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1

Acute and probable chronic Q fever during anti-TNF? and anti B-cell immunotherapy: a case report  

PubMed Central

Background Q fever is caused by the intracellular bacterium Coxiella burnetii. Initial infection can present as acute Q fever, while a minority of infected individuals develops chronic Q fever endocarditis or vascular infection months to years after initial infection. Serology is an important diagnostic tool for both acute and chronic Q fever. However, since immunosuppressive drugs may hamper the humoral immune response, diagnosis of Q fever might be blurred when these drugs are used. Case presentation A 71-year-old Caucasian male was diagnosed with symptomatic acute Q fever (based on positive C. burnetii PCR followed by seroconversion) while using anti-tumor necrosis factor-? (anti-TNF?) drugs for rheumatoid arthritis (RA). He was treated for two weeks with moxifloxacin. After 24 months of follow-up, the diagnosis of probable chronic Q fever was established based on increasing anti-C. burnetii phase I IgG antibody titres in a immunocompromised patient combined with clinical suspicion of endocarditis. At the time of chronic Q fever diagnosis, he had been treated with anti B-cell therapy for 16 months. Antibiotic therapy consisting of 1.5 years doxycycline and hydroxychloroquine was started and successfully completed and no signs of relapse were seen after more than one year of follow-up. Conclusion The use of anti-TNF? agents for RA in the acute phase of Q fever did not hamper the C. burnetii-specific serological response as measured by immunofluorescence assay. However, in the presented case, an intact humoral response did not prevent progression to probable chronic C. burnetii infection, most likely because essential cellular immune responses were suppressed during the acute phase of the infection. Despite the start of anti-B-cell therapy with rituximab after the acute Q fever episode, an increase in anti-C. burnetii phase I IgG antibodies was observed, supporting the notion that C. burnetii specific CD20-negative memory B-cells are responsible for this rise in antibody titres. PMID:24931640

2014-01-01

2

Protection from articular damage by passive or active anti-tumour necrosis factor (TNF)-? immunotherapy in human TNF-? transgenic mice depends on anti-TNF-? antibody levels.  

PubMed

Active anti-tumour necrosis factor (TNF)-? immunization with the kinoid of TNF-? (TNF-K) induces polyclonal anti-TNF-? antibodies and ameliorates arthritis in human TNF-? (hTNF-?) transgenic mice (TTg). We compared the efficacy of TNF-K to that of infliximab (IFX) and of TNF-K and IFX co-administration, and evaluated whether the titres of anti-hTNF-? antibodies induced by immunization were a determinant of TNF-K efficacy. Forty-eight TTg mice received one of the following treatments: TNF-K immunization (TNF-K group); weekly IFX throughout the study duration (IFXw0-15); TNF-K plus weekly IFX for 4 weeks (TNF-K?+?IFX); and weekly IFX for 4 weeks (IFXw0-4); PBS. Animals were killed at week 16. Anti-hTNF-? antibody titres and clinical and histological scores were compared. All TNF-K immunized mice (TNF-K and TNF-K?+?IFX) produced anti-hTNF-? antibodies. Titres were higher in TNF-K?versus?TNF-K?+?IFX (P?anti-TNF-? immunization in human disease. PMID:23480185

Semerano, L; Biton, J; Delavallée, L; Duvallet, E; Assier, E; Bessis, N; Bernier, E; Dhellin, O; Grouard-Vogel, G; Boissier, M-C

2013-04-01

3

Protection from articular damage by passive or active anti-tumour necrosis factor (TNF)-? immunotherapy in human TNF-? transgenic mice depends on anti-TNF-? antibody levels  

PubMed Central

Active anti-tumour necrosis factor (TNF)-? immunization with the kinoid of TNF-? (TNF-K) induces polyclonal anti-TNF-? antibodies and ameliorates arthritis in human TNF-? (hTNF-?) transgenic mice (TTg). We compared the efficacy of TNF-K to that of infliximab (IFX) and of TNF-K and IFX co-administration, and evaluated whether the titres of anti-hTNF-? antibodies induced by immunization were a determinant of TNF-K efficacy. Forty-eight TTg mice received one of the following treatments: TNF-K immunization (TNF-K group); weekly IFX throughout the study duration (IFXw0–15); TNF-K plus weekly IFX for 4 weeks (TNF-K + IFX); and weekly IFX for 4 weeks (IFXw0–4); PBS. Animals were killed at week 16. Anti-hTNF-? antibody titres and clinical and histological scores were compared. All TNF-K immunized mice (TNF-K and TNF-K + IFX) produced anti-hTNF-? antibodies. Titres were higher in TNF-K?versus?TNF-K + IFX (P < 0·001) and correlated inversely with histological inflammation (R = ?0·78; P = 0·0001) and destruction (R = ?0·67; P = 0·001). TNF-K + IFX had higher histological inflammation and destruction versus?TNF-K (P < 0·05). A receiver operating characteristic (ROC) analysis of anti-hTNF-? antibody titres identified the criterion cut-off value to discriminate most effectively between the TNF-K and TNF-K + IFX groups. Mice with high versus low titres had less histological inflammation and destruction (P < 0·05). In a model of TNF-?-dependent arthritis, protection from articular damage by TNF-K correlates with the titres of induced anti-hTNF-? antibodies. The co-administration of TNF-K and a short course of infliximab does not result in less articular damage versus solely TNF-K, due probably to lower anti-hTNF-? antibody production. These results are relevant for future development of active anti-TNF-? immunization in human disease. PMID:23480185

Semerano, L; Biton, J; Delavallée, L; Duvallet, E; Assier, E; Bessis, N; Bernier, E; Dhellin, O; Grouard-Vogel, G; Boissier, M-C

2013-01-01

4

Bronchospasm associated with anti-TNF treatment  

Microsoft Academic Search

The aetiology of breathing difficulties in patients with inflammatory arthritis being treated with anti-TNF agents can be\\u000a multi-factorial. Exacerbation of fibrosing alveolitis in patients recently commencing Infliximab has been previously described.\\u000a Bronchospasm, although reported in some study patients, has not been formally investigated so far. The objective of this study\\u000a is to define the incidence of bronchospasm in patients treated

S. Dubey; N. Kerrigan; K. Mills; D. G. Scott

2009-01-01

5

Anal tuberculosis complicating anti-TNF? therapy.  

PubMed

A 42-year-old man receiving anti-tumour necrosis factor ? (anti-TNF?) therapy with adalimumab due to psoriatic arthritis presented with a 2-month-old anal ulcer. An apical right lung infiltrate was found in his chest X-ray, although he had no pulmonary symptoms. Two biopsies of the ulcer were taken and reported as granulomatous, necrotising, with chronic inflammation (first), and as hyperplasic epidermis with linfocitary infiltrate and the presence of plenty of plasmatic cells (second). Histochemical techniques, including Ziehl-Neelsen, Grocott and periodic acid-Schiff stains, and PCR for Mycobacterium tuberculosis on both biopsies were negative. Serology for HIV, syphilis and hepatitis were also negative. In the second biopsy culture, moderate colonies of M. tuberculosis finally grew. The patient started a four-drug antituberculosis regimen. Adalimumab was discontinued and etanercept introduced after 2?months of antituberculosis therapy. The patient remained on therapy for 9?months with complete ulcer resolution. PMID:25422341

Luquín, Nuria; Masiá, Mar; Noguera, Raúl; Gutiérrez, Félix

2014-01-01

6

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

PubMed Central

Background Anti-TNF-? agents have been hypothesized to increase the risk of interstitial lung disease (ILD), including its most severe manifestation, pulmonary fibrosis. Methods We conducted a cohort study among autoimmune disease patients who were members of Kaiser Permanente Northern California, 1998–2007. We obtained therapies from pharmacy data and diagnoses of ILD from review of X-ray and computed tomography reports. We compared new users of anti-TNF-? agents to new users of non-biologic therapies using Cox proportional hazards analysis to adjust for baseline propensity scores and time-varying use of glucocorticoids. We also made head-to-head comparisons between anti-TNF-? agents. Results Among the 8,417 persons included in the analysis, 38 (0.4%) received a diagnostic code for ILD by the end of follow-up, including 23 of 4,200 (0.5%) who used anti-TNF-? during study follow-up, and 15 of 5,423 (0.3%) who used only non-biologic therapies. The age- and gender-standardized incidence rate of ILD, per 100 person-years, was 0.21 (95% CI 0–0.43) for rheumatoid arthritis and appreciably lower for other autoimmune diseases. Compared to use of non-biologic therapies, use of anti-TNF-? therapy was not associated with a diagnosis of ILD among RA patients (adjusted hazard ratio, 1.03; 95% CI 0.51–2.07). Nor did head-to-head comparisons across anti-TNF-? agents suggest important differences in risk, although the number of cases available for analysis was limited. Conclusion The study provides evidence that compared to non-biologic therapies anti-TNF-? therapy does not increase the occurrence of ILD among patients with autoimmune diseases, and informs research design of future safety studies of ILD. PMID:23359391

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

2013-01-01

7

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

PubMed

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; Hernández-Flórez, Diana; Hernandez, Diana; Martinez, Lina; Gonzalez, Carlos M; Monteagudo, Indalecio; Longo, Javier Lopez; Montoro, Maria; Carreño, Luis

2013-06-01

8

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

PubMed Central

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

2014-01-01

9

Anti-TNF-Alpha Therapy and Systemic Vasculitis  

PubMed Central

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

Kaplanski, Gilles

2014-01-01

10

Anti-TNF-? Therapy May Cause Neonatal Neutropenia.  

PubMed

Although anti-tumor necrosis factor (anti-TNF) antibodies are associated with a clear risk of agranulocytosis in adults and are known to cross the placenta, monitoring of the absolute neutrophil count (ANC) in neonates born to mothers receiving these biological agents is not currently recommended. Here, we report on the first case series of 4 newborn patients with severe neutropenia born to mothers treated for ulcerative colitis with infliximab during pregnancy (including the third trimester). The newborns presented with severe neutropenia at birth, which was subsequently complicated by skin infections. The newborns' ANCs returned to the normal range within 8 to 14 weeks, at which time infliximab could not be detected in the blood. Anti-TNF agents probably exert a direct, toxic effect on the bone marrow. Furthermore, the detection of a CD16 autoantibody in 1 mother-newborn pair suggests that infliximab can induce autoimmune neutropenia. Abnormally high levels of the CD16 autoantibody in newborn serum or immaturity of the fetal bone marrow might explain why neutropenia was observed in the child but not in the mother. We recommend the systematic measurement of ANC on cord blood at birth and (in the event of an infection) in the weeks thereafter. PMID:25266439

Guiddir, Tamazoust; Frémond, Marie-Louise; Triki, Tewfik Bibi; Candon, Sophie; Croisille, Laure; Leblanc, Thierry; de Pontual, Loïc

2014-10-01

11

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

PubMed Central

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

2011-01-01

12

[Anti-TNF alfa therapy in ankylosing spondylitis].  

PubMed

Ankylosing spondylitis (AS) is an inflammatory chronic disease that affects young males and in more than 90% of cases is associated with HLA B27 antigen. Therapeutic options for those patients with spondyloarthropathies have been limited during the last decades. Infliximab and etanercept are both approved for the treatment of patients with active disease that does not respond to conventional therapies. Anti-TNF therapy is very effective in AS, and eventually can be more effective than in rheumatoid arthritis. In 2003 Assessments in Ankylosing Spondylitis Group (ASAS) published international recommendations about the use of these agents in AS, which can be used as guidance in taking decisions and elaborating guidelines. To define their utilization it is necessary more studies about efficacy, toxicity and about ways of use. PMID:17187716

Cravo, Ana Rita; Tavares, Viviana; Da Silva, José Canas

2006-01-01

13

Clinical application and evaluation of anti-TNF-alpha agents for the treatment of rheumatoid arthritis  

PubMed Central

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 DMARD therapy, one recommended therapeutic alternative is anti-TNF-? therapy. Anti-TNF-? agents are effective and have rapid onset of action compared with DMARDs. Elucidating the differences in effectiveness of anti-TNF-? compounds has important clinical implications. By comparing the efficacy, safety and use principle of different treatment options, this review focuses on providing important information about three anti-TNF-? compounds (etanercept, infliximab, and adalimumab) to help define optimal treatments for RA patients. PMID:20711219

Jin, Juan; Chang, Yan; Wei, Wei

2010-01-01

14

Successful Anti-TNF-? Treatment in a Girl with LAD-1 Disease and Autoimmune Manifestations.  

PubMed

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

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

2014-10-01

15

Ten-Year Drug Survival of Anti-TNF Agents in the Treatment of Inflammatory Arthritides.  

PubMed

Postmarketing Phase IV Tumor necrosis factor (TNF) inhibitor therapies (anti-TNFs) are used routinely as first-line biotherapy for the treatment of rheumatoid arthritis (RA) and spondyloarthritis (SpA: psoriatic arthritis [PsA] and ankylosing spondylitis [AS]) in patients who have failed traditional non-biologic disease-modifying anti-rheumatic drugs (DMARDs). However, about 30% of patients experience failure of first-line anti-TNF agent because of inefficacy or adverse events. This study analyzed long-term anti-TNF? drug survival in a clinical practice setting. The overall 10-year retention rate of first-line anti-TNF agent is about 23%, being significantly higher for SpA compared with RA patients. ETN is the most persistent anti-TNF with a drug survival rate significantly higher than IFX and ADA. PMID:25381973

Biggioggero, Martina; Favalli, Ennio Giulio

2014-11-01

16

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

PubMed Central

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

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

2013-01-01

17

Cutaneous sarcoidosis occurring during anti-TNF-alpha treatment: report of two cases.  

PubMed

We report two cases of cutaneous granuloma induced by anti-TNF-alpha therapy: a 47-year-old man suffering from psoriatic arthritis treated with infliximab and a 56-year-old woman treated with adalimumab for polyarticular juvenile rheumatoid arthritis. The biospies confirmed the diagnosis of a 'sarcoidosis-like' reaction. No systemic involvement was observed. Such cases of noninfectious granulomatous diseases occurring during anti-TNF-alpha therapy are becoming increasingly frequent. PMID:20185892

Dhaille, F; Viseux, V; Caudron, A; Dadban, A; Tribout, C; Boumier, P; Clabaut, A; Lok, C

2010-01-01

18

Cutaneous Sarcoidosis Occurring during Anti-TNF-Alpha Treatment: Report of Two Cases  

Microsoft Academic Search

We report two cases of cutaneous granuloma induced by anti-TNF-? therapy: a 47-year-old man suffering from psoriatic arthritis treated with infliximab and a 56-year-old woman treated with adalimumab for polyarticular juvenile rheumatoid arthritis. The biospies confirmed the diagnosis of a ‘sarcoidosis-like’ reaction. No systemic involvement was observed. Such cases of noninfectious granulomatous diseases occurring during anti-TNF-? therapy are becoming increasingly

F. Dhaille; V. Viseux; A. Caudron; A. Dadban; C. Tribout; P. Boumier; A. Clabaut; C. Lok

2010-01-01

19

Anti-TNF therapies: a comprehensive analysis of adverse effects associated with immunosuppression  

Microsoft Academic Search

Knowledge and understanding about the immunosuppressive properties of anti-TNF therapies and the adverse effects these causes\\u000a have advanced over the last 10 years since the first of these drugs was approved. These drugs work by inhibiting tumour necrosis\\u000a factor (TNF) in the body, which plays an essential role in the immune response to invading pathogens. Anti-TNF drugs have\\u000a therapeutic value because

Victoria Connor

2011-01-01

20

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

PubMed Central

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

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

2013-01-01

21

A guide to preparation of patients with inflammatory bowel diseases for anti-TNF-? therapy  

PubMed Central

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

Chebli, Julio Maria Fonseca; Gaburri, Pedro Duarte; Chebli, Liliana Andrade; da Rocha Ribeiro, Tarsila Campanha; Pinto, Andre Luiz Tavares; Ambrogini, Orlando; Damiao, Aderson Omar Mourao Cintra

2014-01-01

22

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

PubMed Central

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

Ventura, Inmaculada; Gomez, Elisa; Perez-Cano, Ramon; Blanca, Miguel; Monteseirin, Javier

2014-01-01

23

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

PubMed Central

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

2014-01-01

24

Surgery for Crohn's disease and anti-TNF agents: the changing scenario.  

PubMed

Surgery has been a mainstay of therapy for Crohn's disease for a long time, essentially as a consequence of the fairly modest efficacy of traditional medications such as immunomodulators, antibiotics and 5-ASA, especially in severe cases. However, in the past decade and half, the advent of anti-TNF agents has greatly changed the medical approach to this disease and may modify its general management as well. Here, we have reviewed the current literature on incidence of surgery, timing of surgery and postoperative recurrence of Crohn's disease before and after the advent of anti-TNF agents. In addition, we have reviewed the risk of perioperative complications in patients on anti-TNF agents before surgery. The data show that the use of these medications is changing or expecting to change shortly a number of surgical aspects of Crohn's disease management. PMID:24161133

Sorrentino, Dario; Fogel, Sandy; Van den Bogaerde, Johan

2013-11-01

25

Current and Future Anti-TNF Therapy for Inflammatory Bowel Disease.  

PubMed

Anti-tumor necrosis factor-alpha (anti-TNF) therapy has become a very important modality in the treatment of patients with inflammatory bowel disease. A number of anti-TNF medications have been investigated for this purpose, many via randomized controlled trials. Infliximab, the most studied of these agents, has shown impressive efficacy in the treatment of luminal and fistulizing Crohn's disease, as well as ulcerative colitis. Adalimumab and certolizumab have shown similar efficacy in Crohn's disease but have not yet been studied in ulcerative colitis. Less impressive results were seen in randomized controlled trials involving CDP-571, etanercept, or onercept for patients with Crohn's disease. Thalidomide and CNI-1493 have been evaluated only preliminarily in small, open-label pilot studies in patients with Crohn's disease. The future of anti-TNF therapy in inflammatory bowel disease is very bright, as exciting new developments continue to be made at a rapid pace. PMID:17547858

Osterman, Mark T; Lichtenstein, Gary R

2007-06-01

26

Novel agents in the future: Therapy beyond anti-TNF agents in inflammatory bowel disease.  

PubMed

Anti-tumor necrosis factor (TNF)-? agents emerge as the hot spot in the last decade for treating patients with inflammatory bowel disease (IBD). The effect of anti-TNF-? agents is satisfactory; however, some patients fail to achieve clinical response. Fortunately, in recent years, great efforts have been made and multiple novel therapies have been developed in the treatment for IBD. In this article, we aim to introduce anti-TNF-? drugs as well as other novel treatments currently undergoing clinical trials for IBD. PMID:25251263

Peng, Jiang Chen; Shen, Jun; Ran, Zhi Hua

2014-11-01

27

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

PubMed Central

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

Angel, Kristin

2012-01-01

28

Differences in Reactivation of Tuberculosis Induced from Anti-TNF Treatments Are Based  

E-print Network

Infectious Disease, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 5 have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used

Kirschner, Denise

29

PTPRC rheumatoid arthritis risk allele is also associated with response to anti-TNF therapy  

E-print Network

is a mainstay of treatment in rheumatoid arthritis (RA). The aim of our study is to test established RA geneticPTPRC rheumatoid arthritis risk allele is also associated with response to anti- TNF therapy Jing Research Center for Arthritis, Department of Medicine, University of California, San Francisco, California

Raychaudhuri, Soumya

30

Neurological adverse events in patients receiving anti-TNF therapy: a prospective imaging and electrophysiological study  

PubMed Central

Introduction The aim was to investigate the frequency of neurological adverse events in patients with rheumatoid arthritis (RA) and spondylarthropathies (SpA) treated with tumor necrosis factor (TNF) ? antagonists. Methods Seventy-seven patients eligible for anti-TNF? therapy were evaluated. There were 36 patients with RA, 41 with SpA [24 psoriatic arthritis (PsA) and 17 with ankylosing spondylitis (AS)]. All patients had a complete physical and neurological examination. Brain and cervical spine magnetic resonance imaging (MRI) and neurophysiological tests were performed in all patients before the initiation of anti-TNF? therapy and after a mean of 18 months or when clinical symptoms and signs indicated a neurological disease. Exclusion criteria included hypertension, diabetes mellitus, dyslipidemia, heart arrhythmias, atherothrombotic events, vitamin B12 and iron deficiency, head and neck trauma and neurological surgeries. Results Two patients did not receive anti-TNF? therapy because brain MRIs at baseline revealed lesions compatible with demyelinating diseases. Thus, 75 patients received anti-TNF? (38 infliximab, 19 adalimumab and 18 etanercept). Three patients developed neurological adverse events. A 35-year-old man with PsA after 8 months of infliximab therapy presented with paresis of the left facial nerve and brain MRI showed demyelinating lesions. Infliximab was discontinued and he was treated with pulses of corticosteroids recovering completely after two months. The second patient was a 45-year-old woman with RA who after 6 months of adalimumab therapy presented with optic neuritis. The third patient was a 50-year-old woman with AS, whom after 25 months of infliximab therapy, presented with tingling and numbness of the lower extremities and neurophysiological tests revealed peripheral neuropathy. In both patients anti-TNF were discontinued and they improved without treatment after 2 months. The rest of our patients showed no symptoms and MRIs showed no abnormalities. The estimated rate of neurological adverse events in patients treated with anti-TNF therapy is 4% (3/75). Conclusions Neurological adverse events after anti-TNF? therapy were observed in our patient. Brain MRI and neurophysiological tests are essential tools to discriminate neurological diseases. PMID:24938855

2014-01-01

31

Lupus attributable to anti-TNF therapy and revealed by interstitial granulomatous dermatitis.  

PubMed

Interstitial granulomatous dermatitis belongs to the group of aseptic cutaneous granulomas. It is a histopathological entity encountered in various pathological situations, such as polyarthritis including rheumatoid arthritis, but also systemic lupus erythematosus. It may also occur after systemic administration of medication, thus representing a drug-induced, interstitial granulomatous outbreak. This has recently been described after anti-TNF therapy was taken. We are reporting the case of a patient treated using adalimumab for rheumatoid arthritis and having developed interstitial granulomatous dermatitis during treatment, which revealed lupus erythematosus attributable to the biotherapy. The clinical appearance of interstitial granulomatous dermatitis can vary, and the diagnosis is confirmed by anatomo-pathological examination. Drug-induced interstitial granulomatous outbreaks have specific histological criteria, and secondary cases involving anti-TNF medication have been described. Cases of lupus attributable to anti-TNF therapy have also been described, and they have specific biological characteristics. Like idiopathic lupus, they may be associated with interstitial granulomatous dermatitis, but the association of an anti-TNF-induced lupus and this type of granulomatous has not, to our knowledge, been described before. We are reporting one case, which emphasises the importance of carrying out a complete and systematic aetiological assessment for all cases of interstitial granulomatous dermatitis, including where there is systemic disease or following medical treatment, either of which may provide an evident cause for the granulomatosis. In particular, the outbreak of interstitial granulomatous dermatitis during anti-TNF treatment should lead to screening for a drug-induced lupus, which would require the patient to stop such treatment. PMID:21800115

Guerin, M; Haettich, B; Bara, C; Artru, L; Prophette, B; Célérier, P; Maillard, H

2012-09-01

32

Risk of tuberculosis higher with monoclonal-antibody than with soluble-receptor anti-TNF therapy in the 3-year prospective French RATIO registry  

E-print Network

1 Risk of tuberculosis higher with monoclonal-antibody than with soluble- receptor anti-TNF therapy * the two authors contributed equally to the work Key words: anti-TNF-alpha, tuberculosis, safety, rheumatoid arthritis, inflammatory chronic diseases Running head: Tuberculosis complicating anti-TNF therapy

Paris-Sud XI, Université de

33

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

PubMed

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

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

2012-10-01

34

Lupus attributable to anti-TNF therapy and revealed by interstitial granulomatous dermatitis  

Microsoft Academic Search

Interstitial granulomatous dermatitis belongs to the group of aseptic cutaneous granulomas. It is a histopathological entity\\u000a encountered in various pathological situations, such as polyarthritis including rheumatoid arthritis, but also systemic lupus\\u000a erythematosus. It may also occur after systemic administration of medication, thus representing a drug-induced, interstitial\\u000a granulomatous outbreak. This has recently been described after anti-TNF therapy was taken. We are

M. Guerin; B. Haettich; C. Bara; L. Artru; B. Prophette; P. Célérier; H. Maillard

35

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  

Microsoft Academic Search

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

36

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

Microsoft Academic Search

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

2011-01-01

37

Off-Label Dermatologic Uses of Anti-TNF-a Therapies  

Microsoft Academic Search

Background  Tumor necrosis factor-alpha (TNF-a) is a proinflammatory cytokine that plays an immunomodulatory role in a variety of systemic\\u000a and dermatologic diseases. Currently, three anti-TNF-a drugs are available in North America— infliximab (approved in the U.S.\\u000a for the treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, ulcerative colitis, and psoriatic arthritis),\\u000a etanercept (approved in the U.S. for the treatment of rheumatoid

Andrew F. Alexis; Bruce E. Strober

2005-01-01

38

The evaluation of latent tuberculosis in rheumatologic diseases for anti-TNF therapy: experience with 192 patients.  

PubMed

It is recommended to evaluate the presence of latent tuberculosis infection (LTBI) before initiating antitumor necrosis factor alpha (anti-TNF) therapy for rheumatologic diseases. We aimed to present the follow-up results of 192 patients with rheumatologic diseases before anti-TNF therapy for LTBI. We enrolled 192 patients who were given anti-TNF therapy for their rheumatologic diseases between April 2005 and January 2008. The demographic characteristics of the patients were recorded. Chest X-ray was obtained and tuberculin skin test (TST) was performed in all patients before anti-TNF therapy. LTBI was assessed by detailed history of close contact with infectious cases within the last year, abnormal chest radiography, and positive TST (> or =5 mm) before initiating anti-TNF therapy. Patients with anti-TNF therapy were followed with 2-month intervals for active tuberculosis by pulmonary and extrapulmonary symptoms, physical examination, and chest X-ray. Of 192 patients, 104 (54.2%) patients were women, age (mean +/- SD) 43.1 +/- 12.7 years and 88 (45.8%) patients were men, age (mean +/- SD) 39.3 +/- 11.2 years. Ninety-one (47.4%) of them had rheumatoid arthritis (RA); 92 (47.9%) had ankylosing spondylitis (AS), and nine (4.7%) had psoriatic arthritis. Isoniazid treatment was started in 129 (67.2%) patients in whom LTBI was detected. No significant difference was observed for TST positivity (TST > or = 5 mm) between the patients with RA and AS (p = 0.101). Similarly, no significant difference was also observed for TST positivity between the patients who received immunosuppressive therapy and those who did not (p = 0.154). Only three (1.6%) patients developed active tuberculosis at the study period. We suggested that in despite of the presence of rheumatologic disease and/or immunosuppressive therapy, TST is an acceptable and available diagnostic test for detecting LTBI before anti-TNF therapy. PMID:18320137

Hanta, Ismail; Ozbek, Suleyman; Kuleci, Sedat; Kocabas, Ali

2008-09-01

39

Validation Study of Existing Gene Expression Signatures for Anti-TNF Treatment in Patients with Rheumatoid Arthritis  

PubMed Central

So far, there are no means of identifying rheumatoid arthritis (RA) patients who will fail to respond to tumour necrosis factor blocking agents (anti-TNF), prior to treatment. We set out to validate eight previously reported gene expression signatures predicting therapy outcome. Genome-wide expression profiling using Affymetrix GeneChip Exon 1.0 ST arrays was performed on RNA isolated from whole blood of 42 RA patients starting treatment with infliximab or adalimumab. Clinical response according to EULAR criteria was determined at week 14 of therapy. Genes that have been reported to be associated with anti-TNF treatment were extracted from our dataset. K-means partition clustering was performed to assess the predictive value of the gene-sets. We performed a hypothesis-driven analysis of the dataset using eight existing gene sets predictive of anti-TNF treatment outcome. The set that performed best reached a sensitivity of 71% and a specificity of 61%, for classifying the patients in the current study. We successfully validated one of eight previously reported predictive expression profile. This replicated expression signature is a good starting point for developing a prediction model for anti-TNF treatment outcome that can be used in a daily clinical setting. Our results confirm that gene expression profiling prior to treatment is a useful tool to predict anti-TNF (non) response. PMID:22457743

Toonen, Erik J. M.; Gilissen, Christian; Franke, Barbara; Kievit, Wietske; Eijsbouts, Agnes M.; den Broeder, Alfons A.; van Reijmersdal, Simon V.; Veltman, Joris A.; Scheffer, Hans; Radstake, Timothy R. D. J.; van Riel, Piet L. C. M.; Barrera, Pilar; Coenen, Marieke J. H.

2012-01-01

40

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

PubMed

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

2012-09-01

41

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

PubMed Central

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

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

2012-01-01

42

The Efficacy of Allergen Immunotherapy with Cat Dander in Reducing Symptoms in Clinical Practice  

PubMed Central

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. PMID:23984343

Williams, Aerik A.; Cohn, John R.; Fung, Shirley M.; Padams, Patricia

2013-01-01

43

Use of (99m)Tc-anti-TNF-? scintigraphy in a patient with non-radiographic axial spondyloarthritis.  

PubMed

The aim of this study was to describe the use of (99m)Tc-anti-TNF-? scintigraphy for detecting inflammation of the sacroiliac joints in a patient with non-radiographic axial spondyloarthritis. A 47-year-old female patient, non-smoker and non-drinker, complained of a low back pain inflammation, which began 4 years before her condition have exacerbated to morning stiffness and anterior uveitis in the last 6 months. Initially diagnosed as mechanical low back pain, she irregularly took non-steroidal anti-inflammatory drugs and corticosteroids, without significant long-lasting results. Radiographic findings were negative. There was increased uptake of (99m)Tc-anti-TNF-? in an area corresponding to the topography of ileum and sacroiliac right joint upon (99m)Tc-anti-TNF-? scintigraphy. Magnetic resonance imaging (MRI), the most used image diagnosis tool, showed minimum impregnation of gadolinium in the right sacroiliac joint and at the iliac face of the inferior third of the right sacroiliac joint. We suggest that (99m)Tc-anti-TNF-? can facilitate early diagnosis of patients with non-radiographic axial spondyloarthritis. More studies are now ongoing. PMID:25052689

de Andrade Alexandre, Dângelo José; de Souza, Sergio Augusto Lopes; Moraes do Carmo, Clarissa Canella; Schau, Bruno; da Fonseca, Lea Mirian Barbosa; Roimicher, Luis; Gutfilen, Bianca

2014-11-01

44

Detection of latent tuberculosis infection in rheumatologic diseases before anti-TNF? therapy: tuberculin skin test versus IFN-? assay.  

PubMed

We aimed to evaluate tuberculin skin test (TST) and interferon-gamma (IFN-?) test results for latent tuberculosis infection (LTBI) in patients with rheumatologic diseases prior to anti-TNF? therapy. Ninety patients were evaluated in the study at the Departments of Chest Diseases and Rheumatology for anti-TNF? therapy for their rheumatologic diseases. Tuberculin skin test was performed (Mantoux method) and peripheral blood samples were collected for IFN-? assay (QuantiFeron TB-Gold In Tube) before the anti-TNF? therapy. Of 90 patients, TST positivity was detected in 56 (62.2%) patients, while IFN-? positivity was detected in 34 (37.8%) patients. Among 56 TST positive patients, IFN-? positivity was detected in 24 (42.9%) patients, and among 34 TST negative patients, IFN-? positivity was detected in 10 (29.4%) patients. There was no significant agreement between TST and IFN-? assay results (Kappa = 0.12, P = 0.2). Forty-three (47.8%) patients were using immunosuppressive drugs owing to their rheumatologic diseases. In this group, TST and IFN-? positivity is significantly lower than in those who did not receive immunosuppressive treatment (P < 0.05). We conclude that the IFN-? assay may not be preferred to TST as a diagnostic test in patients with rheumatologic diseases prior to anti-TNF? treatment. PMID:22095393

Hanta, Ismail; Ozbek, Suleyman; Kuleci, Sedat; Seydaoglu, Gulsah; Ozyilmaz, Ezgi

2012-11-01

45

Anti-TNF Treatment Response in Rheumatoid Arthritis Patients Is Associated with Genetic Variation in the NLRP3-Inflammasome  

PubMed Central

Objective Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-? blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-?B- and pattern recognition receptor signalling pathways. Methods Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3–6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing. Results Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response?=?0.64 (95% confidence interval: 0.44–0.95), p?=?0.025, q?=?0.95) and INFG(rs2430561) (OR?=?0.40 (0.21–0.76), p?=?0.005, q?=?0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36–0.98), p?=?0.040, q?=?0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR?=?0.24 (0.10–0.56), p?=?0.001, q?=?0.04). Conclusions In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-? gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products. PMID:24967817

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

2014-01-01

46

Rate and Predictors of Mucosal Healing in Patients with Inflammatory Bowel Disease Treated with Anti-TNF-Alpha Antibodies  

PubMed Central

Objective Mucosal healing (MH) is an important treatment goal in patients with inflammatory bowel disease (IBD), but factors predicting MH under medical therapy are largely unknown. In this study, we aimed to characterize predictive factors for MH in anti-TNF-alpha antibody-treated IBD patients. Methods We retrospectively analyzed 248 IBD patients (61.3% CD, 38.7% UC) treated with anti-TNF-alpha antibodies (infliximab and/or adalimumab) for MH, defined as macroscopic absence of inflammatory lesions (Mayo endoscopy score 0 or SES-CD score 0) in colonoscopies which were analyzed before and after initiation of an anti-TNF-alpha antibody treatment. Results In patients treated with only one anti-TNF-alpha antibody (“TNF1 group”, n?=?202), 56 patients (27.7%) achieved complete MH at follow-up colonoscopy (median overall follow-up time: 63 months). In a second cohort (n?=?46), which comprised patients who were consecutively treated with two anti-TNF-alpha antibodies (“TNF2 group”), 13 patients (28.3%) achieved complete MH (median overall follow-up time: 64.5 months). Compared to patients without MH, CRP values at follow-up colonoscopy were significantly lower in patients with MH (TNF1 group: p?=?8.35×10?5; TNF2 group: p?=?0.002). Multivariate analyses confirmed CRP at follow-up colonoscopy as predictor for MH in the TNF1 group (p?=?0.012). Overall need for surgery was lower in patients with MH (TNF1 group: p?=?0.01; TNF2 group: p?=?0.03). Conclusions We identified low serum CRP level at follow-up colonoscopy as predictor for MH, while MH was an excellent negative predictor for the need for surgery. PMID:24932476

Beigel, Florian; Deml, Matthias; Schnitzler, Fabian; Breiteneicher, Simone; Goke, Burkhard

2014-01-01

47

Immunotherapy targeting ?-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] ?-synuclein mice.  

PubMed

Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (?-synuclein) in the central nervous system (CNS) is an early pathogenic event in Parkinson's disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against ?-synuclein as a promising novel treatment strategy. Since large ?-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. In support of this, (Thy-1)-h[A30P] ?-synuclein transgenic mice with motor dysfunction symptoms were found to display increased levels of ?-synuclein protofibrils in the CNS. An ?-synuclein protofibril-selective monoclonal antibody (mAb47) was evaluated in this ?-synuclein transgenic mouse model. As measured by ELISA, 14month old mice treated for 14weeks with weekly intraperitoneal injections of mAb47 displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. Besides the lower levels of pathogenic ?-synuclein demonstrated, a reduction of motor dysfunction in transgenic mice upon peripheral administration of mAb47 was indicated. Thus, immunotherapy with antibodies targeting toxic ?-synuclein species holds promise as a future disease-modifying treatment in Parkinson's disease and related disorders. PMID:24851801

Lindström, Veronica; Fagerqvist, Therese; Nordström, Eva; Eriksson, Fredrik; Lord, Anna; Tucker, Stina; Andersson, Jessica; Johannesson, Malin; Schell, Heinrich; Kahle, Philipp J; Möller, Christer; Gellerfors, Pär; Bergström, Joakim; Lannfelt, Lars; Ingelsson, Martin

2014-09-01

48

Biological Treatments in Beh?et's Disease: Beyond Anti-TNF Therapy  

PubMed Central

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

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

2014-01-01

49

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

PubMed

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

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

2014-12-01

50

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

PubMed

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

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

2014-08-15

51

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

PubMed

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

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

2014-07-01

52

Patient experiences, attitudes and expectations towards receiving information about anti-TNF medication - "It could give me two heads and I'd still try it!"  

PubMed Central

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

2013-01-01

53

Therapy of ankylosing spondylitis and other spondyloarthritides: established medical treatment, anti-TNF-? therapy and other novel approaches  

PubMed Central

Therapeutic options for patients with more severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is accumulating evidence that anti-tumor-necrosis-factor (anti-TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis and psoriatic arthritis. The major anti-TNF-? agents currently available, infliximab (Remicade®) and etanercept (Enbrel®), are approved for the treatment of rheumatoid arthritis (RA) in many countries. In ankylosing spondylitis there is an unmet medical need, since there are almost no disease-modifying antirheumatic drugs (DMARDs) available for severely affected patients, especially those with spinal manifestations. Judging from recent data from more than 300 patients with SpA, anti-TNF therapy seems to be even more effective in SpA than in rheumatoid arthritis. However, it remains to be shown whether patients benefit from long-term treatment, whether radiological progression and ankylosis can be stopped and whether long-term biologic therapy is safe. PMID:12223105

Braun, Juergen; Sieper, Joachim

2002-01-01

54

Therapy of ankylosing spondylitis and other spondyloarthritides: established medical treatment, anti-TNF-alpha therapy and other novel approaches.  

PubMed

Therapeutic options for patients with more severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is accumulating evidence that anti-tumor-necrosis-factor (anti-TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis and psoriatic arthritis. The major anti-TNF-alpha agents currently available, infliximab (Remicade(R)) and etanercept (Enbrel(R)), are approved for the treatment of rheumatoid arthritis (RA) in many countries. In ankylosing spondylitis there is an unmet medical need, since there are almost no disease-modifying antirheumatic drugs (DMARDs) available for severely affected patients, especially those with spinal manifestations. Judging from recent data from more than 300 patients with SpA, anti-TNF therapy seems to be even more effective in SpA than in rheumatoid arthritis. However, it remains to be shown whether patients benefit from long-term treatment, whether radiological progression and ankylosis can be stopped and whether long-term biologic therapy is safe. PMID:12223105

Braun, Juergen; Sieper, Joachim

2002-01-01

55

Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: a systematic review of randomized controlled trials.  

PubMed

Abstract Objective. Treatment with tumour necrosis factor antagonists (anti-TNF) has been recognized as a risk factor for tuberculosis (TB) reactivation. Our aim was to evaluate risk of TB reactivation in rheumatologic and non-rheumatologic diseases treated with the same anti-TNF agents with and without concomitant therapies. Methods. We searched for randomized controlled trials (RCTs) evaluating infliximab, adalimumab, and certolizumab in both rheumatologic and non-rheumatologic diseases until 2012. Results were calculated as pooled rates and/or pooled odd ratios (OR). Results. Overall, 40 RCTs with a total of 14,683 patients (anti-TNF: 10,010; placebo: 4673) were included. TB reactivation was 0.26% (26/10,010) in the anti-TNF group and 0% (0/4673) in the control group, corresponding to an OR of 24.8 (95% CI 2.4-133). TB risk was higher when anti-TNF agents were combined with methotrexate or azathioprine as compared with either controls (24/4241 versus 0/4673; OR 54; 95% CI 5.3-88) or anti-TNF monotherapy (24/4241 versus 2/5769; OR 13.3; 95% CI 3.7-100). When anti-TNF was used as monotherapy, TB risk tended to be higher than placebo (2/5769 versus 0/4673; OR 4; 95% CI 0.2-15.7). Conclusions. TB risk with anti-TNF agents appeared to be increased when these agents were used in combination with methotrexate or azathioprine as compared with monotherapy regimen. TB risk seemed to be higher than placebo, even when monotherapy is prescribed. PMID:25105206

Lorenzetti, Roberto; Zullo, Angelo; Ridola, Lorenzo; Diamanti, Andrea Picchianti; Laganà, Bruno; Gatta, Luigi; Migliore, Alberto; Armuzzi, Alessandro; Hassan, Cesare; Bruzzese, Vincenzo

2014-11-01

56

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

Microsoft Academic Search

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

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

2005-01-01

57

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

PubMed Central

Objective. The study aim was to determine treatment persistence rates and to identify causes of discontinuation in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients in clinical practice. Methods. Patients treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) were retrospectively included. Treatment persistence rates were analyzed by means of a stepwise logistic regression. Differences between therapy duration were assessed by means of an analysis of variance model (ANOVA), while a chi-square test was used to evaluate relationships between therapies and causes of treatment discontinuation and the administration of concomitant disease-modifying antirheumatic drugs (DMARDs) among therapies and types of disease considering completed courses of therapy versus courses that were discontinued. Results. 268 patients received a total of 353 anti-TNF treatment courses (97 ADA, 180 ETA, and 76 INF). Comparison among therapies showed significant difference regarding the treatment persistence rates due to the contrast between ETA and INF (P = 0.0062). We observed that 84.7% of patients were still responding after 6 months of follow-up. Comparison among diseases showed that there were significant differences between PsA and AS (P = 0.0073) and PsA and PsA with predominant axial involvement (P = 0.0467) in terms of duration of the therapy, while there were no significant differences with regard to the persistence rate. Conclusions. In this cohort, anti-TNF-? therapy was associated with high drug persistence rates. As in rheumatoid arthritis, switching to another anti-TNF-? agent can be an effective option when, during the treatment of AS or PsA, therapy is suspended because of inefficacy or an adverse event. Combination therapy with DMARDs was associated with a better persistence rate. PMID:25110401

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

2014-01-01

58

Treatment of psoriatic arthritis with anti-TNF agents: a systematic review and meta-analysis of efficacy, effectiveness and safety.  

PubMed

We did a systematic review and meta-analysis on the efficacy and safety of the anti-TNF drugs adalimumab, etanercept, golimumab and infliximab used in psoriatic arthritis (PsA) adult treatment. Additionally, we present results of anti-TNF use in real life settings. We searched Embase, Medline, Cochrane Central and LILACS, from inception to 11/08/2013, for studies comparing anti-TNFs with each other or with controls. We included nine randomized controlled trials and six observational studies. ACR20, ACR50, PsARC and PASI75 responses were achieved by more users of anti-TNF than control after up to 24 weeks of treatment. More participants who used etanercept and infliximab achieved ACR70. After all patients originally randomized to anti-TNF or placebo had used anti-TNF for at least 24 weeks, we observed difference only with regard to ACR70 response. Radiographic end points were achieved by more patients in anti-TNF group, and they seem to be time dependent-the longer patients use the drug the better the results. Etanercept and infliximab had worse results on application site reactions, but in general anti-TNF drugs in the regimens studied were as safe as control/placebo. There seems to be no difference in efficacy and effectiveness among anti-TNFs, but superiority head-to-head studies are still needed. Meanwhile, other factors should be taken into account in the choice of medication, such as costs and patient convenience. PMID:24728068

Lemos, Lívia Lovato Pires; de Oliveira Costa, Juliana; Almeida, Alessandra Maciel; Junior, Haliton Oliveira; Barbosa, Mariana Michel; Kakehasi, Adriana Maria; Acurcio, Francisco Assis

2014-10-01

59

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

PubMed Central

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

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

2012-01-01

60

Using Systems Biology-based Analysis Approaches to Identify Mechanistically Significant Adverse Drug Reactions: Pulmonary Complications from Combined Use of Anti-TNF? Agents and Corticosteroids  

PubMed Central

Anti-TNF drugs are frequently associated with serious Adverse Events (AEs), which necessitates an improved understanding of individual factors that determine efficacy and safety of anti-TNF agents. We mined the US FDA’s Adverse Event Reporting System (AERS) for anti-TNF-associated AEs to identify and stratify patient subgroups and drug combinations that exhibit specifically correlated complications. We demonstrate the existence of patient subgroup and anti-TNF agent-specific associations for relative risks of developing known and novel AEs including infections, edema, and organ damage associated processes. Concomitant use of anti-TNFs with corticosteroids significantly increased risk of AEs (p < 0.001) including pulmonary fibrosis and pulmonary edema. Using these tightly correlated phenotypes, we mined mouse phenotype data to identify the molecular basis of these AEs. Multiple pathways and networks that regulate injury response, fluid regulation, and wound healing were implicated suggesting modification of anti-TNF-based therapeutic strategies to minimize corticosteroid-based combinatorial risk of severe AEs. PMID:24303326

Sarangdhar, Mayur; Kushwaha, Akash; Dahlquist, Jeanine; Jegga, Anil; Aronow, Bruce

2013-01-01

61

Non-systemic juvenile idiopathic arthritis outcome after reaching clinical remission with anti-TNF-? therapy: a clinical practice observational study of patients who discontinued treatment.  

PubMed

TNF-alpha-blocking agents (anti-TNF) used in juvenile idiopathic arthritis (JIA) are well established; however, time to withdraw is unclear. Neither prolonged nor tapering treatment seems to influence risk of relapse. Our aim was to assess relapse percentage after anti-TNF withdrawal of our non-systemic JIA patients after reaching clinical remission. A retrospective review of our non-systemic JIA patients in whom anti-TNF had been withdrawn due to inactive disease was achieved, between December 2000 and November 2011. We analyzed percentages of relapse according to JIA categories and antinuclear antibodies (ANA) positivity. n = 18 patients were included. Eighty-two percentage of patients relapsed after treatment withdrawal, and mean time to relapse was 3.04 months (SD 2.03). The percentage of relapse after anti-TNF discontinuation in the main JIA category was 88 % of negative rheumatoid factor polyarticular JIA and 80 % of persistent oligoarticular JIA. We did not find significant statistical differences according to ANA positivity (9 of 14 were ANA positive), and mean time to relapse (days) was 85.0 (SD 69.4) for ANA-positive versus 102.4 (SD 47.7) for ANA-negative patients (p = NS). Relapse percentage following anti-TNF discontinuation was high (82 %) and occurred within the first 3 months after it. No relationship regarding JIA subtype and ANA positivity was found. PMID:24162563

Iglesias, Estíbaliz; Torrente-Segarra, Vicenç; Bou, Rosa; Ricart, Silvia; González, María Isabel; Sánchez, Judith; Calzada, Joan; Antón, Jordi

2014-08-01

62

Immunotherapy for Alzheimer's Disease  

PubMed Central

Summary In 1999 a vaccine approach was found to reduce amyloid deposits in transgenic mice overproducing the amyloid precursor protein. This was followed closely by demonstrations that vaccines or passive immunotherapy could rescue memory deficits in these mice. Initial human clinical trials revealed apparent autoimmune reactions in a subset of patients, but also some cases of cognitive benefit and amyloid clearance. Further work with passive immunotherapy in mouse models confirmed exceptional clearing abilities of anti-amyloid antibodies even in older mice. However, in parallel with parenchymal amyloid clearance was the appearance of microhemorrhages and increased vascular amyloid deposition. Additional clinical trials with passive immunotherapy confirmed occasional appearance of microhemorrhage and occurrence of vasogenic edema in some patients, particularly those with the apolipoprotein E4 genotype. Recent data with positron emission tomography demonstrates trial participants passively immunized with anti-A? antibodies have reduced signals with amyloid binding ligands after 18 mo of therapy. Several anti-A? immunotherapies have reached phase 3 testing and immunotherapy is likely to be the first test of the amyloid hypothesis of Alzheimer’s disease. Identifying antibody variants that retain amyloid clearance with fewer adverse reactions remains a major focus of translational research in this area. PMID:21158978

Morgan, Dave

2010-01-01

63

NOVEL IMMUNOTHERAPIES  

PubMed Central

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

Yi, Qing

2010-01-01

64

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

PubMed Central

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

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

2013-01-01

65

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

PubMed Central

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

2014-01-01

66

Use of a Disease Risk Score to Compare Serious Infections Associated with Anti-TNF Therapy among High versus Lower Risk Rheumatoid Arthritis Patients  

PubMed Central

Background/Purpose To evaluate whether rates of serious infection with anti-TNF therapy in rheumatoid arthritis (RA) patients differ in magnitude by specific drugs and patient characteristics. Methods Among new non-biologic disease modifying anti-rheumatic drug (DMARD) users enrolled in Medicare/Medicaid or a large U.S. commercial health plan, we created and validated a person-specific infection risk score based upon age, demographics, insurance, glucocorticoid dose, and comorbidities to identify patients at high risk for hospitalized infections. We then applied this risk score to new users of infliximab, etanercept, and adalimumab and compared the observed one-year rate of infection to each other and to the predicted infection risk score estimated in the absence of anti-TNF exposure. Result Among 11,657 RA patients initiating anti-TNF therapy, the observed one year rate of infection was 14.2 per 100 person-years in older patients (>= 65 years) and 4.8 in younger patients (< 65 years). There was a relatively constant rate difference of 1–4 infections per 100 person-years associated with anti-TNF therapy across the range of the infection risk score. Infliximab had a significantly greater adjusted rate of infection compared to etanercept and adalimumab in both high and lower risk RA patients. Conclusion The rate of serious infections for anti-TNF agents was incrementally increased by a fixed absolute difference irrespective of age, comorbidities, and other factors that contributed to infections. Older patients and those with high comorbidity burdens should be reassured that the magnitude of incremental risk with anti-TNF agents is not greater for them than for lower risk patients. PMID:22556118

Curtis, JR; Xie, Fenglong; Chen, Lang; Muntner, Paul; Grijalva, Carlos G.; Spettell, Claire; Fernandes, Joaquim; Mcmahan, Raechele M.; Baddley, John W.; Saag, Kenneth G.; Beukelman, Timothy; Delzell, Elizabeth

2012-01-01

67

Associations between functional polymorphisms in the NF?B signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease.  

PubMed

Antitumor necrosis factor-? (TNF-?) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NF?B-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-? signaling (TNFA (TNF-?) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NF?B (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P?0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NF?B through the Toll-like receptor (TLR) pathways, genes regulating TNF-? signaling and cytokines regulated by NF?B are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1?, IL-6 and IFN-? may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting. PMID:24776844

Bank, S; Andersen, P S; Burisch, J; Pedersen, N; Roug, S; Galsgaard, J; Turino, S Y; Brodersen, J B; Rashid, S; Rasmussen, B K; Avlund, S; Olesen, T B; Hoffmann, H J; Thomsen, M K; Thomsen, V Ø; Frydenberg, M; Nexø, B A; Sode, J; Vogel, U; Andersen, V

2014-12-01

68

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

PubMed

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

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

2013-08-28

69

Peanut immunotherapy  

PubMed Central

Peanut allergy is common and can be a cause of severe, life-threatening reactions. It is rarely outgrown like other food allergies, such as egg and milk. Peanut allergy has a significant effect on the quality of life of sufferers and their families, due to dietary and social restrictions, but mainly stemming from fear of accidental peanut ingestion. The current management consists of strict avoidance, education and provision of emergency medication, but a disease- modifying therapy is needed for peanut allergy. Recent developments involve the use of immunotherapy, which has shown promise as an active form of treatment. Various routes of administration are being investigated, including subcutaneous, oral, sublingual and epicutaneous routes. Other forms of treatment, such as the use of vaccines and anti-IgE molecules, are also under investigation. So far, results from immunotherapy studies have shown good efficacy in achieving desensitisation to peanut with a good safety profile. However, the issue of long-term tolerance has not been fully addressed yet and larger, phase III studies are required to further investigate safety and efficacy. An assessment of cost/benefit ratio is also required prior to implementing this form of treatment. The use of immunotherapy for peanut allergy is not currently recommended for routine clinical use and should not be attempted outside specialist allergy units.

2014-01-01

70

Expression of lymphatic markers and lymphatic growth factors in psoriasis before and after anti-TNF treatment*  

PubMed Central

BACKGROUND Angiogenesis is an early stage of psoriatic lesion development, but less is known about lymphagiogenesis and its role in the development of psoriasis. OBJECTIVE To examine the expression of specific lymphatic markers and lymphatic growth factors in untreated psoriatic skin, in the unaffected skin of patients and skin of healthy volunteers, as well as their alteration after treatment with an anti-TNF agent. METHODS Immunohistochemistry for the lymphatic markers D2-40 and LYVE-1, in addition to the VEGF-C and VEGF-D growth factors, was performed in the skin biopsies of psoriatic lesions and adjacent non-psoriatic skin of 19 patients before and after treatment with etanercept, as well as in the skin biopsies of 10 healthy volunteers. RESULTS The expressions of D2-40, VEGF-C and VEGF-D on lymphatic vessels underwent statistically significant increases in untreated psoriatic skin compared with non-lesional skin, in contrast to LYVE-1, which did not involve significant increase in expression in psoriatic skin. VEGF-C expression on lymphatic vessels diminished after treatment with etanercept. Moreover VEGF-C and VEGF-D staining on fibroblasts presented with higher expression in lesional skin than in non-lesional adjacent skin. CONCLUSION Remodeling of lymphatic vessels possibly occurs during psoriatic lesion development, parallel to blood vessel formation. The exact role of this alteration is not yet clear and more studies are necessary to confirm these results. PMID:25387493

Moustou, Aikaterini Evangelia; Alexandrou, Paraskevi; Stratigos, Alexander J; Giannopoulou, Ioanna; Vergou, Theognosia; Katsambas, Andreas; Antoniou, Christina

2014-01-01

71

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

PubMed Central

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

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

2011-01-01

72

Risk of tuberculosis with the use of anti-TNF medications in psoriasis: incidence, screening and management.  

PubMed

Tumor necrosis factor (TNF) plays an important role in containing mycobacterial infections. With the rapidly increasing role of TNF inhibitors in dermatology, tuberculosis (TB) is becoming an important and worrisome concern to dermatologists. This paper aims to provide a comprehensive review on the incidence of TB in patients treated with anti-TNF, the variety of TB screening methods, and management of these cases. Various national recommendations have been highlighted. The monoclonal antibodies, infliximab and adalimumab, appear to be more associated with the risk of TB reactivation than the soluble receptor etanercept. Tuberculosis associated with TNF inhibitors, in contrast to classical TB, is more likely to be disseminated, atypical, extra pulmonary, and life threatening. Vigilance for typical and atypical presentations of active TB is mandatory until the end of therapy. Although tuberculin standard test (TST) has been the gold standard for screening of latent TB infection (LTBI) for close to a century, it has several inadequacies and may be unreliable in patients with widespread psoriasis. Interferon gamma release assays (IGRAs) with better diagnostic specificity and sensitivity are a promising adjunct to diagnose LTBI at present. Although appropriate screening and treatment of LTBI will lower the risk of reactivation to a great extent, no chemoprophylactic regimen is fully protective. PMID:25148273

Kasiraman, Vijayalakshmi; Atwan, Ausama A; Durojaiye, Oyewole Chris; Kalavala, Manju; Piguet, Vincent

2014-08-01

73

IGF-1 and ADMA Levels Are Inversely Correlated in Nondiabetic Ankylosing Spondylitis Patients Undergoing Anti-TNF-Alpha Therapy  

PubMed Central

Like rheumatoid arthritis, ankylosing spondylitis (AS) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome (MeS) features. AS patients often display osteoporosis as well as new bone formation. Insulin-like growth factor 1 (IGF-1) is a protein involved in both inflammation and bone metabolism. In the present study we assessed whether disease activity, systemic inflammation, MeS features, adipokines, and biomarkers of endothelial activation were associated with IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels in a series of 30 nondiabetic AS patients without CV disease undergoing TNF-? antagonist-infliximab therapy. All determinations were made in the fasting state, immediately before an infliximab infusion. Although no association of IGF-1 and IGFBP-3 levels with angiopoietin-2 or osteopontin was found, an inverse correlation between IGF-1 levels and asymmetric dimethylarginine (ADMA), an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction, was found (r = ?0.397; P = 0.04). However, no significant association was found between IGF-1 and IGFBP-3 levels and disease activity, systemic inflammation, metabolic syndrome features, or adipokines. In conclusion, in nondiabetic patients with AS undergoing periodic anti-TNF-? therapy, IGF-1 and ADMA are inversely correlated. PMID:25295265

Lopez-Mejias, Raquel; Rueda-Gotor, Javier; Miranda-Filloy, Jose A.; Villar-Bonet, Aurelia; Carnero-Lopez, Beatriz; Gomez-Acebo, Ines; Blanco, Ricardo; Pina, Trinitario; Gonzalez-Juanatey, Carlos; Gonzalez-Gay, Miguel A.

2014-01-01

74

Off-Label Uses of Anti-TNF Therapy in Three Frequent Disorders: Beh?et's Disease, Sarcoidosis, and Noninfectious Uveitis  

PubMed Central

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

Sanchez-Cano, Daniel; Callejas-Rubio, Jose Luis; Ruiz-Villaverde, Ricardo; Rios-Fernandez, Raquel; Ortego-Centeno, Norberto

2013-01-01

75

Predictive factors for partial remission according to the Ankylosing Spondylitis Assessment Study working group in patients with ankylosing spondylitis treated with anti-TNF? drugs.  

PubMed

The objective of this study was to evaluate the predictive factors for achieving partial remission (PR) in patients with ankylosing spondylitis (AS) treated with anti-TNF?. We longitudinally enrolled in a multi-center study 214 AS patients, classified according to New York criteria, treated with anti-TNF? drugs adalimumab (ADA), etanercept (ETA) and infliximab (INF) with at least 12 months of follow up. PR was reached when the score was <20 mm (on a visual analogue scale of 0-100 mm) in each of the following 4 domains: 1) patient global assessment (in the last week); 2) pain (spinal pain); 3) function [measured by the bath ankylosing spondylitis functional index (BASFI)]; 4) inflammation [mean of intensity and duration of morning stiffness, from the bath ankylosing spondylitis disease activity index (BASDAI)]. Two hundred fourteen AS patients (M/F=160/54; median age/range=43.2/19-78 years; median disease duration/ range=96/36-189 months) were treated with ADA (15.8%), ETA (28.9%) and INF (55.1%). At 12 and 24 months, high serum level of C reactive protein (CRP) (?2 vs ?0.8 mg/dL) were associated with higher rate of PR in AS patients treated with anti-TNF? drugs. At 24 months, PR was associated with shorter disease duration (?36 vs ?189 months) and higher erythrosedimentation rate (ESR) values (?45 vs ?17 mm/h). In male patients lower bath ankylosing spondylitis metrology index (BASMI) (?2 vs ?6) and absence of psoriasis were associated with higher PR rate only at 12 months. Other parameters assessed before treatment, such as BASDAI, BASFI, peripheral arthritis, inflammatory bowel disease and uveitis were not associated with PR. Our long-term longitudinal study in a setting of clinical practice showed that inflammatory parameters (i.e. CRP, ESR) and disease duration represent the most important predictive variables to achieve PR with an anti-TNF? treatment. PMID:25376955

Perrotta, F M; Addimanda, O; Ramonda, R; D'Angelo, S; Lubrano, E; Marchesoni, A; Olivieri, I; Punzi, L; Salvarani, C; Spadaro, A

2014-01-01

76

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

Microsoft Academic Search

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

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

2004-01-01

77

Effetti collaterali del trattamento con inibitori del TNF? ? nell'artrite idiopatica giovanile* Side effects of anti-TNF? ? therapy in juvenile idiopathic arthritis  

Microsoft Academic Search

SUMMARY Aim of the study: To report adverse events registered in our population affected by JIA and treated with anti-TNF? blockers. Methods: Ninety-five patients were enrolled to be treated with Etanercept, median age 14 years (range 4-34); medi- an duration of therapy 12 months (range1-40). 19 patients were als treated with MTX (median dose 12.5 mg\\/week). Fifty-six patients were enrolled

Irene Pontikaki; Valeria Gerloni; Maurizio Gattinara; Alfredomaria Lurati; Alessandra Salmaso; Gabriele De Marco; Barbara Teruzzi; Elisabetta Valcamonica; Flavio Fantini

78

Anti-TNF-? Activity of Portulaca oleracea in Vascular Endothelial Cells  

PubMed Central

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

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

2012-01-01

79

Clinical efficacy of abatacept, tocilizumab, and etanercept in Japanese rheumatoid arthritis patients with inadequate response to anti-TNF monoclonal antibodies.  

PubMed

The aim of this study was to compare the efficacy and retention rates of three biologics (abatacept, tocilizumab, and etanercept) after switching from first-course anti-TNF monoclonal antibody therapy. We performed a retrospective multicenter study of 89 patients who underwent second-course biologic therapy for 52 weeks after switching from first-course anti-TNF monoclonal antibody therapy. Patients at baseline had a mean age of 58.7 years, mean disease duration of 9.8 years, and mean clinical disease activity index (CDAI) of 22.4. There was no significant difference between the three drugs, except in rheumatoid factor positivity. Retention rates for abatacept, tocilizumab, and etanercept treatment at 52 weeks were 72.0, 89.5 and 84.6 %, respectively. The evaluation of CDAI indicated no significant difference at 52 weeks among the three drugs. Discontinuation due to all unfavorable causes did not significantly differ among the three drugs in hazard ratio-based evaluations. Our results show that patients treated with abatacept, tocilizumab, and etanercept achieved a high response rate with no significant differences in drug retention rates and clinical efficacy. These drugs represent good therapeutic options for patients with RA who are refractory to anti-TNF monoclonal antibody therapy. PMID:24970596

Hirabara, Shinya; Takahashi, Nobunori; Fukaya, Naoki; Miyake, Hiroyuki; Yabe, Yuichiro; Kaneko, Atsushi; Ito, Takayasu; Oguchi, Takeshi; Kida, Daihei; Hirano, Yuji; Fujibayashi, Takayoshi; Sugiura, Fumiaki; Hayashi, Masatoshi; Funahashi, Koji; Hanabayashi, Masahiro; Asai, Shuji; Ishiguro, Naoki; Kojima, Toshihisa

2014-09-01

80

Use of anti-TNF-alpha antiserum to investigate toxic alveolitis arising from cotton dust exposure.  

PubMed

Cotton dust has been associated with byssinosis and toxic alveolitis. A murine animal model has been developed with which to investigate the pathogenesis of these disorders. Studies with the model have reproduced the neutrophilic inflammation characteristic of the alveolitis, and have shown the presence of tumor necrosis factor-alpha (TNF-alpha) in the bronchoalveolar lavage (BAL) fluid. The current study investigated the role of TNF-alpha in the inflammatory response by use of a polyclonal antiserum to recombinant murine TNF-alpha. Following a 4-h exposure to cotton dust, experimental animals showed a 40-fold increase in BAL cells with 92% neutrophils. There was a 24-fold increase in TNF-alpha in the BAL fluid. Up regulation of TNF-alpha mRNA expression was detected in BAL cells. Mice pretreated with anti-TNA-alpha antiserum displayed a marked attenuation of the neutrophilic inflammation; however, the level of TNF-alpha mRNA expression was not reduced in these mice. These studies support a major role of TNF-alpha in the toxic alveolitis induced by cotton dust inhalation. PMID:7988494

Shvedova, A A; Kramarik, J A; Keohavong, P; Chumakov, K M; Karol, M H

1994-01-01

81

Ratio of neutrophil/lymphocyte and platelet/lymphocyte in patient with ankylosing spondylitis that are treating with anti-TNF  

PubMed Central

Ankylosing spondylitis (AS) is a type of chronic inflammatory arthritis resulting in ankylosis of the spine and inflammation in the tendons. After NSAIDs, the use of anti-TNF medications has provided a significant contribution to the treatment of patients with AS. The present study was a retrospective, controlled and multicenter study. A total of 105 patients followed in the outpatient clinics of the Department of Physical Therapy in Abant Izzet Baysal University and Harran University and 50 healthy controls were included in the study. The patients had been receiving anti-TNF therapy at least for 6 months. Hemogram results of the patient and control groups examined retrospectively. There was no significant difference between the groups in terms of N/L ratio; however, the P/L ratio was significantly different between the two groups. The present study found a significantly different P/L ratio in patients with AS when compared to the control group. However, the N/L ratio was not significantly different between the groups. The P/L ratio can be used as a marker to monitor disease progression and indicate subclinical inflammation in patients with AS.

Boyraz, Ismail; Koc, Bunyamin; Boyac?, Ahmet; Tutoglu, Ahmet; Sarman, Hakan; Ozkan, Hilal

2014-01-01

82

The second-generation active A? immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects.  

PubMed

Immunization against amyloid-? (A?) can reduce amyloid accumulation in vivo and is considered a potential therapeutic approach for Alzheimer's disease. However, it has been associated with meningoencephalitis thought to be mediated by inflammatory T-cells. With the aim of producing an immunogenic vaccine without this side effect, we designed CAD106 comprising A?1-6 coupled to the virus-like particle Q?. Immunization with this vaccine did not activate A?-specific T-cells. In APP transgenic mice, CAD106 induced efficacious A? antibody titers of different IgG subclasses mainly recognizing the A?3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area, followed by A?42 and A?40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular A?, which atypically was nonfibrillar. The efficacy of A? immunotherapy depended on the A? levels and thus differed between animal models, brain regions, and stage of amyloid deposition. Therefore, animal studies may not quantitatively predict the effect in human Alzheimer's disease. Our studies provided no evidence for increased microhemorrhages or inflammatory reactions in amyloid-containing brain. In rhesus monkeys, CAD106 induced a similar antibody response as in mice. The antibodies stained amyloid deposits on tissue sections of mouse and human brain but did not label cellular structures containing APP. They reacted with A? monomers and oligomers and blocked A? toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with A? aggregation and its downstream detrimental effects. PMID:21697382

Wiessner, Christoph; Wiederhold, Karl-Heinz; Tissot, Alain C; Frey, Peter; Danner, Simone; Jacobson, Laura H; Jennings, Gary T; Lüönd, Rainer; Ortmann, Rainer; Reichwald, Julia; Zurini, Mauro; Mir, Anis; Bachmann, Martin F; Staufenbiel, Matthias

2011-06-22

83

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

PubMed

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

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

2014-10-01

84

Technology comparisons for anti-therapeutic antibody and neutralizing antibody assays in the context of an anti-TNF pharmacokinetic study.  

PubMed

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

2009-06-30

85

Cancer immunotherapy products  

PubMed Central

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

2012-01-01

86

Colorectal cancer immunotherapy.  

PubMed

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

2013-05-01

87

Colorectal Cancer Immunotherapy  

PubMed Central

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.

2014-01-01

88

Safety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection  

PubMed Central

Tumour necrosis factor ? (TNF?) is a pivotal cytokine in host defences with broad ranging effects on the innate and adaptive immune systems. Clinically, TNF? inhibitors have demonstrated remarkable efficacy in a wide range of autoimmune and inflammatory disorders but clearly at the cost of heightened susceptibility to a variety of infections in those treated with these agents. Most reports to date have described increased susceptibility to intracellular pathogens in patients with underlying chronic viral infections, but little in the way of adverse event reporting in these patients has occurred. While the reported experience to date is rather limited, TNF? inhibitors have displayed a reasonable safety profile in the setting of some chronic viral infections and in certain circumstances have demonstrated adjunctive activity in the treatment of these infections. Given the high prevalence of chronic viral infections in patients who are candidates for anti-TNF therapy and the potential for these agents in the treatment of chronic viral illness, additional studies are urgently needed to assess the risks and benefits of such therapy in these populations. PMID:15479865

Calabrese, L; Zein, N; Vassilopoulos, D

2004-01-01

89

Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: data from the Spanish registry BIOBADASER 2.0.  

PubMed

Data on infections in patients exposed to biologic therapies are mainly focused on rheumatoid arthritis (RA). Little is known about the safety profile in other immune-mediated connective tissue diseases (ICTD). The purpose of this study was to describe and to compare the risk of serious infections (SI) in patients with RA and other ICTD on anti-TNF or rituximab and to identify predictors of SI. We analyzed RA or other ICTD patients on anti-TNF or rituximab included in the Spanish registry BIOBADASER 2.0 (2000-2011). For each disease group, incidence rate (IR), mortality rate (MR) and IR ratio (IRR) of SI with 95% CI were estimated. Risks were then standardized by age and sex to the general population. Risk factors for SI were assessed by Poisson regression models. A total of 3,301 patients on anti-TNF (n = 3,166) or rituximab (n = 135), of which 176 (5%) had ICTD other than RA, were analyzed. IR of SI was higher in non-RA ICTD than in RA, with an IRR of 3.15 (95% CI 1.86, 5.31) before adjustment and 1.96 (95% CI 1.06, 3.65) after adjustment for age, comorbidity and corticoid use. Mortality due to infections was higher in ICTD although it did not reach statistical significance. Age, disease duration, comorbidities, corticosteroids and ICTD different to RA were all independently associated with SI. Patients with ICTD other than RA are at a high risk of SI when prescribed anti-TNF or rituximab, partly due to the excess comorbidity and immunosuppressive co-treatment, but also to the inflammatory disease. When evaluating the risk/benefit ratio of off-label medications in ICTD patients, age, comorbidities and corticoid use should carefully be taken into account, applying adequate preventive measures. PMID:24414744

Cobo-Ibáñez, Tatiana; Descalzo, Miguel Ángel; Loza-Santamaría, Estibaliz; Carmona, Loreto; Muñoz-Fernández, Santiago

2014-07-01

90

Immunotherapy for Ovarian Cancer: What's Next?  

PubMed Central

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

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

2011-01-01

91

Immunotherapy in veterinary oncology.  

PubMed

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

Bergman, Philip J

2014-09-01

92

Advances in Cancer Immunotherapy  

PubMed Central

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 immunotherapy’s transition from experimental to established therapy. PMID:23449114

Snook, Adam E.; Waldman, Scott A.

2014-01-01

93

Cancer immunotherapy – revisited  

Microsoft Academic Search

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

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

2011-01-01

94

Epitope peptides and immunotherapy.  

PubMed

Allergic diseases affect atopic individuals, who synthesize specific Immunoglobulins E (IgE) to environmental allergens, usually proteins or glycoproteins. These allergens include grass and tree pollens, indoor allergens such as house dust mites and animal dander, and various foods. Because allergen-specific IgE antibodies are the main effector molecules in the immune response to allergens, many studies have focused on the identification of IgE-binding epitopes (called B cell epitopes), specific and minimum regions of allergen molecules that binds to IgE. Our initial studies have provided evidence that only four to five amino acid residues are enough to comprise an epitope, since pentapeptide QQQPP in wheat glutenin is minimally required for IgE binding. Afterwards, various kinds of B cell epitope structures have been clarified. Such information contributes greatly not only to the elucidation of the etiology of allergy, but also to the development of strategies for the treatment and prevention of allergy. Allergen-specific T cells also play an important role in allergy and are obvious targets for intervention in the disease. Currently, the principle approach is to modify B cell epitopes to prevent IgE binding while preserving T cell epitopes to retain the capacity for immunotherapy. There is mounting evidence that the administration of peptide(s) containing immunodominant T cell epitopes from an allergen can induce T cell nonresponsiveness (immunotherapy). There have been clinical studies of peptide immunotherapy performed, the most promising being for bee venom sensitivity. Clinical trials of immunotherapy for cat allergen peptide have also received attention. An alternative strategy for the generation of an effective but hypoallergenic preparation for immunotherapy is to modify T cell epitope peptides by, for example, single amino acid substitution. In this article, I will present an overview of epitopes related to allergic disease, particularly stress on allergen specific immunotherapy. In addition, our ongoing study of immunotherapy by 'eating' T cell epitope peptides will be described. Eating T cell epitope peptides as food provides a more practical way of inducing tolerance and a challenge to prevent allergy in daily life, as opposed to therapy by ingesting peptides as medicine. PMID:17305564

Tanabe, Soichi

2007-02-01

95

Lipid Profiles Alter from Pro-Atherogenic into Less Atherogenic and Proinflammatory in Juvenile Idiopathic Arthritis Patients Responding to Anti TNF-? Treatment  

PubMed Central

Objective Dyslipidemia with higher inflammatory states, disease activity, and longer disease duration in juvenile idiopathic arthritis (JIA) patients seemed to increase the risks of atherosclerosis. Tumor necrosis factor- ? (TNF-?) receptor blocking agent etanercept has been proven to be effective in JIA. However, data about the correlation of anti-inflammatory treatment on lipid profiles and atherogenic index in JIA patients remains limited. This study aimed to investigate the longitudinal changes on lipid profiles and atherogenic index in JIA patients after etanercept treatment. Methods Twenty-three patients diagnosed with JIA (polyarticular type n?=?7; oligoarticular type, n?=?2; systemic type, n?=?10, Enthesitis-related arthritis?=?4) received treatment with etanercept during the period 2004–012 in a medical center. We measured their serum lipid profiles at baseline and 2, 4, 6, 12 months later, and determined whether there were differences in complete blood counts, inflammatory mediators, lipid levels and atherogenic indices between patients who had inactive disease (responders) and those who were poor responders (non-responders) to etanercept treatment. Results Analysis of dynamic change in total JIA patients before and after TNF inhibitor therapy showed modest increases in hemoglobin levels (P?=?0.02) and decreases in WBC counts, Platelet and CRP levels progressively (p?=?0.002, p?=?0.006 and p?=?0.006, respectively).Twelve of the 23 patients achieved inactive disease status (responders) after 12-months of treatment. In responders, compared to non-responders, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) increased significantly (P?=?0.007,P?=?0.044,P<0.001), whereas triglyceride and atherogenic index (TC/HDL-C ratio) significantly decreased (P?=?0.04, P?=?0.01, respectively) after etanercept treatment. Conclusion Disease severity was associated with triglyceride level, atherogenic index and was inversely associated with total cholesterol, HDL-C, and LDL-C levels and can be improved substantially by using anti TNF-? treatment. Such treatment may have a beneficial effect on the cardiovascular risk in patients with JIA. PMID:24603504

Chang, Chee-Jen; Lin, Yu-Jr; Huang, Jing-Long

2014-01-01

96

Oral immunotherapy for allergic conjunctivitis.  

PubMed

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

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

2014-11-01

97

Oral immunotherapy for food allergy.  

PubMed

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

2009-01-01

98

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

PubMed Central

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

Szalay, Balazs; Cseh, Aron; Meszaros, Gergo; Kovacs, Laszlo; Balog, Attila; Vasarhelyi, Barna

2014-01-01

99

Carbohydrate modified ultrafine ceramic nanoparticles for allergen immunotherapy  

Microsoft Academic Search

The uses of drug-delivery systems in allergen specific immunotherapy appear to be a promising approach due to their ability to act as adjuvants, transport the allergens to immune-competent cells and tissues and reduce the number of administrations. The aim of this work was to evaluate the carbohydrate modified ultrafine ceramic core based nanoparticles (aquasomes) as adjuvant\\/delivery vehicle in specific immunotherapy

Ravi Shankar Pandey; Satish Sahu; M. S. Sudheesh; Jitender Madan; Manoj Kumar; Vinod Kumar Dixit

2011-01-01

100

New treatments for allergen immunotherapy  

PubMed Central

Allergen-specific immunotherapy (SIT) represents the only curative and specific way for the treatment of allergic diseases, which have reached a pandemic dimension in industrial countries affecting up to 20-30% of the population. Although applied for 100 years to cure allergy, SIT still faces several problems related to side effects and limited efficacy. Currently, allergen-SIT is performed with vaccines based on allergen extracts that can cause severe, often life threatening, anaphylactic reactions as well as new IgE sensitization to other allergens present in the extract. Low patient adherence and high costs due to long duration (3 to 5 years) of treatment have been commonly reported. Several strategies have been developed to tackle these issues and it became possible to produce recombinant allergen-SIT vaccines with reduced allergenic activity. PMID:25258656

2014-01-01

101

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

PubMed

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

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

2012-01-01

102

Regulatory T Cells as Immunotherapy  

PubMed Central

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

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

2014-01-01

103

CCL21 Cancer Immunotherapy.  

PubMed

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

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

2014-01-01

104

Immunotherapy of Genitourinary Malignancies  

PubMed Central

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. PMID:22481927

Inamoto, Teruo; Azuma, Haruhito

2012-01-01

105

Immunotherapy in human glioblastoma.  

PubMed

Glioblastoma patients spontaneously develop anti-tumour immune responses. However, the tumour itself develops several mechanisms that allow the tumor to escape the immune system. Clinical trials using infusion of activated autologous immune cells, or active immunotherapy with tumor antigens and dendritic cells have successfully induced anti-tumour immunity and some radiological responses. More recently, approaches targeting the mechanisms of tolerance have shown promising data in melanoma, and are currently under investigations in gliomas. However, large randomised trials are still needed to prove the usefulness of cancer vaccines in brain tumors. PMID:21885075

Szabo, A T; Carpentier, A F

2011-10-01

106

[Palliative immunotherapy of cancer].  

PubMed

In addition to surgery, chemotherapy and radiation, immunotherapy of cancer resembles a potential treatment strategy for patients with cancer. To strengthen the immune system might help to control or even to eradicate malignant tumors. Immunoaugmentative strategies include biological response modifiers as interferons and interleukins. Recently, monoclonal antibodies directed against tumor associated antigens and coupled with radioisotopes or cytotoxic agents have become available. Adoptive immunotherapy uses immune effector cells, i.e. T-cells or natural-killer cells that are activated in-vitro by appropriate cytokines. Dendritic cells, either unstimulated or pulsed with tumor derived molecules have shown promising anticancer activity in selected tumors. Immunonutrition, that is the manipulation of immune phenomenons through edibles is a new and interesting topic. Immunologic strategies for the treatment of malignant diseases are currently under intensive preclinical and clinical investigation. Further insights into the mechanisms of host-defense against cancer cells and the modification of immune-effector cells might pave the way to efficient treatment strategies, even in the palliative setting. PMID:11508110

Gunsilius, E; Clausen, J; Gastl, G

2001-07-01

107

Immunotherapy of hepatocellular carcinoma  

PubMed Central

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

Pardee, Angela D.; Butterfield, Lisa H.

2012-01-01

108

Ovarian cancer biology and immunotherapy.  

PubMed

Ovarian cancer is the most lethal malignancy of the female reproductive system and the fifth leading cause of cancer death in women. In the year 2012 alone, United States had 22,280 new ovarian cancer cases and 15,500 deaths were reported. About 7%-10% of ovarian cancers result from an inherited tendency to develop the disease. Ovarian cancer has the ability to escape the immune system because of its pathological interactions between cancer cells and host immune cells in the tumor microenvironment create an immunosuppressive network that promotes tumor growth, protects the tumor from immune system. The levels of immune suppressive elements like regulatory T cells, plasmacytoid dendritic cells and cytokines such as IL-10, IL-6, TNF-?, and TGF-? are elevated in the tumor microenvironment. Vascular endothelial growth factor is known to have an immune suppressing role besides its angiogenic role in the tumor microenvironment. Ovarian cancer is associated with high mortality partly due to difficulties in early diagnosis and development of metastases. These problems may overcome by developing accurate mouse models that should mimic the complexity of human ovarian cancer. Such animal models are better suited to understand pathophysiology, metastases, and also for preclinical testing of targeted molecular therapeutics. Immunotherapy is an area of active investigation and off late many clinical trials is ongoing to prevent disease progression. The main aim of dendritic cells vaccination is to stimulate tumor specific effector T cells that can reduce tumor size and induce immunological memory to prevent tumor relapse. PMID:24911597

Latha, T Sree; Panati, Kalpana; Gowd, D Sravan Kumar; Reddy, Madhava C; Lomada, Dakshayani

2014-10-01

109

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

PubMed

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

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

2014-03-01

110

Challenges in Clinical Design of Immunotherapy Trials for Malignant Glioma  

PubMed Central

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

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

2009-01-01

111

Immunotherapy for the treatment of drug abuse.  

PubMed

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 brain, the rate of clearance across the blood-brain barrier, and the volume of drug distribution. Because the antibodies remain primarily in the circulatory system, they have no apparent central nervous system side effects. Active immunization with drug-protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with 1 cocaine and 3 nicotine vaccines in Phase 2 human trials. Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine (PCP) in preclinical animal models. Antibodies have 2 immediate clinical applications in drug abuse treatment: to treat drug overdose and to reduce relapse to drug use in addicted patients. The specificity of the therapies, the lack of addiction liability, minimal side effects, and long-lasting protection against drug use offer major therapeutic benefit over conventional small molecule agonists and antagonists. Immunotherapies can also be combined with other antiaddiction medications and enhance behavioral therapies. Current immunotherapies already show efficacy, but improved antigen design and antibody engineering promise highly specific and rapidly developed treatments for both existing and future addictions. PMID:16023218

Kosten, Thomas; Owens, S Michael

2005-10-01

112

Dendritic cell immunotherapy for melanoma.  

PubMed

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

2006-05-01

113

Current status of cancer immunotherapy  

PubMed Central

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

Kono, K

2014-01-01

114

[Endocrine involvement in immunotherapy].  

PubMed

Thyroid dysfunction and abnormalities in corticosteroid regulation were observed after clinical use of cytokines (IL2, IFN alpha), molecules with immunostimulating properties. Interleukin 2 administration induces hypothyroidism often associated with anti-thyroglobulin and anti-thyroid microsomal antibody. All these features recall Hashimoto's thyroiditis. Frequency of thyroid dysfunction during immunotherapy varies according to authors between 20 and 40 percent of all patients treated. A correlation between thyroid dysfunction and response to IL2 therapy was reported. Hypothyroidism and hyperthyroidism with development of anti-TSH receptor antibody are observed after IFN alpha administration. An auto-immune aetiology of these thyroid side effects was suggested because fine needle aspirates of the thyroid of these patients, when available, revealed a mixed cellular infiltrate with lymphocytes and histiocytes and immunocytochemical staining showed strong HLA-DR expression of all thyrocytes. Involvement of lymphokine activated killer (LAK) or direct effect of cytokines on thyroid are also possible. After intravenous injection of IL2, a marked increase in ACTH levels occurred, peaking at 4 hour with a comparable peak in cortisol level at 5 hour. Expression of IL2-Receptor in pituitary cells suggests a direct action of IL2 on anterior pituitary. Nevertheless, indirect action of IL2 via induction of other cytokines or possible secretion of ACTH by activated lymphocytes, cannot be ruled out. Testosterone serum levels decreased significantly after IL2 or IFN alpha administration. It is noteworthy that these endocrine effects induced by cytokines may modulate the clinical efficacy of these substances underlying the bi-directional communication between the immune and endocrine system. PMID:7755342

Tartour, E; Schlumberger, M; Dorval, T; Baudin, E; Fridman, W H

1995-01-01

115

Amyloid-ß-directed immunotherapy for Alzheimer's disease  

PubMed Central

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

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

2014-01-01

116

Immunological mechanisms in specific immunotherapy  

Microsoft Academic Search

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

2004-01-01

117

Cancer Immunotherapy Comes of Age  

PubMed Central

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

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

2011-01-01

118

Will sublingual immunotherapy offer benefit for asthma?  

PubMed

Evidence shows that sublingual immunotherapy (SLIT) is indicated in patients with allergic rhinitis (AR). In this article we discuss whether SLIT could offer benefit for children and adults with asthma.We reviewed individual trials on SLIT in asthmatic patients, but also asthma data reported in some SLIT trials conducted in AR patients. Findings were complemented with data from systematic reviews and metaanalysis on the subject since 2000 and some guidelines that mention immunotherapy for asthma treatment. In AR patients with concomitant persistent asthma, SLIT reduces medication needs while maintaining symptom control. This holds especially true for house dust mite SLIT. Data on pollen SLIT and lung symptom improvement with SLIT, however, are less convincing. Therefore, we suggest SLIT should be added as an optional add-on therapy for patients with asthma whenever a causative allergen has been demonstrated and AR is associated with asthma. For the future, SLIT should be studied in specifically designed asthma studies in allergic asthmatics without AR. PMID:24022465

Baena-Cagnani, Carlos E; Larenas-Linnemann, Désirée; Teijeiro, Alvaro; Canonica, Giorgio Walter; Passalacqua, Giovanni

2013-12-01

119

Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury  

Microsoft Academic Search

Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury. Previous studies in this laboratory have documented tumor necrosis factor alpha (TNF) release by macrophage laden glomeruli in the accelerated autologous form of nephrotoxic serum nephritis (AA-NTSN). We now report that the administration of anti-TNF antiserum to rats with the AA-NTSN reduces albuminuria in a dose related

Zbigniew W Hruby; Kinji Shirota; Serge Jothy; Robin P Lowry

1991-01-01

120

Nanoparticulate Adjuvants and Delivery Systems for Allergen Immunotherapy  

PubMed Central

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

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

2012-01-01

121

LASSBio-1135: a dual TRPV1 antagonist and anti-TNF-alpha compound orally effective in models of inflammatory and neuropathic pain.  

PubMed

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

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

2014-01-01

122

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

PubMed Central

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

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

2014-01-01

123

Improving the safety of immunotherapy.  

PubMed

We present a 42-year-old woman who experienced a systemic reaction (SR) after a subcutaneous immunotherapy (SCIT) injection. Her physician must make a decision, along with the patient, on how to proceed. We consider the medical evidence pertinent to specific risk factors for SRs to SCIT, including asthma control, concomitant medications and new medical diagnoses, the influence of pollen season, adjustments for large local reactions, initial testing results, type of buildup protocol, and administration and dosing errors. We next discuss the potential risk-mitigating actions that the patient and provider should consider and the available evidence that supports various approaches, including cessation of SCIT, decreasing allergen dose or altering the timing of injections, initiating or changing the medical pretreatment regimen, and changing to sublingual immunotherapy, and also the role for anaphylaxis preparedness. Finally, we highlight the key knowledge gaps identified in this review and provide management recommendations for this 42-year-old woman. PMID:24607038

Rank, Matthew A; Bernstein, David I

2014-01-01

124

Utilization Trends of Anti-TNF Agents and Health Outcomes in Adults and Children with Inflammatory Bowel Diseases: A Single-center Experience  

PubMed Central

Background Utilization trends and health effects of infliximab and adalimumab in inflammatory bowel disease (IBD) are incompletely understood. We aimed to describe utilization trends of these 2 anti–tumor necrosis factor (TNF) agents, determine the correlation between utilization with rates of hospitalization and surgery and describe differences in use between adults and children. Methods Longitudinal data were analyzed for drug utilization, hospitalization, and abdominal surgery. Descriptive statistics were used to show trends, and utilization quotients were compared for standardization. Multivariate logistic regression analysis assessed the association between drug use and rates of hospitalization and surgery. Results Four hundred thirty-eight pediatric and 2514 adult patients with IBD generated a total of 51,882 inpatient and outpatient encounters, representing 1185 Crohn’s disease, 1531 ulcerative colitis, and 236 indeterminate colitis patients. From 2007 through 2012, utilization quotients declined for hospitalization but remained unchanged for surgery; adalimumab saw a 3-fold increase, despite continued dominance of infliximab. Median band and mean fitted plots showed downward hospitalization trends from 2006 to 2012. Utilization of infliximab peaked in 2008, Q4 with gradual decline to 2012, Q2; and adalimumab showed moderate increased utilization since 2007, Q1. Use of infliximab (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.70–0.83) and adalimumab (OR, 0.79; 95% CI, 0.72–0.87) was associated with decreased hospitalization risk but not associated with reduced abdominal surgery risk. Children had increased hospitalization (OR, 2.68; 95% CI, 2.49–2.88) but decreased risk for abdominal surgery (OR, 0.57; 95% CI, 0.46–0.70). Conclusions Current infliximab use remains substantially greater than adalimumab use, despite recent increased use of adalimumab. Although trends for hospitalization for IBD are decreasing, it is not reflected in abdominal surgery rates in a tertiary IBD referral center. PMID:24846718

Park, K. T.; Sin, Aaron; Wu, May; Bass, Dorsey; Bhattacharya, Jay

2014-01-01

125

DNA Vaccines for Cancer Immunotherapy  

Microsoft Academic Search

The introduction of selected genes by direct injection of DNA represents a general strategy for short-term gene expression\\u000a in vivo. DNA vaccines may be especially useful for cancer immunotherapy because DNA allows transient expression of tumor-associated\\u000a antigens and immunostimulatory proteins by a relatively nonimmunogenic vector. This chapter focuses on how DNA vaccines stimulate\\u000a immune responses and how different immunization strategies

Heesun Kwak; Howard L. Kaufman

126

Immunotherapy Targets in Pediatric Cancer  

PubMed Central

Immunotherapy for cancer has shown increasing success and there is ample evidence to expect that progress gleaned in immune targeting of adult cancers can be translated to pediatric oncology. This manuscript reviews principles that guide selection of targets for immunotherapy of cancer, emphasizing the similarities and distinctions between oncogene-inhibition targets and immune targets. It follows with a detailed review of molecules expressed by pediatric tumors that are already under study as immune targets or are good candidates for future studies of immune targeting. Distinctions are made between cell surface antigens that can be targeted in an MHC independent manner using antibodies, antibody derivatives, or chimeric antigen receptors versus intracellular antigens which must be targeted with MHC restricted T cell therapies. Among the most advanced immune targets for childhood cancer are CD19 and CD22 on hematologic malignancies, GD2 on solid tumors, and NY-ESO-1 expressed by a majority of synovial sarcomas, but several other molecules reviewed here also have properties which suggest that they too could serve as effective targets for immunotherapy of childhood cancer. PMID:22645714

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

2011-01-01

127

Radiation and immunotherapy: a synergistic combination  

PubMed Central

Immunotherapy can be an effective treatment for metastatic cancer, but a significant subpopulation will not respond, likely due to the lack of antigenic mutations or the immune-evasive properties of cancer. Likewise, radiation therapy (RT) is an established cancer treatment, but local failures still occur. Clinical observations suggest that RT may expand the therapeutic reach of immunotherapy. We examine the immunobiologic and clinical rationale for combining RT and immunotherapy, two modalities yet to be used in combination in routine practice. Preclinical data indicate that RT can potentiate the systemic efficacy of immunotherapy, while activation of the innate and adaptive immune system can enhance the local efficacy of RT. PMID:23863633

Kalbasi, Anusha; June, Carl H.; Haas, Naomi; Vapiwala, Neha

2013-01-01

128

[Anti-TNF alpha in rheumatoid arthritis].  

PubMed

Thanks to the better understanding of the physiopathological mechanisms in action in rheumatoid arthritis (RA), new therapeutic weapons have appeared, which have dramatically modified our approach of the disease. These so-called "biological" therapies antagonize the action of the cytokine at the top of the cascade which maintains the synovial inflammation, and leads to the joint destruction, i.e. the Tissue Necrosis Factor alpha (TNF alpha). Several controlled clinical studies have clearly demonstrated their short and middle term efficacy and safety profile, and they will soon become at the Belgian clinicians disposal. They have a rapid and dramatic effect on the signs and symptoms of RA and they slow down the radiologic progression. Some questions remain unresolved concerning their place in the general therapeutic strategy against RA, due to the uncertainties of their use in the long run, and to their cost. PMID:11488086

Schreiber, S; Sternon, J

2001-06-01

129

Defining the critical hurdles in cancer immunotherapy  

E-print Network

, reagents, drugs and clinical protocols with potential to significantly improve cancer outcomes. NowhereDefining the critical hurdles in cancer immunotherapy Fox et al. Fox et al. Journal;COMMENTARY Open Access Defining the critical hurdles in cancer immunotherapy Bernard A Fox1,2* , Dolores J

Paris-Sud XI, Université de

130

Immune mechanisms of sublingual immunotherapy.  

PubMed

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

Jay, David C; Nadeau, Kari C

2014-11-01

131

Topical Immunotherapy in Alopecia Areata  

PubMed Central

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

Singh, Gurcharan; Lavanya, MS

2010-01-01

132

Cell-Based Immunotherapy for Metastatic Melanoma  

Cancer.gov

In this phase II trial, researchers are investigating a cell-based form of immunotherapy for stage IV melanoma that produced tumor shrinkage or disappearance in more than 50 percent of patients enrolled in an earlier part of the study.

133

Engineering persistent interleukin-2 for cancer immunotherapy  

E-print Network

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

Gai, Shuning

2012-01-01

134

Local Nasal Specific Immunotherapy for Allergic Rhinitis  

PubMed Central

The possibility of producing local hyposensitization by administering allergens via mucosal routes was envisaged at the beginning of 1900, and local nasal immunotherapy has been extensively studied since the 1970s. Presently, there are 21 randomized controlled trials being conducted with the most common allergens, consistently showing the clinical efficacy of local nasal immunotherapy for rhinitis. Other advantages are that it has an optimal safety profile and can be self-administered at home by the patient. Moreover, there are several data from animal models and from humans that confirm the immunomodulatory effect of intranasally administered antigens. On the other hand, local nasal immunotherapy seems to be effective only on rhinitis symptoms and requires a particular technique of administration. For these reasons, its clinical use is progressively declining in favour of the sublingual route although nasal immunotherapy is validated in official documents and remains a viable alternative to injection. PMID:20525156

2006-01-01

135

Transgenic Rice for Mucosal Vaccine and Immunotherapy  

Microsoft Academic Search

The use of recombinant allergen–based immunotherapy has improved current practical approaches to allergy treatment and has\\u000a revealed potential new clinical strategies for the control of allergic diseases. Oral immunotherapy using a rice-based oral\\u000a vaccine is one attractive strategy that was shown to be effective for the control of pollen allergies. When the peptides for\\u000a a T cell specific to Japanese

Yoshikazu Yuki; Fumio Takaiwa; Hiroshi Kiyono

136

Addition of immunotherapy boosts pediatric cancer survival:  

Cancer.gov

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

137

Cancer Immunotherapy: A Treatment for the Masses  

NASA Astrophysics Data System (ADS)

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.

2004-07-01

138

Immunotherapy for acute myeloid leukemia.  

PubMed

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

2005-09-01

139

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

PubMed Central

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

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

2014-01-01

140

IgE-based Immunotherapy of Cancer -A Comparative Oncology Approach  

PubMed Central

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

Singer, Josef; Jensen-Jarolim, Erika

2014-01-01

141

Immunotherapy in food allergy: towards new strategies.  

PubMed

Allergen avoidance is the standard treatment for managing food allergies. Complete avoidance is difficult, and accidental exposure often occurs. Immunotherapy is a significant focus for treating food allergies, and oral immunotherapy (OIT) appears to be particularly effective in inducing desensitization. The majority of patients who receive OIT show increased threshold doses of their food allergen. The efficacy of OIT is different among food antigen, and milk OIT is relatively difficult to achieve tolerance. OIT may induce mild to moderate symptoms during the therapy, widespread acceptance of OIT for long-term therapy is unclear. Recently, novel immunotherapies for food allergies, such as sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) and using an anti-IgE monoclonal antibody (omalizumab), have been assessed. In addition, a combination of OIT with omalizumab, which was found to increase the threshold doses of the offending foods without producing adverse reactions, may be effective and useful in the treatment of food allergies. These treatments have been used only in research settings; further studies in large numbers of patients are needed to demonstrate their long-term safety and benefits in clinical practice. PMID:25268336

Sato, Sakura; Yanagida, Noriyuki; Ogura, Kiyotake; Asaumi, Tomoyuki; Okada, Yu; Koike, Yumi; Iikura, Katsuhito; Syukuya, Akinori; Ebisawa, Motohiro

2014-09-01

142

Current Studies of Immunotherapy on Glioblastoma  

PubMed Central

Glioblastoma is a form of brain tumor with a very high morbidity and mortality. Despite decades of research, the best treatments currently in clinical practice only extend survival by a number of months. A promising alternative to conventional treatment for glioblastomas is immunotherapy. Although proposed over a century ago, the field of cancer immunotherapy has historically struggled to translate it into effective clinical treatments. Better understanding is needed of the various regulatory and co-stimulatory factors in the glioblastoma patient for more efficient immunotherapy treatments. The tumor microenvironment is anatomically shielded from normal immune-surveillance by the blood-brain barrier, irregular lymphatic drainage system, and it’s in a potently immunosuppressive environment. Immunotherapy can potentially manipulate these forces effectively to enhance anti-tumor immune response and clinical benefit. New treatments utilizing the immune system show promise in terms of targeting and efficacy. This review article attempts to discuss current practices in glioblastoma treatment, the theory behind immunotherapy, and current research into various clinical trials.

Agrawal, Neena Stephanie; Miller, Rickey; Lal, Richa; Mahanti, Harshini; Dixon-Mah, Yaenette N.; DeCandio, Michele L.; Vandergrift, W Alex; Varma, Abhay K.; Patel, Sunil J.; Banik, Naren L.; Lindhorst, Scott M.; Giglio, Pierre; Das, Arabinda

2014-01-01

143

[Specific immunotherapy and relocation in occupational allergic bakers].  

PubMed

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

2007-01-01

144

Exhaled breath condensate, nasal eosinophil cationic protein level and nasal cytology during immunotherapy for cypress allergy.  

PubMed

Interest in cypress allergy is widely rising: an increasing number of studies have pointed out the efficacy of immunotherapy to reduce cypress-related symptoms and drug use. Cypress immunotherapy is well tolerated, but there are few studies dealing with its sub-clinical effects on the airways. The aim of this investigation is to assess the effects of immunotherapy on airways by the analysis of exhaled breath condensate (EBC), nasal lavage fluid (NAL) and nasal cytology. Fifteen mono-sensitized to cypress pollen patients have been observed, among them 9 have been treated with sub-cutaneous immunotherapy (SCIT), 3 with sub-lingual immunotherapy (SLIT) and 3 which were not treated underwent EBC, NAL and nasal cytology out of the pollen season. 8-isoprostane in EBC, Eosinophil cationic protein (ECP) and inflammatory cells in nasal cytology were also evaluated. The median value of 8-isoprostane in EBC was 18.58 pg/ml in patients who did not undergo immunotherapy, 49.38 pg/ml in SCIT patients and 13.41 pg/ml in SLIT subjects. The median value of ECP in nasal lavage was higher in non- treated subjects (27.3 mg/l) than in those treated with SCIT (1 mg/l)(p less than 0,05) or SLIT (2.6 mg/l). All nasal cytology specimens did not show any sign of inflammation. In conclusion SLIT seems to be well tolerated and to reduce significantly the levels of ECP in nasal lavage. In addition the levels of 8-isoprostane in EBC among SCIT patients were unexpectedly high and need to be further evaluated. PMID:24382191

Ventura, M T; Murgia, N; Montuschi, P; Gelardi, M; Ciabattoni, G; Buquicchio, R; Resta, O; Passalacqua, G

2013-01-01

145

Optimization of Immunotherapy in Elderly Cancer Patients  

PubMed Central

Increasing evidence has revealed the incidence of cancer augments with aging, which could be attributed to a multitude of age-associated changes including the dysregulation of the immune system. Although many reports demonstrate the efficacy of cancer immunotherapies in numerous preclinical studies, most experiments have been performed in young animals. Studies from our group and others show that cancer immunotherapy could be ineffective in old mice, even though the same therapeutic treatment works efficiently in young mice. Given that cancer occurs mostly in the elderly, we should take age-associated immune dysregulation into consideration to achieve the effectiveness of immunotherapeutic interventions in the old. Understanding both age-related and tumor-related immune alterations might be equally important in improving the effectiveness of immunotherapy. This article reviews a number of age-associated immune alterations with specific attention given to the impact on antitumor responses, and also discusses possible strategies for optimization of immunotherapeutic interventions in the elderly. PMID:24579736

Tomihara, Kei; Curiel, Tyler J.; Zhang, Bin

2014-01-01

146

Immunotherapy for malignant gliomas: emphasis on strategies of active specific immunotherapy using autologous dendritic cells  

Microsoft Academic Search

ReviewIn this review, we discuss immunotherapy for malignant gliomas.EmphasisThe emphasis is on the novel strategy of active specific immunotherapy using dendritic cells as antigen-presenting cells, especially its theoretical concepts and advantages, specific requirements, critical issues, pre-clinical and early clinical experience. Dendritic cell vaccination is situated in the diversity of other immunotherapeutical approaches.Further discussionFuture directions, challenges, and drawbacks will be discussed.

Steven De Vleeschouwer; Stefaan W. Van Gool; Frank Van Calenbergh

2005-01-01

147

Immunotherapy: a new horizon for egg allergy?  

PubMed

Egg allergy is the second most frequent food allergy in children of the Western Countries, with an overall prevalence of 1-3%. Today strict avoidance diet is the only treatment, but its feasibility is difficult to obtain in childhood because of the large amount of egg proteins present in different foods. From 1998, a growing number of protocols on immunotherapy for egg allergy have been published, but all of them differ for patients' age, inclusion of high-risk patients, amount of allergen administered, duration of the protocols and presence of a control group. We reviewed the protocols performed in the last 15 years, to underline the most important issues in this kind of food immunotherapy, and the rates of tolerance or desensitization induction. PMID:24707950

Praticò, Andrea D; Mistrello, Gianni; La Rosa, Mario; Del Giudice, Michele Miraglia; Marseglia, Gianluigi; Salpietro, Carmelo; Leonardi, Salvatore

2014-05-01

148

[Transcutaneous applications for vaccination and immunotherapy].  

PubMed

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

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

2014-10-15

149

Should we encourage allergen immunotherapy during pregnancy?  

PubMed

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

Lieberman, Jay

2014-03-01

150

Assessing Immunotherapy Through Cellular and Molecular Imaging  

Microsoft Academic Search

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

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

151

Heat Shock Protein (HSP)Based Immunotherapies  

Microsoft Academic Search

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

Hongying Zheng; Alexzander Asea

152

Combining targeted therapy with immunotherapy (interferon-?)  

PubMed Central

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. PMID:22934279

Chen, Lei L.; Gouw, Launce; Sabripour, Mahyar; Hwu, Wen-Jen; Benjamin, Robert S.

2012-01-01

153

Yeast-based vaccine approaches to cancer immunotherapy  

E-print Network

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

Howland, Shanshan W

2008-01-01

154

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

PubMed

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

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

2014-12-01

155

Cancer immunotherapy: sipuleucel-T and beyond.  

PubMed

In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4(+) and CD8(+) T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor-associated antigens aimed at stimulating effector T-cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer. PMID:21923608

Hammerstrom, Aimee E; Cauley, Diana H; Atkinson, Bradley J; Sharma, Padmanee

2011-08-01

156

Cancer Immunotherapy: Sipuleucel-T and Beyond  

PubMed Central

In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4+ and CD8+ T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor-associated antigens aimed at stimulating effector T-cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer. PMID:21923608

Hammerstrom, Aimee E.; Cauley, Diana H.; Atkinson, Bradley J.; Sharma, Padmanee

2014-01-01

157

Adoptive Immunotherapy for Hodgkin’s Lymphoma  

Microsoft Academic Search

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

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

2006-01-01

158

Sublingual immunotherapy: World Allergy Organization position paper 2013 update.  

PubMed

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

Canonica, Giorgio Walter; Cox, Linda; Pawankar, Ruby; Baena-Cagnani, Carlos E; Blaiss, Michael; Bonini, Sergio; Bousquet, Jean; Calderón, Moises; Compalati, Enrico; Durham, Stephen R; van Wijk, Roy Gerth; Larenas-Linnemann, Désirée; Nelson, Harold; Passalacqua, Giovanni; Pfaar, Oliver; Rosário, Nelson; Ryan, Dermot; Rosenwasser, Lanny; Schmid-Grendelmeier, Peter; Senna, Gianenrico; Valovirta, Erkka; Van Bever, Hugo; Vichyanond, Pakit; Wahn, Ulrich; Yusuf, Osman

2014-01-01

159

Immunotherapy for prion diseases: opportunities and obstacles.  

PubMed

Transmissible spongiform encephalopathies (TSEs) represent a unique form of infectious disease based on the misfolding of a self-protein into a pathological conformation. While other human diseases are also attributed to protein misfolding, the TSEs are unique in their zoonotic potential and iatrogenic infectivity. These characteristics are of particular importance in the aftermath of the UK bovine spongiform encephalopathy (BSE) outbreak due to the dual concerns that a subpopulation of individuals exposed to the infectious agent may be serving as asymptomatic carriers, and that TSEs of other food animals may also threaten human health. These potentials, in addition to the ongoing baseline of familial and sporadic human prion diseases, necessitate development of effective treatment options. While TSEs represent a novel paradigm of infection, there is nevertheless the opportunity to apply traditional approaches of medicine for disease treatment and prevention, including vaccines for immunotherapy and immunoprophylaxis. However, vaccine development for TSEs is complicated by the challenges and potential dangers associated with induction of immune responses to a self-epitope, as well as the obstacles to treatment of a chronic infection through immunotherapy. The ongoing threat of TSEs to human health, together with the opportunity to apply information emerging from these investigations to other protein misfolding disorders, justifies the efforts required to overcome these obstacles. PMID:20635933

Li, Li; Napper, Scott; Cashman, Neil R

2010-03-01

160

?? T Cells and Their Potential for Immunotherapy  

PubMed Central

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

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

2014-01-01

161

Immunotherapy for neurodegenerative diseases: focus on ?-synucleinopathies  

PubMed Central

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

Valera, Elvira; Masliah, Eliezer

2013-01-01

162

Immunotherapy and immunoescape in colorectal cancer  

PubMed Central

Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFN? in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma. PMID:17990348

Mazzolini, Guillermo; Murillo, Oihana; Atorrasagasti, Catalina; Dubrot, Juan; Tirapu, Inigo; Rizzo, Miguel; Arina, Ainhoa; Alfaro, Carlos; Azpilicueta, Arantza; Berasain, Carmen; Perez-Gracia, Jose L; Gonzalez, Alvaro; Melero, Ignacio

2007-01-01

163

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

PubMed Central

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

Heimberger, Amy B.; Sampson, John H.

2011-01-01

164

Advances in dendritic cell immunotherapies for HIV-1 infection.  

PubMed

Augmentation of adaptive immunity via HIV therapeutic vaccination may be a key component of curative strategies. Adoptive dendritic cell (DC) immunotherapies may prove useful in enhancing the success of these approaches by circumventing certain defects in DC function during HIV infection. Thus far, DC immunotherapies that utilize autologous, inactivated virus as an immunogen have provided the most promising results however, are beset with practical constraints. Consequently, alternative forms of immunogens are under investigation, with an emphasis on RNA-based approaches. Here we review the data from DC immunotherapy trials for HIV infection and discuss challenges and future directions in the field. PMID:25143151

Miller, Elizabeth; Bhardwaj, Nina

2014-11-01

165

Sublingual (SLIT) Versus Oral Immunotherapy (OIT) for Food Allergy.  

PubMed

Food allergy is a common condition for which the only currently approved treatments are avoidance of the allergenic food and the administration of emergency medications upon accidental exposure. Over the past 10 years, significant advances have been made in the field of food immunotherapy, with efforts focusing on allergen exposure via the oral mucosa. Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are the two modalities that have been most extensively studied, and this article will review recent advances in our knowledge of the efficacy and safety of these treatments. PMID:25297805

McGowan, Emily C; Wood, Robert A

2014-12-01

166

The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) survey: patients' experience with allergen immunotherapy.  

PubMed

Allergen immunotherapy (AIT) is used for the treatment of allergic rhinoconjunctivitis as a subcutaneous injection (subcutaneous immunotherapy [SCIT]). Extracts used for SCIT are also used off-label to formulate a liquid delivered as sublingual drops (sublingual immunotherapy [SLIT]). This study was designed to survey patients' experiences and beliefs regarding SCIT and SLIT. People who had ever been diagnosed with nasal and/or ocular allergies were identified in a 2012 telephone survey of U.S. households. Respondents were asked questions about their or their child's use of SCIT and SLIT and their beliefs about AIT. Of 2765 respondents, 46.5% had ever heard of AIT and 22.7% had ever initiated it: 20.9% with SCIT and 1.8% with SLIT (p < 0.0001). The most frequently cited reason for beginning AIT was that symptoms were unresolved with other medications (SCIT, 32.1%; SLIT, 14.0%). Some or full symptom relief was reported by 74.9% of respondents treated with SCIT and 66.0% of those treated with SLIT (p = 0.17 for SCIT versus SLIT). Approximately one-third of respondents who had ever heard of or had been treated with AIT said "don't know" when asked if immunotherapy controls allergy symptoms for years (33.6%), is a very safe treatment (29.3%), or can cure allergy symptoms (27.5%). Effective relief of allergy symptoms was cited most often as the primary benefit of SCIT (37.8%) and convenience was the primary benefit of SLIT (14%). Only one-fifth of respondents had ever been treated with AIT, largely with SCIT. More than one-half of respondents had never heard of AIT and respondents' beliefs indicated a need for educational efforts. PMID:24801464

Skoner, David P; Blaiss, Michael S; Dykewicz, Mark S; Smith, Nancy; Leatherman, Bryan; Bielory, Leonard; Walstein, Nicole; Craig, Timothy J; Allen-Ramey, Felicia

2014-01-01

167

25-hydroxvitamin D3 promotes the long-term effect of specific immunotherapy in a murine allergy model.  

PubMed

Calcitriol (1?,25-dihydroxyvitamin D3) is the active vitamin D metabolite and mediates immunological functions, which are relevant in allergy. Its therapeutic use is limited by hypercalcaemic toxicity. We have previously shown that the activation of the vitamin D receptor inhibits IgE production and that B cells can synthesize calcitriol from its precursor 25-hydroxyvitamin D3 (inactive precursor) [25(OH)D] upon antigenic stimulation. In this study, we address the impact of 25(OH)D on the development of type I sensitization and determine its role in allergen-specific immunotherapy. BALB/c mice were sensitized to OVA, under 25(OH)D-deficient or sufficient conditions. The humoral immune response over time was measured by ELISA. OVA-specific immunotherapy was established and studied in a murine model of allergic airway inflammation using lung histology, pulmonary cytokine expression analysis, and functional parameters in isolated and perfused mouse lungs. In 25(OH)D-deficient mice, OVA-specific IgE and IgG1 serum concentrations were increased compared with control mice. OVA-specific immunotherapy reduced the humoral immune reaction after OVA recall dose-dependently. Coadministration of 25(OH)D in the context of OVA-specific immunotherapy reduced the allergic airway inflammation and responsiveness upon OVA challenge. These findings were paralleled by reduced Th2 cytokine expression in the lungs. In conclusion, 25(OH)D deficiency promotes the development of type I sensitization and correction of its serum concentrations enhances the benefit of specific immunotherapy. PMID:24951815

Heine, Guido; Tabeling, Christoph; Hartmann, Bjoern; González Calera, Carla R; Kühl, Anja A; Lindner, Juliane; Radbruch, Andreas; Witzenrath, Martin; Worm, Margitta

2014-08-01

168

Targeting nanoparticles to dendritic cells for immunotherapy.  

PubMed

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

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

2012-01-01

169

Sublingual immunotherapy for allergic rhinitis and conjunctivitis.  

PubMed

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

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

2013-03-01

170

Immunotherapy preparation guidelines, rules, and regulation.  

PubMed

Allergen immunotherapy has been used to treat allergic diseases for more than 100 years. In the U.S., the preparation of diagnostic and therapeutic extracts requires the cooperation of the extract manufacturer, who provides the individual allergen concentrates, and the practicing physician who formulates, dilutes, and administers the final patient-specific treatment extract. The guidelines, rules, and regulations for these activities have been established and continue to be developed as progress is made. The molecular characterization and standardization of allergenic extracts has allowed for improvements in defining the potency of these products. In turn, these advances have led to improved dosing regimens and formulation practices. This review will describe in detail some of these interactions and will identify issues that require more attention. PMID:23722699

Esch, Robert E; Plunkett, Greg A

2013-08-01

171

Bacteria and their toxins tamed for immunotherapy.  

PubMed

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

2012-06-01

172

Cancer immunotherapy: potential involvement of mediators  

PubMed Central

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

Ben-Efraim, S.

1997-01-01

173

Rapid Isolation of Central Memory T Cells for Adoptive Immunotherapy  

Cancer.gov

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

174

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

PubMed

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

Lewis, Felisa S; Smith, Laurie J

2007-07-01

175

Combined modality immunotherapy and chemotherapy: a new perspective  

Microsoft Academic Search

The results of recent clinical trials have demonstrated that cancer vaccines continue to struggle to achieve tangible clinical\\u000a benefits as monotherapy. Tumor-induced abnormalities in the immune system hamper anti-tumor T cell responses limiting the\\u000a effectiveness of cancer immunotherapy. Recently, evidence has been mounting to suggest that immunotherapy has the possibility\\u000a of achieving better success when used in combination with conventional

Rupal Ramakrishnan; Scott Antonia; Dmitry I. Gabrilovich

2008-01-01

176

Autoimmune Dementia: Clinical Course and Predictors of Immunotherapy Response  

PubMed Central

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. PMID:20884824

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.

2010-01-01

177

Wilms' tumor gene 1 immunotherapy in pelvic gynecological malignancies.  

PubMed

Pelvic gynecological malignancies account for 6% of all cancers. In the relapsed state, classical treatments are limited. There is an urgent need for new and personalized treatment. Wilms' tumor gene 1 (WT1) is the most important tumor-associated antigen. Although highly present in gynecological tumors, active immunotherapy against it is still underexplored. This review gives an insight into the importance of WT1 in pelvic gynecological malignancies and the first taken steps into the world of WT1 immunotherapy. PMID:24784346

Coosemans, A; Vergote, I; Van Gool, S W

2014-06-01

178

Allergen hybrids - next generation vaccines for Fagales pollen immunotherapy  

PubMed Central

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

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

2014-01-01

179

Anti-TNF therapy for other inflammatory conditions.  

PubMed

The use of biological agents in inflammatory conditions is rapidly increasing. TNFalpha blocking treatments have changed the course of rheumatoid arthritis, Crohn's disease, juvenile rheumatoid arthritis and psoriatic arthritis. Open label studies with TNFalpha inhibitors in other inflammatory conditions such as adult Still's disease, uveitis, Wegener's granulomatosis, Behçet's disease, scleroderma, Sjögren's syndrome, sarcoidosis, pyoderma gangrenosum, polymyositis/dermatomyositis have shown promising results. However, whether anti-TNFalpha therapy can be safely and efficaciously applied to these other inflammatory disorders requires further controlled studies. PMID:12463467

Tutuncu, Z; Morgan, G J; Kavanaugh, A

2002-01-01

180

PLGA microspheres containing bee venom proteins for preventive immunotherapy.  

PubMed

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

2012-02-14

181

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

PubMed

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

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

2014-10-01

182

Effects of laser immunotherapy on tumor microenvironment  

NASA Astrophysics Data System (ADS)

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

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

2014-02-01

183

Immunotherapy for Alzheimer's disease: hoops and hurdles  

PubMed Central

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

2013-01-01

184

Recommendations for appropriate sublingual immunotherapy clinical trials.  

PubMed

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

Passalacqua, Giovanni

2014-01-01

185

Mucosal immunotherapy in an Alzheimer mouse model by recombinant Sendai virus vector carrying A?1-43/IL-10 cDNA.  

PubMed

Based on the amyloid cascade hypothesis, many reports have indicated that immunotherapy is beneficial for Alzheimer's disease (AD). We developed a mucosal immunotherapy for AD by nasal administration of recombinant Sendai virus vector carrying A?1-43 and mouse IL-10 cDNA. Nasal but not intramuscular administration of the vaccine induced good antibody responses to A?. When APP transgenic mice (Tg2576) received this vaccine once nasally, the A? plaque burden was significantly decreased 8 weeks after without inducing inflammation in the brain. The amount of A? measured by ELISA was also reduced in both soluble and insoluble fractions of the brain homogenates, and notably the A? oligomer (12-mer) was also apparently decreased. Tg2576 mice showed significant improvement in cognitive functions examined at 3 months after vaccination. Thus, this is an alternative immunotherapy for AD, which has an advantage in non-invasive, safe and relatively long lasting features. PMID:21803105

Hara, Hideo; Mouri, Akihiro; Yonemitsu, Yoshikazu; Nabeshima, Toshitaka; Tabira, Takeshi

2011-10-01

186

The combined influence of immunotherapy and mite allergen reduction on bronchial hyperresponsiveness in mite-sensitive asthmatic children  

Microsoft Academic Search

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

1998-01-01

187

Radiation as Immunomodulator: Implications for Dendritic Cell-Based Immunotherapy  

PubMed Central

The last decade has witnessed significant progress in the field of cancer immunotherapy. This has, in part, been driven by a growing recognition that elements of the innate immune response can be harnessed to induce robust immunity against tumor-associated targets. Nonetheless, as clinically effective immunotherapy for the majority of cancers remains a distant goal, attention has shifted toward multimodality approaches to cancer therapy, sometimes combining novel immunotherapeutics and conventional therapeutics. The traditional view of radiation therapy as immunosuppressive has been challenged, prompting a re-evaluation of its potential as an adjunct to, or even a component of immunotherapy. Radiation therapy may enhance expression of tumor-associated antigens, induce targeting of tumor stroma, diminish regulatory T-cell activity and activate effectors of innate immunity such as dendritic cells through Toll-like receptor (TLR)-dependent mechanisms. Here, we review recent progress in the field of dendritic cell-based immunotherapy, evidence for radiation-induced antitumor immunity and TLR signaling and the results of efforts to rationally integrate radiation into dendritic cell-based immunotherapy strate gies. PMID:24992163

Roses, Robert E.; Datta, Jashodeep; Czerniecki, Brian J.

2014-01-01

188

The local and systemic side-effects of venom and inhaled-allergen subcutaneous immunotherapy  

Microsoft Academic Search

Summary  BACKGROUND: Although immunotherapy is effective in allergic rhinitis, conjunctivitis, asthma and stinging insect hypersensitivity,\\u000a it carries a risk of anaphylactic reactions. METHODS: In a 4-year retrospective survey, we investigated 1257 adult patients\\u000a who had received venom or inhaled-allergen subcutaneous immunotherapy. The dose-increase phase was performed as the 2-day\\u000a rush protocol for venom immunotherapy and the 6-week protocol for inhaled-allergen immunotherapy.

Katja Adamic; Mihaela Zidarn; Nissera Bajrovic; Renato Erzen; Peter Kopac

2009-01-01

189

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

PubMed Central

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

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

2013-01-01

190

Immunotherapy Approaches for Malignant Glioma From 2007 to 2009  

PubMed Central

Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous treatments were largely unsuccessful, glioma may be an ideal target for immune-based therapy. Recently, translational research led to several clinical trials based on tumor immunotherapy to treat patients with malignant glioma. Here we review 17 recent glioma immunotherapy clinical trials, published over the past 3 years. Various approaches were used, including passive transfer of naked and radiolabeled antibodies, tumor antigen-specific peptide immunization, and the use of patient tumor cells with or without dendritic cells as vaccines. We compare and discuss the current state of the art of clinical immunotherapy treatment, as well as its limited successes, pitfalls, and future potential. PMID:20424975

Sampson, John H.

2012-01-01

191

Interleukin-13 Receptor Alpha 2-Targeted Glioblastoma Immunotherapy  

PubMed Central

Glioblastoma (GBM) is the most lethal primary brain tumor, and despite several refinements in its multimodal management, generally has very poor prognosis. Targeted immunotherapy is an emerging field of research that shows great promise in the treatment of GBM. One of the most extensively studied targets is the interleukin-13 receptor alpha chain variant 2 (IL13R?2). Its selective expression on GBM, discovered almost two decades ago, has been a target for therapy ever since. Immunotherapeutic strategies have been developed targeting IL13R?2, including monoclonal antibodies as well as cell-based strategies such as IL13R?2-pulsed dendritic cells and IL13R?2-targeted chimeric antigen receptor-expressing T cells. Advanced therapeutic development has led to the completion of several clinical trials with promising outcomes. In this review, we will discuss the recent advances in the IL13R?2-targeted immunotherapy and evaluate the most promising strategy for targeted GBM immunotherapy.

Crawford, Andrew C.

2014-01-01

192

Immunotherapy following hematopoietic stem cell transplantation: potential for synergistic effects  

PubMed Central

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. PMID:20635904

Bouchlaka, Myriam N; Redelman, Doug; Murphy, William J

2011-01-01

193

Targeted immunotherapy for non-small cell lung cancer.  

PubMed

Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer (NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities. PMID:24829850

Vasekar, Monali; Liu, Xin; Zheng, Hong; Belani, Chandra P

2014-05-10

194

Novel anti-melanoma treatment: focus on immunotherapy  

PubMed Central

Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma. PMID:25189718

Hao, Meng-Ze; Zhou, Wen-Ya; Du, Xiao-Ling; Chen, Ke-Xin; Wang, Guo-Wen; Yang, Yun; Yang, Ji-Long

2014-01-01

195

Porous silicon advances in drug delivery and immunotherapy  

PubMed Central

Biomedical applications of porous silicon include drug delivery, imaging, diagnostics and immunotherapy. This review summarizes new silicon particle fabrication techniques, dynamics of cellular transport, advances in the multistage vector approach to drug delivery, and the use of porous silicon as immune adjuvants. Recent findings support superior therapeutic efficacy of the multistage vector approach over single particle drug delivery systems in mouse models of ovarian and breast cancer. With respect to vaccine development, multivalent presentation of pathogen-associated molecular patterns on the particle surface creates powerful platforms for immunotherapy, with the porous matrix able to carry both antigens and immune modulators. PMID:23845260

Savage, D; Liu, X; Curley, S; Ferrari, M; Serda, RE

2013-01-01

196

Cancer immunotherapy: are we there yet?  

PubMed

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

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

2013-01-01

197

Early gene expression changes with rush immunotherapy  

PubMed Central

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

2011-01-01

198

Cancer immunotherapy: are we there yet?  

PubMed Central

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

2013-01-01

199

Tumor stroma-associated antigens for anti-cancer immunotherapy  

Microsoft Academic Search

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

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

2006-01-01

200

Productively combining proteasome inhibition with the immunotherapy of cancer  

Microsoft Academic Search

For a number of years, there has been much enthusiasm for harnessing the immune system in order to improve cancer therapy. Immunotherapy of cancer patients has demonstrated that T cells (particularly CD8 + T cells) play a critical role in mediating antitumor responses. However, to date, these immunotherapeutic strategies have only had a modest level of success in cancer patients

Thomas Sayers

2008-01-01

201

Immunotherapy: Using the Immune System to Treat Cancer  

Cancer.gov

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

202

Cancer Immunotherapy Highlights from the 2014 ASCO Meeting.  

PubMed

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

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

2014-08-01

203

On immunotherapies and cancer vaccination protocols: A mathematical modelling approach  

E-print Network

.e. removal of the tumour), chemotherapy (administration of anti-cancer drugs) and radiotherapy (treatment advances in patient care and treatment over the past few decades with refinement of anti-cancer drugsOn immunotherapies and cancer vaccination protocols: A mathematical modelling approach Badal Joshi

Weinberger, Hans

204

From bench to bedside: immunotherapy for prostate cancer.  

PubMed

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

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

2014-01-01

205

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics  

Microsoft Academic Search

Lentiviral vectors have emerged as promising tools for both gene therapy and immunotherapy purposes. They exhibit several advantages over other viral systems in that they are less immunogenic and are capable of transducing a wide range of different cell types, including dendritic cells (DC). DC transduced ex vivo with a whole range of different (tumor) antigens were capable of inducing

K Breckpot; J L Aerts; K Thielemans

2007-01-01

206

Adherence to pharmacological treatment and specific immunotherapy in allergic rhinitis.  

PubMed

The term compliance simply indicates how much doses of the prescribed medication are taken, whereas the term adherence implies also an agreement between patient and physician about the therapeutic plan, and it is therefore preferred. Adherence is a main problem in all long-term treatments. Thus, it represents a problem also in the case of rhinitis, expecially concerning specific immunotherapy that must be assumed continuously for several years. Many factors can affect the adherence, depending on patient, on treatment itself and on the healthcare context, and all those factors usually interact. The adherence measured in controlled trials is usually good, but this does not reflect what happens in real life, where adherence should be preferably measured. There are few data on the adherence in real life for pharmacological treatments of allergic rhinitis (e.g. nasal steroids or antihistamines), whereas more data are available for specific immunotherapy. In this latter case, in real life, adherence seems to be far from optimal, for both sublingual and subcutaneous immunotherapy, although the recent studies agree on the fact that some interventions (i.e. patients' education, strict follow-up, regular contacts) could effectively improve the adherence. In this article, the literature concerning the adherence to pharmacological treatments and immunotherapy in allergic rhinitis was searched and reviewed. PMID:23278877

Passalacqua, G; Baiardini, I; Senna, G; Canonica, G W

2013-01-01

207

Adoptive immunotherapy for cancer: harnessing the T cell response  

Microsoft Academic Search

Immunotherapy based on the adoptive transfer of naturally occurring or gene-engineered T cells can mediate tumour regression in patients with metastatic cancer. Here, we discuss progress in the use of adoptively transferred T cells, focusing on how they can mediate tumour cell eradication. Recent advances include more accurate targeting of antigens expressed by tumours and the associated vasculature, and the

Mark E. Dudley; Nicholas P. Restifo; Steven A. Rosenberg

2012-01-01

208

From Bench to Bedside: Immunotherapy for Prostate Cancer  

PubMed Central

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

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

2014-01-01

209

Toward effective immunotherapy for the treatment of malignant brain tumors  

PubMed Central

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

Mitchell, Duane A.; Sampson, John H.

2009-01-01

210

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

PubMed Central

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

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

2012-01-01

211

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

PubMed

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

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

1996-05-01

212

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

PubMed Central

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

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

2013-01-01

213

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

E-print Network

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

Milchberg, Howard

214

[Hymenoptera venom allergy. Analysis of double sensitization to wasp and bee venom in own material--diagnosis and classification for immunotherapy].  

PubMed

According to scientific societies guidelines the indication for venom immunotherapy is based on the clinical history of the patient. Diagnostic tests, like skin prick test or specific IgE serum estimation are conduct to prove IgE dependent mechanism of allergy and insect identification. Recent guidelines indicates for group of patients with severe systemic reactions as a candidates for diagnostic testing and in consequence for immunotherapy. In some countries diagnostic tests are also performed in patient who have a history of large local reactions, if they are considered as a candidates for immunotherapy. Double sensitization in cases of patients unable to identify the culprit insect is a diagnostic and therapeutic problem. In our group of patients (n = 113) we confirmed the double sensitization in 30% cases. The addition of a major allergen labeling reduced the number of people actually double-sensitized to 8.84%. It was observed that in patients who are not able to identify insect double sensitization phenomenon is particularly frequent as much as 45.5% and in the determination of the major allergens in 18.2%. Such patients needed detailed diagnosis and in many cases the use of two vaccines to conduct immunotherapy. PMID:24720122

Stobiecki, Marcin; Dyga, Wojciech; Czarnobilska, Ewa

2013-01-01

215

Job Description: Research Associate I for Cancer Immunotherapy Lab The Tumor Immunology Laboratory in the Animal Cancer Center (ACC) is seeking a Research  

E-print Network

Job Description: Research Associate I for Cancer Immunotherapy Lab The Tumor Immunology Laboratory in tumor immunology and immunotherapy. The studies will involve investigations of tumor immunotherapy training and expertise in immunological assays and methodologies. Particular preference will be given

Birner, Thomas

216

Macrophage-dependent nitric oxide expression regulates tumor cell detachment and metastasis after IL-2/anti-CD40 immunotherapy  

PubMed Central

Using an orthotopic model of renal cell carcinoma, we showed previously that IL-2/anti-CD40 immunotherapy resulted in synergistic anti-tumor responses, whereas IL-2 or ?-CD40 alone mediated partial transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/?-CD40, but not IL-2 or ?-CD40, induced significant nitric oxide synthase (NOS) 2 expression in tumor-associated macrophages. In control-treated mice (low NO), NOS2 inhibition reduced tumor burden. However, during immunotherapy (high NO), NOS2 inhibition or macrophage depletion reversed the ability of IL-2/?-CD40 treatment to reduce lung metastases but had no effect on primary tumor burden. Furthermore, IL-2/?-CD40 induced the IFN-?– and NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with increases in tissue inhibitor of metalloproteinase (TIMP) 1 and E-cadherin expression within tumors. Finally, treatment of tumor-bearing mice with the NO donor JS-K significantly reduced metastases. These data differentiate the mechanism for primary anti-tumor effects of IL-2/?-CD40 immunotherapy, which are independent of NO, from the NO-dependent inhibition of metastases. Furthermore, reduced MMP9 activity implicates M1-polarized macrophages within the tumor microenvironment as critical components of therapeutic response. Our data demonstrate the mechanistic basis for IL-2/?-CD40–mediated control of metastases and suggest that the context-dependent application of NO donors may hold promise for prevention of metastatic disease. PMID:20921282

Weiss, Jonathan M.; Ridnour, Lisa A.; Back, Tim; Hussain, S. Perwez; He, Peijun; Maciag, Anna E.; Keefer, Larry K.; Murphy, William J.; Harris, Curtis C.; Wink, David A.

2010-01-01

217

Is Sublingual Immunotherapy the Final Answer? Implications for the Allergist  

PubMed Central

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

2008-01-01

218

Current role of immunotherapy for the treatment of prostate cancer.  

PubMed

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

Porfyris, O; Kalomoiris, P

2013-01-01

219

Monitoring Regulatory Immune Responses in Tumor Immunotherapy Clinical Trials  

PubMed Central

While immune monitoring of tumor immunotherapy often focuses on the generation of productive Th1-type inflammatory immune responses, the importance of regulatory immune responses is often overlooked, despite the well-documented effects of regulatory immune responses in suppressing anti-tumor immunity. In a variety of malignancies, the frequency of regulatory cell populations has been shown to correlate with disease progression and a poor prognosis, further emphasizing the importance of characterizing the effects of immunotherapy on these populations. This review focuses on the role of suppressive immune populations (regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) in inhibiting anti-tumor immunity, how these populations have been used in the immune monitoring of clinical trials, the prognostic value of these responses, and how the monitoring of these regulatory responses can be improved in the future. PMID:23653893

Olson, Brian M.; McNeel, Douglas G.

2013-01-01

220

Immunotherapy for Non-Small Cell Lung Cancer  

PubMed Central

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

2014-01-01

221

Alerjen Spesifik ‹mmünoterapide Lokal ve Sistemik Reaksiyonlar Local and Systemic Reactions in Allergen Specific Immunotherapy  

Microsoft Academic Search

SUMMARY Aim: Local or fatal systemic reactions can be seen in allergen specific immunotherapy. This study was designed to inves- tigate the possible reactions in subcutaneous conventional allergen specific immunotherapy in childhood. Materials and Methods: Subjects receiving immunotherapy for house dust mite-mix (D.Pteronyssinus 50%, D.Farinae 50%) or grasses-cereals pollens mix (Grasses pollens 55%, Hordeum vulgare 10%, Avena sativa 10%, Secale

Yakup Can; Nihat Sapan

222

Determination of the optimal therapeutic protocols in cancer immunotherapy.  

PubMed

Cancer immunotherapy aims at eliciting an immune system response against the tumor. However, it is often characterized by toxic side-effects. Limiting the tumor growth and, concurrently, avoiding the toxicity of a drug, is the problem of protocol design. We formulate this question as an optimization problem and derive an algorithm for its solution. Unlike the standard optimal control approach, the algorithm simulates impulse-like drug administrations. It relies on an exact computation of the gradient of the cost function with respect to any protocol by means of the variational equations, that can be solved in parallel with the system. In comparison with previous versions of this method [F. Castiglione, B. Piccoli, Optimal control in a model of dendritic cell transfection cancer immunotherapy, Bull. Math. Biol. 68 (2006) 255-274; B. Piccoli, F. Castiglione, Optimal vaccine scheduling in cancer immunotherapy, Physica A. 370 (2) (2007) 672-680], we optimize both the timing and the dosage of each administration and introduce a penalty term to avoid clustering of subsequent injections, a requirement consistent with the clinical practice. In addition, we implement the optimization scheme to simulate the case of multi-therapies. The procedure works for any ODE system describing the pharmacokinetics and pharmacodynamics of an arbitrary number of therapeutic agents. In this work, it was tested for a well known model of the tumor-immune system interaction [D. Kirschner, J.C. Panetta, Modeling immunotherapy of tumor-immune interaction, J. Math. Biol. 37 (1998) 235-252]. Exploring three immunotherapeutic scenarios (CTL therapy, IL-2 therapy and combined therapy), we display the stability and efficacy of the optimization method, obtaining protocols that are successful compromises between various clinical requirements. PMID:17416392

Cappuccio, Antonio; Castiglione, Filippo; Piccoli, Benedetto

2007-09-01

223

Advances in Chimeric Antigen Receptor Immunotherapy for Neuroblastoma  

PubMed Central

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

Heczey, Andras; Louis, Chrystal U.

2014-01-01

224

Specific immunotherapy in Albanian patients with anaphylaxis to hymenoptera venoms  

Microsoft Academic Search

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

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

2002-01-01

225

Immunotherapy for melanoma: The good, the bad, and the future  

Microsoft Academic Search

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

2005-01-01

226

Adoptive T-cell transfer in cancer immunotherapy  

Microsoft Academic Search

Adoptive T-cell therapy has definite clinical benefit in relapsed leukaemia after allogeneic transplant and in Epstein–Barr virus-associated post-transplant lymphoproliferative disease. However, the majority of tumour targets are weakly immunogenic self-antigens and success has been limited in part by inadequate persistence and expansion of transferred T cells and by tumour-evasion strategies. Adoptive immunotherapy presents the opportunity to activate, expand and genetically

Siok-Keen Tey; Catherine M Bollard; Helen E Heslop

2006-01-01

227

A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12  

PubMed Central

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales. PMID:20843320

2010-01-01

228

Tumour immunogenicity, antigen presentation and immunological barriers in cancer immunotherapy  

PubMed Central

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

Escors, David

2014-01-01

229

The Immune Response to Tumors as a Tool toward Immunotherapy  

PubMed Central

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

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

2011-01-01

230

Combination treatment with comprehensive cryoablation and immunotherapy in metastatic hepatocellular cancer  

PubMed Central

AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intra- and extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immunotherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryo-immunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy. PMID:23801841

Niu, Li-Zhi; Li, Jia-Liang; Zeng, Jian-Ying; Mu, Feng; Liao, Meng-Tian; Yao, Fei; Li, Li; Liu, Chun-Yan; Chen, Ji-Bing; Zuo, Jian-Sheng; Xu, Ke-Cheng

2013-01-01

231

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

PubMed Central

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

Rutella, Sergio; Locatelli, Franco

2012-01-01

232

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

PubMed

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

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

2014-11-01

233

Venom immunotherapy for stinging insect allergy  

Microsoft Academic Search

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

1987-01-01

234

Passive immunotherapy against A? in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage  

Microsoft Academic Search

BACKGROUND: Anti-A? immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-A? antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-A? antibody treatment on radial-arm water-maze performance,

Donna M Wilcock; Amyn Rojiani; Arnon Rosenthal; Sangeetha Subbarao; Melissa J Freeman; Marcia N Gordon; Dave Morgan

2004-01-01

235

Clinical data and inflammation parameters in patients with cypress allergy treated with sublingual swallow therapy and subcutaneous immunotherapy.  

PubMed

The clinical efficacy of immunotherapy, either by high dose sublingual-swallow therapy (SLIT) or subcutaneous immunotherapy (SCIT), has been demonstrated in patients with pollinosis but few studies have been carried out analysing differences in these treatments in terms of an improvement of clinical and allergic phlogosis parameters. The aim of this double-blind placebo-controlled study is to investigate the efficacy of high dose SLIT and SCIT using a purified standardized Juniperus ashei extract in a population of allergic patients monosensitized to cypress. Forty patients with cypress-allergic rhino conjunctivitis were administered therapeutic or placebo SLIT or SCIT for 12 months. Laboratory parameters were studied, namely the eosinophil cationic protein (ECP) level in nasal lavage and in serum, as well as the number of eosinophils (EOS) in peripheral blood and in nasal lavage and the level of eosinophil chemotactic activity (ECA). These parameters were correlated with clinical symptoms, evaluated by means of the clinical symptoms score (CSS). After SCIT and SLIT the levels of ECP and ECA were reduced in nasal lavage. We also observed a significant reduction in the values of ECP in serum in the patients treated with SLIT. EOS were unchanged in peripheral blood, but significantly reduced in nasal lavage. These data were in accordance with the improvement of clinical symptoms, supported by the close correlation between CSS and laboratory parameters. Our data confirm a clinical improvement correlated with a decline in inflammation parameters after one year of immunotherapy, supporting the hypothesis that treatment with a major allergen of cypress is able to change the course of allergic rhinitis. PMID:19505393

Ventura, M T; Carretta, A; Tummolo, R A; Buquicchio, R; Arsieni, A; Murgia, N

2009-01-01

236

SAPHO syndrome with bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer  

Microsoft Academic Search

The authors describe a case of SAPHO syndrome with bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer. The patient had undergone transurethral resection (TUR) and was treated with BCG immunotherapy following TUR. Two years after treatment for bladder cancer, the patient had palmoplantar pustulosis, and in the past 1 month suffered from pain localised to the anterior chest wall. The bone

Katsuhiko Matsumaru; Kazuki Nagai; Takayuki Murakami; Kazuo Andoh

2010-01-01

237

Early predictive value of multifunctional skin-infiltrating lymphocytes in anticancer immunotherapy  

PubMed Central

Bioassays that predict clinical outcome are essential to optimize cellular anticancer immunotherapy. We have recently developed a robust and simple skin test to evaluate the capacity of tumor-specific T cells to migrate, recognize their targets and exert effector functions. This bioassay detects T cells with an elevated antineoplastic potential and hence rapidly identifies patients responding to immunotherapy. PMID:24653961

Wimmers, Florian; Aarntzen, Erik HJG; Schreibelt, Gerty; Jacobs, Joannes FM; JA Punt, Cornelis; Figdor, Carl G; de Vries, I Jolanda M

2014-01-01

238

Rush Hymenoptera venom immunotherapy: A safe and practical protocol for high-risk patients  

Microsoft Academic Search

Background: Hymenoptera venom immunotherapy in allergic patients is a well-established treatment modality for the prevention of systemic anaphylactic reactions caused by insect stings. A variety of therapy regimens exists, from conventional to rush and ultrarush modalities that operate on continuous or intermittent schedules. Objective: The aim of this study was to report the 8-year experience with our rush venom immunotherapy

Gunter Sturm; Birger Kränke; Christina Rudolph; Werner Aberer

2002-01-01

239

Analysis of Safety, Risk Factors and Pretreatment Methods during Rush Hymenoptera Venom Immunotherapy  

Microsoft Academic Search

Background: The safety profile of venom immunotherapy is a relevant issue. We evaluated the frequency of severe adverse events (SAE), associated risk factors, retrospective comparison of pretreatment protocols including solely H1 receptor blockers and a combination of H1 and H2 receptor blockers during rush Hymenoptera venom immunotherapy. Methods: The study group comprised 118 patients. The treatment was initiated according to

Lucyna Gorska; Marta Chelminska; Krzysztof Kuziemski; Marcin Skrzypski; Marek Niedoszytko; Iwona Damps-Konstanska; Amelia Szymanowska; Beata Wajda; Adrianna Drozdowska; Marek Jutel; Ewa Jassem

2008-01-01

240

Nonmyeloablative stem cell transplantation for solid tumors: Expanding the application of allogeneic immunotherapy  

Microsoft Academic Search

In the arena of tumor immunology, there is a growing perception that the graft-versus-leukemia (GVL) reaction that follows allogeneic stem cell transplantation represents the most potent form of cancer immunotherapy currently in clinical use. While allogeneic stem cell transplantation has become an accepted form of “immunotherapy” for the treatment of hematological malignancies, its efficacy in inducing antitumor effects against nonhematological

Richard Childs; John Barrett

2002-01-01

241

The value of an in-hospital insect sting challenge as a criterion for application or omission of venom immunotherapy  

Microsoft Academic Search

Background: Venom immunotherapy is a generally accepted treatment for serious allergy to bee and yellow jacket venom. However, it is not precisely known to whom venom immunotherapy should be offered. Objective: The purpose of this study was to determine whether an in-hospital insect sting challenge (IHC) can be used as a criterion for application or omission of venom immunotherapy. Methods:

Pieter J. Blaauw; Otto L. M. J. Smithuis; Armin R. W. Elbers

1996-01-01

242

Immunotherapy in mantle cell lymphoma: anti-CD20-based therapy and beyond.  

PubMed

Mantle cell lymphoma (MCL), an aggressive non-Hodgkin's lymphoma characterized by t(11; 14)(q13; q32) chromosomal translocation and overexpression of cyclin D1, has the worst prognosis among all lymphomas. Recent advances in biology, genetics, and immunology have supported the development of immunotherapy in MCL. Rituximab monotherapy in MCL has limited activity. It is more effective when used in combination with chemotherapy such as R-CHOP, R-hyperCVAD/MTX-Ara-C, or R-FCM as front-line or salvage therapy for mantle cell lymphoma. Maintenance with Rituximab was shown to prolong response duration. Although most results have suggested that combining autologous stem cell transplantation with Rituximab may lead to durable remission, the sample size was not sufficient to declare survival benefit. Anti-CD20 radioimmunoconjugates (RICs) (90)Yttrium-ibritumomab tiuxetan and (131)Iodine-tositumomab have been used in mantle cell lymphoma even when patients are relatively resistant to Rituximab-based therapy. Allogeneic stem cell transplantation is a treatment modality in advanced or relapsed MCL, particularly using reduced-intensity conditioning. MCL may have high response rates and sustained remissions after donor lymphocyte infusion. Dendritic cells (DCs) fused with MCL cells for immunostimulation have preliminarily shown anti-lymphoma effects as well. Idiotype vaccination in MCL patients following Rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells. Other immunotherapy, such as the combination of thalidomide with Rituximab, has shown substantial antitumor activity. A Phase I/II study is ongoing to determine the maximum tolerated dose (MTD) and the efficacy of lenalidomide in combination with Rituximab for relapsed/refractory MCL. This review summarizes the latest and exciting advances in MCL. PMID:17722077

Zhou, Yuhong; Zhang, Liang; Romaguera, Jorge; Delasalle, Kay; Han, Xiaohong; Du, Xin; Kwak, Larry; Yi, Qing; Wang, Michael

2008-02-01

243

NK cell-based immunotherapy for malignant diseases  

PubMed Central

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

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

2013-01-01

244

Targeted alpha-particle immunotherapy for acute myeloid leukemia.  

PubMed

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

Jurcic, Joseph G; Rosenblat, Todd L

2014-01-01

245

Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm  

PubMed Central

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

Khattak, Muhammad; Fisher, Rosalie; Turajlic, Samra

2013-01-01

246

Use of lectin-functionalized particles for oral immunotherapy  

PubMed Central

Immunotherapy, in recent times, has found its application in a variety of immunologically mediated diseases. Oral immunotherapy may not only increase patient compliance but may, in particular, also induce both systemic as well as mucosal immune responses, due to mucosal application of active agents. To improve the bioavailability and to trigger strong immunological responses, recent research projects focused on the encapsulation of drugs and antigens into polymer particles. These particles protect the loaded antigen from the harsh conditions in the GI tract. Furthermore, modification of the surface of particles by the use of lectins, such as Aleuria aurantia lectin, wheatgerm agglutinin or Ulex europaeus-I, enhances the binding to epithelial cells, in particular to membranous cells, of the mucosa-associated lymphoid tissue. Membranous cell-specific targeting leads to an improved transepithelial transport of the particle carriers. Thus, enhanced uptake and presentation of the encapsulated antigen by antigen-presenting cells favor strong systemic, but also local, mucosal immune responses. PMID:22834202

Diesner, Susanne C; Wang, Xue-Yan; Jensen-Jarolim, Erika; Untersmayr, Eva; Gabor, Franz

2013-01-01

247

Immunotherapy for Lung Cancer: Has it Finally Arrived?  

PubMed Central

The possible link between infection/inflammation/immune activation and a cancer patient’s outcome from both a causative and outcome point of view has long been postulated. Substantial progress in the understanding of tumor-associated antigens/epitopes, immune cellular subpopulations, cytokine pathways/expression, the tumor microenvironment, and the balance between tumor-immune suppression and stimulation have been made over the past decade. This knowledge has heralded a new era of tumor immunotherapy utilizing vaccines, immune checkpoint inhibition, and oncolytic viruses. Despite significant progress in the molecular era now with targeted therapeutics such as EGFR tyrosine kinase inhibitors and ALK fusion protein inhibitors that have significantly improved the outcome of these specific lung cancer subpopulations, the overall 5?year survival for all non-small cell lung cancer (NSCLC) is still <20%. Unlike malignancies such as malignant melanoma, renal cell carcinoma, and neuroblastoma given their documented spontaneous remission rates lung cancer historically has been felt to be resistant to immune approaches likely related to an immunosuppressive tumor microenvironment and/or lack of immune recognition. Defining responding populations, understanding the mechanism(s) underlying durable immune responses, and the role of chemotherapy, radiation, oncolytic viruses, and other tumor disrupting agents in augmenting immune responses have led to improved optimization of immune therapeutic strategies. The purpose of this review is to focus on the recent advances in lung immunotherapy with an emphasis on recent clinical trials in the last 5?years in NSCLC. PMID:25374843

Mostafa, Ahmed A.; Morris, Don G.

2014-01-01

248

New Approaches to Immunotherapy for HPV Associated Cancers  

PubMed Central

Cervical cancer is the second most common cancer of women worldwide and is the first cancer shown to be entirely induced by a virus, the human papillomavirus (HPV, major oncogenic genotypes HPV-16 and -18). Two recently developed prophylactic cervical cancer vaccines, using virus-like particles (VLP) technology, have the potential to prevent a large proportion of cervical cancer associated with HPV infection and to ensure long-term protection. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and do not prevent their progression to HPV-associated malignancy. In animal models, therapeutic vaccines for persisting HPV infection can eliminate transplantable tumors expressing HPV antigens, but are of limited efficacy in inducing rejection of skin grafts expressing the same antigens. In humans, clinical trials have reported successful immunotherapy of HPV lesions, providing hope and further interest. This review discusses possible new approaches to immunotherapy for HPV associated cancer, based on recent advances in our knowledge of the immunobiology of HPV infection, of epithelial immunology and of immunoregulation, with a brief overview on previous and current HPV vaccine clinical trials. PMID:24212964

Bergot, Anne-Sophie; Kassianos, Andrew; Frazer, Ian H; Mittal, Deepak

2011-01-01

249

Adherence issues related to sublingual immunotherapy as perceived by allergists  

PubMed Central

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

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

2010-01-01

250

Engulfing tumors with synthetic extracellular matrices for cancer immunotherapy  

PubMed Central

Local immunotherapies are under investigation for treatment of unresectable tumors and sites of solid tumor resection to prevent local recurrence. Successful local therapy could also theoretically elicit systemic immune responses against cancer. Here we explored the delivery of therapeutic dendritic cells (DCs), cytokines, or other immunostimulatory factors to tumors via the use of ‘self-gelling’ hydrogels based on the polysaccharide alginate, injected peritumorally around established melanoma lesions. Peritumoral injection of alginate matrices loaded with DCs and/or an interleukin-15 superagonist (IL-15SA) around 14-day established ova-expressing B16F0 murine melanoma tumors promoted immune cell accumulation in the peritumoral matrix, and matrix infiltration correlated with tumor infiltration by leukocytes. Single injections of IL-15SA-carrying gels concentrated the cytokine in the tumor site ~40-fold compared to systemic injection and enabled a majority of treated animals to suppress tumor growth for a week or more. Further, we found that single injections of alginate matrices loaded with IL-15SA and the Toll-like receptor ligand CpG or two injections of gels carrying IL-15SA alone could elicit comparable anti-tumor activity without the need for exogenous DCs. Thus, injectable alginate gels offer an attractive platform for local tumor immunotherapy and facilitates combinatorial treatments designed to promote immune responses locally at a tumor site while limiting systemic exposure to potent immunomodulatory factors. PMID:19766305

Hori, Yuki; Stern, Patrick; Hynes, Richard O.; Irvine, Darrell J.

2009-01-01

251

Can calcium signaling be harnessed for cancer immunotherapy?  

PubMed

Experimental evidence shows the importance of the immune system in controlling tumor appearance and growth. Immunotherapy is defined as the treatment of a disease by inducing, enhancing or suppressing an immune response. In the context of cancer treatment, it involves breaking tolerance to a cancer-specific self-antigen and/or enhancing the existing anti-tumor immune response, be it specific or not. Part of the complexity in developing such treatment is that cancers are selected to escape adaptive or innate immune responses. These escape mechanisms are numerous and they may cumulate in one cancer. Moreover, different cancers of a same type may present different combinations of escape mechanisms. The limited success of immunotherapeutics in the clinic as stand-alone products may in part be explained by the fact that most of them only activate one facet of the immune response. It is important to identify novel methods to broaden the efficacy of immunotherapeutics. Calcium signaling is central to numerous cellular processes, leading to immune responses, cancer growth and apoptosis induced by cancer treatments. Calcium signaling in cancer therapy and control will be integrated to current cancer immunotherapy approaches. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau. PMID:24524821

Rooke, Ronald

2014-10-01

252

HDAC inhibitors and immunotherapy; a double edged sword?  

PubMed Central

Epigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. Histone deacetylase (HDAC) inhibitors are well known to affect cancer cell viability and biology and are already in use for the treatment of cancer patients. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer. PMID:25115382

Kroesen, Michiel; Armandari, Inna; Hoogerbrugge, Peter M.; Adema, Gosse J.

2014-01-01

253

Molecular Recognition of Gangliosides and Their Potential for Cancer Immunotherapies  

PubMed Central

Gangliosides are sialic-acid-containing glycosphingolipids expressed on all vertebrate cells. They are primarily positioned in the plasma membrane with the ceramide part anchored in the membrane and the glycan part exposed on the surface of the cell. These lipids have highly diverse structures, not the least with respect to their carbohydrate chains, with N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) being the two most common sialic-acid residues in mammalian cells. Generally, human healthy tissue is deficient in NeuGc, but this molecule is expressed in tumors and in human fetal tissues, and was hence classified as an onco-fetal antigen. Gangliosides perform important functions through carbohydrate-specific interactions with proteins, for example, as receptors in cell–cell recognition, which can be exploited by viruses and other pathogens, and also by regulating signaling proteins, such as the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), through lateral interaction in the membrane. Through both mechanisms, tumor-associated gangliosides may affect malignant progression, which makes them attractive targets for cancer immunotherapies. In this review, we describe how proteins recognize gangliosides, focusing on the molecular recognition of gangliosides associated with cancer immunotherapy, and discuss the importance of these molecules in cancer research. PMID:25101077

Krengel, Ute; Bousquet, Paula A.

2014-01-01

254

Carbon monoxide-releasing micelles for immunotherapy.  

PubMed

With the discovery of important biological roles of carbon monoxide (CO), the use of this gas as a therapeutic agent has attracted attention. However, the medical application of this gas has been hampered by the complexity of the administration method. To overcome this problem, several transition-metal carbonyl complexes, such as Ru(CO)(3)Cl(glycinate), [Ru(CO)(3)Cl(2)](2), and Fe(?(4)-2-pyrone)(CO)(3), have been used as CO-releasing molecules both in vitro and in vivo. We sought to develop micellar forms of metal carbonyl complexes that would display slowed diffusion in tissues and thus better ability to target distal tissue drainage sites. Specifically, we aimed to develop a new CO-delivery system using a polymeric micelle having a Ru(CO)(3)Cl(amino acidate) structure as a CO-releasing segment. The CO-releasing micelles were prepared from triblock copolymers composed of a hydrophilic poly(ethylene glycol) block, a poly(ornithine acrylamide) block bearing Ru(CO)(3)Cl(ornithinate) moieties, and a hydrophobic poly(n-butylacrylamide) block. The polymers formed spherical micelles in the range of 30-40 nm in hydrodynamic diameter. Further characterization revealed the high CO-loading capacity of the micelles. CO-release studies showed that the micelles were stable in physiological buffer and serum and released CO in response to thiol-containing compounds such as cysteine. The CO release of the micelles was slower than that of Ru(CO)(3)Cl(glycinate). In addition, the CO-releasing micelles efficiently attenuated the lipopolysaccharide-induced NF-?B activation of human monocytes, while Ru(CO)(3)Cl(glycinate) did not show any beneficial effects. Moreover, cell viability assays revealed that the micelles significantly reduced the cytotoxicity of the Ru(CO)(3)Cl(amino acidate) moiety. This novel CO-delivery system based on CO-releasing micelles may be useful for therapeutic applications of CO. PMID:21128648

Hasegawa, Urara; van der Vlies, André J; Simeoni, Eleonora; Wandrey, Christine; Hubbell, Jeffrey A

2010-12-29

255

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

PubMed

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

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

2014-12-01

256

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

PubMed

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

Joshi, Jyoti; Malla, Nancy; Kaur, Sukhbir

2014-08-01

257

Scope for innovation in immunotherapy from the financial market's point of view: Phacilitate Immunotherapy Leaders' Forum 2012.  

PubMed

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

Zilian, Olav

2012-10-01

258

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

PubMed Central

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.

1997-01-01

259

Novel strategy to create hypoallergenic peanut protein-polyphenol edible matrices for oral immunotherapy.  

PubMed

Peanut allergy is an IgE-mediated hypersensitivity. Upon peanut consumption by an allergic individual, epitopes on peanut proteins bind and cross-link peanut-specific IgE on mast cell and basophil surfaces triggering the cells to release inflammatory mediators responsible for allergic reactions. Polyphenolic phytochemicals have high affinity to bind proteins and form soluble and insoluble complexes with unique functionality. This study investigated the allergenicity of polyphenol-fortified peanut matrices prepared by complexing various polyphenol-rich plant juices and extracts with peanut flour. Polyphenol-fortified peanut matrices reduced IgE binding to one or more peanut allergens (Ara h 1, Ara h 2, Ara h 3, and Ara h 6). Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) suggested changes in secondary protein structure. Peanut protein-cranberry polyphenol fortified matrices triggered significantly less basophil degranulation than unmodified flour in an ex vivo assay using human blood and less mast cell degranulation when used to orally challenge peanut-allergic mice. Polyphenol fortification of peanut flour resulted in a hypoallergenic matrix with reduced IgE binding and degranulation capacity, likely due to changes in protein secondary structure or masking of epitopes, suggesting potential applications for oral immunotherapy. PMID:24758688

Plundrich, Nathalie J; Kulis, Mike; White, Brittany L; Grace, Mary H; Guo, Rishu; Burks, A Wesley; Davis, Jack P; Lila, Mary Ann

2014-07-23

260

Composite peptide?based vaccines for cancer immunotherapy (Review).  

PubMed

The use of peptide?based vaccines as therapeutics aims to elicit immune responses through antigenic epitopes derived from tumor antigens. Peptide?based vaccines are easily synthesized and chemically stable entities, and of note, they are absent of oncogenic potential. However, their application is more complicated as the success of an effective peptide?based vaccine is determined by numerous parameters. The success thus far has been limited by the choice of tumor antigenic peptides, poor immunogenicity and incorporation of strategies to reverse cancer?mediated immune suppression. In the present review, an overview of the mechanisms of peptide?based vaccines is provided and antigenic peptides are categorized with respect to their tissue distribution in order to determine their usefulness as targets. Furthermore, certain approaches are proposed that induce and maintain T cells for immunotherapy. The recent progress indicates that peptide?based vaccines are preferential for targeted therapy in cancer patients. PMID:25395173

Yang, Jie; Zhang, Qing; Li, Ke; Yin, Hong; Zheng, Jun-Nian

2015-01-01

261

A mathematical model of the dynamics of antitumor laser immunotherapy  

NASA Astrophysics Data System (ADS)

We use a mathematical model to describe and predict the population dynamics of tumor cells, immune cells, and other immune components in a host undergoing laser immunotherapy treatment against metastatic cancer. We incorporate key elements of the treatment into the model: a function describing the laser-induced primary tumor cell death and parameters capturing the role and strength of the primary immunoadjuvant, glycated chitosan. We focus on identifying conditions that ensure a successful treatment. In particular, we study the patient response (i.e., anti-tumor immune dynamics and treatment outcome) in two different but related mathematical models as we vary quantitative features of the immune system (supply, proliferation, death, and interaction rates). We compare immune dynamics of a `baseline' immune model against an `augmented' model (with additional cell types and antibodies) and in both, we find that using strong immunoadjuvants, like glycated chitosan, that enhance dendritic cell activity yields more promising patient outcomes.

Dawkins, Bryan A.; Laverty, Sean M.

2014-02-01

262

Cytomegalovirus as a Novel Target for Immunotherapy of Glioblastoma Multiforme  

PubMed Central

Progress in the treatment of glioblastoma multiforme (GBM) over the last few decades has remained marginal and GBM is still universally fatal with short survival times after initial diagnosis. Much research is focused on finding new therapeutics for GBM and immune-based approaches have shown great promise. The detection of cytomegalovirus (CMV) antigens in malignant cells has suggested that treatment strategies based on immunological intervention, such as adoptive transfer of antiviral T cells or vaccination with viral epitopes, could be exploited as cancer therapy. Here, we review the rationale for using CMV as a therapeutic target and discuss the first clinical evidence for safety and efficacy of CMV-specific cellular immunotherapy for GBM. PMID:25340042

Schuessler, Andrea; Walker, David G.; Khanna, Rajiv

2014-01-01

263

Future aspects of immunotherapy and gene therapy in neuroblastoma.  

PubMed

Immunotherapy against cancer aims at stimulating the immune system or building an immune response against targeted tumor-associated antigens (TAAs). It was proposed theoretically as a potential therapy for cancer over a century ago but it became popular in the past two decades. Gene therapy represents a promising approach for reversing the neoplastic phenotype or driving tumor cells to self-destruction. Although survival rates of neuroblastoma (NB) with biologically favorable disease are greater than 90%, outcomes of patients with high risk disease are less than 40%. Stage 4 metastatic NB cases over 18 months of age are often incurable with multimodality chemotherapy regimens. In this article, translation of immuno-gene therapy strategies into clinical trials for NB are reviewed. Future aspects of immuno-gene therapy are discussed. PMID:19785063

Aktas, S

2009-09-01

264

IMMUNOTHERAPY FOR ALLERGIES AND ASTHMA: PRESENT AND FUTURE  

PubMed Central

Allergen immunotherapy (IT) is a proven approach for treating allergic rhinitis and allergic asthma that has been practiced since 1911 and has undergone significant development in the last two decades. As currently practiced, IT involves subcutaneous or sublingual administration of allergens, both methods of which have been extensively investigated. In addition to allergen IT, a number of additional nonspecific IT approaches are being used or are in phase II/phase III clinical trials, which may be available in clinics within the next one to three years. Such therapies include anti-IgE antibodies and the soluble IL-4 receptor. Other experimental IT approaches are at the preclinical research stage and may proceed to clinical trials and the clinic within the next five to ten years. This review discusses the pros and cons of recent developments in both currently practiced and experimental IT approaches. PMID:20573547

Mohapatra, Shyam S.; Qazi, Momina; Hellermann, Gary

2010-01-01

265

Ingenol mebutate: potential for further development of cancer immunotherapy.  

PubMed

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

2012-10-01

266

Cancer-associated CD43 glycoforms as target of immunotherapy.  

PubMed

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

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

2014-03-01

267

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens.  

PubMed

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

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

2014-11-27

268

Immunotherapy: What It Is and How It Can Help Fight Cancer  

MedlinePLUS

... skin) or systemic (taken by pill, injection, or infusion). Topical Immunotherapy In mid-2004, a topical medication ... alpha is administered . Following one month of intravenous infusion, interferon-alpha is usually given as a shot ...

269

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

E-print Network

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

Stachowiak, Agnieszka (Agnieszka N.)

2007-01-01

270

Immunotherapy of Brain Cancers: The Past, the Present, and Future Directions  

PubMed Central

Treatment of brain cancers, especially high grade gliomas (WHO stage III and IV) is slowly making progress, but not as fast as medical researchers and the patients would like. Immunotherapy offers the opportunity to allow the patient's own immune system a chance to help eliminate the cancer. Immunotherapy's strength is that it efficiently treats relatively small tumors in experimental animal models. For some patients, immunotherapy has worked for them while not showing long-term toxicity. In this paper, we will trace the history of immunotherapy for brain cancers. We will also highlight some of the possible directions that this field may be taking in the immediate future for improving this therapeutic option. PMID:21437175

Ge, Lisheng; Hoa, Neil; Bota, Daniela A.; Natividad, Josephine; Howat, Andrew; Jadus, Martin R.

2010-01-01

271

MSK team makes key discovery in understanding immunotherapy's successes -- and its failures  

Cancer.gov

A collaborative team of leaders in the field of cancer immunology from Memorial Sloan Kettering Cancer Center has made a key discovery that advances the understanding of why some patients respond to ipilimumab, an immunotherapy drug, while others do not.

272

Immunotherapy in Alzheimer's disease: do we have all the pieces of the puzzle?  

PubMed

Results of Phase III studies involving a large number of Alzheimer's disease (AD) patients treated by passive immunotherapy with humanized anti-amyloid ? monoclonal antibodies have recently been released. These approaches failed to show a significant clinical benefit in patients with mild to moderate AD. The most considered explanation is that the patients have been treated too late. Whereas targeting patients at asymptomatic stages of the disease is a critical step in the goal of improving the efficacy of such antibody-based strategies, several other important factors should be considered in the development and clinical evaluation of anti-amyloid ? immunotherapies, including the as yet poorly understood relationship of AD with the immune system and the importance of cerebral amyloid angiopathy. Better understanding the role of immune responses in AD and their impact on immunotherapy appears essential in the design of alternative or combinatorial immunotherapy approaches in AD, which may imply effectors other than antibodies and even additional antigenic targets. PMID:23683656

Sarazin, Marie; Dorothée, Guillaume; de Souza, Leonardo Cruz; Aucouturier, Pierre

2013-09-01

273

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

E-print Network

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

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

2008-01-01

274

On Optimal Protocols for Combinations of Chemo-and Immunotherapy* Urszula Ledzewicz and Mozhdeh Faraji  

E-print Network

control problem for combinations of cancer chemotherapy with immunotherapy in form of a boost at the terminal point as a negative term, the overall amount of therapeutic agents given as a measure for the side

Ledzewicz, Urszula

275

The kinetics of change in cytokine production by CD4 + T cells during conventional allergen immunotherapy  

Microsoft Academic Search

Background: The effect of conventional allergen immunotherapy on allergen-specific T lymphocyte cytokine production is incompletely understood, particularly during the initial phase of treatment. Objective: The purpose of this study was to prospectively follow the kinetics of change in CD4+ T cell cytokine secretion during the course of conventional immunotherapy. Methods: Six allergic individuals were treated with extracts of Dermatophagoides farinae\\/Dermatophagoides

Suwat Benjaponpitak; Amy Oro; Peter Maguire; Vince Marinkovich; Rosemarie H. DeKruyff; Dale T. Umetsu

1999-01-01

276

Harmful effect of immunotherapy in children with combined snail and mite allergy  

Microsoft Academic Search

Background: With respect to allergy, the possibility of cross-reactivity between snail and mite is well recognized, and anecdotal reports suggesting that allergen immunotherapy with mite extract can worsen snail-induced allergy exist. Objective: We describe the effect of immunotherapy in 4 children with snail-mite allergy. Methods: Four children (1 boy and 3 girls; 9-13 years of age) had consistent clinical histories

Giovanni Battista Pajno; Stefania La Grutta; Giovanni Barberio; Giorgio Walter Canonica; Giovanni Passalacqua

2002-01-01

277

Immunotherapy for pythiosis: Effect on NTPDase activity in lymphocytes of an experimental model.  

PubMed

NTPDase (EC 3.6.1.5) occurs in lymphocytes and plays an important role in immune function, in that hydrolyzes extracellular nucleoside tri- and/or diphosphates to form AMP. Pythium insidiosum causes the disease pythiosis, a pyogranulomatous disease of horses, dogs, cattle, cats and humans. Most antifungal drugs are ineffective against this pathogen, and immunotherapy, a treatment approach that relies on the injection of P. insidiosum antigen, has been successfully used in humans and horses to manage this disease. In this study, we investigated NTPDase activity in lymphocytes from rabbits inoculated with zoospores of P. insidiosum. After immunotherapy, we investigated the relationship between enzymatic activity and the pattern of the immune response. One milliliter of zoospores was inoculated subcutaneously into the coastal region of each rabbit. An average of 17,500 viable mobile zoospores/mL of induction medium was administered. Inoculated rabbits were checked weekly, and the subcutaneous nodular area (cm²) was measured 28 days after inoculation. Rabbits that developed lesions received four doses of immunotherapy at intervals of 14 days. Blood samples were collected by heart puncture twice a month for the determination of NTPDase activity. The results demonstrated that NTPDase activity in lymphocytes was increased in relation to ATP hydrolysis (by about 100%) in pythiosis and returned to normal values after immunotherapy. The data demonstrating NTPDase activity before and after immunotherapy reinforce the previously elaborated hypothesis that the change from a Th2 to a Th1 immune response is responsible for the curative properties of immunotherapy. PMID:20970953

Bach, Barbara Charlotte; Leal, Daniela Bitencourt Rosa; Ruchel, Jader Betsch; Souza, Viviane do Carmo Gonçalves; Maboni, Grazieli; Dal Pozzo, Marcelo; Schlemmer, Karine Bizzi; Alves, Sydney Hartz; Santurio, Janio Morais

2010-12-01

278

Immunoediting and Antigen Loss: Overcoming the Achilles Heel of Immunotherapy with Antigen Non-Specific Therapies  

PubMed Central

Cancer immunotherapy has emerged as a mainstream therapy option in the battle against cancer. Pre-clinical data demonstrates the ability of immunotherapy to harness the immune system to fight disseminated malignancy. Clinical translation has failed to recapitulate the promising results of pre-clinical studies although there have been some successes. In this review we explore some of the short-comings of cancer immunotherapy that have limited successful clinical translation. We will give special consideration to what we consider the most formidable hurdle to successful cancer immunotherapy: tumor-induced immune suppression and immune escape. We will discuss the need for antigen-specific immune responses for successful immunotherapy but also consider the need for antigen specificity as an Achilles heel of immunotherapy given tumor heterogeneity, immune editing, and antigen loss. Finally, we will discuss how combinatorial strategies may overcome some of the pitfalls of antigen specificity and highlight recent studies from our lab which suggest that the induction of antigen non-specific immune responses may also produce robust anti-tumor effects and bypass the need for antigen specificity. PMID:23898464

Monjazeb, Arta Monir; Zamora, Anthony E.; Grossenbacher, Steven K.; Mirsoian, Annie; Sckisel, Gail D.; Murphy, William J.

2013-01-01

279

Active immunotherapy of Walker-256 carcinosarcoma by tumor-infiltrating lymphocytes associated with photodynamic therapy  

NASA Astrophysics Data System (ADS)

Experiments were performed on five batches of Wistar inbred rats with Walker-256 carcinosarcoma receiving as sole treatment photodynamic therapy (PDT), tumor-infiltrating lymphocytes (TIL), or associated therapy (PDT + TIL - A; PDT + TIL - B). The control batch (HBSS) consisted of animals with untreated Walker-256 tumors. The results were as follows: the sole treatment (PDT, TIL) gave survival rates between 41.4 and 52.9%, the cure rates ranging from 13.8 to 38.2%. The `combined' therapy in multiple doses increased significantly (92.8%) the survival rate of tumor bearing rats as well as the highest incidence of complete tumor regression (82.1%). Cell-mediated immunity test values in batches III and IV exposed to multiple doses of PDT + TIL showed higher values as compared to the values noticed in batches I - II and the control batch V, performed at 10 and 21 days post-treatment. Summing up, this work demonstrates that `combined' photodynamic therapy with immunotherapy with TIL stimulates cell-mediated antitumoral activity, increases survival rates, and reduces incidence of Walker-256 carcinosarcoma in the rat model.

Dima, Vasile F.; Vasiliu, Virgil V.; Laky, Dezideriu; Ionescu, Paul; Dima, Stefan V.

1995-01-01

280

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

PubMed

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

Gabai, Vladimir L; Shifrin, Victor I

2014-10-01

281

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

PubMed Central

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

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

2014-01-01

282

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

PubMed Central

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

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

2013-01-01

283

Immunotherapy for neuroblastoma using syngeneic fibroblasts transfected with IL-2 and IL-12.  

PubMed

Cytokine-modified tumour cells have been used in clinical trials for immunotherapy of neuroblastoma, but primary tumour cells from surgical biopsies are difficult to culture. Autologous fibroblasts, however, are straightforward to manipulate in culture and easy to transfect using nonviral or viral vectors. Here we have compared the antitumour effect of fibroblasts and tumour cells transfected ex vivo to coexpress interleukin-2 (IL-2) and IL-12 in a syngeneic mouse model of neuroblastoma. Coinjection of cytokine-modified fibroblasts with Neuro-2A tumour cells abolished their in vivo tumorigenicity. Treatment of established tumours with three intratumoral doses of transfected fibroblasts showed a significant therapeutic effect with reduced growth or complete eradication of tumours in 90% of mice, associated with extensive leukocyte infiltration. Splenocytes recovered from vaccinated mice showed enhanced IL-2 production following Neuro-2A coculture, and increased cytotoxicity against Neuro-2A targets compared with controls. Furthermore, 100% of the tumour-free mice exhibited immune memory against tumour cells when rechallenged three months later. The potency of transfected fibroblasts was equivalent to that of tumour cells in all experiments. We conclude that syngeneic fibroblasts cotransfected with IL-2 and IL-12 mediate therapeutic effects against established disease, and are capable of generating immunological memory. Furthermore, as they are easier to recover and manipulate than autologous tumour cells, fibroblasts provide an attractive alternative immunotherapeutic strategy for the treatment of neuroblastoma. PMID:17595664

Barker, S E; Grosse, S M; Siapati, E K; Kritz, A; Kinnon, C; Thrasher, A J; Hart, S L

2007-07-16

284

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

PubMed

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

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

2014-09-29

285

Molecular Alterations in Pediatric Sarcomas: Potential Targets for Immunotherapy  

PubMed Central

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

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

1998-01-01

286

Immunocompetent murine models for the study of glioblastoma immunotherapy  

PubMed Central

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

2014-01-01

287

Immunotherapy earns its spot in the ranks of cancer therapy  

PubMed Central

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. PMID:22330682

Drake, Charles

2012-01-01

288

Cancer immunotherapy using a potent immunodominant CTL epitope.  

PubMed

Immunotherapy has emerged as a promising approach that can be used in conjunction with conventional chemotherapy and radiotherapy to further improve the survival rate of patients with advanced cancer. We have recently shown in previous studies that chemotherapy and radiation therapy can alter the tumor microenvironment and allow intratumoral vaccination to prime the adaptive immune system leading to the generation of antigen-specific cell-mediated immune responses. Here, we investigated whether intratumoral injection of a foreign immunodominant peptide (GP33) and the adjuvant CpG into tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and GP33 was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and GP33 also enhanced the generation of GP33-specific and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci, a process found to be mediated by the Fas-FasL apoptosis pathway. The treatment regimen presented here represents a universal approach to cancer control. PMID:25245934

Song, Liwen; Yang, Ming-Chieh; Knoff, Jayne; Sun, Zu-Yue; Wu, T-C; Hung, Chien-Fu

2014-10-21

289

A new take on comparative immunology; Relevance to immunotherapy  

PubMed Central

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

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

2012-01-01

290

Lentiviral vectors for cancer immunotherapy and clinical applications.  

PubMed

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

2013-09-01

291

EXPANSION AND ACTIVATION OF NATURAL KILLER CELLS FOR CANCER IMMUNOTHERAPY  

PubMed Central

Natural killer (NK) cells can kill a wide range of cancer cells and are a promising tool for cell therapy of cancer. NK cells cytotoxicity is regulated by a balance between stimulatory and inhibitory signals. Interleukin-2 is known to increase NK cell cytotoxicity. Although many cytokines have been studied in efforts to induce durable NK cell expansions, most reports indicate a rather modest effect and the requirement for additional stimuli. We found that contact with the K562 myeloid leukemia cell line, genetically modified to express a membrane-bound form of interleukin-15 and the ligand for the costimulatory molecule 4-1BB, induced vigorous expansion of NK cells from peripheral blood. Based on these findings, we developed a method for large-scale clinical-grade expansion of NK cells. This method is currently used to expand allogeneic NK cells for infusion in patients with leukemia and solid tumors. We here summarize methods for expansion and activation of NK cells from human peripheral blood mononuclear cells as well as clinical-scale methods to produce NK cells for immunotherapy under Current Good Manufacturing Practices (cGMP) conditions. PMID:19411773

Cho, Duck; Campana, Dario

2009-01-01

292

Role of immunotherapy in castration-resistant prostate cancer (CRPC).  

PubMed

Initial therapy for metastatic prostate cancer consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that usually lasts 12-24 months. Historically, castration-resistant prostate cancer (CRPC) had been considered a chemoresistant tumour. In 2004, docetaxel received USA Food and Drug Administration approval as a first-line treatment for metastatic prostate cancer, after two independent phase III trials showed an increased survival benefit. Recently, five new drugs have shown increased survival in CRPC: sipuleucel-T (assymptomatic or minimally symptomatic), abiraterone acetate (before and after docetaxel), cabazitaxel (after docetaxel), MDV3100 (after docetaxel) and radium-223 (not suitable for docetaxel or after docetaxel). The identification of antigens in normal prostate tissue or prostate cancer that are recognised by immune effectors cells has resulted in several new studies based on immunotherapy. Prostate cancer disease provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only with biochemical progression), there is a biological marker that can predict prognosis and outcome (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti-androgen therapy, chemotherapy, or radiotherapy. Here we provide a review of the main important immune treatments in CRPC. PMID:23650874

Suárez, Cristina; Morales-Barrera, Rafael; Ramos, Victor; Núñez, Isaac; Valverde, Claudia; Planas, Jacques; Morote, Juan; Maldonado, Xavier; Carles, Joan

2014-03-01

293

Interleukin-12 in anti-tumor immunity and immunotherapy.  

PubMed

Interleukin-12 (IL-12) has an essential role in the interaction between the innate and adaptive arms of immunity by regulating inflammatory responses, innate resistance to infection, and adaptive immunity. Endogenous IL-12 is required for resistance to many pathogens and to transplantable and chemically induced tumors. In experimental tumor models, recombinant IL-12 treatment has a dramatic anti-tumor effect on transplantable tumors, on chemically induced tumors, and in tumors arising spontaneously in genetically modified mice. IL-12 utilizes effector mechanisms of both innate resistance and adaptive immunity to mediate anti-tumor resistance. IFN-gamma and a cascade of other secondary and tertiary pro-inflammatory cytokines induced by IL-12 have a direct toxic effect on the tumor cells or may activate potent anti-angiogenic mechanisms. The stimulating activity of IL-12 on antigen-specific immunity relies mostly on its ability to determine or augment Th1 and cytotoxic T lymphocyte responses. Because of this ability, IL-12 has a potent adjuvant activity in cancer and other vaccines. The promising data obtained in the pre-clinical models of anti-tumor immunotherapy have raised much hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity and modest clinical response observed in the clinical trials point to the necessity to plan protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. PMID:11900991

Colombo, Mario P; Trinchieri, Giorgio

2002-04-01

294

Scientific foundations of allergen-specific immunotherapy for allergic disease.  

PubMed

Allergen-specific immunotherapy (AIT) was described as a therapeutic option for the treatment of allergies > 100 years ago. It is based on administration of allergen extracts and leads to the development of clinical allergen tolerance in selected patients. According to current knowledge, AIT results in the restoration of immune tolerance toward the allergen of interest. It is mainly accompanied by the induction of regulatory and suppressive subsets of T and B cells, the production of IgG4 isotype allergen-specific blocking antibodies, and decreased inflammatory responses to allergens by effector cells in inflamed tissues. Currently, AIT is mainly applied subcutaneously or sublingually and is suitable for both children and adults for pollen, pet dander, house dust mite, and venom allergies. It not only affects rhinoconjunctival symptoms but also has documented short- and long-term benefits in asthma treatment. Clinically, a fast onset of tolerance is achieved during desensitization, with a tolerable amount of side effects. The disease modification effect leads to decreased disease severity, less drug usage, prevention of future allergen sensitizations, and a long-term curative effect. Increasing safety while maintaining or even augmenting efficiency is the main goal of research for novel vaccine development and improvement of treatment schemes in AIT. This article reviews the principles of allergen-specific immune tolerance development and the effects of AIT in the clinical context. PMID:25367471

Soyka, Michael B; van de Veen, Willem; Holzmann, David; Akdis, Mübeccel; Akdis, Cezmi A

2014-11-01

295

Mast cells as targets for immunotherapy of solid tumors.  

PubMed

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

Oldford, Sharon A; Marshall, Jean S

2015-01-01

296

Novel Recombinant Alphaviral and Adenoviral Vectors for Cancer Immunotherapy  

PubMed Central

Although cellular immunotherapy based on autolgous dendritic cells (DCs) targeting antigens expressed by metastatic cancer has demonstrated clinical efficacy, the logistical challenges in generating an individualized cell product create an imperative to develop alternatives to DC-based cancer vaccines. Particularly attractive alternatives include in situ delivery of antigen and activation signals to resident antigen-presenting cells (APCs), which can be achieved by novel fusion molecules targeting the mannose receptor and by recombinant viral vectors expressing the antigen of interest and capable of infecting DCs. A particular challenge in the use of viral vectors is the well-appreciated clinical obstacles to their efficacy, specifically vector-specific neutralizing immune responses. Because heterologous prime and boost strategies have been demonstrated to be particularly potent, we developed two novel recombinant vectors based on alphaviral replicon particles and a next-generation adenovirus encoding an antigen commonly overexpressed in many human cancers, carcinoembryonic antigen (CEA). The rationale for developing these vectors, their unique characteristics, the preclinical studies and early clinical experience with each, and opportunities to enhance their effectiveness will be reviewed. The potential of each of these potent recombinant vectors to efficiently generate clinically active anti-tumor immune response alone, or in combination, will be discussed. Semin Oncol 39:305-310 PMID:22595053

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

2013-01-01

297

Immunotherapy of Malignant Gliomas Using Autologous and Allogeneic Tissue Cells  

PubMed Central

Immunotherapy of brain tumors is rapidly emerging as a potential clinical option [1–3]. The quality and magnitude of immune responses evoked by the new generation anti-tumor vaccines is in general highly dependent on the source or choice of peptide antigens, and as well, a suitable immunopotentiator. Poorly immunogenic antigens, such as those present in tumor cell lysates, may not reliably provide stimulation like recombinant or DNA-encoded protein antigens might be expected to. In addition, the efficacy of the vaccine may depend on inherent counteracting measures of the tumor which dampen immune surveillance and immune effector activity triggered by immunization [4]. Our body has many means of limiting an immune response to our own (self) proteins. In particular, patients with gliomas exhibit a broad suppression of cell-mediated immunity [5–8]. Unfortunately, for most tumor vaccines the induction of local or systemic immune effector cells does not necessarily translate into objective clinical responses or increased survival [9]. Here we review immunotherapeutic approaches against gliomas and recent pre-clinical and clinical initiatives based on cellular or active immunization of the patient’s immune system using autologous and allogeneic tissues or cultured cells. Available evidence shows that single modality cancer therapies likely remain suboptimal. Combination regimens targeting the immune system at multiple coordinated levels must be developed, and possibly combined with strategies to inhibit immune suppressive factors if significant clinical benefit is to be achieved. PMID:20879986

Stathopoulos, A.; Kruse, C.A.; Chen, T. C.

2014-01-01

298

Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy  

PubMed Central

Sub-cutaneous immunotherapy is an effective treatment for allergy. It works by helping to modify or re-balance an individual’s immune response to allergens and its efficacy is greatly improved by the use of adjuvants, most commonly, aluminium hydroxide. Aluminium salts have been used in allergy therapy for many decades and are assumed to be safe with few established side-effects. This assumption belies their potency as adjuvants and their potential for biological reactivity both at injection sites and elsewhere in the body. There are very few data purporting to the safety of aluminium adjuvants in allergy immunotherapy and particularly so in relation to longer term health effects. There are, if only few, published reports of adverse events following allergy immunotherapy and aluminium adjuvants are the prime suspects in the majority of such incidents. Aluminium adjuvants are clearly capable of initiating unwanted side effects in recipients of immunotherapy and while there is as yet no evidence that such are commonplace it is complacent to consider aluminium salts as harmless constituents of allergy therapies. Future research should establish the safety of the use of aluminium adjuvants in sub-cutaneous allergy immunotherapy. PMID:24444186

2014-01-01

299

Higher frequency of early local side effects with aqueous versus depot immunotherapy for hymenoptera venom allergy.  

PubMed

Venom immunotherapy has proven a very effective method for the treatment of allergy to Hymenoptera venom. Aqueous instead of depot extracts are prevalently used for this immunotherapy. The advantage of using aqueous extracts has not been fully investigated. We made an open, non-controlled study on 45 subjects sensitized to either Apis mellifera or Vespula spp. Patients were assigned to either a depot (N=27) or an aqueous (N=18) immunotherapy regimen, and side effects were monitored during the induction and the 3-year maintenance phase. The effect of naturally occurring stings during the treatment and after its interruption was recorded as well. Side effects were less frequent with the depot extract both on a "per patient" (22.2% versus 50.0%) and on a "per dose" (2.9% versus 10,2%) basis (p=0.026 and p<0.000, respectively). Better tolerance was mainly due to the lower frequency of local side effects occurring at early times after vaccination. The efficacy of vaccination was comparable in the 2 cohorts, as expected. We conclude that depot immunotherapy to Hymenoptera venom should be preferred to aqueous immunotherapy for the lower occurrence of local side effects. This might influence a better compliance with this potentially life-saving treatment. PMID:15301302

Cadario, G; Marengo, F; Ranghino, E; Rossi, R; Gatti, B; Cantone, R; Bona, F; Pellegrino, R; Feyles, G; Puccinelli, P; Burastero, S E

2004-01-01

300

Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma.  

PubMed

Historically, the median overall survival for patients with stage IV melanoma was less than 1 year and the 5-year survival rate was ?10%. Recent advances in therapy have raised 5-year survival expectations to ?20%. Notably, a subset of melanoma patients who receive immunotherapy with high-dose interleukin-2, and now ipilimumab, can achieve long-term survival of at least 5 years. A major goal in melanoma research is to increase the number of patients who experience this overall survival benefit. In this review, we discuss the attributes of immunotherapy and newer targeted agents, and consider how combination strategies might improve the chances of achieving durable benefit and long-term survival. We also discuss three areas that we believe will be critical to making further advances in melanoma treatment. To better understand the clinical profile of patients who achieve long-term survival with immunotherapy, we first present data from ipilimumab clinical trials in which a subset of patients experienced durable responses. Second, we discuss the limitations of traditional metrics used to evaluate the benefits of immunotherapies. Third, we consider emerging issues that clinicians are currently facing when making treatment decisions regarding immunotherapy. A better understanding of these novel treatments may improve survival outcomes in melanoma, increase the number of patients who experience this overall survival benefit, and inform the future use of these agents in the treatment of other cancer types. PMID:25060490

McDermott, David; Lebbé, Celeste; Hodi, F Stephen; Maio, Michele; Weber, Jeffrey S; Wolchok, Jedd D; Thompson, John A; Balch, Charles M

2014-10-01

301

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

PubMed Central

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

2013-01-01

302

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

PubMed

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

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

2014-11-20

303

Adoptive immunotherapy and combined chemo-immunotherapy in transplantable leukaemia of AKR mice (TAL); occurrence of natural killers.  

PubMed

Allo- and syngeneic lymphoid effector cells were injected I. P. into transplantable leukaemia (TAL)-bearing AKR recipients. Effector cells were collected from the peritoneal cavity, lymph nodes, spleen, or thymus, of either non-immunized donors or of donors previously immunized with TAL cells. The ratio, injected number of effector cells divided by injected number of TAL target cells varied in individual experiments from 10:1 to 10 000 : 1. Some AKR recipients were given prior to the leukaemia inoculation a whole-body sublethal X-ray irradiation and/or an I.P. injection of cyclophosphamide. Mean survival of TAL leukaemia was most often prolonged in recipients given viable allogeneic thymocytes derived from non-immunized donors. In some leukaemia-bearing mice treated with chemo-immunotherapy, permanent survival (greater than 70 days) could be observed. As a rule, effector cells derived from non-immunized allogeneic donors were more effective than effector cells from the immunized areas. Syngeneic effectors were ineffective. The occurrence of natural killers (NK cells) to Gross virus-infected cells in the lymphoid organs of low-leukaemic inbred mouse strains is postulated. These NK cells are lacking in high-leukaemic AKR mice. PMID:7274781

Schneiberg, K; Rytwi?ski, K; Tabe?ska, J

1981-01-01

304

Clinical and immunologic effects of a rush sublingual immunotherapy to Parietaria species: A double-blind, placebo-controlled trial  

Microsoft Academic Search

Background: The local (noninjection) routes of immunotherapy are presently regarded as viable therapeutic options for respiratory allergy, and their mechanisms of action are currently undergoing investigation. Objective: We evaluated the clinical efficacy of a preseasonal rush sublingual-swallow immunotherapy and its effects on allergic inflammation in patients with seasonal rhinoconjunctivitis caused by Parietaria species. Methods: Thirty patients with Parietaria species–induced rhinoconjunctivitis

Giovanni Passalacqua; Monica Albano; Annamaria Riccio; Laura Fregonese; Paola Puccinelli; Silvano Parmiani; Giorgio Walter Canonica

1999-01-01

305

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

Microsoft Academic Search

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

1998-01-01

306

SAPHO syndrome with bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer  

PubMed Central

The authors describe a case of SAPHO syndrome with bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer. The patient had undergone transurethral resection (TUR) and was treated with BCG immunotherapy following TUR. Two years after treatment for bladder cancer, the patient had palmoplantar pustulosis, and in the past 1 month suffered from pain localised to the anterior chest wall. The bone scintigraphy showed a strong focal enrichment in the right chest wall, suggesting spondyloarthropathy rather than malignant disease. On the basis of clinical and scintigraphy findings, SAPHO syndrome was diagnosed. The patient was treated with topical therapy and non-steroidal anti-inflammatory drugs and symptoms improved. The authors suggest that SAPHO syndrome might be caused by an association with BCG immunotherapy. PMID:22767524

Matsumaru, Katsuhiko; Nagai, Kazuki; Murakami, Takayuki; Andoh, Kazuo

2010-01-01

307

SAPHO syndrome with bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer.  

PubMed

The authors describe a case of SAPHO syndrome with bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer. The patient had undergone transurethral resection (TUR) and was treated with BCG immunotherapy following TUR. Two years after treatment for bladder cancer, the patient had palmoplantar pustulosis, and in the past 1 month suffered from pain localised to the anterior chest wall. The bone scintigraphy showed a strong focal enrichment in the right chest wall, suggesting spondyloarthropathy rather than malignant disease. On the basis of clinical and scintigraphy findings, SAPHO syndrome was diagnosed. The patient was treated with topical therapy and non-steroidal anti-inflammatory drugs and symptoms improved. The authors suggest that SAPHO syndrome might be caused by an association with BCG immunotherapy. PMID:22767524

Matsumaru, Katsuhiko; Nagai, Kazuki; Murakami, Takayuki; Andoh, Kazuo

2010-01-01

308

[Evaluation of the pediatric aspects of the WHO document and meta-analysis of immunotherapy].  

PubMed

In spite of the existence of numerous scientific studies on the beneficial effect of immunotherapy with specific allergens in the treatment of allergic diseases, their results have not been easily accepted as the methodology and the valuation of the studies have been very heterogeneous. Over the last few years the meta-analysis technology has been developed as a useful tool to globally value the results on the different research studies related to a specific problem. When meta-analyse are carried out correctly, they are accepted as an optimum way to express the results obtained from the different studies from a common view point. In 1995 Abramson MJ, Puy RM and Weiner INI published the first meta-analysis on the efficiency of immunotherapy with specific allergens in the treatment of asthma. The same authors continued to carry out systematic reviews of this theme, and their results were published in the Cochrane Library Document. In october 1999 the latest meta-analysis on immunotherapy in asthma, also carried out by Abramson et al was published in Allergy. In this study 62 investigations published from 1954 to 1998 were included. None of the meta-analyses published to date have separately analysed the studies carried out on children, nor have special considerations been made with respect to the 105 patients who were of paediatric age. The first meta-analysis studies, as well as the ones carried out in 1999, only value random clinical tests, in which there is a valuation of the evolution of asthma and in which mite, pollen, animal, fungi or epithelial allergenic vaccinations are used. Only the subcutaneous administration of the vaccine was allowed. Although this meta-analysis has not been designed to obtain specific conclusions of the effectiveness of immunotherapy in children, probably of conclusions of some of the sections can be applied to the children and/or adolescent population. The authors point out, by valuing the results of the effect of immunotherapy on the clinical evolution, that the studies carried out on children were more homogenous than on adults, which means that their significance on this population is more important. Approximately 50% of the studies that evaluate the clinical evolution, the medicines taken and the specific BHR study with allergens, included children and/or adolescents. It is very probable that these conclusions can be applied to the population between 5 and 18 years old that suffer from allergic asthma, but it is clear that a meta-analysis of the efficiency of immunotherapy in paediatrics is needed. Recently regulations on immunotherapy have been published that appeared after the immunotherapy experts from the World Health Organisation met in Geneva in 1997 (1). The recommendations for immunotherapy in children are clear and similar to those applied to adults: 1. Rhonoconjunctivitis and allergic asthma mediated by IgE. 2. Serious anaphylactic reactions caused by hymenoptera bites. 3. The same diagnosis and treatment considerations recommended are applied to children as well as adults. It is not indicated for allergies to food substances and atopic dermatitis. The patients age is another factor to be considered and, except in the case of allergy to hymenoptera poison, when the patient is under 5 it is a relative counter indication to administer immunotherapy. In general it is admitted that immunotherapy is more efficient on children than on adults, but more studies need to be carried out on the efficiency and safety on children under 5. The early treatment with immunotherapy in children who suffer from allergic respiratory illnesses can have an important significance, as this type of treatment could have a preventive nature as it prevents the rhinitis developing into asthma, as well as the beneficial effect that has been shown on children with allergic asthma. PMID:10867375

Ibáñez Sendín, M D

2000-01-01

309

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy  

PubMed Central

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

2012-01-01

310

State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous.  

PubMed

IgE-mediated food allergy is a global health problem that affects millions of persons and affects every aspect of life for the patient. Developing effective treatment strategies to augment current practice standards of strict dietary avoidance of antigens and availability of self-injectable epinephrine has been a major focus of research teams, advocacy groups, funding agencies, and patients and their families. Significant progress has been made through the development of allergen-specific immunotherapy encompassing 3 major forms of treatment: oral, sublingual, and epicutaneous immunotherapy. These therapies are in various stages of clinical investigation, with some successes noted in clinical outcomes and modulation of immune mechanisms toward effective therapy. Here we review recent progress and areas of concern for the role of these forms of immunotherapy as an emerging treatment for food allergy. PMID:24636471

Jones, Stacie M; Burks, A Wesley; Dupont, Christophe

2014-02-01

311

Evidence of pathway-specific basophil anergy induced by peanut oral immunotherapy in peanut-allergic children  

PubMed Central

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. PMID:22805467

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.

2013-01-01

312

Venom immunotherapy modulates interleukin-4 and interferon-gamma messenger RNA expression of peripheral T lymphocytes.  

PubMed Central

The mechanism by which specific immunotherapy exerts its beneficial effect remains unclear. In order to evaluate the influence of venom immunotherapy on the T-cell cytokine pattern of allergic reactions, we studied interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) mRNA expression of peripheral T lymphocytes from 12 patients undergoing rush venom desensitization, before treatment at Day 0 (D0), at Day 15 (D15) and Day 90 (D90) after treatment, and from seven controls. Antigen-specific T-cell proliferation was also determined. Cytokine mRNA expression was evaluated using in situ hybridization, 24 hr after culture of peripheral T cells with medium, venom, or an unrelated allergen. Allergen-induced T-cell proliferation decreased at D15 and D90 of rush immunotherapy (P < or = 0.02). In venom-stimulated cultures of the patient group, there was a decrease in IL-4 mRNA-positive cells at D15 and D90 (P < or = 0.001). Before desensitization, IFN-gamma mRNA expression was lower in patients than in controls and did not increase after in vitro allergen stimulation. In contrast, after immunotherapy, spontaneous IFN-gamma mRNA expression increased, but only at D90 (P < or = 0.001). The cytokine pattern observed at D90 after immunotherapy was similar to that observed in control subjects. In conclusion, venom immunotherapy induced an altered cytokine mRNA pattern in allergen-stimulated T cells which was dissociated from the early changes of allergen-induced T-cell responsiveness. PMID:8675214

Akoum, H; Tsicopoulos, A; Vorng, H; Wallaert, B; Dessaint, J P; Joseph, M; Hamid, Q; Tonnel, A B

1996-01-01

313

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

PubMed Central

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

2014-01-01

314

Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice  

PubMed Central

Background: Myeloid-derived suppressor cells (MDSCs) are present in large numbers in blood of mice and humans with cancer, and they strongly inhibit T-cell and natural killer (NK) cell responses, at young and old age. We found that a highly attenuated bacterium Listeria monocytogenes (Listeriaat)-infected MDSC and altered the immune-suppressing function of MDSC. Methods: Young (3?months) and old (18?months) BALB/cByJ mice with metastatic breast cancer (4T1 model) were immunised with Listeriaat semi-therapeutically (once before and twice after tumour development), and analysed for growth of metastases and primary tumour, in relation to MDSC-, CD8 T-cell and NK cell responses. Results: We found that Listeriaat-infected MDSC, which delivered Listeriaat predominantly to the microenvironment of metastases and primary tumours, where they spread from MDSC into tumour cells (infected tumour cells will ultimately become a target for Listeria-activated immune cells). Immunotherapy with Listeriaat significantly reduced the population of MDSC in blood and primary tumours, and converted a remaining subpopulation of MDSC into an immune-stimulating phenotype producing IL-12, in correlation with significantly improved T-cell and NK cell responses to Listeriaat at both ages. This was accompanied with a dramatic reduction in the number of metastases and tumour growth at young and old age. Conclusions: Although preclinical studies show that immunotherapy is less effective at old than at young age, our study demonstrates that Listeriaat-based immunotherapy can be equally effective against metastatic breast cancer at both young and old age by targeting MDSC. PMID:23640395

Chandra, D; Jahangir, A; Quispe-Tintaya, W; Einstein, M H; Gravekamp, C

2013-01-01

315

MRP3: a molecular target for human glioblastoma multiforme immunotherapy.  

PubMed Central

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. PMID:20809959

2010-01-01

316

Intratumoral temozolomide synergizes with immunotherapy in a T cell-dependent fashion.  

PubMed

Despite temozolomide (TMZ) treatment, the prognosis for patients with glioblastoma multiforme is still dismal. As dose escalation of TMZ is limited by systemic toxicity, intratumoral delivery emerges as an attractive treatment modality, which may sustain cytotoxic drug concentrations intratumorally and induce immunogenic cell death. Both clinical and experimental gliomas have responded to immunotherapy, but the benefit of simultaneous chemo- and immunotherapy is inadequately studied. Here, we monitored survival of GL261-bearing C57BL/6 mice following a 3-day treatment with either intratumoral TMZ (micro-osmotic pump, 4.2 mg/kg/day) or systemic TMZ (i.p. injections, 50 mg/kg/day) alone, or combined with immunization using GM-CSF secreting GL261 cells. Peripheral and intratumoral leukocytes were analyzed by flow cytometry and immunohistochemistry. Intratumoral TMZ induced higher survival rate than systemic TMZ (45 vs. 8%). When T cells were depleted following intratumoral TMZ, the therapeutic effect was completely abrogated (0 % survival). Intratumoral TMZ synergistically increased survival rate of immunized mice (from 25 to 83%), while systemic TMZ failed (0%). While systemic TMZ induced a transient leukopenia, intratumoral TMZ and immunotherapy sustained the proliferation of CD8+ T cells and decreased the number of intratumoral immunosuppressive cells. In conclusion, intratumoral TMZ alone or in combination with immunotherapy could cure glioma-bearing mice, due to attenuation of local immunosuppression and increase in potential effector immune cells. PMID:23775421

Fritzell, Sara; Sandén, Emma; Eberstål, Sofia; Visse, Edward; Darabi, Anna; Siesjö, Peter

2013-09-01

317

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

PubMed Central

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

2010-01-01

318

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

SciTech Connect

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

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

2013-11-15

319

Importance of helper T-cell activation in dendritic cell-based anticancer immunotherapy  

PubMed Central

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. PMID:23894702

Schreibelt, Gerty; Bol, Kalijn F.; Aarntzen, Erik HJG; Gerritsen, Winald R; Punt, Cornelis JA; Figdor, Carl G; de Vries, I Jolanda M

2013-01-01

320

Cancer immunotherapy in children: How does it differ from approaches in adults?  

Cancer.gov

More often than not, cancer immunotherapies that work in adults are used in modified ways in children. Seldom are new therapies developed just for children, primarily because of the small number of pediatric patients relative to the adult cancer patient population. Depicted are members of NCI’s Pediatric Oncology Branch. From left: Drs. Crystal Mackall, Daniel Lee, and Alan Wayne

321

Emerging role of protectin (CD59) in humoral immunotherapy of solid malignancies.  

PubMed

Over the past two decades, complement (C)-activating monoclonal antibodies (mAb), directed to specific tumor-associated antigens (TAA), have been extensively utilized for passive immunotherapy of solid tumors of different histology. However, the clinical outcome of this therapeutic approach has been substantially disappointing; antigenic heterogeneity of neoplastic cells and their limited accessibility by therapeutic mAb, have been provided as substantial explanations for the poor clinical results obtained. Nevertheless, in light of the recent advances in the knowledge of the mechanisms regulating C-activity, it begins to be evident that membrane and soluble C-inhibitory proteins play a key role in the protection of neoplastic cells from C-attack, providing additional insights on biological features of transformed cells that may hamper the clinical efficacy of humoral immunotherapy. Among C-regulatory proteins investigated, this review will focus on protectin (CD59) that represents the main restriction factor of C-susceptibility of neoplastic cells from solid malignancies. In view of the functional role of CD59, we will describe its tissue distribution and biological features in malignant neoplasms; major emphasis will be given to cutaneous melanoma, in which the C-regulatory role of CD59 has been extensively investigated, and clinical approaches of humoral immunotherapy have been implemented. According to the available data, the foreseeable strategies to improve the therapeutic efficacy of humoral immunotherapy of solid malignancies will be discussed. PMID:10958054

Fonsatti, E; Altomonte, M; Coral, S; De Nardo, C; Lamaj, E; Sigalotti, L; Natali, P G; Maio, M

2000-01-01

322

Combining conventional chemotherapy and ?? T cell-based immunotherapy to target cancer-initiating cells  

PubMed Central

According to common beliefs, conventional anticancer chemotherapy is deleterious for the immune system. We have recently provided in vitro evidence indicating that conventional chemotherapy may potentiate, rather than impair, the long-term efficacy of ?? T cell-based anticancer immunotherapy. PMID:24244907

Todaro, Matilde; Meraviglia, Serena; Caccamo, Nadia; Stassi, Giorgio; Dieli, Francesco

2013-01-01

323

Maintenance venom immunotherapy administered at 3-month intervals is both safe and efficacious  

Microsoft Academic Search

Background: Maintenance venom immunotherapy (MVIT) is usually administered to patients with venom allergy at 4- to 6-week intervals for at least 3 to 5 years. The small number of studies assessing the possibility of extending the maintenance interval (MI) included either too small a population and patients with only vespid and not bee venom (BV) allergy or relied on reaction

Arnon Goldberg; Ronit Confino-Cohen

2001-01-01

324

Three Days Rush Venom Immunotherapy in Bee Allergy: Safe, Inexpensive and Instantaneously Effective  

Microsoft Academic Search

Background: Rush venom immunotherapy (VIT) is highly effective in vespid venom allergy, but comparable data regarding bee venom (BV) allergy are sparse. We evaluated its safety, efficacy and cost in BV-allergic patients. Methods: Conventional or rush VIT were offered to all patients with systemic reaction to insect sting. Rush VIT was also given to hyperreactive patients who failed to reach

Arnon Goldberg; Ayala Yogev; Ronit Confino-Cohen

2011-01-01

325

Different patterns of antigen-induced histamine release during immunotherapy in insect venom and pollen allergy  

Microsoft Academic Search

Antigen-induced histamine release from whole blood was shown to be a suitable parameter for the diagnosis of hypersensitivity in both patients allergic to bee or wasp venom as well as in patients suffering from seasonal tree pollen allergy. Although both groups were treated successfully by specific immunotherapy, only in patients with insect allergy venom induced histamine release decreased significantly during

H. G. Nüsslein; M. Kleinlein; B. Hemmerlein; J. R. Kalden

1986-01-01

326

Toward Maximizing Immunotherapy in Metastatic Castration-Resistant Prostate Cancer - Rationale for Combinatorial Approaches Using Chemotherapy  

PubMed Central

Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellular product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine GVAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true antitumor immunity. PMID:22662316

Slovin, Susan R.

2012-01-01

327

Tailored cancer immunotherapy using combinations of chemotherapy and a mixture of antibodies  

E-print Network

Tailored cancer immunotherapy using combinations of chemotherapy and a mixture of antibodies implicated in cell proliferation and in resistance of solid tumors to chemotherapy. We quantified ligand of chemotherapy to inhibit BxPC3 tumors in mice, we propose a gen- eral cancer therapeutic strategy that entails

Maoz, Shahar

328

Radiation-induced survival responses promote immunogenic modulation to enhance immunotherapy in combinatorial regimens  

PubMed Central

Tumor cells that survive radiation are more sensitive to T-cell-mediated lysis due to a spectrum of biological adaptations to cellular stress (defined as immunogenic modulation), including enhanced antigen processing and cell-surface presence of calreticulin. This mechanism can be exploited to maximize clinical benefit in patients receiving radiotherapy plus immunotherapy. PMID:25097803

Gameiro, Sofia R; Ardiani, Andressa; Kwilas, Anna; Hodge, James W

2014-01-01

329

Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape  

PubMed Central

Malignant melanoma is on the rise. There have been recent advances in targeted agents and immunotherapies that have improved the management and treatment of patients with advanced melanoma. This review discusses the clinical efficacy and unique side effects of targeted immunotherapy and the role of predictive biomarkers in better selection of patients who would derive most benefit from specific treatments. Additionally, this review addresses concerns about the best sequencing algorithms for the currently available targeted agents. By thoroughly and extensively researching through PubMed and the American Society of Clinical Oncology, 69 published articles and abstracts were identified as addressing topics related to malignant melanoma and immunotherapy. The research was divided into subcategories discussing cytokine-based therapy, immunotherapy, molecularly targeted agents, other novel targeted agents, and combination regimens for malignant melanoma. New immune checkpoint inhibitors and targeted agents are able to improve immune-mediated regulatory effects against tumors and, specifically in advanced melanoma, are associated with improvement in overall survival. These new agents have distinct side effects that are often controlled and reversed with dose reductions and/or use of corticosteroids. Currently, there are clinical trials underway to assess the role of combination therapy, whereas other trials are focusing on devising algorithms to delineate how best to sequentially administer these drugs. Although there has been tremendous progress in the management of advanced melanoma with immunotherapy and targeted agents, there is still much to be learned about clinically useful predictive biomarkers and combination therapies as well as how to administer these agents safely. PMID:25018651

Srivastava, Neeharika; McDermott, David

2014-01-01

330

Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation.  

PubMed

Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4(+) and CD8(+) T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8(+) T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM. PMID:24947180

De Keersmaecker, Brenda; Fostier, Karel; Corthals, Jurgen; Wilgenhof, Sofie; Heirman, Carlo; Aerts, Joeri L; Thielemans, Kris; Schots, Rik

2014-10-01

331

Mycobacterium poriferae infection in a psoriasis patient on anti-TNF-? therapy.  

PubMed

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. 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 TNF-? 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

2013-09-01

332

Multicentric reticulohistiocytosis associated arthritis responding to anti-TNF and methotrexate.  

PubMed

We present a patient with therapy resistant multicentric reticulohistiocytosis (MRH). MRH is a rare granulomatous, multisystem disease characterised most frequently by disfiguring papulonodular skin lesions and sometimes a destructive polyarthritis, though any organ can be involved. Abnormal histiocytic reactions to an undetermined stimulus (possibly an associated mycobacterial infection, auto immune process or neoplastic process) have been proposed as an underlying mechanism. The diagnosis is confirmed by histopathology of the cutaneous nodules and/or synovial membrane by the presence of CD68-positive histiocytes and multinucleated giant cells with an eosinophilic 'ground-glass' cytoplasm. Recent studies have identified TNFalpha and other inflammatory cytokines to be highly expressed in the synovium and synovial fluid of affected joints in patients with MRH. Based on these findings, we treated our patient with infliximab in combination with methotrexate with marked improvement of morning stiffness, tender and swollen joint count, visual analogue scale and health assessment questionnaire after his third infusion. However, the nodules did not markedly resolve. When treating patients with MRH with TNFa neutralizing drugs, one has to keep the possible association with malignancy in 15-30% of cases in mind and these products should be used with caution. PMID:21485770

De Knop, K J; Aerts, N E; Ebo, D G; Van Offel, J F; Stevens, W J; De Clerck, L S

2011-01-01

333

Ulcerative Necrobiosis Lipoidica: Is There a Place for Anti-TNF? Treatment?  

PubMed Central

Necrobiosis lipoidica is a rare granulomatous and inflammatory disease. Its management is particularly difficult when ulceration is present. The authors describe the clinical case of a 65-year-old female patient with necrobiosis lipoidica, who had been submitted in the past to several topical and systemic treatments with little or no improvement. She started treatment with subcutaneous etanercept and showed significant improvement without adverse events until today. The aim of this article is to report a valid and efficient alternative treatment to recalcitrant cases. PMID:22675367

Guedes, Rita; Leite, Ines; Baptista, Armando; Rocha, Natividade

2012-01-01

334

A potential therapeutic effect of CYP2C8 overexpression on anti-TNF-? activity  

PubMed Central

Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid catalysed by cytochrome P450 (CYP) epoxygenases. In addition to regulating vascular tone EETs may alleviate inflammation and ROS. The present study was conducted to determine whether CYP2C8 gene overexpression was able to increase the level of EETs, and subsequently prevent TNF-? induced inflammation and reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) and macrophages. Peroxisome proliferator-activated receptor ? (PPAR?) activation, nuclear factor-?B (NF-?B) activation, endothelial nitric oxide synthase (eNOS) activation, gp-91 activation, and inflammatory cytokine expression were detected by western blot analysis or enzyme-linked immunosorbent assay. Intracellular reactive oxygen species (ROS) was measured by flow cytometry, while the migration of vascular smooth muscle cells (VSMCs) was detected by Transwell assay. pCMV-mediated CYP2C8 overexpression and its metabolites, EETs, markedly suppressed TNF-? induced inflammatory cytokines IL-6 and MCP-1 expression via the activation of NF-?B and degradation of I?B?. Moreover, pretreatment with 11,12-EET significantly blocked TNF-?-induced ROS production. CYP2C8-derived EETs also effectively alleviated the migration of VSMCs and improved the function of endothelial cells through the upregulation of eNOS, which was significantly decreased under the stimulation of TNF-?. Furthermore, these protective effects observed were mediated by PPAR? activation. To the best of our knowledge, the results of the present study demonstrated for the first time that CYP2C8-derived EETs exerted antivascular inflammatory and anti-oxidative effects, at least in part, through the activation of PPAR?. Thus, the CYP2C8 gene may be useful in the prevention and treatment of vascular inflammatory diseases. PMID:25017038

LIU, WANJUN; WANG, BEI; DING, HU; WANG, DAO WEN; ZENG, HESONG

2014-01-01

335

Long-term Effects of Specific Allergen Immunotherapy Against House Dust Mites in Polysensitized Patients With Allergic Rhinitis  

PubMed Central

Purpose Allergen-specific immunotherapy is the only currently available treatment to modify the natural history of allergic rhinitis (AR). If patients are polysensitized, it is difficult to identify the allergen causing the allergic symptoms. We evaluated the effectiveness of immunotherapy against house dust mites (HDMs) in AR patients polysensitized to both HDMs and seasonal allergens. Methods Thirty AR patients polysensitized to both HDMs and seasonal allergens (group A) and 30 patients sensitized to HDMs only (group B) were enrolled in this study. All subjects who received immunotherapy against HDMs for more than 2 years were evaluated by the multiple allergen simultaneous test (MAST) to determine the specific IgE level in luminescence units, total eosinophil counts in peripheral blood, serum total IgE, total nasal symptom scores, and the rhinoconjunctivitis quality of life questionnaire (RQLQ) before and after immunotherapy. Results There were no statistical differences in levels of total and specific IgE, or total eosinophil count between the two groups. The total nasal symptom scores, RQLQ and medication scores significantly decreased after immunotherapy in both groups, however no significant differences were noted between the two groups. Conclusions We determined that the primary causative allergen of AR in Seoul, Korea is perennial allergens, such as HDMs, rather than seasonal allergens. This study provides a reference for the selection of allergens to use in immunotherapy for polysensitized AR patients living in an urban environment. PMID:25374753

Kim, Sang Hoon; Lee, Kun Hee; Kim, Sung Wan; Cho, Joong Saeng

2014-01-01

336

A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer  

PubMed Central

Purpose A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer. Experimental Design T cells with reactivity against the ovarian cancer – associated antigen ?-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor ? chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells. Results Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells. Conclusions Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer. PMID:17062687

Kershaw, Michael H.; Westwood, Jennifer A.; Parker, Linda L.; Wang, Gang; Eshhar, Zelig; Mavroukakis, Sharon A.; White, Donald E.; Wunderlich, John R.; Canevari, Silvana; Rogers-Freezer, Linda; Chen, Clara C.; Yang, James C.; Rosenberg, Steven A.; Hwu, Patrick

2007-01-01

337

Granulomatous prostatitis following bacillus Calmette-Guerin immunotherapy of bladder cancer.  

PubMed

Granulomatous prostatitis is a recognized complication of intravesical bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. Of 32 patients receiving such therapy 13 underwent prostatic core biopsy and/or fine needle aspiration for clinical indications. Prostatic induration or nodularity developed in 12 patients and 1 underwent biopsy for staging of known prostatic carcinoma. Granulomatous prostatitis was found in 100 per cent of those patients who underwent biopsy or aspiration, indicating that the incidence of this finding is at least 41 per cent following bacillus Calmette-Guerin immunotherapy. Acid-fast bacilli were demonstrated within the prostate of 3 patients with granulomatous prostatitis. The mean interval between the initiation of therapy and diagnosis of granulomatous prostatitis was 11.5 months. Bacillus Calmette-Guerin related granulomas of the prostate may be differentiated histologically from nonspecific granulomatous prostatitis, allergic prostatitis and postoperative granulomas. The clinical implications of these findings are discussed. PMID:3418796

Oates, R D; Stilmant, M M; Freedlund, M C; Siroky, M B

1988-10-01

338

Targeting Activation Induced Cytidine Deaminase Overcome Tumor Evasion of Immunotherapy by Cytotoxic T Lymphocytes  

PubMed Central

Activation induced cytidine deaminase (AID) is an enzyme essential for the generation of antibody diversity in B cells and is considered to be a general gene mutator. In addition, AID expression was also implicated in the pathogenesis of human B cell malignancies and associated with poor prognosis. Here we report that siRNA silencing of AID in plasmacytoma dramatically increased its susceptibility to immunotherapy by cytotoxic T lymphocytes. AID silencing did not decrease the mutation frequencies of tumor antigen gene P1A. Gene-array analysis showed dramatically altered expression of a number of genes in AID-silenced plasmacytoma cells and upregulation of CD200 was shown to be in favor of tumor eradication by CTL. Taken together, we demonstrate a novel function of AID in tumor evasion of CTL therapy and that targeting AID should be beneficial in the immunotherapy of AID positive tumors. PMID:20404277

Liu, Jin-Qing; Joshi, Pramod S.; Wang, Chuansong; El-Omrani, Hani Y.; Xiao, Yi; Liu, Xiuping; Hagan, John P.; Liu, Chang-Gong; Wu, Lai-Chu; Bai, Xue-Feng

2010-01-01

339

Cancer immunotherapy in clinical practice--the past, present, and future  

PubMed Central

Considerable progress has been made in the field of cancer immunotherapy in recent years. This has been made possible in large part by the identification of new immune-based cellular targets and the development of novel approaches aimed at stimulating the immune system. The role played by the immunosuppressive microenvironment in the development of tumors has been established. The success of checkpoint-inhibiting antibodies and cancer vaccines has marked the beginning of a new era in cancer treatment. This review highlights the clinically relevant principles of cancer immunology and various immunotherapeutic approaches that have either already entered mainstream oncologic practice or are currently in the process of being evaluated in clinical trials. Furthermore, the current barriers to the development of effective immunotherapies and the potential strategies of overcoming them are also discussed. PMID:25189717

Goel, Gaurav; Sun, Weijing

2014-01-01

340

Omalizumab in the prevention of anaphylaxis during immunotherapy: a case report  

PubMed Central

Omalizumab is approved for the treatment of chronic severe persistent asthma. As a trigger for anaphylaxis, the frequency of subcutaneous specific immunotherapy (SCIT) is high. We report the case of a 11-year-old boy with severe allergic asthma. During the initial phase of immunotherapy he experienced anaphylaxis and SCIT was discontinued. Because of uncontrolled asthma, despite the inhaled steroids and ?-agonists were taken into consideration, omalizumab 300 mg once every 4 weeks was initiated. Currently, the maintenance dose has been reached and SCIT is continued without any side effects. The clinical implication of the above case report is that children with severe allergic asthma who are pre-treated with omalizumab might also benefit in the future from SIT as a causal treatment option. PMID:25097493

Sztafinska, Anna; Woicka-Kolejwa, Katarzyna; Jerzynska, Joanna

2014-01-01

341

IMA901 for metastatic renal cell carcinoma in the context of new approaches to immunotherapy.  

PubMed

The promising option of immunotherapy for metastatic renal cell carcinoma has evolved from rather unspecific approaches to a specific activation of an anti-tumor T-cell response. The latest step is a synthetic peptide vaccine called IMA901, which demonstrated a clear association between a provoked T-cell response and a prolonged overall survival. The results of IMA901 for the treatment of metastatic renal cell carcinoma are discussed together with new approaches to immunotherapy, such as local and systemic immunomodulation with adjuvants, checkpoint inhibitors, classical chemotherapeutics, such as cyclophosphamide or tyrosine kinase inhibitors. The capability of theses substances to modulate leukocytes subsets, such as myeloid-derived suppressor cells, Tregs or Th17 cells, are outlined together with the possibility to combine them with tumor vaccination strategies to achieve a higher cancer specificity and immunogenicity. PMID:24941980

Rausch, Steffen; Kruck, Stephan; Stenzl, Arnulf; Bedke, Jens

2014-05-01

342

Cancer Immunotherapy Utilized Bubble Liposomes and Ultrasound as Antigen Delivery System  

NASA Astrophysics Data System (ADS)

In dendritic cells (DCs)-based cancer immunotherapy, it is important to present the epitope peptide derived from tumor associated antigens (TAAs) on MHC class I in order to induce tumor specific cytotoxic T lymphocytes (CTLs). However, MHC class I molecules generally present the epitope peptides derived from endogenous antigens for DCs but not exogenous ones such as TAAs. Recently, we developed the novel liposomal bubbles (Bubble liposomes) encapsulating perfluoropropane nanobubbles. In this study, we attempted to establish the novel antigen delivery system to induce MHC class I presentation using the combination of ultrasound and Bubble liposomes. Using ovalbumin (OVA) as model antigen, the combination of Bubble liposomes and ultrasound exposure for the DC could induce MHC class I presentation. In addition, the viability of DCs was more than 80%. These results suggest that Bubble liposomes might be a novel ultrasound enhanced antigen delivery tool in DC-based cancer immunotherapy.

Oda, Yusuke; Otake, Shota; Suzuki, Ryo; Otake, Shota; Nishiie, Norihito; Hirata, Keiichi; Taira, Yuichiro; Utoguchi, Naoki; Maruyama, Kazuo

2010-03-01

343

Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies.  

PubMed

Ingenol-3-angelate is a new local chemotherapeutic agent in clinical trails that induces primary necrosis of tumour cells and transient local inflammation. Here we show that cure of subcutaneous tumours with ingenol-3-angelate (PEP005) resulted in the generation of anti-cancer CD8 T cells that could regress metastases. Furthermore, PEP005-mediated cure synergized with several CD8 T cell-based immunotherapies to regress further distant metastases. PEP005 was shown to have adjuvant properties, being able to upregulate CD80 and CD86 expression on dendritic cells in vivo, and to promote CD8 T cell induction when co-delivered with a protein antigen. PEP005 thus emerges as a unique local chemotherapeutic immunostimulatory debulking agent that could be used in conjunction with immunotherapies to promote regression of metastases. PMID:19428919

Le, Thuy T T; Gardner, Joy; Hoang-Le, Diem; Schmidt, Chris W; MacDonald, Kelli P; Lambley, Eleanore; Schroder, Wayne A; Ogbourne, Steven M; Suhrbier, Andreas

2009-05-18

344

Retrospective study of clinical observations on insect hypersensitivity and response to immunotherapy in allergic dogs.  

PubMed

A retrospective study was conducted to evaluate the importance of insect hypersensitivity in atopic dogs in the northeastern United States. Fifty (63%) of 79 dogs tested with 7 insect allergens, other than flea, had positive reactions to one or more insects. No dog had positive reactions to insects only. Forty-four dogs underwent immunotherapy. Thirty-one had insect antigens in their prescription mixture and 13 had only conventional environmental allergens. There was no statistical difference in the response rate between the 2 groups. Thus, testing with insect allergens did not decrease the number of dogs with negative skin tests, and including insect allergens in immunotherapy mixtures did not improve the response rate. PMID:11360857

Rothstein, E; Miller, W H; Scott, D W; Mohammed, H O

2001-05-01

345

Maintenance treatment with chemotherapy and immunotherapy in non-small cell lung cancer: a case report  

PubMed Central

A 53-years-old woman was diagnosed with lung adenocarcinoma state IV (synchronous pleural involvement) in April 2009. First-line systemic treatment included six cycles of Carboplatin, Paclitaxel, and Bevacizumab. Partial response was achieved. Maintenance therapy with Bevacizumab and Pemetrexed was given from September 2009 to February 2010. No response changes were observed. Immunotherapy was initiated, and then Pemetrexed was given with the same disease status. Both treatments were well tolerated. Immunotherapy toxicity included reaction at the site of injection grade 2. At present, the patient is still on this treatment. Given the poor prognosis of patients with advanced lung cancer, the combination of both treatments during the stable phase of the disease may improve progression-free survival. PMID:23112957

Llanos, Anabella; Savignano, Mariana; Cinat, Gabriela

2012-01-01

346

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

PubMed Central

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-? (TGF-?), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-? inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses. PMID:22797827

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

2013-01-01

347

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

PubMed

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

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

2014-11-17

348

Progress in the development of specific immunotherapies for house dust mite allergies.  

PubMed

Allergen-specific immunotherapy is used to treat patients exposed and co-sensitized to the two common house dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae. Based on seroepidemiological studies and a detailed characterization of mite allergens, an optimal immunotherapeutic product should associate extracts from the two Dermatophagoides species, and include both bodies and fecal particles. Both subcutaneous and sublingual immunotherapies performed with aqueous mite extracts are safe and efficacious in children and adults with mite-induced rhinitis and/or asthma. Double-blind placebo-controlled studies are conducted to further document the efficacy of immunotherapeutic products, with promising results that were obtained already with sublingual tablets. Current developments of second-generation products relying upon recombinant allergens and peptides are reviewed. PMID:25187166

Moingeon, Philippe

2014-12-01

349

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy  

PubMed Central

The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4+ and CD8+ T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8+ T-cell–dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies. PMID:23045683

Huang, Yuhui; Yuan, Jianping; Righi, Elda; Kamoun, Walid S.; Ancukiewicz, Marek; Nezivar, Jean; Santosuosso, Michael; Martin, John D.; Martin, Margaret R.; Vianello, Fabrizio; Leblanc, Pierre; Munn, Lance L.; Huang, Peigen; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.; Poznansky, Mark C.

2012-01-01

350

Adjuvants and the promotion of Th1-type cytokines in tumour immunotherapy  

Microsoft Academic Search

Immunotherapy includes both active and passive mechanisms that have the potential to treat many tumour types. Whereas monoclonal antibodies may kill cells by merely binding to them, 'cancer vaccines' involve the induction of an active immune response. The activation of tumour antigen-specific T-helper and cytotoxic T lymphocytes or non-specific macrophages and natural killer (NK) cells using immunotherapeutic approaches may lead

Keith Dredge; Blake J. Marriott; Stephen M. Todryk; Angus G. Dalgleish

2002-01-01

351

Anti-inflammatory pretreatment enables an efficient dendritic cell-based immunotherapy against established tumors  

Microsoft Academic Search

Although animals can be immunized against the growth of some tumor implants, most of the attempts to use immunotherapy to\\u000a cause the regression of animal and human tumors once they have become established have been disappointing even when strongly\\u000a immunogenic tumors were used as target. In this paper, we demonstrate that the failure to achieve an efficient immunological\\u000a treatment against

Paula Chiarella; Marisa Vulcano; Juan Bruzzo; Mónica Vermeulen; Silvia Vanzulli; Andrea Maglioco; Gabriela Camerano; Víctor Palacios; Gabriela Fernández; Romina Fernández Brando; Martín A. Isturiz; Graciela I. Dran; Oscar D. Bustuoabad; Raúl A. Ruggiero

2008-01-01

352

Immunology in the clinic review series; focus on cancer: glycolipids as targets for tumour immunotherapy  

PubMed Central

Research into aberrant glycosylation and over-expression of glycolipids on the surface of the majority of cancers, coupled with a knowledge of glycolipids as functional molecules involved in a number of cellular physiological pathways, has provided a novel area of targets for cancer immunotherapy. This has resulted in the development of a number of vaccines and monoclonal antibodies that are showing promising results in recent clinical trials. PMID:22235996

Durrant, L G; Noble, P; Spendlove, I

2012-01-01

353

Alternative Concepts of Suicide Gene Therapy for Graft-versus-Host Disease after Adoptive Immunotherapy  

Microsoft Academic Search

T-cell suicide gene therapy represents a promising novel treatment strategy for graft-versus-host disease following adoptive immunotherapy after allogeneic hematopoietic stem cell transplantation. The clinical efficiency of this approach is still hampered by several obstacles including induction of alloresponses due to the use of immunogenic suicide and selection genes, genetic inactivation of suicide genes, and functional immunological impairment after retroviral transduction

Christof M. Kramm

2003-01-01

354

Impact of Sublingual Immunotherapy on Specific Antibody Levels in Asthmatic Children Allergic to House Dust Mites  

Microsoft Academic Search

Objective: To evaluate the clinical outcome and changes in allergen-specific antibodies during sublingual immunotherapy (SLIT) in house dust mite (HDM)-allergic asthma patients and to compare levels of allergen-specific antibodies in HDM-allergic patients before and after treatment with that of healthy controls. Method: Thirty-one asthma patients allergic to HDM were studied. Patients in groups I (n = 17) and II (n

Nerin N. Bahceciler; Cigdem Arikan; Alison Taylor; Mubeccel Akdis; Kurt Blaser; Isil B. Barlan; Cezmi A. Akdis

2005-01-01

355

Patients on subcutaneous allergen immunotherapy are at risk of intramuscular injections  

PubMed Central

Background Allergen-specific subcutaneous immunotherapy is an effective treatment for certain allergic disorders. Ideally, it should be administered into the subcutaneous space in the mid-posterolateral upper arm. Injections are commonly given using a standard allergy syringe with a needle length of 13 mm. Therefore, there is a risk of intramuscular administration if patients have a skin-to-muscle depth <13 mm, which may increase the risk of anaphylaxis. The objective of this study was to determine whether the needle length of a standard allergy syringe is appropriate for patients receiving subcutaneous immunotherapy. Methods Ultrasounds of the left posterolateral arm were performed to measure skin-to-muscle depth in 200 adults receiving subcutaneous immunotherapy. The proportion of patients with a skin-to-muscle depth >13 mm vs. ?13 mm was assessed and baseline characteristics of the two groups were compared. The proportion of patients with skin-to-muscle depths?>?4 mm, 6 mm, 8 mm and 10 mm were also calculated. Multivariable logistic regression was performed to identify predictors of skin-to-muscle depth. Results Of the 200 patients included in the study, 80% had a skin-to-muscle depth ?13 mm; the majority (91%) had a skin-to-muscle depth >4 mm. Body mass index was found to be a significant predictor of skin-to-muscle-depth. Conclusions Most patients receiving subcutaneous immunotherapy have a skin-to-muscle depth less than the needle length of a standard allergy syringe (13 mm). These patients are at risk of receiving injections intramuscularly, which may increase the risk of anaphylaxis. Using a syringe with a needle length of 4 mm given at a 45° angle to the skin may decrease this risk. PMID:24822074

2014-01-01

356

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

PubMed Central

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

2014-01-01

357

Immunotherapy for pythiosis: Effect on NTPDase activity in lymphocytes of an experimental model  

Microsoft Academic Search

NTPDase (EC 3.6.1.5) occurs in lymphocytes and plays an important role in immune function, in that hydrolyzes extracellular nucleoside tri- and\\/or diphosphates to form AMP. Pythium insidiosum causes the disease pythiosis, a pyogranulomatous disease of horses, dogs, cattle, cats and humans. Most antifungal drugs are ineffective against this pathogen, and immunotherapy, a treatment approach that relies on the injection of

Barbara Charlotte Bach; Daniela Bitencourt Rosa Leal; Jader Betsch Ruchel; Viviane do Carmo Gonçalves Souza; Grazieli Maboni; Marcelo Dal Pozzo; Karine Bizzi Schlemmer; Sydney Hartz Alves; Janio Morais Santurio

2010-01-01

358

Analysis of HLA class I expression in progressing and regressing metastatic melanoma lesions after immunotherapy  

Microsoft Academic Search

Despite the potential efficacy of cancer immunotherapy in preclinical studies, it did not show yet significant positive clinical\\u000a results in humans with only a small number of cancer patients demonstrating objective tumor regression. This poor clinical\\u000a outcome can be explained by the generation of sophisticated tumor immune escape mechanism, in particular, abnormalities in\\u000a the expression of HLA class I antigens.

Rafael Carretero; José M. Romero; Francisco Ruiz-Cabello; Isabel Maleno; Felix Rodriguez; Francisco M. Camacho; Luis M. Real; Federico Garrido; Teresa Cabrera

2008-01-01

359

NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy  

Microsoft Academic Search

Insights into the molecular basis for natural killer (NK) cell recognition of human cancer have been obtained in recent years.\\u000a Here, we review current knowledge on the molecular specificity and function of human NK cells. Evidence for NK cell targeting\\u000a of human tumors is provided and new strategies for NK cell-based immunotherapy against human cancer are discussed. Based on\\u000a current

Karl-Johan Malmberg; Yenan T. Bryceson; Mattias Carlsten; Sandra Andersson; Andreas Björklund; Niklas K. Björkström; Bettina C. Baumann; Cyril Fauriat; Evren Alici; M. Sirac Dilber; Hans-Gustaf Ljunggren

2008-01-01

360

Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines  

Microsoft Academic Search

This Review deals with recent progress in the immunotherapy of established (pre)malignant disease of viral or non-viral origin by synthetic vaccines capable of inducing robust T-cell responses. The most attractive vaccine compounds are synthetic long peptides (SLP) corresponding to the sequence of tumour viral antigens or tumour-associated non-viral antigens. Crucial to induction of therapeutic T-cell immunity is the capacity of

Cornelis J. M. Melief; Sjoerd H. van der Burg

2008-01-01

361

Intralymphatic Injections as a New Administration Route for Allergen-Specific Immunotherapy  

Microsoft Academic Search

Background: IgE-mediated allergy can be treated by subcutaneous allergen-specific immunotherapy (SIT). However, the percentage of allergic patients undergoing SIT is low, mainly due to the long duration of the therapy and the risk of severe systemic allergic reactions associated with the allergen administration. To improve the safety and attractiveness of SIT for patients, alternative routes of allergen administration are being

Julia M. Martínez-Gómez; Pål Johansen; Iris Erdmann; Gabriela Senti; Reto Crameri; Thomas M. Kündig

2009-01-01

362

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

PubMed Central

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

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

2008-01-01

363

ADAM10 Inhibition of Human CD30 Shedding Increases Specificity of Targeted Immunotherapy In vitro  

Microsoft Academic Search

CD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleav- age of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)-

Dennis A. Eichenauer; Vijaya Lakshmi Simhadri; Elke Pogge von Strandmann; Andreas Ludwig; Vance Matthews; Katrin S. Reiners; Bastian von Tresckow; Paul Saftig; Stefan Rose-John; Andreas Engert; Hinrich P. Hansen

364

Robust amyloid clearance in a mouse model of AD provides novel insights into the mechanism of A? immunotherapy  

PubMed Central

Many new therapeutics for Alzheimer's disease delay the accumulation of A? in transgenic mice, but evidence for clearance of pre-existing plaques is often lacking. Here we demonstrate that anti-A? immunotherapy combined with suppression of A? synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP mice with doxycycline to suppress transgenic A? production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for 3 months afterwards to assess whether improvements attained during combined treatment could be maintained by monotherapy. This strategy reduced amyloid load by 52% and A?42 content by 28% relative to pre-treatment levels, with preferential clearance of small deposits and diffuse A? surrounding fibrillar cores. We demonstrate that peripherally administered anti-A? antibody crossed the blood-brain barrier, bound to plaques, and was still be found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain independent of plasma A? levels, where it enhanced microglial internalization of aggregated A?. Our data support a mechanism by which passive immunization acts centrally to stimulate microglial phagocytosis of aggregated A?, but is opposed by the continued aggregation of newly secreted A?. By arresting the production of A?, combination therapy allows microglial clearance to work from a static amyloid burden towards a significant reduction in plaque load. Our findings suggest that combining two therapeutic approaches currently in clinical trials may improve neuropathological outcome over either alone. PMID:21411653

Wang, Allan; Das, Pritam; Switzer, Robert C.; Golde, Todd E.; Jankowsky, Joanna L.

2011-01-01

365

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

PubMed Central

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

Wang, Xiang-Yang; Subjeck, John R.

2013-01-01

366

Novel Strategies for Immunotherapy in Multiple Myeloma: Previous Experience and Future Directions  

PubMed Central

Multiple myeloma (MM) is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation is a relatively effective treatment, but residual malignant sites may cause relapse. Allogeneic transplantation may result in durable responses due to antitumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-versus-host disease remain a challenge. Recent advances in understanding the interaction between the immune system of the patient and the malignant cells are influencing the design of clinically more efficient study protocols for MM. Cellular immunotherapy using specific antigen-presenting cells (APCs), to overcome aspects of immune incompetence in MM patients, has received great attention, and numerous clinical trials have evaluated the potential for dendritic cell (DC) vaccines as a novel immunotherapeutic approach. This paper will summarize the data investigating aspects of immunity concerning MM, immunotherapy for patients with MM, and strategies, on the way, to target the plasma cell more selectively. We also include the MM antigens and their specific antibodies that are of potential use for MM humoral immunotherapy, because they have demonstrated the most promising preclinical results. PMID:22649466

Danylesko, Ivetta; Beider, Katia; Shimoni, Avichai; Nagler, Arnon

2012-01-01

367

Intracavitary Immunotherapy and Chemotherapy for Upper Urinary Tract Cancer: Current Evidence  

PubMed Central

A review of the literature was performed to summarize current evidence regarding the efficacy of topical immunotherapy and chemotherapy for upper urinary tract urothelial cell carcinoma (UUT-UCC) in terms of post-treatment recurrence rates. A Medline database literature search was performed in March 2012 using the terms upper urinary tract, urothelial cancer, bacillus Calmette-Guérin (BCG), and mitomycin C. A total of 22 full-text articles were assessed for eligibility, and 19 studies reporting the outcomes of patients who underwent immunotherapy or chemotherapy with curative or adjuvant intent for UUT-UCC were chosen for quantitative analysis. Overall, the role of immunotherapy and chemotherapy for UUT-UCC is not firmly established. The most established practice is the treatment of carcinoma in situ (CIS) with BCG, even if a significant advantage has not yet been proven. The use of BCG as adjuvant therapy after complete resection of papillary UUT-UCC has been studied less extensively, even if recurrence rates are not significantly different than after the treatment of CIS. Only a few reports describe the use of mitomycin C, making it difficult to obtain significant evidence. PMID:24659911

Carmignani, Luca; Bianchi, Roberto; Cozzi, Gabriele; Grasso, Angelica; Macchione, Nicola; Marenghi, Carlo; Melegari, Sara; Rosso, Marco; Tondelli, Elena; Maggioni, Augusto

2013-01-01

368

Lack of neo-sensitization to Pen a 1 in patients treated with mite sublingual immunotherapy  

PubMed Central

Background Some studies reported the possible induction of food allergy, caused by neo-sensitization to cross-reacting allergens, during immunotherapy with aeroallergens, while other studies ruled out such possibility. Objectives The aim of this study was to evaluate the development of neo-sensitization to Pen a 1 (tropomyosin) as well as the appearance of reactions after ingestion of foods containing tropomyosin as a consequence of sublingual mite immunization. Materials and methods Specific IgE to Tropomyosin (rPen a 1) before and after mite sublingual immunotherapy in 134 subjects were measured. IgE-specific antibodies for mite extract and recombinant allergen Pen a 1 were evaluated using the immunoenzymatic CAP system (Phadia Diagnostics, Milan, Italy). Results All patients had rPen a 1 IgE negative results before and after mite SLIT and did not show positive shrimp extract skin reactivity and serological rPen a 1 IgE conversion after treatment. More important, no patient showed systemic reactions to crustacean ingestion. Conclusions Patients did not show neo-sensitization to tropomyosin, a component of the extract (namely mite group 10) administered. An assessment of a patient's possible pre-existing sensitisation to tropomyosin by skin test and/or specific IgE prior to start mite extract immunotherapy is recommended. Trial Registration This trial is registered in EudraCT, with the ID number of 2010-02035531. PMID:20230633

2010-01-01

369

[Granulomatous pneumonia as a complication of intravesical BCG immunotherapy--a case report].  

PubMed

BCG (Bacillus Calmette-Guerin) comprises an attenuated strain of Mycobacterium bovis and is used for vaccination against tuberculosis. An additional use of BCG is for immunotherapy of cancer in which the vaccine is administered intravesically for the treatment of superficial bladder cancer. The efficacy of immunotherapy with BCG in the prevention of recurrence is estimated at 70-99%, which is higher than for local chemotherapy. The most frequent complications of such treatment include fever and urinary bladder inflammation, while serious complications of haematogenous organ inflammation, especially inflammation of the lungs with the formation of pulmonary caseosus granulomas, are rarely seen. The authors reported a case of a 68-year-old man who was treated with intravesical BCG instillations due to a superficial bladder cancer. The patient underwent transurethral resection of bladder cancer and then periodically received intravesical BCG instillations. A few days after one instillation, systemic symptoms with a high fever appeared. Further examinations showed features of hepatitis and spread pulmonary changes. The patient underwent videothoracoscopy, and a fragment of lung parenchyma was collected. The histopathological examination revealed the presence of granulomas with central caseosus necrosis. Suspecting BCG infection, diagnostics were enhanced to include bacteriological and genetic tests for the presence of acid-resistant bacilli, which finally gave negative results. The authors diagnosed granulomatous pneumonia as a complication of intravesical BCG immunotherapy. Treatment with antituberculous drugs was initiated. After completing pharmacological treatment, radiological control was performed, which showed significant but not complete remission of pulmonary changes. PMID:24615200

Rogozi?ski, Pawe?; Taracha-Guz, Daria; P?cikiewicz, Pawe?; Kachel, Tomasz; Dubiel, Grzegorz; Wandzel, Piotr; Bruli?ski, Krzysztof

2014-01-01

370

Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model.  

PubMed

Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-? (A?) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first A? vaccination trial suggest that this approach has limited effect on tau pathology and that A? plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe whether targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L presenilin mutation. Here, we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future. PMID:21147995

Boutajangout, Allal; Quartermain, David; Sigurdsson, Einar M

2010-12-01

371

Analysis of HLA class I expression in progressing and regressing metastatic melanoma lesions after immunotherapy.  

PubMed

Despite the potential efficacy of cancer immunotherapy in preclinical studies, it did not show yet significant positive clinical results in humans with only a small number of cancer patients demonstrating objective tumor regression. This poor clinical outcome can be explained by the generation of sophisticated tumor immune escape mechanism, in particular, abnormalities in the expression of HLA class I antigens. We have studied the expression of HLA class I antigens in ten metastatic lesions obtained from a melanoma patient undergoing immunotherapy. Five lesions were obtained after Interferon-alpha-2b treatment and five after autologous vaccination plus BCG (M-VAX). Eight metastases were regressing after immunotherapy while two were progressing. The eight regressing metastases showed high level of HLA class I expression, whereas the two progressing lesions had low levels as measured by real time PCR and immunohistological techniques. These results indicate a strong association between HLA class I expression and progression or regression of the metastatic lesions. Our data support the hypothesis that the level of HLA class I expression is an important parameter of tumor immune escape that needs to be monitored. PMID:18545995

Carretero, Rafael; Romero, José M; Ruiz-Cabello, Francisco; Maleno, Isabel; Rodriguez, Felix; Camacho, Francisco M; Real, Luis M; Garrido, Federico; Cabrera, Teresa

2008-08-01

372

Ranking in importance of allergen extract characteristics for sublingual immunotherapy by Italian specialists.  

PubMed

The efficacy of allergen immunotherapy (AIT) is well supported by evidence from trials and meta-analyses. However, its actual performance in daily practice may be diminished by several pitfalls, including inappropriate patient selection, and, especially, the use of allergen extracts of insufficient quality. We performed a survey, the Allergen Immunotherapy Decision Analysis, to evaluate which criteria specialists use to choose products for sublingual immunotherapy (SLIT) in adult patients suffering from allergic respiratory disease. We surveyed a total of 169 Italian allergists randomly chosen from a database belonging to a market research company (Lexis Ricerche, Milan, Italy). The survey was performed between October and November 2012 under the aegis of the European Center for Allergy Research Foundation and consisted of a questionnaire-based electronic survey prepared by a scientific board of 12 AIT experts. The questionnaire comprised two parts, the first of which contained 14 items to be ranked by each participant according to the importance assigned to each when choosing SLIT products. The physicians' rankings assigned major importance to the level of evidence-based validation of efficacy and safety, standardization of the product, efficacy based on personal experience, and defined content(s) of the major allergen(s) in micrograms. The results of this survey show that Italian allergists rank the quality-related characteristics of allergen extracts as highly important when choosing products for AIT. The allergists' preference for high-quality products should be addressed by regulatory agencies and by producers. PMID:24433596

Canonica, Giorgio Walter; Passalacqua, Giovanni; Incorvaia, Cristoforo; Cadario, Gianni; Fiocchi, Alessandro; Senna, Gianenrico; Rossi, Oliviero; Romano, Antonino; Scala, Enrico; Romano, Catello; Ingrassia, Antonino; Zambito, Marcello; Dell'Albani, Ilaria; Frati, Franco

2014-01-01

373

92 Serum CTLA-4 AND IL-10 in Hymenoptera Venom Immunotherapy: Equivalence of Different Induction Regimens  

PubMed Central

Background Cytotoxic T lymphocyte associated gene-4 (CTLA-4) is involved in the activation pathways of T lymphocytes. It has been shown that the circulating form of CTLA-4 is elevated in patients with hymenoptera allergy and can be downregulated by immunotherapy. We assessed the effects on CTLA4 of venom immunotherapy given by different induction protocols (classic, rush or ultra rush). Methods Sera from patients with hymenoptera allergy were collected at baseline and at the end of the induction phase. In the classical regimen, the induction lasted 6 weeks, in the rush protocol it lasted 3 days, and in the ultra-rush maintenance was achieved in 24 hours. Soluble IL-10 was assayed in the same samples for comparison. CTLA-4 and IL10 were measured by commercial immuoassays. Results Seventy-six patients (52 male, mean age 35 years) were studied. Of them, 30 underwent the classic induction, 22 the rush and 24 the ultra rush. Soluble CTLA-4 was detectable in all patients at baseline, and significantly decreased at the end of the induction in all groups, thus irrespective of its duration. Of note, a significant decrease of sCTLA-4 could be seen already at 24 hours. In parallel, the same behaviour was observed with IL-10 that significantly increased at the end of the induction. Conclusions Soluble CTLA-4 is a useful immunological marker of the effect of immunotherapy for hymenoptera allergy. From an immunologic point of view, there is no difference among the various protocol of induction.

Riccio, Anna Maria; Saverino, Daniele; Rogkakou, Anthi; Bagnasco, Marcello; Bonadonna, Patrizia; Canonica, Giorgio Walter; Ridolo, Erminia; Severino, Maurizio; Pesce, Giampaola; Passalacqua, Giovanni

2012-01-01

374

Regulation of cancer germline antigen gene expression: implications for cancer immunotherapy  

PubMed Central

Cancer germline (CG; also known as cancer-testis) antigen genes are normally expressed in germ cells and trophoblast tissues and are aberrantly expressed in a variety of human malignancies. CG antigen genes have high clinical relevance as they encode a class of immunogenic and highly selective tumor antigens. CG antigen-directed immunotherapy is undergoing clinical evaluation for the treatment of a number of solid tumor malignancies and has been demonstrated to be safe, provoke immune responses and be of therapeutic benefit. Achieving an improved understanding of the mechanisms of CG antigen gene regulation will facilitate the continued development of targeted therapeutic approaches against tumors expressing these antigens. Substantial evidence suggests epigenetic mechanisms, particularly DNA methylation, as a primary regulator of CG antigen gene expression in normal and cancer cells as well as in stem cells. The roles of sequence-specific transcription factors and signal transduction pathways in controlling CG antigen gene expression are less clear but are emerging. A combinatorial therapeutic approach involving epigenetic modulatory drugs and CG antigen immunotherapy is suggested based on these data and is being actively pursued. In this article, we review the mechanisms of CG antigen gene regulation and discuss the implications of these mechanisms for the development of cancer immunotherapy approaches targeting CG antigens. PMID:20465387

Akers, Stacey N; Odunsi, Kunle; Karpf, Adam R

2010-01-01

375

Immunotherapy for primary brain tumors: no longer a matter of privilege.  

PubMed

Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor for which standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviewing modalities that are currently used or are undergoing active investigation. Tumor immunosuppressive countermeasures, peculiarities of central nervous system immune access, and opportunities for rational treatment design are discussed. See all articles in this CCR Focus section, "Discoveries, Challenges, and Progress in Primary Brain Tumors." Clin Cancer Res; 20(22); 5620-9. ©2014 AACR. PMID:25398845

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

2014-11-15

376

Characterization of the MUC1.Tg/MIN Transgenic Mouse as a Model for Studying Antigen-Specific Immunotherapy of Adenomas  

PubMed Central

A bigenic MUC1.Tg/MIN mouse model was developed by crossing Apc/MIN/+ (MIN) mice with human MUC1 transgenic mice to evaluate MUC1 antigen-specific immunotherapy of intestinal adenomas. The MUC1.Tg/MIN mice developed adenomas at a rate comparable to that of MIN mice and had similar levels of serum MUC1 antigen. A MUC1-based vaccine consisting of MHC class I-restricted MUC1 peptides, a MHC class II-restricted pan-helper peptide, unmethylated CpG oligodeoxynucleotide and GM-CSF caused flattening of adenomas and significantly reduced the number of large adenomas. Immunization was successful in generating a MUC1-directed immune response evidenced by increased MUC1 peptide-specific anti-tumor cytotoxicity and IFN-? secretion by lymphocytes. PMID:17707958

Akporiaye, Emmanuel T.; Bradley-Dunlop, Deborah; Gendler, Sandra J.; Mukherjee, Pinku; Madsen, Cathy S.; Hahn, Tobias; Besselsen, David G.; Dial, Sharon M.; Cui, Haiyan; Trevor, Katrina

2007-01-01

377

Clinical Implications of Minimal Residual Disease Monitoring for Stem Cell Transplantation after Reduced Intensity and Nonmyeloablative Conditioning  

Microsoft Academic Search

Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for a variety of hematological malignancies; however, relapse and treatment-related toxicities are major obstacles to cure. Nonmyeloablative and reduced-intensity conditioning regimens were designed not to eradicate the malignancy completely, but rather to be immunosuppressive enough to allow engraftment, and to serve as a platform for additional cellular immunotherapy. Minimal residual

Avichai Shimoni; Arnon Nagler

2004-01-01

378

Immunotherapy Using Autoclaved L. major Antigens and M. vaccae with Meglumine Antimoniate, for the Treatment of Experimental Canine Visceral Leishmaniasis  

PubMed Central

Background To evaluate immunotherapy against canine visceral leishmaniasis, Leishmania major antigen and heat-killed Mycobacterium vaccae (SRL172) were used as stimulators of immune defense mechanisms and the results were compared with standard chemotherapy meglumine antimoniate. Methods Nineteen mongrel dogs aging 1-3 years old were used in this experiment. Infection was carried out in 15 out of 19 dogs using L. infantum, isolated from a naturally infected poly-symptomatic dog. Results All the cases showed positive serologic results by direct agglutination test during 30-60 days following inoculation. In the first group, which was under chemotherapy (GlucantimeR), one of the members showed recurrence of the disease despite rapid effect of the therapeutic protocol. Immunotherapy using SRL172 caused complete cleaning of the parasite in group 2, but the speed was less than Glucantime. Immunotherapy using L. major antigen combined with M. vaccae in group 3 and combine administration of immunotherapy and chemotherapy in group 4 both were with relapsing of one case in each group. Group 5 and 6 were consisted of positive and negative control dogs, respectively. Conclusion Immunotherapy seems to be an adjuvant in treatment of canine leishmaniasis but it needs more investigation for final confirmation. PMID:22347294

Jamshidi, Sh; Avizeh, R; Mohebali, M; Bokaie, S

2011-01-01

379

Efficacy of Mycobacterium indicus pranii Immunotherapy as an Adjunct to Chemotherapy for Tuberculosis and Underlying Immune Responses in the Lung  

PubMed Central

Background The 9-month-long chemotherapy of tuberculosis often results in poor compliance and emergence of drug-resistant strains. So, improved therapeutic strategy is urgently needed. Immunotherapy could be beneficial for the effective management of the disease. Previously we showed the protective efficacy of Mycobacterium indicus pranii (MIP) when given as prophylactic vaccine in animal models of tuberculosis. Methods We sought to investigate whether MIP can be used as an adjunct to the chemotherapy in guinea pig models of tuberculosis. Efficacy of MIP was evaluated when given subcutaneously or by aerosol. Results MIP-therapy as an adjunct to the chemotherapy was found to be effective in accelerating bacterial killing and improving organ pathology. MIP-immunotherapy resulted in higher numbers of activated antigen-presenting cells and lymphocytes in the infected lungs and also modulated the granulomatous response. Early increase in protective Th1 immune response was observed in the immunotherapy group. Following subsequent doses of MIP, decrease in the inflammatory response and increase in the immunosuppressive response was observed, which resulted in the improvement of lung pathology. Conclusion MIP immunotherapy is a valuable adjunct to chemotherapy for tuberculosis. Aerosol route of immunotherapy can play a crucial role for inducing immediate local immune response in the lung. PMID:22844392

Gupta, Ankan; Ahmad, Farhan J.; Ahmad, Faiz; Gupta, Umesh D.; Natarajan, Mohan; Katoch, Vishwamohan; Bhaskar, Sangeeta

2012-01-01

380

Autologous Tumor Lysate-Pulsed Dendritic Cell Immunotherapy with Cytokine-Induced Killer Cells Improves Survival in Gastric and Colorectal Cancer Patients  

PubMed Central

Gastric and colorectal cancers (GC and CRC) have poor prognosis and are resistant to chemo- and/or radiotherapy. In the present study, the prophylactic effects of dendritic cell (DC) vaccination are evaluated on disease progression and clinical benefits in a group of 54 GC and CRC patients treated with DC immunotherapy combined with cytokine-induced killer (CIK) cells after surgery with or without chemo-radiotherapy. DCs were prepared from the mononuclear cells isolated from patients using IL-2/GM-CSF and loaded with tumor antigens; CIK cells were prepared by incubating peripheral blood lymphocytes with IL-2, IFN-?, and CD3 antibodies. The DC/CIK therapy started 3 days after low-dose chemotherapy and was repeated 3–5 times in 2 weeks as one cycle with a total of 188.3±79.8×106 DCs and 58.8±22.3×108 CIK cells. Cytokine levels in patients' sera before and after treatments were measured and the follow-up was conducted for 98 months to determine disease-free survival (DFS) and overall survival (OS). The results demonstrate that all cytokines tested were elevated with significantly higher levels of IFN-? and IL-12 in both GC and CRC cohorts of DC/CIK treated patients. By Cox regression analysis, DC/CIK therapy reduced the risk of post-operative disease progression (p<0.01) with an increased OS (<0.01). These results demonstrate that in addition to chemo- and/or radiotherapy, DC/CIK immunotherapy is a potential effective approach in the control of tumor growth for post-operative GC and CRC patients. PMID:24699863

Gao, Daiqing; Li, Changyou; Xie, Xihe; Zhao, Peng; Wei, Xiaofang; Sun, Weihong; Liu, Hsin-Chen; Alexandrou, Aris T.; Jones, Jennifer; Zhao, Ronghua; Li, Jian Jian

2014-01-01

381

Active-specific immunotherapy for non-small cell lung cancer  

PubMed Central

Non-small cell lung cancer constitutes about 85% of all newly diagnosed cases of lung cancer and continues to be the leading cause of cancer-related deaths worldwide. Standard treatment for this devastating disease, such as systemic chemotherapy, has reached a plateau in effectiveness and comes with considerable toxicities. For all stages of disease fewer than 20% of patients are alive 5 years after diagnosis; for metastatic disease the median survival is less than one year. Until now, the success of active-specific immunotherapy for all tumor types has been sporadic and unpredictable. However, the active-specific stimulation of the host’s own immune system still holds great promise for achieving non-toxic and durable antitumor responses. Recently, sipuleucel-T (Provenge®; Dendreon Corp., Seattle, WA) was the first therapeutic cancer vaccine to receive market approval, in this case for advanced prostate cancer. Other phase III clinical trials using time-dependent endpoints, e.g. in melanoma and follicular lymphoma, have recently turned out positive. More sophisticated specific vaccines have now also been developed for lung cancer, which, for long, was not considered an immune-sensitive malignancy. This may explain why advances in active-specific immunotherapy for lung cancer lag behind similar efforts in renal cell cancer, melanoma or prostate cancer. However, various vaccines are now being evaluated in controlled phase III clinical trials, raising hopes that active-specific immunotherapy may become an additional effective therapy for patients with lung cancer. This article reviews the most prominent active-specific immunotherapeutic approaches using protein/peptide, whole tumor cells, and dendritic cells as vaccines for lung cancer. PMID:22263073

Winter, Hauke; van den Engel, Natasja K.; Rusan, Margareta; Schupp, Nina; Poehlein, Christian H.; Hu, Hong-Ming; Hatz, Rudolf A.; Urba, Walter J.; Jauch, Karl-Walter; Fox, Bernard A.; Ruttinger, Dominik

2011-01-01

382

Patients' compliance with different administration routes for allergen immunotherapy in Germany  

PubMed Central

Background Allergen immunotherapy (AIT) is the practice of administering gradually increasing quantities of an allergen extract to an allergic subject to ameliorate the symptoms associated with the subsequent exposure to the causative allergen. It is the only treatment that may alter the natural course of allergic diseases. According to AIT guidelines and summary of product characteristics (SmPCs), the treatment should be carried out for at least 3 years. It is controversially discussed whether subcutaneous or sublingual administration routes cause higher patients’ compliance. Methods German sales data for different preparations of the allergen manufacturer Allergopharma GmbH & Co. KG were retrospectively evaluated for 5 consecutive years, based on prescriptions per patient: pollen sublingual immunotherapy (SLIT) and high-dose hypoallergenic (allergoid) or unmodified depot pollen and mite preparations for subcutaneous immunotherapy (SCIT). To identify patients’ compliance, “completed treatment years” were determined. A completed treatment year was defined by the required number of prescribed allergen preparations according to the recommended dosage scheme given in the respective SmPCs. Results Prescription data of 85,241 patients receiving pollen or mite SCIT and 706 patients receiving pollen SLIT were included in this analysis. Patients’ compliance for at least 3 treatment years with high-dose hypoallergenic pollen SCIT was higher when administered perennially (60%) compared to preseasonally (27%). Prescriptions for at least 3 years were received from 42% of patients with pollen SCIT and from 45% of patients with mite SCIT. Compliance with SLIT was lowest with only 16% of patients receiving prescriptions for at least 3 treatment years. Children and adolescents were more compliant than adults, independent of whether they received SLIT or SCIT. Conclusion In general, patients’ compliance with SCIT using high-dose hypoallergenic or unmodified depot preparations was higher than with pollen SLIT. Perennial application of SCIT seems to increase compliance in comparison to the preseasonal application. Children and adolescents were most compliant, independent of the preparation applied. PMID:25368517

Egert-Schmidt, Anne-Marie; Kolbe, Jan-Marcel; Mussler, Sabine; Thum-Oltmer, Susanne

2014-01-01

383

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

NASA Astrophysics Data System (ADS)

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

Popov, Dmitri; Maliev, Slava

384

Enhancement of T-cell mediated anti-tumor response: angiostatic adjuvant to immunotherapy against cancer  

PubMed Central

Purpose Tumor-released pro-angiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy. Experimental Design Intravital microscopy, multiple-color flow cytometry, immunohistochemistry, and various tumor mouse (normal and T cell-deficient) models were used to investigate the temporal dynamics of cellular and molecular events that occur in the tumor microenvironment during tumor progression and angiostatic intervention. Results We report that while EAM levels and T cell infiltration are highly attenuated early on in tumor growth, angiostatic therapy modulates these effects. In tumor models with normal and T cell-deficient mice, we demonstrate the active involvement of the adaptive immune system in cancer, and differentiate anti-angiogenic effects from anti-angiogenic-mediated enhancement of immuno-extravasation. Our results indicate that a compromised immune response in tumors can be obviated by the use of anti-angiogenic agents. Lastly, with adoptive transfer studies in mice, we demonstrate that a phased combination of angiostatic therapy and T cell transfer significantly (P<0.0013) improves tumor growth inhibition. Conclusions This research contributes to understanding the cellular mechanism of action of angiostatic agents and the immune response within the tumor microenvironment, in particular as a consequence of the temporal dynamics of EAM levels. Moreover, our results suggest that adjuvant therapy with angiogenesis inhibitors holds promise for cellular immunotherapy in the clinic. PMID:21252159

Dings, Ruud P.M.; Vang, Kieng B.; Castermans, Karolien; Popescu, Flavia; Zhang, Yan; oude Egbrink, Mirjam G. A.; Mescher, Matthew F.; Farrar, Michael A.; Griffioen, Arjan W.; Mayo, Kevin H.

2011-01-01

385

Penn study finds two-step immunotherapy attacks advanced ovarian cancer  

Cancer.gov

Most ovarian cancer patients are diagnosed with late stage disease that is unresponsive to existing therapies. In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine (home to the Abramson Cancer Center) show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using patients’ own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in these type of patients. Four of the six patients treated in the trial responded to the therapy, the investigators report this month in OncoImmunology.

386

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

NASA Astrophysics Data System (ADS)

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

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

2014-02-01

387

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

PubMed Central

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

2013-01-01

388

Cellular immunotherapy for neuroblastoma: a review of current vaccine and adoptive T cell therapeutics.  

PubMed

Immunotherapy is an attractive option for patients with high risk neuroblastoma due to their poor long-term survival rates after conventional treatment. Neuroblastoma cells are derived from the embryonic neural crest and therefore express tumor antigens not widely seen in normal cells, making them potential targets for immunologic attack. There is already considerable experience with monoclonal antibodies that target these tumor associated antigens, and in this review we focus on more exploratory approaches, using tumor vaccines and adoptive transfer of tumor-directed T cells. PMID:19199969

Louis, C U; Brenner, M K

2009-01-01

389

[Immunotherapy of poor-prognosis neuroblastoma in children: from bench to bedside].  

PubMed

During the last two decades, improvements in the induction and consolidation treatment phases in patients with high-risk neuroblastoma have not translated into significant increases in survival rates. Efforts to improve outcome have used high-dose chemotherapy with stem cell rescue and more recently, differentiating (retinoids) and antiangiogenic agents. In parallel, immunotherapy has become an increasingly important part of the treatment of high-risk neuroblastoma. We review here the biological concepts underlying these new approaches and their clinical applications, with a particular emphasis on applications that manipulate the immune system, including monoclonal antibodies, gene-modified tumor cells (vaccines) or immune effectors. PMID:16517413

Rousseau, Raphaël; Combaret, Valérie; Yvon, Eric; Schell, Matthias; Philip, Irène; Puisieux, Alain; Frappaz, Didier; Philip, Thierry; Bergeron, Christophe

2006-02-01

390

Sticky and smelly issues: lessons on tumour cell and leucocyte trafficking, gene and immunotherapy of cancer.  

PubMed Central

The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College (London, UK) on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion in immunosurveillance and tumour dissemination. In addition, recent achievements in the areas of chemokines, cytotoxic T-lymphocyte (CTL) and natural killer (NK) cells, co-stimulation, gene and adoptive immunotherapy were also addressed. The purpose of this report is to outline current trends in tumour immunology. Images Figure 1 PMID:9667650

Alexandroff, A. B.; McIntyre, C. A.; Porter, J. C.; Zeuthen, J.; Vile, R. G.; Taub, D. D.

1998-01-01

391

Intestinal transplantation in children: a review of immunotherapy regimens.  

PubMed

This review summarizes the outcomes and known adverse effects of current immunosuppression strategies in use in pediatric intestinal transplantation. Intestinal transplantation has evolved from an experimental therapy to a highly successful treatment for children with intestinal failure who have complications with total parenteral nutrition. Because of continued success with intestinal transplantation over the past decade, the focus of clinicians and researchers is shifting from short-term patient survival to optimizing long-term outcomes. Current 5-year patient and graft survival rates after intestinal transplantation are 58% and 40%, respectively, in the US; single centers have reported nearly 80% patient and 60% graft survival rates at 5 years. The immunosuppression strategy in intestinal transplantation includes a tacrolimus-based regimen, usually in conjunction with an antibody induction therapy such as rabbit-antithymocyte globulin, interleukin-2 receptor antagonists, or alemtuzumab. The use of these immunosuppressive regimens, along with improved medical and surgical care, has contributed significantly toward improved outcomes. Optimization of post-transplant immunosuppression strategies to reduce adverse effects while minimizing acute and chronic graft rejection is a strong clinical and research focus. PMID:21500869

Nayyar, Navdeep S; McGhee, William; Martin, Dolly; Sindhi, Rakesh; Soltys, Kyle; Bond, Geoffrey; Mazariegos, George V

2011-06-01

392

Development of an affinity-matured humanized anti-epidermal growth factor receptor antibody for cancer immunotherapy.  

PubMed

We showed previously that humanization of 528, a murine anti-epidermal growth factor receptor (EGFR) antibody, causes reduced affinity for its target. Here, to improve the affinity of the humanized antibody for use in cancer immunotherapy, we constructed phage display libraries focused on the complementarity-determining regions (CDRs) of the antibody and carried out affinity selection. Two-step selections using libraries constructed in a stepwise manner enabled a 32-fold affinity enhancement of humanized 528 (h528). Thermodynamic analysis of the interactions between the variable domain fragment of h528 (h528Fv) mutants and the soluble extracellular domain of EGFR indicated that the h528Fv mutants obtained from the first selection showed a large increase in negative enthalpy change due to binding, resulting in affinity enhancement. Furthermore, mutants from the second selection showed a decrease in entropy loss, which led to further affinity maturation. These results suggest that a single mutation in the heavy chain variable domain (i.e. Tyr(52) to Trp) enthalpically contributed for overcoming the energetic barrier to the antigen-antibody interaction, which was a major hurdle for the in vitro affinity maturation of h528. We reported previously that the humanized bispecific diabody hEx3 Db, which targets EGFR and CD3, shows strong anti-tumor activity. hEx3 Db mutants, in which the variable domains of h528 were replaced with those of the affinity-enhanced mutants, were prepared and characterized. In a growth inhibition assay of tumor cells, the hEx3 Db mutants showed stronger anti-tumor activity than that of hEx3 Db, suggesting that affinity enhancement of h528Fv enhances the anti-tumor activity of the bispecific diabody. PMID:23118340

Nakanishi, Takeshi; Maru, Takamitsu; Tahara, Kazuhiro; Sanada, Hideaki; Umetsu, Mitsuo; Asano, Ryutaro; Kumagai, Izumi

2013-02-01

393

BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Anti-tumor Activity of Adoptive Immunotherapy in Mice  

PubMed Central

Purpose Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAF-mutant tumors. Experimental Design BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T-cells were used as xenograft models to assess melanocyte differentiation antigen-independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of vascular endothelial growth factor (VEGF) was determined by enzyme-linked immunosorbent assay, protein array and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the pre-clinical murine model. Conclusion These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell based immunotherapy for the treatment of melanoma patients. PMID:23204132

Liu, Chengwen; Peng, Weiyi; Xu, Chunyu; Lou, Yanyan; Zhang, Minying; Wargo, Jennifer A.; Chen, Jie Qing; Li, Haiyan S.; Watowich, Stephanie S.; Yang, Yan; Frederick, Dennie Tompers; Cooper, Zachary A.; Mbofung, Rina M; Whittington, Mayra; Flaherty, Keith T.; Woodman, Scott E.; Davies, Michael A.; Radvanyi, Laszlo G.; Overwijk, Willem W.; Lizee, Gregory; Hwu, Patrick

2014-01-01

394

Polymorphisms in the Pseudomonas aeruginosa Type III secretion protein, PcrV - implications for anti-PcrV Immunotherapy  

PubMed Central

The type III secretion system of P. aeruginosa, responsible for acute infection, is composed of over twenty proteins that facilitate cytotoxin injection directly into host cells. Integral to this process is production and secretion of PcrV. Administration of a recently developed, anti-PcrV immunoglobulin, either as a therapeutic or prophylactic has previously demonstrated efficacy against laboratory strains of P. aeruginosa in a murine model. To determine if this therapy is universally applicable to a variety of P. aeruginosa clinical isolates, genetic heterogeneity of pcrV was analyzed among strains collected from three geographically distinct regions; United States, France and Japan. Sequence analysis of PcrV demonstrated limited variation among the clinical isolates examined. Strains were grouped according to the presence of non-synonymous single nucleotide polymorphisms. Representative isolates from each mutant group were examined for the ability of anti-PcrV to bind the protein secreted by these strains. The protective effect of anti-PcrV IgG against each strain was determined using an epithelial cell line cytotoxicity assay. The majority of strains tested demonstrated reduced cytotoxicity in the presence of anti-PcrV IgG. This study provides insights into the natural sequence variability of PcrV and an initial indication of the amino acid residues that appear to be conserved across strains. It also demonstrates the protective effect of anti-PcrV immunotherapy against a multitude of P. aeruginosa strains from diverse global regions with a variety of mutations in PcrV. PMID:20211240

Lynch, Susan V.; Flanagan, Judith L.; Sawa, Teiji; Fang, Alice; Baek, Marshall S.; Rubio-Mills, Amua; Ajayi, Temitayo; Yanagihara, Katsunori; Hirakata, Yoichi; Kohno, Shigeru; Misset, Benoit; Nguyen, Jean-Claude; Wiener-Kronish, Jeanine P.

2010-01-01

395

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

SciTech Connect

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

Fujii, Masakazu, E-mail: masakazu731079@yahoo.co.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Inoguchi, Toyoshi, E-mail: toyoshi@intmed3.med.kyushu-u.ac.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan) [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Batchuluun, Battsetseg, E-mail: battsetseg.batchuluun@gmail.com [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Sugiyama, Naonobu, E-mail: nao1@intmed1.med.kyushu-u.ac.jp [Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Kobayashi, Kunihisa, E-mail: nihisak@fukuoka-u.ac.jp [Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, 1-1-1 Zokumyoin, Chikushino, Fukuoka 818-8502 (Japan)] [Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, 1-1-1 Zokumyoin, Chikushino, Fukuoka 818-8502 (Japan); Sonoda, Noriyuki, E-mail: noriyuki@intmed3.med.kyushu-u.ac.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan) [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Takayanagi, Ryoichi, E-mail: takayana@intmed3.med.kyushu-u.ac.jp [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

2013-08-16

396

Scope for innovation in immunotherapy from the financial market's point of view  

PubMed Central

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)1 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 fo