpose of the grant proposal is to rescuing high avidity tumor-antigen specific T cells that can respond effectively to prostate cancer c...
Background The specific active immunotherapy, employing vaccine of allergen of mite is a treatment considered as effective for the respiratory allergy and asthma. The sublingual route has minor risk of systematises reactions. The objective of this study was to determine the therapeutic effect and security of sublingual immunotherapy (ITSL) employing the standard vaccine VALERGEN-DP (BIOCEN, CUBA) in a population of asthmatic Cuban patients. Methods A phase II Clinical Trials double blind, placebo controlled in a total of 40 adult patients with mild or moderate asthma and specific sensibility preponderant to this mite. Half of patients received drops by sublingual route with growing doses up to 2000 UB. Results The treatment was effective in the reduction of clinical symptoms and medication intake as compared to conventional treatment in control group. The cutaneous sensibility to this mite was significant reduced, increasing in 1.9 log; the amount of necessary allergen to provoke a positive Prick Test. An improvement of the lung function was observed with a significant reduction (P < 0.05) of expiratory pick flow variability. The frequency of local reactions were only 0.58% of administration. Conclusions The VALERGEN-DP vaccine is an effective treatment and profitable against asthma in our population and guarantee its generalization in the Allergy Services of our health system.
Rodriguez, Jose; Castro, Raul; Labrada, Alexis; Alvarez, Mirta; Ronquillo, Mercedes; Gonzalez, Mayda; Navarro, Barbara; Mateo, Maytee; Oliva, Yunia; Garcia, Iris; Enriquez, Irene
The apolipoprotein E (APOE) ?4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid ? (A?) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with A? and facilitates A? fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-A? antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1?E9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble A?40 and A?42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around A? plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in A? binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
Kim, Jungsu; Eltorai, Adam E.M.; Jiang, Hong; Liao, Fan; Verghese, Philip B.; Kim, Jaekwang; Stewart, Floy R.; Basak, Jacob M.
While tumor incidence increases with age, tumor growth and metastasis often proceed at a slower rate in aged organisms. The mechanisms underlying this age-related reduced tumor development may suggest therapeutic modalities appropriate for the aged. Decreased tumor aggressiveness in the old was shown to be related to altered immune response. Consequently, the aim of the present study was to assess whether cancer immunotherapy has an age-dependent effect. Only a few studies have compared cancer immunotherapy efficiency as a function of age, most showing lower inhibition in older animals. In the present study, we tested the effect of two immunomodulators, levamisole and BCG, on two tumors, B16 melanoma and AKR lymphoma, in mice of different ages. We demonstrated a higher efficiency of immunotherapy in aged as compared to young mice, particularly at low immunomodulator doses. While decreased T cell function during aging is apparently established, nonspecific immunity is more preserved or even enhanced in later life. We found an increased number of macrophages in tumors of old compared to young mice and an increase in MAC-1+ cells in old levamisole-treated compared to non-treated mice. The stronger therapeutic effect of this immunomodulator in old mice might thus be due to an increased macrophage-mediated anti-tumoral effect. PMID:15236763
Kaptzan, Tanya; Skutelsky, Ehud; Itzhaki, Orit; Sinai, Judith; Michowitz, Moshe; Yossipov, Yosef; Schiby, Ginnete; Leibovici, Judith
Antibody therapy (as either active or passive immunization) is designed primarily to prevent drugs of abuse from entering the central nervous system (CNS). Antidrug antibodies reduce rush, euphoria, and drug distribution to the brain at doses that exceed the apparent binding capacity of the antibody. This is accomplished through a pharmacokinetic antagonism, which reduces the amount of drug in the
Thomas Kosten; S. Michael Owens
The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles.
Sapoznik, Sivan; Hammer, Ohad; Ortenberg, Rona; Besser, Michal J.; Ben-Moshe, Tehila; Schachter, Jacob; Markel, Gal
The recent approval of Provenge has brought new hope for anticancer vaccine therapies. However, the immunosuppressive tumor microenvironment seems to impair the efficacy of vaccine therapies. The abnormal tumor vasculature creates a hypoxic microenvironment that polarizes inflammatory cells toward immune suppression. Moreover, tumors systemically alter immune cells' proliferation, differentiation, and function via secretion of growth factors and cytokines. For example, VEGF, a major proangiogenic cytokine induced by hypoxia, plays a critical role in immunosuppression via these mechanisms. Hence, antiangiogenic treatment may be an effective modality to potentiate immunotherapy. Here, we discuss the local and systemic effects of VEGF on tumor immunity and propose a potentially translatable strategy to re-engineer the tumor-immune microenvironment and improve cancer immunotherapy by using lower "vascular normalizing" doses of antiangiogenic agents. PMID:23440426
Huang, Yuhui; Goel, Shom; Duda, Dan G; Fukumura, Dai; Jain, Rakesh K
High grade gliomas (HGG) including glioblastomas (GBM) are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients.
Vauleon, Elodie; Avril, Tony; Collet, Brigitte; Mosser, Jean; Quillien, Veronique
Immunotherapy, in recent times, has found its application in a variety of immunologically mediated diseases. Oral immunotherapy may not only increase patient compliance but may, in particular, also induce both systemic as well as mucosal immune responses, due to mucosal application of active agents. To improve the bioavailability and to trigger strong immunological responses, recent research projects focused on the encapsulation of drugs and antigens into polymer particles. These particles protect the loaded antigen from the harsh conditions in the GI tract. Furthermore, modification of the surface of particles by the use of lectins, such as Aleuria aurantia lectin, wheatgerm agglutinin or Ulex europaeus-I, enhances the binding to epithelial cells, in particular to membranous cells, of the mucosa-associated lymphoid tissue. Membranous cell-specific targeting leads to an improved transepithelial transport of the particle carriers. Thus, enhanced uptake and presentation of the encapsulated antigen by antigen-presenting cells favor strong systemic, but also local, mucosal immune responses.
Diesner, Susanne C; Wang, Xue-Yan; Jensen-Jarolim, Erika; Untersmayr, Eva; Gabor, Franz
Active immunotherapy based on live attenuated bacterial vectors has matured in terms of industrial development and develops through a combination of three phenomena. First, active immunotherapy that stimulates an antigen-specific cytotoxic T-cell immune response has become a reality after several years of work. Second, there is still a need to identify vectors that can deliver antigens to the cytosol of antigen-presenting cells in vivo. Third, the recent progress in the understanding of bacterial lifestyle and in developing genetic engineering tools has enabled the design of bioengineered bugs that are capable of delivering antigens. Here, we review the mechanisms by which clinical bacterial vectors deliver antigens into the cytosol of antigen-presenting cells and summarize the development strategy of the three identified firms in this field.
Le Gouellec, Audrey; Chauchet, Xavier; Polack, Benoit; Buffat, Laurent; Toussaint, Bertrand
The RFA for the Cancer Immunotherapy Trials Network was recently awarded to the Fred Hutchinson Cancer Research Center, M. A. Cheever, PI., as the Central Operations and Statistical Office. The NCI is now accepting applications for clinical Member Sites, as described in NOT-CA-10-034. Please click on the link below to obtain the specific information and documents that should be submitted to the NCI for application for Member Site status.
The aim of this report was to answer the question how specific immunotherapy influences the antioxidant enzyme system in patients\\u000a with respiratory allergy and in longer perspective to find markers suitable to assess the efficacy of treatment. In open prospective\\u000a randomised study 28 patients (18 females and 10 males, age 14–48 years) with seasonal respiratory allergy were treated with\\u000a allergen
N. Lukan; O. Racz; I. Mocnejova; I. Tkac
The past 20 years have seen remarkable advances in our understanding of the molecular and cellular processes controlling the\\u000a development of an anticancer immune response. These advances have spawned a renaissance in the field of cancer immunotherapy,\\u000a the original targeted therapy, during which investigators have pushed the envelope and translated promising strategies into\\u000a investigational therapeutics in patients with cancer. An
Christian H. Poehlein; Dominik Rüttinger; Jun Ma; Hong-Ming Hu; Walter J. Urba; Bernard A. Fox
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
Chera L Maarouf; Ian D Daugs; Tyler A Kokjohn; Walter M Kalback; R Lyle Patton; Dean C Luehrs; Eliezer Masliah; James AR Nicoll; Marwan N Sabbagh; Thomas G Beach; Eduardo M Castaño; Alex E Roher
Telomerase reverse transcriptase hTERT is an attractive target for cancer immunotherapy given its broad expression in human tumors and its demonstrated immunogenicity. Human and murine model systems demonstrate that CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes can recognize dominant epitopes derived from TERT. CTL kill TERT-positive tumor cells of multiple histologies, although there is some disagreement regarding the level
Kunal P. Patel; Robert H. Vonderheide
Dendritic cells are bone marrow-derived professional antigen-presenting cells that exert critical functions in innate and\\u000a adaptive immune responses. Depending on their functional maturation status, dendritic cells trigger primary immune responses\\u000a or promote immunological tolerance. This functional ambivalence has taken dendritic cells into the focus of attention of immunotherapy\\u000a protocols for both vaccination and tolerance induction. The capacity of dendritic cells
L. Aragoneses-Fenoll; A. L. Corbí
Allogeneic human-leukocyte-antigen-matched stem cell transplantation is associated with a lower risk of relapse of leukaemia than autologous transplantation due to a T-cell-mediated graft-vs.-leukaemia effect. Replacement of patient haematopoiesis by donor haematopoiesis allows the application of donor-derived specifically targeted cellular immunotherapy for the treatment of leukaemia. Following allogeneic transplantation, donor-derived T cells recognizing minor histocompatibility antigens expressed on haematopoietic cells from
J. H. Frederik Falkenburg; Roel Willemze
Immunotherapy is an appealing therapeutic modality for malignant gliomas because of its potential to selectively target residual tumor cells that have invaded the normal brain. Most immunotherapeutic studies are designed to exploit the capacity of dendritic cells for inducing cell-mediated effects as well as immune memory responses for destroying residual tumor cells and preventing recurrence. Although initial clinical studies on dendritic cell-based immunotherapy resulted in very limited success, they have prompted many new studies on exploring strategies to induce a more robust antitumor immune response by using novel adjuvants for maturation and activation of dendritic cells. More studies have focused on the mechanisms of immune suppression by tumor cells and the role of regulatory T cells in tumor growth and progression. In this article, the authors review the evolution of dendritic cell-based immunotherapeutic strategies for adjuvant treatment of malignant gliomas. The authors also discuss how new knowledge on tumor-intrinsic mechanisms of tolerance induction and immunosuppression are likely to shape the future of immunotherapy for high-grade gliomas. PMID:17373896
Parajuli, Prahlad; Mathupala, Saroj; Mittal, Sandeep; Sloan, Andrew E
Studies on mite allergy had been launched by the Shanghai First Medical College since 1970's in this country. The preparations of SMU-Df from the local specimens of Dermatophagoides farinae (Df) in Shanghai have been shown the highest allergenic potency in comparison with that of the foreign ones, including the Df preparations from USFDA, VUS and ALK. Similar patterns of the protein curves were yielded by gel filtration, indicating almost similar allergenicities with both Df pure mite body and its spent culture medium. Around 80% of the allergic cases were sensitive to mite allergen and can be diagnosed by skin prick test, nasal provocation test and serum IgE level assay. Seasonal classic immunotherapy for allergic patients by Injection Dermatophagoides farinae, the first commercial allergen licensed by the Chinese government, achieved significant effect in relieving symptoms of allergic disorders in majority of cases, and long lasting effect of mite specific immunotherapy was also documented with minimal adverse reactions. Modifications of the Df crude extract and various modes of treatment have been studied. Studies on sublingual mite vaccine for mite allergic disorders developed synchronously with foreign trend since 1992. Sublingual drops were well acceptable by child cases almost without age restriction with higher efficacy. Rush schedule of mite immunotherapy led to a quick relief of allergic symptoms and long lasting curative effects. The Df allergen induced immunological regulation of human beings was established not only among the atopic patients, but also in healthy persons. PMID:20066974
Allergen immunotherapy (AIT) is the only treatment able to act on the causes and not merely on the symptoms of allergy. AIT was introduced 100 years ago but remained an empirical treatment for more than 40 years, when the first controlled trial in 1954 opened the era of scientific evidence. A major advance was the introduction of venom immunotherapy to prevent anaphylaxis from insect stings in 1978. Concerning inhalant allergens, currently AIT may be administered in two forms, subcutaneous (SCIT), and sublingual immunotherapy (SLIT). A large number of trials, globally analyzed in a number of meta-analyses, gave sound evidence to the efficacy and safety of SCIT and SLIT in allergic rhinitis and asthma. Adverse systemic reactions are still a drawback for SCIT while safety and tolerability of SLIT are very good, provided recommended doses and schedules of administration are used A significant advance for SLIT development was the registration in Europe of the standardized quality tablets. New applications, such as food allergy and atopic dermatitis, as well as new routes of administration, are currently under evaluation. After 100 years of use, AIT has a central role in the management of allergy and the ongoing improvement seems able to warrant to AIT an even brighter future. PMID:22905590
Frati, F; Incorvaia, C; Lombardi, C; Senna, G
From mouse studies to recently published clinical trials, evidence has accumulated on the potential use of regulatory T cells (Treg) in preventing and treating graft-versus-host disease following hematopoietic-cell transplantation (HCT). However, controversies remain as to the phenotype and stability of various Treg subsets and their respective roles in vivo, the requirement of antigen-specificity of Treg to reduce promiscuous suppression, and the molecular mechanisms by which Treg suppress, particularly in humans. In this review, we discuss recent findings that support a heterogeneous population of human Treg, address advances in understanding how Treg function in the context of HCT, and present data on recent clinical trials that highlight the feasibility and limitations on Treg immunotherapy for graft-versus-host disease.
Generalized reactions to insect stings were recognized as hypersensitivity phenomena in the early part of this century. 1 Attempts at reducing human hypersensitivity with specific immunologic treatment were reported in the 1920s and 1930s. 2-4 In part because Benson 4 concluded that \\
David F. Graft
Dendritic cells (DC) have become particularly attractive candidates for cancer immunotherapy due to their potent ability to stimulate antigen specific T cells responses. To date DC-based immunotherapy has demonstrated only limited clinical success in the ...
Background: Studies using rush immunotherapy (RIT) have shown that rapid protection can be achieved using protocols allowing a fast increment of allergen dose. We examined the early effects of RIT on basophil numbers and expression of CD203c, production of interleukin (IL)-4 and IL-13 and histamine release by basophils in the peripheral blood of patients treated with immunotherapy and controls. Methods:
Halina Plewako; Monica Arvidsson; Janne Björkander; Per Stahl Skov; Lena Håkansson; Sabina Rak
Background: Specific immunotherapy with allergen is the only causative treatment for IgE-mediated allergies such as stinging insect allergy or hay fever and works by the induction of blocking antibodies and regulatory T lymphocytes. Objective: Does a hypothetical obstruction of tumor surveillance presupposing the induction of regulatory T cells really justify detaining immunotherapy to oncologic patients as suggested by recent guidelines?
Stefan Wöhrl; Tamar Kinaciyan; Ahmad Jalili; Georg Stingl; Katharina B. Moritz
A total of 30 horses with single or multiple sarcoid tumors of the skin were randomly divided into three treatment groups: (i) cryosurgical treatment, (ii) intralesional immunotherapy with a live BCG vaccine, (iii) intralesional immunotherapy with a BCG cell wall preparation. Complete tumour regression was obtained in all 10 crysurgically treated horses, in 6 of 10 live BCG treated horses,
Wim R. Klein; Goosen E. Bras; Wim Misdorp; Peter A. Steerenberg; Wim H. de Jong; Rudy H. Tiesjema; Adolf W. Kersjes; E. Joost Ruitenberg
Acute renal failure with preserved renal plasma flow induced by cancer immunotherapy. Adoptive immunotherapy in patients with advanced cancer produces significant regression of metastatic disease in selected patients, but it is complicated by severe side effects. Prevention of these complications is still limited because their precise mechanisms remain unknown. For this reason we have investigated renal function and hemodynamic parameters
Alain Mercatello; Aoumeur Hadj-Aïssa; Sylvie Négrier; Bernard Allaouchiche; Bernard Coronel; Eve Tognet; Monique Bret; Marie Favrot; Nicole Pozet; Jean-François Moskovtchenko; Thierry Philip
Rush immunotherapy (RIT) is effective for the treatment of experimental feline allergic asthma. In humans, the safety profile of immunotherapy is improved by delivering allergen by a mucosal route. We hypothesized that mucosal (intranasal) RIT would have similar efficacy to subcutaneous RIT with improved safety.Twelve cats sensitized and challenged with Bermuda grass allergen (BGA) were randomized to receive subcutaneous (SC)
Tekla M. Lee-Fowler; Leah A. Cohn; Amy E. DeClue; Christine M. Spinka; Carol R. Reinero
Oncolytic viruses (OVs) are highly immunogenic and this limits their use in immune-competent hosts. Although immunosuppression may improve viral oncolysis, this gain is likely achieved at the cost of antitumoral immunity. We have developed a strategy wherein the immune response against the OV leads to enhanced therapeutic outcomes. We demonstrate that immunization with an adenoviral (Ad) vaccine before treatment with an oncolytic vesicular stomatitis virus (VSV) expressing the same tumor antigen (Ag) leads to significantly enhanced antitumoral immunity. Intratumoral replication of VSV was minimally attenuated in Ad-immunized hosts but extending the interval between treatments reduced the attenuating effect and further increased antitumoral immunity. More importantly, our combination approach shifted the immune response from viral Ags to tumor Ags and further reduced OV replication in normal tissues, leading to enhancements in both efficacy and safety. These studies also highlight the benefits of using a replicating, OV to boost a pre-existing antitumoral immune response as this approach generated larger responses versus tumor Ag in tumor-bearing hosts than could be achieved in tumor-free hosts. This strategy should be applicable to other vector combinations, tumor Ags, and tumor targets. PMID:20551919
Bridle, Byram W; Stephenson, Kyle B; Boudreau, Jeanette E; Koshy, Sandeep; Kazdhan, Natasha; Pullenayegum, Eleanor; Brunellière, Jérôme; Bramson, Jonathan L; Lichty, Brian D; Wan, Yonghong
The prevalence of asthma continues to increase. Asthma is caused by a Th2 cell–driven immune response. Its optimal treatment remains a challenge, and a sufficient immunotherapeutic approach to treating asthma has yet to be found. Using a murine asthma model, we show that a single injection of an anti-CD137 (4-1BB) mAb prevents the development of airway hyperreactivity, eosinophilic airway inflammation, excessive mucus production, and elevated IgE during the observation period of 7 weeks. Most importantly, even established disease is completely reversed by anti-CD137 mAb administration. The protection is associated with markedly reduced Th2 cytokine production and increased secretion of the Th1 cytokine IFN-?. While B lymphocytes are partly depleted, the number of CD8+ T cells is increased. Blockade of IFN-? and depletion of CD8+ T cells during treatment with anti-CD137 mAb reduces in part but does not abrogate the protective effect of CD137 mAb. In contrast, CD137 mAb–mediated CD4+ T cell anergy is critical for the observed effects, since transfer of CD4+ T cells from CD137 mAb–treated mice conveyed protection. These data demonstrate, for the first time to our knowledge, the capacity of anti-CD137 mAb to ameliorate allergic asthma, and they indicate CD137 as a possible target for therapeutic intervention in this disease.
Polte, Tobias; Foell, Juergen; Werner, Christoph; Hoymann, Heinz-Gerd; Braun, Armin; Burdach, Stefan; Mittler, Robert S.; Hansen, Gesine
Cervical cancer is caused by high-risk, cancer-causing human papillomaviruses (HPV) and is the second highest cause of cancer deaths in women globally. The majority of cervical cancers express well-characterized HPV oncogenes, which are potential targets for immunotherapeutic vaccination. Here we develop a rabbit haemorrhagic disease virus (RHDV) virus-like particle (VLP)-based vaccine designed for immunotherapy against HPV16 positive tumours. An RHDV-VLP, modified to contain the universal helper T cell epitope PADRE and decorated with an MHC I-restricted peptide (aa 48–57) from the HPV16 E6, was tested for its immunotherapeutic efficacy against the TC-1 HPV16 E6 and E7-expressing tumour in mice. The E6-RHDV-VLP-PADRE was administered therapeutically for the treatment of a pre-existing TC-1 tumour and was delivered with antibodies either to deplete regulatory T cells (anti-CD25) or to block T cell suppression mediated through CTLA-4. As a result, the tumour burden was reduced by around 50% and the median survival time of mice to the humane endpoint was almost doubled the compared to controls. The incorporation of PADRE into the RHDV-VLP was necessary for an E6-specific enhancement of the anti-tumour response and the co-administration of the immune modifying antibodies contributed to the overall efficacy of the immunotherapy. The E6-RHDV-VLP-PADRE shows immunotherapeutic efficacy, prolonging survival for HPV tumour-bearing mice. This was enhanced by the systemic administration of immune-modifying antibodies that are commercially available for use in humans. There is potential to further modify these particles for even greater efficacy in the path to development of an immunotherapeutic treatment for HPV precancerous and cancer stages.
Jemon, Khairunadwa; Young, Vivienne; Wilson, Michelle; McKee, Sara; Ward, Vernon; Baird, Margaret; Young, Sarah; Hibma, Merilyn
Background Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models. Methodology/Principal Findings We developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R2?=?0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients. Conclusions/Significance Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols.
Kronik, Natalie; Kogan, Yuri; Elishmereni, Moran; Halevi-Tobias, Karin
Cytoreductive chemotherapy and immunosuppression have been postulated as possible adjuncts to cancer immunotherapy in studies using murine tumour-infiltrating lymphocytes (TIL). Treatment of animals with cyclophosphamide (Cy) therapy alone caused two distinct biological activities that altered the relationship between host and tumour. These two in vivo activities were distinguished by altering the timing and dose of Cy administration relative to tumour implantation. Cy administered 3 days following tumour injection caused a significant decline in the number of pulmonary micrometastases and greater survival compared to untreated controls in proportion to the dose of Cy administered. Further reduction in pulmonary disease was observed when Cy-treated mice were given TIL therapy. The possible role(s) of Cy-induced immunosuppression was studied by injecting Cy 24 h prior to tumour injection. This treatment failed to cause the cytoreductive effect observed when Cy was administered 3 days after tumour since Cy-administration prior to tumour resulted in a significantly higher number of pulmonary metastases and diminished survival compared to untreated controls. Despite the increased number of pulmonary metastases and decreased survival in mice treated with Cy before administration of tumour, therapy with TIL significantly diminished pulmonary disease compared to animals treated with Cy alone. Immunosuppression (without concomitant cytoreductive therapy) prior to TIL treatment significantly prolonged survival. Additional studies with TIL therapy indicate that the survival of animals immunosuppressed prior to tumour injection was significantly longer than controls which received immunotherapy alone. These results suggest that the combustion of immunosuppression plus cellular immunotherapy, which leads to significant survival advantage in these murine tumour models, may possibly augment the clinical response in human TIL trials. PMID:1341232
Schoof, D D; Massaro, A F; Obando, J A; Kusack, J C; Eberlein, T J
The first drugs developed for Alzheimer's disease (AD), anticholinesterase inhibitors (AchEI), increase acetylcholine levels, previously demonstrated to be reduced in AD. To date, four AchEI are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. These treatments are symptomatic, whereas drugs under development are supposed to modify pathological steps leading to AD, thus acting on the evolution of the disease. For this reason they are currently termed "disease modifying" drugs. To block the progression of the disease, they have to interfere with pathogenic steps at the basis of clinical symptoms, including the deposition of extracellular amyloid beta (A?) plaques and of intracellular neurofibrillary tangles. The most innovative approach is represented by the vaccination and passive immunization against A? peptide. In this article, current knowledge about concluded and ongoing clinical trials with both vaccination with different antigens and passive immunization will be reviewed and discussed. PMID:23299047
Galimberti, Daniela; Ghezzi, Laura; Scarpini, Elio
Tumour-associated antigens and specific immune response to these antigens have been clearly demonstrated in patients with melanoma. Impaired cellular immune reactions are evident in patients with progressive and disseminated disease. Immunotherapy is used to heighten the host resistance and hence prevent recurrence and spread of the tumour. BCG vaccine has been used to produce nonspecific stimulation of the immune system. Preliminary evaluation of the effect of adjuvant systemic BCG therapy suggests that the treatment may have a beneficial effect on patients with early melanoma. Images Fig. 1 Fig. 2
El-Domeiri, A. A.
Plasmacytoid dendritic cells (pDCs) are specialized APCs implicated in the pathogenesis of many human diseases. Compared with other peripheral blood mononuclear cells, pDCs express a high level of TLR9, which recognizes viral DNA at the initial phase of viral infection. Upon stimulation, these cells produce large amounts of type I interferon and other proinflammatory cytokines and are able to prime T lymphocytes. Thus, pDCs regulate innate and adaptive immune responses. This article reviews select aspects of pDC biology relevant to the disease pathogenesis and immunotherapy in multiple sclerosis. Many unresolved questions remain in this area, promising important future discoveries in pDC research.
von Glehn, Felipe; Santos, Leonilda M; Balashov, Konstantin E
Adoptive cell therapy (ACT) using autologous tumour-infiltrating lymphocytes has emerged as the most effective treatment for patients with metastatic melanoma and can mediate objective cancer regression in approximately 50% of patients. The use of donor lymphocytes for ACT is an effective treatment for immunosuppressed patients who develop post-transplant lymphomas. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment.
Rosenberg, Steven A.; Restifo, Nicholas P.; Yang, James C.; Morgan, Richard A.; Dudley, Mark E.
Immunotherapy is the most effective treatment for the snake bites. The antivenoms are commonly obtained by hyperimmunization of animals that suffer from venom toxicity. The present report describes gamma irradiation effects on Cerastes cerastes venom. Doses of 1 kGy and 2 kGy gamma radiations were used for venom detoxification. These treated venoms did not have any residual lethal effects until 10 LD(50). Immunological analysis of sera raised against native and irradiated venoms, showed that elicited antibodies to irradiated venoms were able to recognize native venom. Anti-2 kGy irradiated venom had more protective ability than anti-native venom, as tested in mice. PMID:18306103
Oussedik-Oumehdi, Habiba; Laraba-Djebari, Fatima
Medical advances such as allogeneic transplantation can expose patients to periods of marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Control of infection will depend ultimately on the restoration of adequate antiviral immunity, and cellular immunotherapy is an attractive approach to improving immune protection. Developments in basic immunology have led to a greater understanding of the nature of protective immunity in immunocompetent donors, and this knowledge is now being used to direct immunotherapeutic protocols. Moreover, immunological techniques that have recently been developed as research tools, such as peptide-HLA tetramers and cytokine-secretion assays, have potential application for clinical use in this setting. PMID:15630425
Moss, Paul; Rickinson, Alan
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.
Hamblin, Michael R.; Castano, Ana P.; Mroz, Pawel
Background Epicutaneous immunotherapy (EPIT) on intact skin with an epicutaneous delivery system has already been used in preclinical and clinical studies. In epicutaneous vaccination and immunotherapy, the stripping of skin before application of the allergen is suggested to facilitate the passage of allergen through immune cells. Objectives The aim of this study was to compare the immunological response induced by EPIT performed on intact and stripped skin in a mouse model of peanut allergy. Methods After oral sensitization with peanut and cholera toxin, BALB/c mice were epicutaneously treated using an epicutaneous delivery system (Viaskin® (DBV Technologies, Paris) applied either on intact skin or on stripped skin. Following EPIT, mice received an exclusive oral peanut regimen, aimed at triggering esophageal and jejunal lesions. We assessed eosinophil infiltration by histology, mRNA expression in the esophagus, antibody levels and peripheral T-cell response. Results EPIT on intact skin significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal eosinophilia (2.7?±?0.9, compared to Sham 19.9?±?1.5, p?0.01), mRNA expression of Th2 cytokines in tissue and intestinal villus sub-atrophia (2.9?±?0.2 vs Sham, 2.1?±?0.2, p?0.05). By contrast, EPIT on stripped skin reinforced Th2 systemic immunological response as well as eosinophil infiltration (26.8?±?15.1), mRNA expression of Th2 cytokines and duodenal villus/crypt-ratio (2.4?±?0.3). Conclusions Epicutaneous allergen-specific immunotherapy needs the integrity of superficial layers of the stratum corneum to warranty safety of treatment and to induce a tolerogenic profile of the immune response.
Allogeneic stem cell transplantation has a well-defined indication in the treatment of hematological malignancies. The beneficial immune effect of allogeneic marrow transplantation has long been known, but only recently have methods been developed to separate the graft-versus-leukemia (GVL) effect from graft-versus-host disease (GVHD). Animal experiments have shown that lymphocytes from the marrow donor can be transfused without causing severe GVHD if stable chimerism and tolerance is established. First clinical studies have been preformed in patients with recurrent chronic myelogenous leukemia. In these patients complete molecular remissions were induced that persist without further maintenance treatment. These results have been confirmed in larger multicenter studies in Europe and the USA. The best results were obtained in chronic myelogenous leukemia (CML); repeated successes have been reported in relapsing acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma (MMY), and rare responses were reported for acute lymphoid leukemia. Contrary to animal experiments GVHD has been observed in human patients although to a lesser extent than expected in transplants not given immunosuppression. Secondly myelosuppression has been observed in patients treated with relapsing CML. In CML the incidence of GVHD could be reduced by depleting CD8+ T cells from the donor lymphocyte concentrate. Alternatively only small numbers of T lymphocytes can be transfused and in the case of failing responses, the numbers of donor lymphocytes may be increased. Results in recurrent AML have been improved by the use of low-dose cytosine arabinoside, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor mobilized blood cells as compared to lymphocytes only. In MMY the response rate is higher than in AML, but the remissions are of limited duration in most patients. Several protocols have been designed to include preemptive donor lymphocyte transfusion in patients with a high relapse risk after transplantation. Problems remain to avoid chronic GVHD and to circumvent the immune escape mechanisms of leukemia. PMID:14583671
Kolb, Hans-Jochem; Schmid, Christoph; Chen, Xiao; Woiciechowski, Anja; Roskrow, Marie; Weber, Martin; Guenther, Wolfgang; Ledderose, Georg; Schleuning, Michael
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.
Thomas, J W; Plenderleith, I H; Clements, D V; Landi, S
T lymphocytes are classified into 2 subsets based on their T-cell receptor (TCR) expression. The vast majority of T cells expresses an alphabeta TCR heterodimer. These alphabeta T cells recognize antigenic peptides presented by MHC class I (for CD8(+) T cells) or MHC class II molecules (for CD4(+) T cells). Concepts of cancer immunotherapy are mostly concerned with activation of these MHC-restricted alphabeta T cells. Until recently, a numerically small subset of T cells, which expresses an alternative TCR composed of a CD3-associated gammadelta heterodimer, has received far less attention as a potential agent in cancer therapy. These gammadelta T cells share with alphabeta T cells certain effector functions such as cytokine production and potent cytotoxic activity but recognize different sets of antigens, usually in a non-MHC-restricted fashion. Different subsets of human gammadelta T cells recognize stress-inducible MHC class I-related molecules frequently expressed on epithelial tumor cells or phosphorylated metabolites which can be generated by tumor cells. In line with this, many tumor cells are highly susceptible to gammadelta T-cell mediated lysis. In our article, we summarize the available evidence for a contribution of human gammadelta T cells in tumor defense and discuss potential strategies for the immunotherapy of tumors based on the endogenous activation and/or adoptive transfer of tumor-reactive gammadelta T lymphocytes. PMID:15386388
Kabelitz, Dieter; Wesch, Daniela; Pitters, Elke; Zöller, Margot
Epitope-based vaccination strategies designed to induce tumor-specific CD8 CTL are being widely considered for cancer immunotherapy. Here we describe a recombinant poxvirus vaccine that codes for ten HLA-A2-restricted epitopes derived from five melanoma Ags conjoined in an artificial polyepitope or polytope construct. Target cells infected with the melanoma polytope vaccinia were recognized by three different epitope-specific CTL lines derived from HLA-A2 melanoma patients, and CTL responses to seven of the epitopes were generated in at least one of six HLA-A2-transgenic mice immunized with the construct. CTL lines derived from vaccinated transgenic mice were also able to kill melanoma cells in vitro. Multiple epitopes within the polytope construct were therefore shown to be individually immunogenic, illustrating the feasibility of the polytope approach for melanoma immunotherapy. Tumor escape from CTL surveillance, through down regulation of individual tumor Ags and MHC alleles, might be overcome by polytope vaccines, which simultaneously target multiple cancer Ags. PMID:10491010
Mateo, L; Gardner, J; Chen, Q; Schmidt, C; Down, M; Elliott, S L; Pye, S J; Firat, H; Lemonnier, F A; Cebon, J; Suhrbier, A
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
Le, Dung T; Dubenksy, Thomas W; Brockstedt, Dirk G
The immune system plays a dual role against cancer: it prevents tumor cell outgrowth and also sculpts the immunogenicity of the tumor cells. Cancer cells are able to escape from the immune system by inhibiting T lymphocytes activation. New immunotherapies have been developped to target these T lymphocytes activation modulators: the immune checkpoints. These novel therapies are showing promising results with durable objective responses in some patients. Ipilimumab (anti-CTLA4) was the first of these new therapeutics to be approved by the FDA in March 2011 for advanced melanoma and other immunomodulators trials are ongoing in other cancers with similar encouraging results like with the anti PD-1/PD-L1. These drugs are already challenging our future practice like for evaluation of tumor response or for management of immune related toxicities. Many immune checkpoints have been identified and could potentially be targeted. Future studies will help to identify predictive factors but also to coordinate these new immunotherapies with our classic treatment strategies. PMID:23735730
Ileana, Ecaterina; Champiat, Stéphane; Soria, Jean-Charles
The concept of immunotherapy as a treatment for cancer patients has been in existence for decades. However, more recent immune therapeutic approaches have involved targeting of tumor-specific antigens. While improvements have been made in using such immune stimulatory treatment strategies for a variety of solid cancers, the use of these strategies for patients with head and neck squamous cell carcinoma (HNSCC) is lagging behind. Immunotherapeutic approaches for HNSCC are particularly complicated by the profound immune suppression that is induced by HNSCC, which potentially lessens the effectiveness of immune stimulatory efforts. Trials involving patients with various solid cancers have shown the enhanced effectiveness of combining various immunotherapeutic approaches or combining immunotherapy with chemotherapy or radiation therapy. Treatment of HNSCC with such combination approaches has not been extensively investigated and has the added challenge of the need to overcome the HNSCC-induced immune suppression. This review focuses on clinical trials that have tested immunotherapeutic approaches for HNSCC patients and the challenges associated with such approaches. In addition, it will call attention to immunotherapeutic strategies that have been demonstrated as successful in the treatment of other solid cancers in order to identify potential strategies that may apply to the treatment of HNSCC.
De Costa, Anna-Maria A.; Young, M. Rita I.
Introduction: Malignant melanoma is a highly aggressive, immunogenic tumor that has the ability to modulate the immune system to its own advantage. Patients with melanoma present numerous cellular immune defects and cytokine abnormalities, all leading to suppression of the host anti-tumor immune response. Innovative treatment strategies can be achieved through employing our knowledge of the melanoma-induced immune alterations. Areas covered: The authors review comprehensively the immune abnormalities in individuals with melanoma, and provide a summary of currently available melanoma immunotherapy agents that are currently on the market or undergoing clinical trials. Expert opinion: Ipilimumab, a monoclonal antibody directed against the CTLA-4, is one of the current forefront treatment strategies in malignant melanoma. Novel immunomodulating agents have shown clear activity in patients with malignant melanoma. These include anti-PD-1 and anti-PD-1 ligand antibodies that may soon become important items in the anti-melanoma armamentarium. Combinations of different immunotherapy agents, between themselves or with other agents, are currently being studied in an attempt to further enhance the antineoplastic effect in patients with malignant melanoma. PMID:23930800
Shimanovsky, Alexei; Jethava, Ashif; Dasanu, Constantin A
Purpose of Review Thyroid eye disease (TED) is a poorly understood autoimmune manifestation most commonly associated with Graves’ disease. Current nonspecific treatment paradigms offer symptomatic improvement but fail to target the underlying pathogenic mechanisms and thus, do not significantly alter the long-term disease outcome. The purpose of this review is to provide an update of the current understanding of the immunopathogenesis of TED and explore these implications for targeted immunotherapy. Recent Findings Orbital fibroblasts are integral to the pathogenesis of TED and may modulate immune responses by production of cytokines and hyaluronan in response to activation of shared autoantigens including thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-R1). Fibrocytes share many of these phenotypic and functional features, suggesting a link between systemic and site-specific disease. Use of targeted immunotherapies in TED is limited, though data from the use Rituximab (RTX), a B cell depleting agent, are encouraging. Sustained clinical response has been seen with RTX in several reports, despite return of peripheral B cell levels to pretreatment levels. Additionally, this response appears to be independent to cytokine and antibody production, suggesting possible modulation of antigen presentation as a mechanism of its effect. Summary Progressive advances in the understanding of the immunopathogenesis of TED continue to spur clinical trials utilizing targeted immune therapies. Continued understanding of the molecular mechanisms of disease will expand potential treatments for TED patients and obviate the need for reconstructive surgical therapies.
Gupta, Shivani; Douglas, Raymond
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.
Scurati, Silvia; Frati, Franco; Passalacqua, Gianni; Puccinelli, Paola; Hilaire, Cecile; Incorvaia, Cristoforo
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.
Le, Dung T.; Dubensky, Thomas W.; Brockstedt, Dirk G.
The response of the body to cancer is not a unique mechanism and has many parallels with inflammation and wound healing. Unresolved inflammation generates a microenvironment favorable for cellular transformation and the growth of cancer cells. Chronic tissue damage triggers a repair response that includes the production of growth factors, cytokines and chemokines. Cytokines and chemokines have a crucial role in cancer-related inflammation with consequent, direct and indirect effects on the proliferative and invasive properties of tumor cells. In view of the multifactorial functions of cytokines and chemokines in tumorigenesis, the elucidation of their roles will further advance our understanding of the patho-physiological processes of tumor development and highlights potential innovative anti-cancer strategies. Despite recent advances, main anti-cancer therapies, namely surgery, radiation therapy and chemotherapy, are limited in their ability to treat minimal and metastatic residual disease. Furthermore, the benefit of conventional therapies is often limited by collateral damage to normal tissues. Immunotherapy is a new avenue of cancer treatment being investigated by researchers and clinicians for different cancer types. The aim of this paper is to analyze the recent patents and scientific reviews on the major cytokine/chemokine pathways involved in cancer immunotherapy and discuss their basic biology, clinical relevance and potential directions for future anti-cancer therapeutic applications. PMID:22894642
Amedei, Amedeo; Prisco, Domenico; D' Elios, Mario M
In the vast area of immunotherapies, the development of monoclonal antibodies as a therapeutic concept emerged as a quantum leap out of the area of traditional vaccines (Köhler and Milstein) in vitro selection and optimisation made it possible to elaborate a single biological molecule from the molecular plethora of an individual adaptive immune response and to utilize such a cloned antibody repeatedly in a generalized fashion whenever the therapeutic indication is given to humans. At present, some 25 therapeutic monoclonal antibodies are currently being marketed in oncology, exceeding sales of USD20bn in 2011. A total of about 270 antibodies are currently in Phase II and III clinical development. Working on the assumption of usually lower attrition rates for antibody candidates, we expect approximately 120 of these 270 antibodies to be finally approved. This poses some key questions. What level of differentiation is required so that the coming new antibody drugs can command premium pricing when members of the founding generation become generic and inexpensive? What will global demand for antibody drugs be in view of the rising buying power in emerging pharmaceutical ('pharmerging') markets, but which is still not comparable with that of developed ones? What would the next quantum leaps be that might potentially push antibody technology on to a next level by disruptive innovation? Presentations given at the Phacilitate Immunotherapy Leaders' Forum 2012 (9-11 May in Barcelona) reflected on these questions and provided some stimulating perspectives. PMID:22894946
Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is expected to open new perspectives for the development of novel experimental treatment strategies to enhance the efficacy of cancer immunotherapy in the future. PMID:23441073
Background: Allergen immunotherapy is inconvenient and associated with the risk of anaphylaxis. Efforts to improve the safety of immunotherapy by means of chemical modification of allergens have not been successful because it greatly reduced their antigenicity. Recently, immunostimulatory DNA sequences (ISS or CpG motifs) have been shown to act as strong T1 response–inducing adjuvants. Objective: We sought to determine whether
Helen Tighe; Kenji Takabayashi; David Schwartz; Gary Van Nest; Stephen Tuck; Joseph J. Eiden; Anne Kagey-Sobotka; Peter S. Creticos; Lawrence M. Lichtenstein; Hans L. Spiegelberg; Eyal Raz
Background Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown. Methods and Findings Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFN?/STAT1 activation and attenuated tumor metastasis. IFN? neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFN?/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis. Conclusion and Significance Our studies suggest that activation of IFN?/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis.
Yan, Jun; Wang, Zi-Yan; Yang, Hong-Zhen; Liu, Han-Zhi; Mi, Su; Lv, Xiao-Xi; Fu, Xiao-Ming; Yan, Hui-Min; Zhang, Xiao-Wei; Zhan, Qi-Min; Hu, Zhuo-Wei
The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours. PMID:9010027
Korbelik, M; Naraparaju, V R; Yamamoto, N
The effect of Photofrin-based photodynamic therapy (PDT) and adjuvant treatment with serum vitamin D3-binding protein-derived macrophage-activating factor (DBPMAF) was examined using a mouse SCCVII tumour model (squamous cell carcinoma). The results show that DBPMAF can markedly enhance the curative effect of PDT. The most effective DBPMAF therapy consisted of a combination of intraperitoneal and peritumoral injections (50 and 0.5 ng kg-1 respectively) administered on days 0, 4, 8 and 12 after PDT. Used with a PDT treatment curative to 25% of the treated tumours, this DBPMAF regimen boosted the cures to 100%. The DBPMAF therapy alone showed no notable effect on the growth of SCCVII tumour. The PDT-induced immunosuppression, assessed by the evaluation of delayed-type contact hypersensitivity response in treated mice, was greatly reduced with the combined DBPMAF treatment. These observations suggest that the activation of macrophages in PDT-treated mice by adjuvant immunotherapy has a synergistic effect on tumour cures. As PDT not only reduces tumour burden but also induces inflammation, it is proposed that recruitment of the activated macrophages to the inflamed tumour lesions is the major factor for the complete eradication of tumours.
Korbelik, M.; Naraparaju, V. R.; Yamamoto, N.
Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.
Campbell, John D.; Buckland, Karen F.; McMillan, Sarah J.; Kearley, Jennifer; Oldfield, William L.G.; Stern, Lawrence J.; Gronlund, Hans; van Hage, Marianne; Reynolds, Catherine J.; Boyton, Rosemary J.; Cobbold, Stephen P.; Kay, A. Barry; Altmann, Daniel M.; Larche, Mark
Cancer is a complex disease with interactions between normal and neoplastic cells. Since current therapies for cancer largely rely on drugs or radiation that kill dividing cells or block cell division, these treatments may have severe side effects on normal proliferating cells in patients with cancer. Recently, immunotherapeutic approaches for cancer therapy, by which monoclonal antibodies (Mabs) target tumor specific antigens, have shown great potential. Glycoprotein non-metastatic melanoma protein B(Gpnmb)/Osteoactivin (OA) is a transmembrane glycoprotein highly expressed in various types of cancer. Gpnmb/OA promotes the migration, invasion and metastasis of tumor cells. CR 011-vcMMAE is a Mab-drug conjugate being developed for the treatment of Gpnmb/OA-expressing cancers. Gpnmb/OA represents an attractive target in cancer immunotherapy and CR011-vcMMAE holds promise as a reagent in targeted therapy for Gpnmb/OA-expressing malignancies. PMID:22017590
Zhou, L T; Liu, F Y; Li, Y; Peng, Y M; Liu, Y H; Li, J
Hematological malignancies were the first diseases in clinical oncology for which the potential of harnessing the immune system as targeted therapy was unequivocally demonstrated. Unfortunately the use of this highly efficacious modality has been limited to only a subset of patients and diseases due to immune-mediated toxicities resulting from incomplete specificity, and disease-specific determinants of sensitivity versus resistance to immune effector mechanisms. Recent studies however, have begun to elucidate the molecular basis of the observed clinical effects allowing the rational development of next generation of immunotherapeutic combinations. We discuss here cancer antigen targets in hematological malignancies and the specific approaches to induce immunity being pursued, the importance of modulating the host immunoregulatory environment, and the special features of immunological monitoring in clinical investigation. The hematological malignancies represent an ideal setting for the development of immunotherapy due to logistical, clinical monitoring and disease biology factors and may represent an exemplar for immune based treatment in other cancer types.
Hourigan, Christopher; Levitsky, Hyam I.
The past 20 years have seen remarkable advances in our understanding of the molecular and cellular processes controlling the development of an anticancer immune response. These advances have spawned a renaissance in the field of cancer immunotherapy, the original targeted therapy, during which investigators have pushed the envelope and translated promising strategies into investigational therapeutics in patients with cancer. An approach that combined nonmyeloablative lymphodepleting chemotherapy with adoptive transfer of tumor-specific CD4 and CD8 T cells exhibited an initial objective response rate of 51% for patients with stage IV melanoma. Although this strategy is extremely challenging, one can expect technological advances that may simplify this approach and further improve outcome. PMID:16091201
Poehlein, Christian H; Rüttinger, Dominik; Ma, Jun; Hu, Hong-Ming; Urba, Walter J; Fox, Bernard A
Nearly a century has passed since the first report describing antigen-specific immunotherapy (antigen-SIT) was published. Research into the use of antigen-SIT in the treatment of both allergic and autoimmune disease has increased dramatically since, although its mechanism of action is only slowly being unravelled. It is clear though, from recent studies, that success of antigen-SIT depends on the induction of regulatory T (T reg) cell subsets that recognise potentially disease-inducing epitopes. The major challenge remaining for the widespread use of antigen-SIT is to safely administer high doses of immunodominant and potentially pathogenic epitopes in a manner that induces T cell tolerance rather than activation. This review illustrates that intelligent design of treatment agents and strategies can lead to the development of safe and effective antigen-SIT. PMID:20850958
Sabatos-Peyton, Catherine A; Verhagen, Johan; Wraith, David C
Th9 is a new T cell subset characterized by IL-9 production. It has been reported that serum IL-9 levels are related with symptom severity in patients with allergic rhinitis (AR). This study is aimed at investigating whether serum IL-9 may be modulated by sublingual immunotherapy (SLIT) in patients with persistent AR due to Parietaria allergy. Twenty-one AR patients (9 males, median age 41 years) successfully treated with SLIT and 52 AR patients (25 males, median age 34 years) treated only with drugs were evaluated during the pollen season. Serum IL-9 was dosed in all patients. SLIT-treated patients showed significantly lower serum IL-9 levels than untreated AR patients (p <0.0001). In conclusion, this preliminary study shows that a single pre-seasonal SLIT course might modulate serum IL-9. PMID:21880201
Ciprandi, G; De Amici, M; Marseglia, G L
Ingenol mebutate is a diterpene ester derived from the plant Euphorbia peplus and is FDA approved for the topical treatment of actinic keratoses (AK). Shown to be efficacious with as little as a 3-day trial, this compound is being further tested for the topical treatment of other nonmelanoma skin cancers with promising preclinical data. In an effort to elucidate the molecular mechanism of this novel drug, Stahlhut et al. (2012) suggest a role for calcium and apoptosis. Further studies are needed to evaluate the intracellular mechanisms of ingenol mebutate-mediated cytotoxicity. Additionally, studies such as this not only shed light on the mechanism of ingenol mebutate and its derivatives, but also pave the way for evaluating the involvement of the immune system in eliminating drug-treated cells and tissues. This has important implications for the development of novel topical immune modulatory products and the field of topical immunotherapy. PMID:23134979
Doan, Hung Q; Gulati, Nicholas; Levis, William R
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.
Turtle, Cameron J.; Riddell, Stanley R.
Accumulating evidence supports the role of leukemic stem cells (LSCs) in the high relapse rate of acute myeloid leukemia (AML) patients. The clinical relevance of LSCs, which were originally characterized in xenograft models, has recently been confirmed by the finding that stem cell-like gene expression signatures can predict the clinical outcome of AML patients. The targeted elimination of LSCs might hence constitute an efficient therapeutic approach to AML. Here, we review immunotherapeutic strategies that target LSC-associated antigens, including T cell-mediated and monoclonal antibody-based regimens. Attention is given to the issue of antigen specificity because this is relevant to the therapeutic window and determines the superiority of LSC-targeting immunotherapy.
Snauwaert, Sylvia; Vandekerckhove, Bart; Kerre, Tessa
Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field.
Matar, Pablo; Alaniz, Laura; Rozados, Viviana; Aquino, Jorge B; Malvicini, Mariana; Atorrasagasti, Catalina; Gidekel, Manuel; Silva, Marcelo; Scharovsky, O Graciela; Mazzolini, Guillermo
Controversy exists as to the role that the immune system plays in cancer therapy. While the immune system has been proposed to scavenge the body to prevent microscopic transformation from forming cancer, it has been difficult to mount its potential of shrinking established tumors. NK cells are components of the innate immune system. They can recognize targets without prior sensitization, making them ideal candidates to manipulate for therapeutic use against cancer. Initially, autologous NK cells were directed against tumors but it was realized that NK cells that recognize self cells are inhibited. More encouraging advances have been made with allogeneic NK cell therapy in clinical trials to overcome this limitation. In this article, we present developments in NK cell adoptive immunotherapy for hematologic and solid tumor malignancies.
Geller, Melissa A; Miller, Jeffrey S
The promise of cancer immunotherapy has not been translated into clinical successes in large part due to tumor-associated immune suppression that blocks effective antitumor immunity. Recent findings demonstrate a tumor-induced immunosuppressive mechanism whereby tumor-derived CD73 functions as an ecto-enzyme to produce extracellular adenosine that promotes tumor growth by limiting antitumor T cell immunity via adenosine receptor (AR) signaling. Results with small molecule inhibitors or monoclonal antibodies targeting CD73 in murine tumor models suggest that targeted CD73 therapy is an important alternative and realistic approach to effective control of tumor growth. In particular, it helps T cell-based therapy by enhancing the adaptive immune response machinery, which may increase the function of tumor-infiltrating T lymphocytes, and subsequently lead to improved survival in cancer patients.
Background By now, the efficacy and safety of sublingual immunotherapy (SLIT) have been well established, but as for all long-term treatments, adherence to the treatment is essential. Patient-related outcome measures, such as the patients' satisfaction with the treatment, have become more crucial for they may affect treatment adherence. Methods To evaluate patient satisfaction with SLIT treatment (Staloral, Stallergenes S.A., France) we designed a prospective, observational, multicenter study. Treatment satisfaction was measured using the QUARTIS questionnaire (= Questionnaire on Respiratory Allergies Treated by Sublingual Immunotherapy). As medical parameters effectiveness and adverse events were documented. Patients with allergic rhinitis and/or conjunctivitis due to tree pollen, grass pollen or house dust mites were included in the study. Results 226 patients (94 male, 132 female, median age 37 years) participated in this study. Treatment satisfaction: Compared to a period before treatment, patients reported improved nasal symptoms (13.03 vs. 9.70; P < 0.0001) and eye symptoms (6.11 versus 4.43; P < 0.0001). After treatment, the allergy was less bothersome in everyday life (9.62 versus. 7.27; P < 0.0001). 69.2% of treated patients experienced a better tolerability than they had expected. No relevant differences were observed between the different allergen groups. Effectiveness: The severity of nasal symptoms was reduced by 53.2% (2.35 versus 1.10; P < 0.0001). For eye symptoms the severity was reduced by 57.0% (2.14 versus 0.92; P < 0.0001). Only 36.1% of the patients needed symptomatic medication in the treatment period compared to 70.1% before treatment. 88.0% of the investigators assessed the patients' well-being as "much better" or "better" after treatment. Adverse events: The overall tolerability was assessed as "good" or "very good" in approximately 90% of the evaluable cases. Only 11.9% of patients experienced adverse events (AEs). The most common AEs were gastrointestinal disorders. Conclusions Patients treated with SLIT in a real-life setting were satisfied with the treatment: It was tolerated well, patients' symptoms improved and their allergy had less impact on daily life. The patients' high level of treatment satisfaction as well as the good tolerability and effectiveness of the extract are important factors for they may help to improve treatment adherence.
Hadler, Meike; Schnitzer, Silvia; Schnitker, Jorg; Sieber, Jochen
Venom immunotherapy (VIT) induces immune tolerance to Hymenoptera venom but the underlying mechanisms are not clarified. Regulatory T cells are thought to play an important role in tolerance induction during specific immunotherapy. Our objective was to determine the effects of rush VIT on the percentage of regulatory T cells and immunosuppressive cytokines interleukin (IL)-10 and transforming growth factor beta (TGF-beta) in children. Blood samples were collected from 18 children with a previous systemic allergic reaction to a Hymenoptera sting, with a positive skin test and positive specific IgE, before rush VIT, after 6 weeks and 6 months of rush VIT. Ten children with no history of venom allergy were studied as controls. Isolated peripheral blood mononuclear cells were stained with specific markers for regulatory T cells and analyzed by flow cytometry. The percentage of regulatory T cells did not change during rush VIT in children. No change was noticed in the percentage of IL-10 and TGF-beta secreting cells after 6 weeks or 6 months of VIT. No difference in expression of cytotoxic T-lymphocyte antigen 4 on CD4(+)CD25(+high) was found. Rush VIT is a safe and effective treatment for patients allergic to Hymenoptera venom. Although regulatory T cells are considered to be responsible for this effect; no significant changes in the percentage of these cells or immunosuppressive cytokines were noticed during rush VIT in children. Additional investigations are needed to clarify the role of regulatory T cells in the induction of tolerance during rush VIT in children. PMID:23394512
Ajduk, Jakov; Turkalj, Mirjana; Gagro, Alenka
Circulating immune complexes (CIC) were determined from dog-allergic asthmatic children (n = 35) receiving immunotherapy with dog dander and hair extract. The results from CIC are expressed in SDU (standard deviation units) and presented as follows: pretreatment results (n = 20), rush results (n = 11), mid-schedule results (n = 20), maintenance results (n = 15) and the results of the placebo-treated group (n = 12). The results of the placebo-treated group (n = 12) and those of the untreated atopic (n = 12) and non-atopic (n = 14) were controls. CIC levels were analysed by means of KgB-ELISA (conglutinin binding enzyme linked immunosorbent assay), C1qB-ELISA (C1q-binding enzyme linked immunososrbent assay), RFb-ELISA (rheumatoid factor binding enzyme linked immunosorbent assay) and by PIPA (platelet 125J-labelled staphylococcal protein-A test). The CIC level determined by KgB-ELISA in dog-allergic asthmatic children was higher than that of the atopic controls (P less than 0.05) already before the onset of the hyposensitization. During conventional hyposensitization with dog dander and hair the CIC level remained the same as before treatment. On day 5 of rush hyposensitization the mean level of CIC showed no increase when compared with the pretreatment values. A statistically significant correlation (P less than 0.01) was observed between the dog dander and hair-specific IgG antibodies and the CIC level measured by KgB-ELISA during the maintenance period of conventional immunotherapy. The samples of sera to measure this correlation were collected before the injection of allergen and after 2 weeks of injection during maintenance treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2785775
Valovirta, E; Viander, M; Koivikko, A; Vanto, T; Lindström, P; Wager, O; Pekkola-Heino, K; Ingeman, L; Kekomäki, R
Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML). Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML.
Kadowaki, Norimitsu; Kitawaki, Toshio
Immunotherapy was introduced 100 years ago and still is the only treatment that modifies the course of allergic diseases. The success of its use depends on correct indications, use of standardized extracts and monitoring the therapeutic response. PMID:23072584
Zuberbier, Torsten; Canonica, Giorgio Walter; da Silva, Barbara
ObjectiveTo investigate the health and monetary consequences of treating allergy with specific immunotherapy (SIT) compared with symptomatic treatment\\/standard care among patients with grass pollen or mite allergy.
K. D. Petersen; D. Gyrd-Hansen; R. Dahl
Over the last 50 years, development in the field of cancer immunotherapy has been fluctuating, ranging from exciting expectations to disappointing clinical outcomes. Now, the time has come again, for cancer immunotherapy. Since 2010, new immunotherapeutics have been approved one after another in the United States of America and other countries. Thus, immunotherapy has definitely been recognized as the fourth therapy for cancer after surgery, radiotherapy, and chemotherapy. Under this establishment, there has been progress not only in the fundamental understanding of the immune system but also in the design of scientific clinical trials, in which delayed-type tumor responses and survival benefits with less tumor shrinkage are used as indicators. The next 3 papers provide exciting insights on novel cancer immunotherapy as an innovative treatment modality for cancer. PMID:24047770
Prostate cancer is the second leading cause of cancer death in men in the United States. Novel immunotherapies are being investigated to improve survival in patients with advanced disease. Sipuleucel-T (PROVENGE), the first autologous cellular immunotherapy approved by the U. S. Food and Drug Administration, improves survival in men with asymptomatic or minimally symptomatic metastatic castration-resistant (hormone refractory) prostate cancer. PMID:22046617
Peskin, Steven R
A number of cortical and spinal excitability variables have been tested in a patient with Stiff Person Syndrome (SPS), before\\u000a and after immunotherapy with mycophenolate mofetil, intravenous immunoglobulin and corticosteroids, which normalized plasma\\u000a levels of anti-GAD antibodies and dramatically improved the clinical picture. The overlapping time-course of neurophysiological,\\u000a clinical and bio-umoral findings suggests that immunotherapy might have changed GABA\\/Glutamate balance
Simone Rossi; Monica Ulivelli; Maria Malentacchi; Giuseppe Greco; Sabina Bartalini; Patrizia Borgogni; Fabio Giannini
Nearly twenty years of experimental immunotherapy for malignant glioma yielded important insights in the mechanisms governing\\u000a glioma immunology. Still considered promising, it is clear that immunotherapy does not on its own represent the magic bullet\\u000a in glioma therapy. In this review, we summarize the major immunotherapeutic achievements in the mouse GL261 glioma model,\\u000a which has emerged as the gold standard
Wim Maes; Stefaan W. Van Gool
Therapy for non-Hodgkin’s lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of rituximab catalyzed the development of new passive immunotherapy strategies that are currently undergoing clinical evaluation. These include improvement of rituximab efficacy, newer generation anti-CD20 antibodies, drug-conjugated and radio labeled anti-CD20 antibodies, monoclonal antibodies targeting non-CD20 lymphoma antigens, and bispecific antibodies. Active immunotherapy aims at inducing long-lasting antitumor immunity, thereby limiting the likelihood of relapse. Current clinical studies of active immunotherapy for lymphoma consist largely of vaccination and immune checkpoint blockade. A variety of protein- and cell-based vaccines are being tested in ongoing clinical studies. Recently completed phase III clinical trials of an idiotype protein vaccine suggest that the vaccine may have clinical activity in a subset of patients. Efforts to enhance the efficacy of active immunotherapy are ongoing with an emphasis on optimization of antigen delivery and presentation of vaccines and modulation of the immune system toward counteracting immunosuppression, using antibodies against immune regulatory checkpoints. This article discusses results of the various immunotherapy approaches applied to date for B-cell lymphoma and the ongoing trials to improve their effect.
In this study, a mathematical model of tumor growth with a combination of immunotherapy and chemotherapy is considered. A numerical simulation using human data in clinical literature is conducted. A numerical method based on the continuation technique is employed to locate the unstable fixed-point curve as the dosage varies. A combination of chemotherapy and immunotherapy can employ low dosages of drugs. The effect of the combined dosages is also investigated in this work.
Wei, Hsiu-Chuan; Hwang, Shin-Feng; Chen, Yuh-Yih; Chen, Tze-Jang
The efficacy of immunotherapy using a streptococcal preparation, OK-432, was evaluated in each clinical stage of uterine cervical cancer. The 382 eligible patients were stratified by clinical stage and presence/absence of surgery. Within each stratum, patient's were randomly allocated to OK-432 treatment or to control treatment. OK-432 significantly inhibited recurrence in patients with stage II cervical cancer; the recurrence-free interval and survival time were remarkably prolonged in patients with stage II disease who underwent surgery. However, OK-432 did not significantly prolong these parameters in patients with stage III disease. Retrospective analyses revealed that in patients with or without lymph node metastases who underwent surgery, the recurrence-free interval and survival time were significantly prolonged by OK-432 treatment. These results indicate that OK-432 is an effective and useful postoperative immunotherapeutic agent for uterine cervical cancer. PMID:2689304
Noda, K; Teshima, K; Tekeuti, K; Hasegawa, K; Inoue, K; Yamashita, K; Sawaragi, I; Nakajima, T; Takashima, E; Ikeuchi, M
This study compares the immune response of ten patients treated with polymerized grass (PG) immunotherapy with that of 12 patients treated with conventional monomer grass (MG) immunotherapy. The patients treated with PG immunotherapy received a mean cumulative dose of 44,840 protein nitrogen units (PNU), and those treated with MG immunotherapy received a mean cumulative dose of 46,083 PNU. Total antibody binding of perennial rye grass groups I, II, and III (RGGI, RGGII, and RGGIII) was measured in the serum of each individual. In addition, IgG titers to partially purified extracts of Bermuda, timothy, and orchard grass were also determined. A significant increase in the total antibody binding of RGGI, as well as an increase in the mean IgG titer to Bermuda, timothy, and orchard grass was demonstrated after treatment in the patients who had received PG immunotherapy. The mean total antibody binding of RGGII and RGGIII also increased in these patients, although not significantly. No significant difference in the mean total antibody binding of RGGI, RGGII, or RGGIII nor in the mean IgG titer to the three grass extracts was found in the sera of the two groups of patients. This study demonstrates a comparable immune response between immunotherapy with PG and MG, and retention of antigenic determinants during the polymerization process. PMID:3767091
Fitzsimons, R; Grammer, L C; Shaughnessy, M A; Patterson, R
Over the past 8 years, 244 patients with Stage II or III melanoma have been treated by cutaneous injection of a crude acellular homogenate of allogeneic melanoma cells (V-I) or a more concentrated fraction (V-II), followed in most patients by exchanges of WBC between paired partners. Patients with Stage III disease exhibited an overall response rate of 24% and prolongation of survival compared with control data. Stage II patients also had prolonged survival and reduced rate of recurrence over historic peers' data. Breakdown of subgroup data revealed that V-II plus exchange of WBC is similar to V-I plus exchange or V-II alone. However, recent experience of LTF suggests a higher response rate than in either V-I or V-II groups, particularly when autochthonous tumor is used for cross-immunization. The most meaningful immunologic data resulted from analysis of DNCB and MIF data. Patients negative to DNCB rarely respond to immunotherapy. A positive pretreatment MIF or positive conversion following treatment correlates with response, whereas, conversion of positive to negative predicts poor clinical performance.
Jewell, W R; Thomas, J H; Sterchi, J M; Morse, P A; Humphrey, L J
Targeting tumors using cancer vaccine-therapeutics has several advantages including the induction of long-term immunity, prime boost strategies for additional treatments and reduced side effects compared to conventional chemotherapeutics. However, one problem in targeting tumor antigens directly is that this can lead to antigen loss or immunoediting. We hypothesized that directing the immune response to a normal cell type required for tumor growth and survival could provide a more stable immunotherapeutic target. We thus examined the ability of an anti-angiogenesis, Listeria monocytogenes (Lm) based vector to deliver extracellular and intracellular fragments of the mouse VEGFR2/Flk-1 molecule, Lm-LLO-Flk-E1 and Lm-LLO-Flk–I1 respectively, in an autochthonous model for Her-2/neu+ breast cancer. We found that these vaccines could cause epitope spreading to the endogenous tumor protein Her-2/neu and significantly delay tumor onset. However, tumors that grew out overtime accumulated mutations in the Her-2/neu molecule near or within CTL epitopes. We show here for the first time how an anti-angiogenesis immunotherapy can be used to delay the onset of a spontaneous tumor through epitope spreading and determine a possible mechanism of how immunoediting of an endogenous tumor protein can allow for tumor escape and outgrowth in an autochthonous mouse model for Her-2/neu+ breast cancer.
Seavey, Matthew M.; Paterson, Yvonne
One approach to adoptive cancer immunotherapy is based on the use of bispecific monoclonal antibodies (mAb) capable to redirect ex vivo generated cytolytic T lymphocytes (CTL) onto tumour cells. The efficiency of the CD28 T-cell activation pathway to induce CD3-dependent cytolytic activity was investigated while avoiding modulation of the TCR/CD3 complex needed for targeting by bispecific mAb. When used e.g. in conjunction with anti-CD2 antibodies or diacylglycerol derivatives, the in vitro stimulation of T cells with anti-CD28 mAb resulted within 36 h in high levels of CD3-dependent cytolysis (tested on a FcR+ target in the presence of anti-CD3 mAb) and sustained lymphokine production, such as TNF alpha, IFN gamma and IL-2, which may affect tumour growth when delivered locally by the transferred T cells. Rapid activation may reduce costly in vitro procedures, preserve homing capacities of retransfused T cells, and thus facilitate implementation of clinical trials based on the use of bispecific antibodies. PMID:7584490
Blum, S; Milesi, R; Tratkiewicz, J; Olive, D; Gallati, H; Cerottini, J C; von Fliedner, V
Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes). PMID:23725600
Adair, Patrick; Su, Yan; Scott, David W
This report describes the use of 131I-labeled monoclonal antibodies in two experimental models for tumor immunotherapy. In vitro treatment of the radiation-induced murine thymoma ITT-1-75NS with radiolabeled anti-Ly-2.1 significantly impaired subsequent tumor growth in vivo. However, in vivo treatment of this tumor, which previously had been injected into C57BL/6 mice, was unsuccessful. By contrast, in vitro treatment of a human colorectal tumor cell line (COLO 205) with 131I-labeled 250-30.6--a monoclonal antibody directed against a secretory component of normal and malignant gastrointestinal epithelium--completely inhibited subsequent tumor growth in BALB/c nude (nu/nu) mice. Furthermore, in vivo treatment of preexisting human colorectal tumor xenografts significantly impaired progressive tumor growth. Although some tumor inhibition was also produced by unlabeled 250-30.6 antibody, this response was considerably amplified by treatment with (131I)-labeled 250-30.6 (P less than .05), suggesting that in vivo treatment of human tumors with the use of 131I-labeled monoclonal antibodies may be clinically beneficial. The antithyroid drug propylthiouracil was used to reduce dehalogenation of the radiolabeled immunoglobulins in an attempt to improve their therapeutic efficacy.
Zalcberg, J.R.; Thompson, C.H.; Lichtenstein, M.; McKenzie, I.F.
In the current study, exposure of mammary tumor cells derived from mice transgenic for the polyomavirus middle T oncogene to ionizing radiation resulted in the generation of a tumor cell population that preferentially expressed cancer stem cell markers. In addition, these cells were more resistant to subsequent radiation treatments and appeared to acquire an enhanced capacity for dissemination to the lungs of mice. Therefore, we tested an immunotherapy approach to the treatment of local and disseminated mammary tumor cells in a murine model using a recently developed molecular chaperone-based vaccine that specifically targets the radioresistant subpopulation of tumor cells. Heat shock protein 70-peptide complexes (Hsp70.PC-F) were extracted from fusions of dendritic cells and radiation-enriched tumor cells, and the resulting chaperone vaccines were used to treat mice with pre-existing lung metastases. Immunization of mice with the Hsp70.PC-F vaccine resulted in a T cell-mediated immune response, including a significant increase in CD4 and CD8 T cell proliferation and the induction of effector T cells capable of targeting radioresistant tumor cells. Importantly, the growth of primary tumors was inhibited, and the number of tumor cells metastasizing to lung was reduced significantly by combining chaperone vaccine with radiotherapy. These results indicate that Hsp70.PC-F vaccine can induce specific immunity to radioresistant populations of mammary tumor cells and, thus, can complement radiotherapy, leading to synergistic killing. PMID:23772032
Weng, Desheng; Song, Baizheng; Koido, Shigeo; Calderwood, Stuart K; Gong, Jianlin
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  in mastocytosis, (3) probably should be done life long , (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 , (6) VIT is able to reduce systemic reactions, but to a lesser extent compared to the general insect venom allergic population , 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 . PMID:19627278
Niedoszytko, M; de Monchy, J; van Doormaal, J J; Jassem, E; Oude Elberink, J N G
Acute myeloid leukaemia (AML) is a difficult to treat disease and strategies, such as immunotherapy, which have the potential to eliminate residual tumour cells at first remission are required to reduce the incidence of relapse with its high associated mortality rates. T cells play an important role in tumor immunity and two signals are traditionally thought to be required to activate naive T cells; signal one through the major histocompatibility:antigen:T-cell receptor complex and signal two through costimulation. Many tumor associated antigens have been identified in AML suggesting it may be possible to target the immune system of AML patients; however AML develops due to tumour and immune editing, two systems by which AML cells can escape immune surveillance. By genetically modifying AML cells to express costimulatory molecules and/or cytokines, it has been possible to transform AML cells into antigen presenting cells and this has the potential to re-activate the immune system in patients. Here we summarize the rationale for using a whole cell vaccine approach to treat AML, and discuss current progress in the field of whole cell vaccine development against AML. PMID:17981688
Cheuk, Adam T C; Guinn, Barbara-ann
Background Allergen immunotherapy has been used in the management of allergic diseases for nearly 100 years. It is the only specific treatment for hymenoptera venom anaphylaxis. Various venom immunotherapy schedules have been designed to treat anaphylaxis. Although the effect of venom immunotherapy is well documented, there is also an increased risk of side-effects in bee-venom-treated patients and in those with rapid dose increase. Methods This report describes the first case of a patient in the literature with Jessner's Lymphocytic infiltration as a side effect of venom immunotherapy. This is a chronic, benign, T cell pseudolymphoma characterized by the occurrence of recurrent, asymptomatic, smooth, erythematous, non-scaling papules or plaques. However, the exact cause of Jessner's Lymphocytic Infiltration is unknown. Results The case here reported was a 61 year-old male pediatrician, who has been followed by at our Immunology Service because of an immediate allergy to a bee sting managed with venom immunotherapy. His chief complaint was an anaphylactic reaction after 5 minutes of a bee sting. The onset of his symptoms was gradual and began just 25 minutes after the sting. The venom immunotherapy regimen was planned and the protocol immediately began without premedication. But during the initial phases of treatment, on the third dose of immunotherapy, he reported severe itching. After complaining of itching, many erythematous papules and plaques on his chest were developed. The lesions flared up for 3 days period just after injection and decreased afterwards. The type of lesions and their location supported the diagnosis of Jessner disease, which had also a histopathological confirmation. Conclusions We herein report this case to call attention to this side effect of VIT that there may be more similar cases never reported.
Yalcin, Arzu Didem; Bisgin, Atil; Gorczynski, Reginald M.; Akman, Ayse; Erdo?an, Gulgun; Yegin, Olcay
Advances in treating and preventing AIDS depend on understanding how human immunodeficiency virus (HIV) is eliminated in vivo and on the manipulation of effective immune responses to HIV. During the development of assays quantifying the elimination of fluorescent autologous cells coated with overlapping 15-mer simian immunodeficiency virus (SIV) or HIV-1 peptides, we made a remarkable observation: the reinfusion of macaque peripheral blood mononuclear cells, or even whole blood, pulsed with SIV and/or HIV peptides generated sharply enhanced SIV- and HIV-1-specific T-cell immunity. Strong, broad CD4+- and CD8+-T-cell responses could be enhanced simultaneously against peptide pools spanning 87% of all SIV- and HIV-1-expressed proteins—highly desirable characteristics of HIV-specific immunity. De novo hepatitis C virus-specific CD4+- and CD8+-T-cell responses were generated in macaques by the same method. This simple technique holds promise for the immunotherapy of HIV and other chronic viral infections.
Chea, S.; Dale, C. J.; De Rose, R.; Ramshaw, I. A.; Kent, S. J.
Photodynamic therapy (PDT) is a promising treatment modality. It offers alternative options in the treatment of cancer and vascular diseases. In cancer treatment, PDT has been used primarily for localized superficial or endoluminal malignant and premalignant conditions. More recently, its application has also been expanded to solid tumors. However, its antitumor efficacy remains debatable and its acceptance still variable. Pre-clinical studies demonstrate that, in addition to the primary local cytotoxicity, PDT might induce secondary host immune responses, which may further enhance PDT's therapeutic effects on primary tumor as well as metastasis. Therefore, PDT-induced local and systemic antitumor immune response might play an important role in successful control of malignant diseases. Furthermore, PDT's antitumor efficacy might also be enhanced through an effective immunoadjuvant or immunomodulator. Our recent clinical data also indicate that improved clinical outcomes can be obtained by a combination of PDT and immunomodulation therapy for the treatment of pre-malignant skin diseases. For instance, the combination of topical ALA-PDT and Imiquimod is effective for the treatment of genital bowenoid papulosis. This presentation will also report our preliminary data in developing combination approaches of PDT and immunotherapy for actinic keratosis (AK), basal cell carcinomas (BCCs) and Bowen's disease.
Wang, Xiu-Li; Wang, Hong-Wei; Huang, Zheng
Since it became clear that all cancer cells express tumor-specific and tumor-selective antigens generated by genetic alterations and epigenetic dysregulation, the immunology community has embraced the possibility of designing therapies to induce targeted antitumor immune responses. The potential therapeutic specificity and efficacy of such treatments are obvious to anyone who studies the exquisite specificity and cytocidal potency of immune responses. However, the value assigned to a therapeutic modality by the oncology community at large does not depend on scientific principle; all that matters is how patients respond. The bar for the ultimate acceptance of a therapy requires more than anecdotal clinical responses; rather, the major modalities of cancer therapeutics, including surgery, chemotherapy, radiation therapy, and, more recently, drugs targeting oncogenes, have earned their place only after producing dramatic frequent clinical responses or demonstrating statistically significant survival benefits in large randomized phase 3 clinical trials, leading to FDA approval. Although tumor-targeted antibodies have certainly cleared this bar, immunotherapies aimed at harnessing antitumor cellular responses have not—until now.
The rational manipulation of antigen-specific T cells to reignite a tumor-specific immune response in cancer patients is a challenge for cancer immunotherapy. Targeting coinhibitory and costimulatory T cell receptors with specific antibodies in cancer patients is an emerging approach to T cell manipulation, namely "immune modulation." Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor family receptor (GITR) are potential targets for immune modulation through anti-CTLA-4 blocking antibodies and anti-GITR agonistic antibodies, respectively. In this review, we first discuss preclinical findings key to the understanding of the mechanisms of action of these immunomodulatory antibodies and the preclinical evidence of antitumor activity which preceded translation into the clinic. We next describe the outcomes and immune related adverse effects associated with anti-CTLA-4 based clinical trials with particular emphasis on specific biomarkers used to elucidate the mechanisms of tumor immunity in patients. The experience with anti-CTLA-4 therapy and the durable clinical benefit observed provide proof of principle to effective antitumor immune modulation and the promise of future clinical immune modulatory antibodies. PMID:20563707
Avogadri, Francesca; Yuan, Jianda; Yang, Arvin; Schaer, David; Wolchok, Jedd D
Treatment options for malignant mesothelioma are limited, and the results with conventional therapies have been rather disappointing to this date. Chemotherapy is the only evidence-based treatment for mesothelioma patients in good clinical condition, with an increase in median survival of only 2 months. Therefore, there is urgent need for a different approach to battle this malignancy. As chronic inflammation precedes mesothelioma, the immune system plays a key role in the initiation of this type of tumour. Also, many immunological cell types can be found within the tumour at different stages of the disease. However, mesothelioma cells can evade the surveillance capacity of the immune system. They build a protective tumour microenvironment to harness themselves against the immune system's attacks, in which they even abuse immune cells to act against the antitumour immune response. In our opinion, modulating the immune system simultaneously with the targeting of mesothelioma tumour cells might prove to be a superior treatment. However, this strategy is challenging since the tumour microenvironment possesses numerous forms of defence strategies. In this paper, we will discuss the interplay between immunological cells that can either inhibit or stimulate tumour growth and the challenges associated with immunotherapy. We will provide possible strategies and discuss opportunities to overcome these problems.
Cornelissen, R.; Heuvers, M. E.; Maat, A. P.; Hendriks, R. W.; Hoogsteden, H. C.; Aerts, J. G. J. V.; Hegmans, J. P. J. J.
The development of immunotherapies for T1DM has lagged the development T2DM drugs, but with more clarity around regulatory requirements, large pharmaceutical companies have recently entered the field to support late stage programs. This clarity around regulatory expectations has emerged because of the convergence among regulators and clinical experts in how efficacy of these therapies should be assessed. The key agreement is that the primary efficacy endpoint for treatments directed at the underlying autoimmune cause of T1DM should be endogenous insulin secretion as reflected by standardized C-peptide measurements. Important secondary endpoints include glycemic control, total daily insulin dose, and hypoglycemia rates. Most T1DM therapeutic development efforts are directed at new onset disease, which represents a small proportion of the entire T1DM population. A new frontier in T1DM therapeutic development is emerging around combination treatment of established T1DM, a population that far outnumbers those with new onset T1DM. Fully effective therapies of new onset or established T1DM will almost certainly require a combination of two or more therapies. A T1DM prevention vaccine will not be feasible until after extensive experience with the agent as a treatment of new onset and/or established T1DM. PMID:21242726
The Hymenoptera order is divided into three families: Apids, Vespidae, and Formicidae. Apids include the honeybee, bumblebee, and sweat bee, which are all docile and tend to sting mostly on provocation. The Africanized killer bee, a product of interbreeding between the domestic and African honeybee, is very aggressive and is found mostly in Mexico, Central America, Arizona, and California. The yellow jacket, yellow hornet, white (bald)-faced hornet, and paper wasp all belong to the Vespidae family. The Formicidae family includes the harvester ant and the fire ant. When a "bee" sting results in a large local reaction, defined as >5 in. and lasting >24 hours, the likelihood of anaphylaxis from a future sting is ?5%. For comparison, when there is a history of anaphylaxis from a previous Hymenoptera sting and the patient has positive skin tests to venom, at least 60% of adults and 20-32% of children will develop anaphylaxis with a future sting. Both patient groups should be instructed about avoidance measures and carrying and knowing when to self-inject epinephrine, but immunotherapy (IT) with Hymenoptera venom is indicated for those patients with a history of anaphylaxis from the index sting and not for patients who have experienced a large local reaction. IT is highly effective in that by 4 years of injections, the incidence of subsequent sting-induced anaphylactic reactions is 3%. This incidence may increase modestly after discontinuation of injections but has not been reported >10% in follow-up. PMID:22794677
Koterba, Alan P; Greenberger, Paul A
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.
Liechtenstein, Therese; Perez-Janices, Noemi; Escors, David
Prostate cancer (PCa) is the most common noncutaneous cancer diagnosis and the second leading cause of cancer-related deaths among men in the United States. Effective treatment modalities for advanced metastatic PCa are limited. Immunotherapeutic strategies based on T cells and antibodies represent interesting approaches to prevent progression from localized to advanced PCa and to improve survival outcomes for patients with advanced disease. CD8+ cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4+ T cells augment the antigen-presenting capacity of dendritic cells and promote the expansion of tumor-reactive CTLs. Antibodies mediate their antitumor effects via antibody-dependent cellular cytotoxicity, activation of the complement system, improving the uptake of coated tumor cells by phagocytes, and the functional interference of biological pathways essential for tumor growth. Consequently, several tumor-associated antigens (TAAs) have been identified that represent promising targets for T cell- or antibody-based immunotherapy. These TAAs comprise proteins preferentially expressed in normal and malignant prostate tissues and molecules which are not predominantly restricted to the prostate, but are overexpressed in various tumor entities including PCa. Clinical trials provide evidence that specific immunotherapeutic strategies using such TAAs represent safe and feasible concepts for the induction of immunological and clinical responses in PCa patients. However, further improvement of the current approaches is required which may be achieved by combining T cell- and/or antibody-based strategies with radio-, hormone-, chemo- or antiangiogenic therapy.
Kiessling, Andrea; Wehner, Rebekka; Fussel, Susanne; Bachmann, Michael; Wirth, Manfred P.; Schmitz, Marc
Burkholderia mallei and B. pseudomallei are important human pathogens and cause the diseases glanders and melioidosis, respectively. Both organisms are highly infectious when inhaled and are inherently resistant to many antimicrobials, thus making it difficult to treat pneumonic Burkholderia infections. We investigated whether it was possible to achieve rapid protection against inhaled Burkholderia infection by using inhaled immunotherapy. For this purpose, cationic liposome DNA complexes (CLDC), which are potent activators of innate immunity, were used to elicit the activation of pulmonary innate immune responses. We found that mucosal CLDC administration before or shortly after bacterial challenge could generate complete or nearly complete protection from inhalational challenge with 100% lethal doses of B. mallei and B. pseudomallei. Protection was found to be dependent on the CLDC-mediated induction of gamma interferon responses in lung tissues and was partially dependent on the activation of NK cells. However, CLDC-mediated protection was not dependent on the induction of inducible nitric oxide synthase, as assessed by depletion studies. We concluded that the potent local activation of innate immune responses in the lung could be used to elicit rapid and nonspecific protection from aerosol exposure to both B. mallei and B. pseudomallei. PMID:19179415
Goodyear, Andrew; Kellihan, Lisa; Bielefeldt-Ohmann, Helle; Troyer, Ryan; Propst, Katie; Dow, Steven
Purpose/results/discussion. Recurrent chromosomal translocations are common features of many human malignancies. While such translocations often serve as diagnostic markers, molecular analysis of these breakpoint regions and the characterization of the affected genes is leading to a greater understanding of the causal role such translocations play in malignant transformation. A common theme that is emerging from the study of tumor-associated translocations is the generation of chimeric genes that, when expressed, frequently retain many of the functional properties of the wild-type genes from which they originated. Sarcomas, in particular, harbor chimeric genes that are often derived from transcription factors, suggesting that the resulting chimeric transcription factors contribute to tumorigenesis. The tumor-specific expression of the fusion proteins make them likely candidates for tumor-associated antigens (TAA) and are thus of interest in the development of new therapies. The focus of this review will be on the translocation events associated with Ewing's sarcomas/PNETs (ES), alveolar rhabdomyosarcoma (ARMS), malignant melanoma of soft parts (MMSP) (clear cell sarcoma), desmoplastic small round cell tumor (DSRCT), synovial sarcoma (SS), and liposarcoma (LS), and the potential for targeting the resulting chimeric proteins in novel immunotherapies.
Goletz, Theresa J.; Mackall, Crystal L.; Berzofsky, Jay A.
Subcutaneous allergen immunotherapy (SCIT) is beneficial for the treatment of allergic rhinitis, asthma, and in preventing stinging insect anaphylaxis, but is not without risks. Four retrospective surveillance surveys and one on-going national prospective study have attempted to characterize the incidence and risk factors for fatal and non-fatal SCIT reactions. These studies have contributed significantly to currently recommended SCIT safety guidelines. Recent surveillance studies indicate stable SR rates, and a possible decline in the incidence of fatal reactions since the implementation of evidence-based safety guidelines. This review will provide a detailed summary of the evidence from surveillance studies for risk factors associated with SCIT reactions, including: uncontrolled asthma, prior systemic reactions, dosing during peak pollen seasons, epinephrine being delayed or not given, dosing or administration errors, inadequate waiting times, reactions occurring more than 30 min after injections, injections given in medically unsupervised settings, concomitant beta-blocker and angiotensin-converting enzyme inhibitor (ACEi) use, and accelerated build-up regimens. PMID:23636820
Kannan, Jennifer A; Epstein, Tolly G
Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including A?, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action.
Huang, Liang; Su, Xiaomin; Federoff, Howard J.
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
Liechtenstein, Therese; Perez-Janices, Noemi; Escors, David
Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice. PMID:24081947
Bouchlaka, Myriam N; Sckisel, Gail D; Chen, Mingyi; Mirsoian, Annie; Zamora, Anthony E; Maverakis, Emanual; Wilkins, Danice E C; Alderson, Kory L; Hsiao, Hui-Hua; Weiss, Jonathan M; Monjazeb, Arta M; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L; Blazar, Bruce R; Wiltrout, Robert H; Redelman, Doug; Taub, Dennis D; Murphy, William J
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
In human cancer cells, a constitutive activation of MAPK, STAT3, ?-catenin, and various other signaling pathways triggers multiple immunosuppressive cascades. These cascades result in the production of immunosuppressive molecules (e.g., TGF-?, IL-10, IL-6, VEGF, and CCL2) and induction of immunosuppressive immune cells (e.g., regulatory T cells, tolerogenic dendritic cells, and myeloid-derived suppressor cells). Consequently, immunosuppressive conditions are formed in tumor-associated microenvironments, including the tumor and sentinel lymph nodes. Some of these cancer-derived cytokines and chemokines impair immune cells and render them immunosuppressive via the activation of signaling molecules, such as STAT3, in the immune cells. Thus, administration of signal inhibitors may inhibit the multiple immunosuppressive cascades by acting simultaneously on both cancer and immune cells at the key regulatory points in the cancer-immune network. Since common signaling pathways are involved in manifestation of several hallmarks of cancer, including cancer cell proliferation/survival, invasion/metastasis, and immunosuppression, targeting these shared signaling pathways in combination with immunotherapy may be a promising strategy for cancer treatment.
Kawakami, Yutaka; Yaguchi, Tomonori; Sumimoto, Hidetoshi; Kudo-Saito, Chie; Iwata-Kajihara, Tomoko; Nakamura, Shoko; Tsujikawa, Takahiro; Park, Jeong Hoon; Popivanova, Boryana K.; Miyazaki, Junichiro; Kawamura, Naoshi
Accumulation of misfolded proteins has been implicated in a variety of neurodegenerative diseases including prion diseases, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In the past decade, single-chain fragment variable (scFv) -based immunotherapies have been developed to target abnormal proteins or various forms of protein aggregates including A?, SNCA, Htt, and PrP proteins. The scFvs are produced by fusing the variable regions of the antibody heavy and light chains, creating a much smaller protein with unaltered specificity. Because of its small size and relative ease of production, scFvs are promising diagnostic and therapeutic reagents for protein misfolded diseases. Studies have demonstrated the efficacy and safety of scFvs in preventing amyloid protein aggregation in preclinical models. Herein, we discuss recent developments of these immunotherapeutics. We review efforts of our group and others using scFv in neurodegenerative disease models. We illustrate the advantages of scFvs, including engineering to enhance misfolded conformer specificity and subcellular targeting to optimize therapeutic action. PMID:24048248
Huang, Liang; Su, Xiaomin; Federoff, Howard J
Photodynamic therapy (PDT) is a clinically approved new treatment modality. It has been used for treatment of non-malignant and malignant diseases. Over the last decade its clinical application has gained increasing acceptance around the world after regulatory approvals. PDT offers various treatment options in cancer management and has been used primarily for localized superficial or endoluminal malignant and premalignant conditions. Recently, its application has also been expanded to solid tumors. However, its efficacy for the treatment of malignant tumors remains debatable and its acceptance still variable. Pre-clinical studies demonstrate that, in addition to the direct local cytotoxicity, PDT can induce host immune responses, which may further enhance the therapeutic effects on primary tumor as well as metastasis. Therefore, PDT-induced antitumor immune response might play an important role in successful control of malignant diseases. Furthermore, the antitumor efficacy of PDT might also be enhanced through an effective immunoadjuvant to further expand its usefulness for a possible control of distant metastases. Recent clinical data also indicate that improved clinical outcomes are seen in the combination of PDT and immunomodulation therapy for non-malignant disease. This review will summarize recent progress in developing innovative approaches of PDT combined with immunotherapy for non-malignant and malignant diseases.
The primary goal of this project is to assess the degree of thermal damage in malignant tumors using Laser Assisted Cancer Immunotherapy (LACI). In our laboratory, superficial tumors were grown in Balb/c mice by injection (s.c.) of the highly aggressive metastatic mammary cell line CRL-2539. When the tumors reached 5-7 mm in diameter, Indocyanine Green, a light absorbing dye, and Glycated Chitosan, the immunoadjuvant, were injected into the tumors. Following injection, the tumors were irradiated interstitially with an infrared Diode laser (1-15 W) operating at 805nm. Following the laser therapy, at a particular temperature, the tumors were excised at various time intervals ranging from immediately after treatment to 120 hours later. Using a Hematoxylin and Eosin stain, each slide was examined under the light microscope to map out the thermal damage induced by the diode laser and the dye-immunoadjuvant combination. The goal of this experiment is to quantify and map the thermal damage for 55^oC, 65^oC and 75^oC, and to determine the temperature range that evokes maximum immune response.
Fitzmaurice, Megan; Bandyopadhyay, Pradip
Laser Assisted Cancer Immunotherapy is an experimental modality used to treat superficial tumors implanted on sterile Balb/C mice. The goal of the project is to induce a positive immune response toward a complete eradication of the primary tumor. Optimal necrosis results from depositing the maximum amount of thermal energy into the tumor without damaging the surrounding healthy tissue. In our laboratory, the optical dye, indocyanine green (ICG), is injected into the center of the tumor prior to surface and interstitial laser irradiation. A diode laser operating at a wavelength near 804 nm exerts thermal energy into the tumor via ICG absorption at 790 nm. Maximum immune response should occur with a uniform distribution of ICG throughout the tumor. By mapping the ICG distribution, the spatial homogeneity of the dye can be determined, which, in turn, mimics the tumor temperature profile. After excision, the tumors were cut into samples of approximately 250 microns thick and dissolved in a chemical detergent. Each sample was run through an absorption spectrometer to determine the distribution of ICG throughout the tumor. Results for both radial and depth profiles of ICG tumor distribution will be presented.
For the last four years the Journal of Translational Medicine (JTM) has hosted the Section of Tumor Immunology and Biological Cancer Therapy. Under the editorial leadership of Dr. Pedro Romero and with the direct support of the Society for Immunotherapy of Cancer (SITC), this section enriched the communication between basic immunological sciences and the clinical investigation arena in oncology. We are re-launching this Section of JTM, now entitled Immunobiology and Immunotherapy, succeeding Tumor Immunology and Biological Cancer Therapy. While aiming to build on the editorial success and focus of its predecessor, this novel Section will have a broader scope, hosting translational immunology topics pertaining to immunotherapy beyond oncology, including disciplines such as inflammation, autoimmunity, transplantation, metabolic disorders and others. As the vision of this re-launched Section of JTM broadens up to serve a communication need for translational immunologists involved with immunotherapy irrespectively of the therapeutic area, a novel and focused journal entitled Journal for Immunotherapy of Cancer (JITC) has just been initiated, sponsored by the SITC.
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.
Chang, A.E.; Shu, S.Y.; Chou, T.; Lafreniere, R.; Rosenberg, S.A.
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
Nelson, Michael R; Petersen, Maureen M; Wolverton, Wayne O; Mikita, Cecilia P
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.
Background: Specific immunotherapy with honeybee venom (BV) is highly effective, but allergic side effects can occur during treatment. Immunotherapy with peptides containing major T-cell epitopes of the relevant allergen or allergens provides an alternative strategy without these problems. Objective: The study investigates the immunologic mechanisms and clinical effects of immunotherapy with T-cell epitope peptides of the major BV allergen, the
Ulrich Müller; Cezmi A. Akdis; Michael Fricker; Mübeccel Akdis; Thorsten Blesken; Florence Bettens; Kurt Blaser
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 beta-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 x 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 x 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
Speiser, D E; Miranda, R; Zakarian, A; Bachmann, M F; McKall-Faienza, K; Odermatt, B; Hanahan, D; Zinkernagel, R M; Ohashi, P S
Background Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been reported to have antitumor activity in different malignancies and immunomodulatory effects. Herein, we report the Tregs-targeting and immune-promoting effect of a class I specific HDAC inhibitor, entinostat, in combination with either IL-2 in a murine renal cell carcinoma (RENCA) model or a survivin-based vaccine therapy (SurVaxM) in a castration resistant prostate cancer (CR Myc-CaP) model. Methods and Results RENCA or CR Myc-CaP tumors were implanted orthotopically or subcutaneously, respectively. Inoculated mice were randomized into four treatment groups: vehicle, entinostat, cytokine or vaccine, and combination. Tregs in the blood were assessed by FACS analysis. Real time quantitative PCR and Western blot analysis of isolated T cell subpopulations from spleen were performed to determine Foxp3 gene and protein expression. The suppressive function of Tregs was tested by T cell proliferation assay. Low dose (5 mg/kg) entinostat reduced Foxp3 levels in Tregs and this was associated with enhanced tumor growth inhibition in combination with either IL-2 or a SurVaxM vaccine. Entinostat down-regulated Foxp3 expression transcriptionally and blocked Tregs suppressive function without affecting T effector cells (Teffs). In vitro low dose entinostat (0.5 µM) induced STAT3 acetylation and a specific inhibitor of STAT3 partially rescued entinostat-induced down-regulation of Foxp3, suggesting that STAT3 signaling is involved in Foxp3 down-regulation by entinostat. Conclusions These results demonstrate a novel immunomodulatory effect of class I HDAC inhibition and provide a rationale for the clinical testing of entinostat to enhance cancer immunotherapy.
Shen, Li; Ciesielski, Michael; Ramakrishnan, Swathi; Miles, Kiersten M.; Ellis, Leigh; Sotomayor, Paula; Shrikant, Protul; Fenstermaker, Robert; Pili, Roberto
Background In Westernized countries, over 1% of the population is allergic to peanuts or tree nuts, which carries a risk of severe allergic reactions. Several studies support the efficacy of peanut oral immunotherapy (OIT) for reducing the clinical sensitivity of affected individuals; however, the mechanisms of this effect are still being characterized. One mechanism that may contribute is the suppression of effector cells, such as basophils. Basophil anergy has been characterized in vitro as a pathway-specific hyporesponsiveness; however, this has not been demonstrated to occur in vivo. Objective To evaluate the hypothesis that basophil anergy occurs in vivo due to chronic allergen exposure in the setting of a clinical oral immunotherapy trial. Methods Samples of peripheral blood were obtained from subjects during a placebo-controlled clinical trial of peanut OIT. Basophil reactivity to in vitro stimulation with peanut allergen and controls was assessed by the upregulation of activation markers, CD63 and CD203c, measured by flow cytometry. Results The upregulation of CD63 following stimulation of the IgE receptor, either specifically with peanut allergen or non-specifically with anti-IgE antibody, was strongly suppressed by active OIT. However, OIT did not significantly suppress this response in basophils stimulated by the distinct fMLP receptor pathway. In the subset of subjects with egg sensitization, active peanut OIT also suppressed CD63 upregulation in response to stimulation with egg allergen. Allergen OIT also suppressed the upregulation of CD203c including in response to stimulation with IL-3 alone. Conclusion Peanut OIT induces a hyporesponsive state in basophils that is consistent with pathway-specific anergy previously described in vitro. This suggests the hypothesis that effector cell anergy could contribute to clinical desensitization.
Thyagarajan, Ananth; Jones, Stacie M.; Calatroni, Agustin; Pons, Laurent; Kulis, Mike; Woo, Caitlin S.; Kamalakannan, Mohanapriya; Vickery, Brian P.; Scurlock, Amy M.; Burks, A. Wesley; Shreffler, Wayne G.
Recent years have witnessed much progress in both basic research and clinical trials regarding cancer immunotherapy with chimeric antigen receptor (CAR)-engineered T cells. The unique structure of CAR endows T cell tumor specific cytotoxicity and resistance to immunosuppressive microenvironment in cancers, which helps patients to better tackle the issue of immunological tolerance. Adoptive immunotherapy (AIT) using this supernatural T cell have gained momentum after decades of intense debates because of the promising results obtained from preclinical models and clinical trials. However, it is very important for us to evaluate thoroughly the challenges/obstacles before widespread clinical application, which clearly warrants more studies to improve our understanding of the mechanism underlying AIT. In this review, we focus on the critical issues related to the clinical outcomes of CAR-based adoptive immunotherapy and discuss the rationales to refine this new cancer therapeutic modality.
While there has been significant progress in advancing novel immune therapies to the bedside, much more needs to be done to fully tap into the potential of the immune system. It has become increasingly clear that besides practical and operational challenges, the heterogeneity of cancer and the limited efficacy profile of current immunotherapy platforms are the two main hurdles. Nevertheless, the promising clinical data of several approaches point to a roadmap that carries the promise to significantly advance cancer immunotherapy. A new annual series sponsored by Arrowhead Publishers and Conferences aims at bringing together scientific and business leadership from academia and industry, to identify, share and discuss most current priorities in research and translation of novel immune interventions. This Editorial provides highlights of the first event held earlier this year and outlines the focus of the second meeting to be held in 2013 that will be dedicated to stem cells and immunotherapy.
Natural killer (NK) cells are part of the innate immune system and are an alluring option for immunotherapy due to their ability to kill infected cells or cancer cells without prior sensitization. Throughout the past 20 years, different groups have been able to reproduce NK cell development in vitro, and NK cell ontogeny studies have provided the basis for the establishment of protocols to produce NK cells in vitro for immunotherapy. Here, we briefly discuss NK cell development and NK cell immunotherapy approaches. We review the factors needed for NK cell differentiation in vitro, which stem cell sources have been used, published protocols, challenges and future directions for Good Manufacturing Practice protocols. PMID:22705914
Luevano, Martha; Madrigal, Alejandro; Saudemont, Aurore
Background Severe allergic reactions during rush-specific immunotherapy (Rush-SIT) may occur in the treatment of hymenoptera sting allergy. The objective of the present study was to examine the characteristics of allergic reactions during Rush-SIT in a cohort of patients with allergy towards hymenoptera venom in the mediterranean population of Albania. Methods A retrospective study was performed using the clinical reports of 37 patients with venom of bee (apinae), wasp (vespidae, subfamily vespinae) or paperwasp (vespidae, subfamily polistinae) allergy treated with Rush-SIT between 1987 and 1996. After hymenoptera sting allergy diagnosis according to anamnesis and intracutaneous tests the patient were treated with Rush-SIT. The protocol lasted 3 – 4 d with an increase in the concentration from 0.01 ?g/ml to 100 ?g/ml. Anaphylactic reactions were classified according to the Mueller-classification. Results The frequency of reactions during Rush-SIT for bee-venom was 4.7% and for wasp-venom was 1.5% (p < 0.01). The mean frequency of reactions of Mueller grade II for the bee-venom Rush-SIT patients during the first 4 d (= 26 injections) was 0.73 and for the wasp-venom Rush-SIT patients 0.15. No patient experienced a third-degree reaction. 94.6% of the patient supported an end dose of 100 ?g. Conclusions Rush-SIT is a reliable method for the treatment of anaphylactic reactions to hymenoptera venom even in less developed countries. Bee-venom Rush-SIT was found to cause higher numbers allergic reactions than wasp or paperwasp Rush-SIT.
Mingomataj, Ervin; Priftanji, Alfred; Qirko, Etleva; Dinh, Q Thai; Fischer, Axel; Peiser, Christian; Groneberg, David A
How the immune system attacks medulloblastoma (MB) tumors effectively is unclear, although natural killer (NK) cells play an important role in immune defense against tumor cells. Interactions between receptors on NK cells and ligands expressed by tumor cells are critical for tumor control by immunotherapy. In this study, we analyzed tumor samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA) and UL16 binding protein (ULPB-2), which are ligands for the NK group 2 member D activatory receptor (NKG2D). The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a MB cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently killed tumor cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo.
Fernandez, Lucia; Portugal, Raquel; Valentin, Jaime; Martin, Roberto; Maxwell, Hannah; Gonzalez-Vicent, Marta; Diaz, Miguel Angel; de Prada, Inmaculada; Perez-Martinez, Antonio
Fifty-four patients with evidence of locally advanced primary squamous cell bronchial carcinoma (SCC), and three patients with adenocarcinoma (AC) had lung resection to remove all the visible tumour. After operation an randomly chosen group of 20 SCC patients received adjuvant BCG immunostimulation by scarifications (BCG-A). An additional group of 14 SCC patients, and three AC patients received initially intrapleural BCG treatment and subsequently scarifications (BCG-B). A control group of 20 SCC patients received no adjuvant treatment. Follow-up studies were done from three to 51 months. Immune reactivity was monitored in vivo with PPD skin tests in 33 treated and in 18 untreated patients. In both the BCG-treated SCC groups recurrence rates decreased statistically significant during follow-up (BCG-A; six to 51 months, p less than 0.001; BCG: 6-9 months, p less than 0.01 and nine to 24 months, p less than 0.001). However, no difference could be demonstrated between systemic and combined systemic and intrapleural treatment. The three BCG-treated AC patients all relapsed within nine months of follow-up. A pronounced increase in skin reactivity to PPD was seen six months after surgery in the BCG-treated patients (BCG-A, p less than 0.001; BCG-B, p less than 0.01), whereas the control patients remained anergic after surgery. This improved immune reactivity went in parallel with a more favourable outcome of the individual patients (BCG-A, p less than 0.02; BCG-B, p less than 0.05). It is concluded that adjuvant BCG immunotherapy used in strongly selected patients with minimal residual squamous cell bronchial carcinoma improves the prognosis. Intrapleural treatment did not improve the prognosis further. A favourable clinical outcome was mirrored by an increase in cellular immune reactivity. PMID:7466726
Jansen, H M; The, T H; Orie, N G
How the immune system attacks medulloblastoma (MB) tumors effectively is unclear, although natural killer (NK) cells play an important role in immune defense against tumor cells. Interactions between receptors on NK cells and ligands expressed by tumor cells are critical for tumor control by immunotherapy. In this study, we analyzed tumor samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA) and UL16 binding protein (ULPB-2), which are ligands for the NK group 2 member D activatory receptor (NKG2D). The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a MB cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently killed tumor cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo. PMID:23626949
Fernández, Lucia; Portugal, Raquel; Valentín, Jaime; Martín, Roberto; Maxwell, Hannah; González-Vicent, Marta; Díaz, Miguel Ángel; de Prada, Inmaculada; Pérez-Martínez, Antonio
The success of immunotherapy relies on the participation of all arms of the immune system and the role of CD4+ T lymphocytes in preventing tumor growth is now well established. Understanding how tumors evade immune responses holds the key to the development of cancer immunotherapies. In this review, we discuss how MHC Class II expression varies in cancer cells and how this influences antitumor immune responses. We also discuss the means that are currently available for harnessing the MHC Class II antigen presentation pathway for the development of efficient vaccines to activate the immune system against cancer.
Thibodeau, Jacques; Bourgeois-Daigneault, Marie-Claude; Lapointe, Rejean
Mature B cells (BCs) express CD23 and B cell receptors. Whether activation of CD23 and B cell receptors has different effects on BC activities is unclear. This study aims to investigate the mechanism by which the specific antigen immunotherapy regulates the activation of BCs in the skewed Th2 responses. Mice were sensitized to ovalbumin. The specific antigen vaccination (SAV) at graded doses was employed to modulate the activities of BCs in which the expression of IL-10, IgE, matrix metalloproteinase-9 (MMP9), CD23, and serum soluble CD23 by BCs was evaluated. The immune regulatory effect of BCs primed by lower or higher SAV doses was observed with an adoptive transfer mouse experiment. SAV activated CD23 to produce IL-10 in BCs at lower doses. The higher doses of SAV increased the expression of MMP9 in BCs that reduced the amounts of CD23 in BCs and increased the serum levels of soluble CD23, which was abrogated by the pretreatment with MMP9 inhibitor. Adoptively transfer with BCs primed by lower doses of SAV inhibited the ongoing antigen-specific Th2 responses whereas the BCs primed by higher doses of SAV exacerbated the ongoing Th2 responses. Exposure to specific antigens at optimal doses can activate BCs to produce IL-10 to suppress the skewed antigen-specific Th2 responses. The antigen doses of SAV higher than the optimal doses may promote the production of soluble CD23 to exacerbate the ongoing immune responses. PMID:23589293
Yang, Qihong; Liang, Yong; Si, Liangyi; Ji, Qing; Xu, Qiang; Zhang, Yi; Li, Xuejun
The most common cause of seasonal allergic rhinitis in Japan is the Japanese cedar (JC). Recently, a pullulan-conjugated antigen (CS-560) has been developed to reduce adverse effects and to enhance the effect of JC-specific immunotherapy (IT). If the mechanism of IT can be fully elucidated and the treatment can be used safely and with specificity, IT should be reconsidered as a superior treatment for JC pollinosis. Thirteen patients with JC pollinosis who received IT were compared to 10 patients who did not receive IT. All patients were followed through two pollen seasons by means of allergy diaries. Peripheral blood mononuclear cells (PBMC) were collected before IT and just before each pollen season, and these were stimulated with pollen extract. The concentrations of IL-4, IL-5, IL-13 and IFN-gamma in the culture supernatants were determined using an ELISA. Furthermore, messenger (m)RNA expressions of IL-4 and IL-5 from cultured PBMC were also studied. As a result of the allergy diaries, we confirmed the clinical efficacy of CS-560. The symptom-medication scores were significantly decreased by IT. The levels of IL-4, IL-5 and IL-13 declined only in the IT group. However, the level of IFN-gamma did not change in either group. IL-4 and IL-5 mRNA expressions were inhibited in the IT group compared to that in the non-IT group. In conclusion, specific IT for JC pollinosis using CS-560 clearly modified cytokine expression by PBMC. PMID:11876600
Nakano, Atsuko; Nakano, Koichi; Okawa, Toru; Yamakoshi, Takayuki; Terada, Nobuhisa; Numata, Tsutomu; Konno, Akiyoshi
Allergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA-4-Ig) has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co-stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA-4-Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA-4-Ig acts as an adjuvant for experimental SIT. We evaluated the adjuvant effects of CTLA-4-Ig on SIT in a mouse model of ovalbumin-driven asthma. We used both wild-type and IDO-deficient mice to assess the role of IDO in the adjuvant effects of CTLA-4-Ig. Co-administration of CTLA-4-Ig strongly increased SIT-induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA-4-Ig, as an adjuvant for SIT, is equally effective in IDO-deficient and wild-type mice, demonstrating that the effect of CTLA-4-Ig is independent of IDO expression. We show that CTLA-4-Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA-4-Ig is independent of IDO, we conclude that it acts by blocking CD28-mediated T cell co-stimulation. PMID:23480191
Maazi, H; Shirinbak, S; den Boef, L E; Fallarino, F; Volpi, C; Nawijn, M C; van Oosterhout, A J M
Current therapies for non-Hodgkin lymphoma commonly include CD20 mAb to deplete tumor cells. However, the response is not durable in a substantial proportion of patients. Herein, we report our studies in mice testing the hypothesis that heterogeneity in endogenous tissue CD20+ B cell depletion influences in vivo lymphoma therapy. Using highly effective CD20 mAbs that efficiently deplete endogenous mature B cells and homologous CD20+ primary lymphoma cells through monocyte- and antibody-dependent mechanisms, we found that lymphoma depletion and survival were reduced when endogenous host B cells were not depleted, particularly a rare IL-10–producing B cell subset (B10 cells) known to regulate inflammation and autoimmunity. Even small numbers of adoptively transferred B10 cells dramatically suppressed CD20 mAb–mediated lymphoma depletion by inhibiting mAb-mediated monocyte activation and effector function through IL-10–dependent mechanisms. However, the activation of innate effector cells using a TLR3 agonist that did not activate B10 cells overcame the negative regulatory effects of endogenous B10 cells and enhanced lymphoma depletion during CD20 immunotherapy in vivo. Thus, we conclude that endogenous B10 cells are potent negative regulators of innate immunity, with even small numbers of residual B10 cells able to inhibit lymphoma depletion by CD20 mAbs. Consequently, B10 cell removal could provide a way to optimize CD20 mAb–mediated clearance of malignant B cells in patients with non-Hodgkin lymphoma.
Horikawa, Mayuka; Minard-Colin, Veronique; Matsushita, Takashi; Tedder, Thomas F.
Hyperimmunized bovine plasma containing antibodies to a mutant Escherichia coli O111:B4 (J5) was used to conduct a prospective double-blind clinical trial to evaluate its efficacy as an immunotherapy to bovine neonates in field conditions. Two- to three-day-old calves (N=150) were randomized into three groups (n=50) to receive (1) no plasma (NP) or (2) control (traces or no J5 antibody) bovine
Sheikh A. Selim; Charles A. Holmberg; James S. Cullor
Background Glioblastoma multiforme (GBM) is refractory to conventional therapies. To overcome the problem of heterogeneity, more brain tumor markers are required for prognosis and targeted therapy. We have identified and validated a promising molecular therapeutic target that is expressed by GBM: human multidrug-resistance protein 3 (MRP3). Methods We investigated MRP3 by genetic and immunohistochemical (IHC) analysis of human gliomas to determine the incidence, distribution, and localization of MRP3 antigens in GBM and their potential correlation with survival. To determine MRP3 mRNA transcript and protein expression levels, we performed quantitative RT-PCR, raising MRP3-specific antibodies, and IHC analysis with biopsies of newly diagnosed GBM patients. We used univariate and multivariate analyses to assess the correlation of RNA expression and IHC of MRP3 with patient survival, with and without adjustment for age, extent of resection, and KPS. Results Real-time PCR results from 67 GBM biopsies indicated that 59/67 (88%) samples highly expressed MRP3 mRNA transcripts, in contrast with minimal expression in normal brain samples. Rabbit polyvalent and murine monoclonal antibodies generated against an extracellular span of MRP3 protein demonstrated reactivity with defined MRP3-expressing cell lines and GBM patient biopsies by Western blotting and FACS analyses, the latter establishing cell surface MRP3 protein expression. IHC evaluation of 46 GBM biopsy samples with anti-MRP3 IgG revealed MRP3 in a primarily membranous and cytoplasmic pattern in 42 (91%) of the 46 samples. Relative RNA expression was a strong predictor of survival for newly diagnosed GBM patients. Hazard of death for GBM patients with high levels of MRP3 RNA expression was 2.71 (95% CI: 1.54-4.80) times that of patients with low/moderate levels (p = 0.002). Conclusions Human GBMs overexpress MRP3 at both mRNA and protein levels, and elevated MRP3 mRNA levels in GBM biopsy samples correlated with a higher risk of death. These data suggest that the tumor-associated antigen MRP3 has potential use for prognosis and as a target for malignant glioma immunotherapy.
A Phase I trial of active specific immunotherapy for melanoma was performed to measure the toxicity and immunological effects of the therapy. A mixture of mechanical lysates (homogenates) of two melanoma cell lines was injected together with a novel adjuvant, DETOX, into 22 patients. Several types of cell-mediated and humoral immunity to mela noma-associated antigens were measured serially. In the
Malcolm S. Mitchell; June Kan-Mitchell; Raymond A. Kempf; Hungyi Shau; Susan Lind
Summary Based on exciting results in animal models, a number of relying on modern biotechnology. For each approach, the underlying immunological principles, experimental and novel immunotherapies employing biotechnological products, rather than conventional immunosuppressants, are being clinical evidence, and foreseeable problems are separately addressed. Thus, it is hoped that this article serves a dual developed for the treatment of multiple sclerosis.
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 provideclinical benefit are not completely understood. However, knowledge of these mechanisms will be crucial for probing human immune responses and tumour biology in order
Klaus Wagner; Jedd D. Wolchok; Padmanee Sharma; James P. Allison
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
Dmitri Popov; Slava Maliev
Unlike other tumors, lung cancer appears to be poorly sensitive to immunotherapy. We have recently demonstrated an alternative pathway of lung cancer immunosurveillance. Our data indicate a failure of the adaptive immune system to mediate the immunosurveillance of lung cancer and emphasize the prominent role of natural killer cells in this setting.
Chang, Stephanie; Lin, Xue; Higashikubo, Ryuji; Toth, Kelsey; Gelman, Andrew E.; Kreisel, Daniel; Krupnick, Alexander S.
Immunotherapy with a vaccine consisting of autoclaved Mycobacterium w, was given in addition to standard chemotherapy (multidrug therapy (MDT)) to 93 multibacillary (MB) leprosy patients. One hundred and seven patients with similar types of disease served as controls and received MDT + placebo injections. The study was a double-blind randomised trial. On opening the codes, results obtained were in concordance
S. A. Zaheer; K. R. Beena; H. K. Kar; A. K. Sharma; R. S. Misra; A. Mukherjee; R. Mukherjee; H. Kaur; R. M. Pandey; R. Walia; A. Mukhopadhyay; G. P. Talwar
Extensive studies have established a role of scavenger receptor CD204 in pattern recognition and ligand uptake. Strikingly, we recently revealed a previously unrecognized feature of CD204 action in attenuating T-cell activation and antitumor immunity. Blocking its activity in dendritic cells represents a promising approach to the improvement of cancer immunotherapy.
Yu, Xiaofei; Wang, Xiang-Yang
Fc receptors for IgG (Fc?Rs) can trigger the inflammatory, cytotoxic and hypersensitivity functions of immune effector cells. Activation or deactivation of effector cells via Fc?Rs can be exploited to develop novel therapies for cancer, infectious diseases and autoimmune disorders. Initial results of clinical trials for several Fc?R-directed immunotherapies show the potential promise of this approach.
Yashwant M. Deo; Robert F. Graziano; Roland Repp
Allergen-specific immunotherapy (ASIT) has been used for years to treat dogs with atopic dermatitis (AD) and humans with atopic diseases. The efficacy of ASIT has been well documented for humans with respiratory atopic diseases and stinging insect allergy, but its effectiveness seems more controversial for patients with AD. In spite of insufficient evidence derived from randomized controlled trials, multiple open
Craig E Griffin; Andrew Hillier
Background: Peanut allergy is a life-threatening condition for which new efficient and safe treatment is expected. We evaluated epicutaneous immunotherapy (EPIT) as a new alternative treatment for peanut allergy in sensitized mice. Methods: Sixty BALB\\/c mice were sensitized by gavages with peanut protein extract (PPE) mixed with cholera toxin. An epicutaneous delivery system, coated with 100 ?g PPE (Viaskin®, DBV
Lucie Mondoulet; Vincent Dioszeghy; Jeroen A. J. Vanoirbeek; Benoit Nemery; Christophe Dupont; Pierre-Henri Benhamou
In dendritic cells (DCs)-based cancer immunotherapy, it is important to present the epitope peptide derived from tumor associated antigens (TAAs) on MHC class I in order to induce tumor specific cytotoxic T lymphocytes (CTLs). However, MHC class I molecules generally present the epitope peptides derived from endogenous antigens for DCs but not exogenous ones such as TAAs. Recently, we developed
Yusuke Oda; Shota Otake; Ryo Suzuki; Norihito Nishiie; Keiichi Hirata; Yuichiro Taira; Naoki Utoguchi; Kazuo Maruyama
Bladder cancer is the fifth most common malignant disease in the United States with an annual incidence of around 63,210 new cases and 13,180 deaths. The cost for providing care for patients with bladder cancer disease is high. Bladder cancer treatment options such as immunotherapy, chemotherapy, radiation therapy, transurethral resection, and cystectomy, are used with varying success rates. In this
Shital C. Shah; Andrew Kusiak; Michael A. O’Donnell
Background: Allergen-specific sublingual immunotherapy is a potential treatment for allergic diseases. Its effective dose and underlying mechanism are still to be explored. Here, we investigated the efficacy and mechanism of sublingually administered Dermatophagoides farinae (Der f) vaccine in a murine asthma model. Methods: BALB\\/c mice were sensitized intraperitoneally with Der f extract absorbed to alum, followed by sublingual treatment with
Hai-qiong Yu; Xiang-hui Li; Hua Guo; Zhi-gang Liu; Pei-xin Ran; Kun-mei Ji; Jun Wang
Pythium insidiosum is an oomycete, a fungal like microorganism, which infects mammals, causing pythiosis in animals and humans, especially in tropical and subtropical regions around the world. The treatment for this infection is very difficult, and therapeutic options commonly comprise surgery, immunotherapy and antimicrobial drugs. The present report describes the clinical healing of a dog with gastrointestinal pythiosis by treatment with a combination of antifungals and immunotherapy, as well as reviews the cases reported in the literature that used some type of therapy for canine pythiosis. A 2.5-year-old male beagle initially showed sporadic vomiting episodes, and this symptom became more frequent 5 months after the onset of clinical signs. Celiotomy procedure found thickness of the stomach wall extending to the pylorus and duodenum. A biopsy was performed, and the diagnosis of pythiosis was made by mycological, histopathological analyses and molecular identification. Therapy was based on an association of terbinafine plus itraconazole during 12 months and immunotherapy for 2.5 months. The healing of the dog reported here allows us to propose the use of immunotherapy associated with antifungal therapy to treat canine gastrointestinal pythiosis. However, additional studies should be performed on a larger number of patients to establish a standard treatment protocol for canine pythiosis. PMID:23918089
Pereira, Daniela I B; Botton, Sônia A; Azevedo, Maria I; Motta, Marco A A; Lobo, Raulene R; Soares, Mauro P; Fonseca, Anelise O S; Jesus, Francielli P K; Alves, Sydney H; Santurio, Janio M
Background: Sublingual immunotherapy (SLIT) allergy vaccines have an excellent safety profile, but opinions vary on their efficacy, and treatment regimens are often lengthy. This study assessed the effects of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPL®) on safety\\/tolerability and clinical and immunological efficacy when combined with grass pollen SLIT formulations in treating patients with seasonal allergic rhinitis. This
Oliver Pfaar; Christine Barth; Christine Jaschke; Karl Hörmann; Ludger Klimek
Among the different therapeutic approaches to treat superficial malignant tumors, Laser Assisted Cancer Immunotherapy (LACI) shows promise. Experiments are in progress in our laboratory based on the concept of LACI which utilizes a light absorbing dye (Indocyanine Green, ICG), an immunoadjuvant (Glycated Chitosan, GC), and an infrared diode laser (1-15w) operating at 804 nm. Superficial tumors (5 to 7 mm
This pocket guide is the result of a consensus reached during several GA(2) LEN and EAACI meetings. The aim of the current pocket guide is to offer a comprehensive set of recommendations on the use of immunotherapy in allergic rhinoconjunctivitis and asthma in daily practice. This pocket guide is meant to give simple answers to the most frequent questions of practitioners in Europe, including 'practising allergists', general practitioners and any other physicians with special interest in allergen-specific immunotherapy (SIT). It is not a long or detailed scientific review of the topic. However, the recommendations in this pocket guide were compiled following an in-depth review of existing guidelines and publications, including the 1998 EAACI position paper, the 1998 WHO Position Paper on SIT and the 2001 Allergic Rhinitis and its Impact on Asthma (ARIA). It is also based on the ARIA update 2008 (prepared in collaboration with GA(2) LEN), the 'Sub-lingual Immunotherapy: WAO Position Paper 2009' (from the World Allergy Organisation) and the Methodology paper of ARIA. The recommendations cover patient selection, allergen extract to be used, route of administration of SIT (in particular, sublingual and subcutaneous immunotherapy), and necessary precautions to be followed in using SIT. PMID:21039596
Zuberbier, T; Bachert, C; Bousquet, P J; Passalacqua, G; Walter Canonica, G; Merk, H; Worm, M; Wahn, U; Bousquet, J
Substantial progress in understanding the biology of regulatory T cells and their roles in health and disease has been achieved in the past 10 years. This has led to an increasing interest in the possibility of using regulatory T cells as a biological therapy to preserve and restore tolerance to self antigens and alloantigens. Immunotherapy by the adoptive transfer of
Manuela Battaglia; Maria-Grazia Roncarolo
Immune system is a complex network of highly specialized cells (such as lymphocytes) and organs, all of which work together to clear infection (antigens), such as bacteria, a virus or tumor cell, from the body. Biologic Response Modifiers (BRM), also called immunotherapy, is a type of treatment that mobilizes and trigger the body's immune system. Our study concentrates on immunotherapeutic
Sankar Karan; Dwijesh Dutta Majumder; Swapna Chaudhuri
Dendritic cell-based anticancer immunotherapy is feasible, safe and results in the induction of tumor-specific immune responses, at least in a fraction of vaccinated patients. The concomitant activation of cytotoxic and helper T cells, by loading DCs with peptides or electroporating them with the corresponding mRNAs, may further enhance vaccine-induced antitumor responses.
Schreibelt, Gerty; Bol, Kalijn F.; Aarntzen, Erik HJG; Gerritsen, Winald R; Punt, Cornelis JA; Figdor, Carl G; de Vries, I Jolanda M
The Russian experience with the preparation and clinical application of an antitoxic antistaphylococcal hyperimmune plasma and immunoglobulin is described. The immunotherapies were developed in the late 1960s and put into widespread use in the Soviet Union for the prophylaxis and treatment of sepsis, pneumonia, and other conditions caused by an epidemic of antibiotic-resistant Staphylococcus aureus.
Immunotherapy has been shown to be an effective adjuvant in the management of septic shock. A neurtopenic rat model of septic shock induced by infection with Pseudomonas aeruginosa 12.4.4 was used to determine the relative efficacy of single, double, and ...
A. S. Cross S. M. Opal J. E. Palardy M. W. Bodmer J. C. Sadoff
Specific immunotherapy comprises a special form of allergy treatment which consists of stepwise increasing doses of the allergen, given subcutaneously or orally with the aim to reprogram the specific immunity (from allergy to tolerance). This requires some experience and an exact allergological workup, since the main mistake in the treatment of this specific immunotherapy is the selection of unsuitable patients. The effectivity of specific immunotherapy is well documented for bee and wasp venom allergy, pollinosis and more and more also for asthma bronchiale. A type of unspecific passive immunotherapy is the injection of anti-IgE antibodies. However they block only soluble IgE and are not able to remove mast cell bound IgE. Thus, the allergic reactivity persists. Clinical studies have shown some efficacy in asthma as well as in pollinosis. However, at present it is unclear, whether this drug, which has to be given every two to four weeks in relatively high concentrations, is effective in patients with polysensitization (i.e. patients suffering from mite, fungal and pollen allergy) or is effective in patients which have manifestations of their allergy in different organs. PMID:11407237
Pichler, W J
BACKGROUND: Subcutaneous Immunotherapy (SCIT) modifies the allergic response and relieves allergic symptoms. SCIT is the only and a very effective treatment for insect venom allergy. We hypothesized that basophil sensitivity, measured through the basophil activation test, would decrease during SCIT up dosing. Expression of CD203c was compared to CD63 as marker for basophil activation, using a Bland Altman plot and
Susan Mikkelsen; Bo Martin Bibby; Mette Konow Bøgebjerg Dolberg; Ronald Dahl; Hans Jürgen Hoffmann
In preclinical models of cancer, gene therapy with interleukin 12 (IL-12) has reached unprecedented levels of success when combined with immunotherapy approaches such as gene transfer of other cytokines and\\/or chemokines, costimulatory molecules or adoptive cell therapy. These combinations have been found to produce synergistic rather than additive effects. Meanwhile, IL-12 gene therapy is beginning clinical testing as a single
Ignacio Melero; Guillermo Mazzolini; Iñigo Narvaiza; Cheng Qian; Lieping Chen; Jesús Prieto
Abnormal tumor vasculature and subsequent tumor hypoxia contribute to immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma and inhibiting their antitumor efficacy. These obstacles might explain why the promising approach of adoptive cell immunotherapy does not exert significant antitumor activity. Hypoxia contributes to immune suppression by activating hypoxia-inducible factor (HIF-1) and the vascular endothelial growth factor pathway, which plays a determining role in promoting tumor cell growth and survival. Tumor hypoxia creates an immunosuppressive microenvironment via the accumulation and subsequent polarization of inflammatory cells toward immune suppression phenotypes, such as myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. Antiangiogenic therapy could normalize tumor vasculature and decrease hypoxic tumor area and thus may be an effective modality to potentiate immunotherapy. Adoptive cell immunotherapy alone is not efficient enough to decrease tumor growth as its antitumor effect is inhibited by the immunosuppressive hypoxic tumor microenvironment. This review describes that combination of antiangiogenic therapy with adoptive cell immunotherapy can exert synergistic antitumor effect, which will contribute to improve strategies for future anticancer therapies. PMID:23982676
Shi, Shujing; Chen, Longbang; Huang, Guichun
Capecitabine is a novel fluoropyrimidine carbamate, orally administered and selectively activated to fluorouracil by a sequential triple-enzyme pathway in liver and tumor cells. This prospective trial aims to evaluate the therapeutic effects and systemic toxicities of capecitabine in patients with metastatic renal cell carcinoma in which immunotherapy failed. Twenty-six patients (median age, 58 years; range, 47 to 76 years) with
Catharina Wenzel; Gottfried J. Locker; Manuela Schmidinger; Robert Mader; Gero Kramer; Michael Marberger; Michael Rauchenwald; Cristoph C. Zielinski; Guenther G. Steger
Psoriasis is a chronic, auto-inflammatory disease affecting millions of individuals worldwide. In addition to classic cutaneous manifestations, the condition is linked to significant co-morbidities including cardiovascular disease, metabolic syndrome, melanoma and non-melanoma skin cancer, and psychiatric disease [1,2]. Therefore, more aggressive treatment and multi-disciplinary care is critical. Measures of disease burden (quantified by anatomic location, body surface area (BSA) of involvement, and impact on daily life) assist in determining the severity of disease and have been integral in objective assessment of treatment regimens and new drug therapies . Biologic agents have entered the clinical armamentarium as treatment options for patients with moderate-to-severe psoriasis who have failed traditional systemic therapies. Three of the four FDA-approved biologic agents for psoriasis suppress TNFa mediated pathways , which are essential for granuloma formation and maintenance, key components of host defenses against intracellular pathogens . Subsequently, the increased use of these agents is accompanied by increased reporting of granulomatous infectious diseases such as tuberculosis, histoplasmosis, nocardia, and nontuberculous mycobacteria . Report of any unusual infection is therefore vitally important in the care of this immune suppressed patient population. PMID:24050284
Laquer, Vivian; Ta, Tuan; Nguyen, Tien; Tan, Belinda
TNF? plays a pivotal role not only in the inflammatory process but also in the normal response against pathogens and therefore, interfering with this cytokine may increase the risk of infection. TNF? antagonists are commonly used in daily clinical practice for the treatment of inflammatory rheumatic diseases including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis since the
Eric Toussirot; Gerald Streit; Daniel Wendling
Crohn's disease (CD) and Takayasu's arteritis (TA) are inflammatory granulomatous autoimmune disorders. Simultaneous occurrence of CD and TA in the same individual is rare. We report two cases treated with biologic agents. Case 1: A 16-year-old male presented with abdominal pain, nausea, vomiting. CT angiogram showed thickening of the terminal ileum, wall thickening and narrowing of multiple large and medium arteries including aorta and left common carotid. Colonoscopy with biopsy of the stenotic ileocecal valve confirmed CD. Resected carotid artery pathology was consistent with TA. Treatment was initially begun with prednisone, then methotrexate was started followed by infliximab. Due to side effects, methotrexate was switched to azathioprine. He remained asymptomatic. Case 2: A 38-year-old male with well-characterized Crohn's ileocolitis for 15 years, who had been treated with prednisone, mesalamine, sulfasalazine, and azathioprine presented with chest, upper back and abdominal pain. CT angiogram showed vasculitis of large and medium arteries, with stenosis of the right renal artery, and wall thickening of the sigmoid colon. He was diagnosed with TA. He underwent treatment with infliximab and adalumimab on different occasions, which were later discontinued due to fever, bacteremia and complications from sepsis. He remained on prednisone and azathioprine. In these two patients with both CD and TA the diagnoses were confirmed by imaging and pathologic findings. Both patients developed vascular complications. Tumor necrosis factor inhibitor therapy was effective in one patient but discontinued in the other due to infection. Further research into the association of CD and TA may provide clues to their etiologies and guide effective interventions.
Ratuapli, S.; Mazlumzadeh, M.; Gurudu, S.; Money, S.; Heigh, R.
Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation. PMID:22801493
Gregory, Adam P; Dendrou, Calliope A; Attfield, Kathrine E; Haghikia, Aiden; Xifara, Dionysia K; Butter, Falk; Poschmann, Gereon; Kaur, Gurman; Lambert, Lydia; Leach, Oliver A; Prömel, Simone; Punwani, Divya; Felce, James H; Davis, Simon J; Gold, Ralf; Nielsen, Finn C; Siegel, Richard M; Mann, Matthias; Bell, John I; McVean, Gil; Fugger, Lars
AbstractRheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality, which may be attenuated by anti-inflammatory treatment. Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelium and have a potentially reparative role protecting against ischemia and atherosclerosis.
Jacob N. Ablin; Viktoria Boguslavski; Valerie Aloush; Ori Elkayam; Daphna Paran; Dan Caspi; Jacob George
A patient with long-standing rheumatoid arthritis was admitted with Streptococcus pneumoniae septicaemia and bilateral septic knee joints. He was treated conservatively with intravenous antibiotics and arthroscopic washouts and discharged home on oral antibiotics. Six months posthospital discharge, following re-exacerbation of arthritis, an informed consent was given by the patient to continue antitumour necrosis factor therapy. After 5 years of observation, there has been no recurrence of sepsis and the rheumatoid arthritis remains in remission. PMID:23839609
Manolios, Nicholas; Burneikis, Anthony; Spencer, David; Howe, Graydon
: 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,