***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Cytotoxic T lymphocyte-associated antigen 4 ( CTLA4 ) delivers inhibitory signals to activated T cells . CTLA4 is constitutively expressed on regulatory CD4(+ ) T cells ( Tregs ) , but its role in these cells remains unclear . CTLA4 blockade has been shown to induce antitumor immunity . In this study , we examined the effects of anti-CTLA4 antibody on the endogenous CD4(+ ) T cells in cancer patients . We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4(+ ) T cells , but also in the number of CD4(+ ) FoxP3(+ ) Tregs . Although the effects were dose-dependent , CD4(+ ) FoxP3(+ ) regulatory T cells could be exp and ed at lower antibody doses . In contrast , expansion of effector T cells was seen only at the highest dose level studied . Moreover , these exp and ed CD4(+ ) FoxP3(+ ) regulatory T cells are induced to proliferate with treatment and possess suppressor function . Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4(+ ) FoxP3(+ ) Tregs in vivo , but rather may mediate its effects through the activation of effector T cells . Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells . This study is registered at http://www . clinical trials.gov/ct2/show/NCT00064129 , registry number NCT00064129 Given that the FcgammaRIIIa receptor 158V allotype displays a higher affinity for human immunoglobulin G1 and increased antibody-dependent cellular cytotoxicity , the aim of this study was to determine the influence of that FCGR3A polymorphism on the therapeutic response to rituximab , an anti-CD20 humanized immunoglobulin G1 increasingly used in the treatment of non-Hodgkin lymphomas . The FCGR3A-158V/F genotype was determined in 49 patients having received rituximab for a previously untreated follicular non-Hodgkin lymphoma . The clinical response and the disappearance of the BCL2-JH gene rearrangement in both peripheral blood and bone marrow were evaluated at 2 months ( M2 ) and at 1 year ( M12 ) . The study population consisted of 20 % FCGR3A-158V homozygous patients , 35 % FCGR3A-158F homozygous patients , and 45 % heterozygous patients ( FCGR3A-158F carriers ) . The objective response rates at M2 and M12 were 100 % and 90 % , respectively , in FCGR3A-158V homozygous patients compared with 67 % ( P = .03 ) and 51 % ( P = .03 ) , respectively , in FCGR3A-158F carriers . A disappearance of the BCL2-JH gene rearrangement in both peripheral blood and marrow was observed at M12 in 5 of 6 of homozygous FCGR3A-158V patients compared with 5 of 17 of FCGR3A-158F carriers ( P = .03 ) . The homozygous FCGR3A-158V genotype was confirmed to be the single parameter associated with clinical and molecular responses by multivariate analysis . This study showed an association between the FCGR3A genotype and clinical and molecular responses to  rituximab .  This finding will certainly give rise to new pharmacogenetic approaches to the management of patients with non-Hodgkin lymphomas Cytotoxic T lymphocyte-associated antigen 4 ( CTLA-4 ) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity . The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects . Nonetheless , patients that respond also frequently manifest serious inflammatory pathologies , raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked . Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated , autologous tumor cells engineered to secrete GM-CSF ( GVAX ) generate clinical ly meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients . The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated , although further refinements are required to increase clinical responses and to minimize toxicity in this population . The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8 + effector T cells to FoxP3 + regulatory T cells ( Tregs ) in posttreatment biopsies . Together , these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy Purpose : To study the effect of autologous tumor cell vaccinations on the presence and numbers of circulating CD8 + T cells specific for tumor-associated antigens ( TAA ) in metastatic melanoma patients . To investigate the correlation between the presence of tumor-infiltrating lymphocytes ( TIL ) and circulating TAA-specific CD8 + T cells before and after autologous tumor cell vaccination with overall survival . Experimental design : Twenty-five stage III and resected stage IV metastatic melanoma patients were adjuvantly treated with a series of intracutaneously injected autologous tumor cell vaccinations , of which the first two contained BCG as an immunostimulatory adjuvant . Tumor sample s and blood sample s obtained before and after vaccination of these patients were studied for the presence of TAA-specific T cells using HLA-tetramers and results were correlated with survival . Results : In 5 of 17 ( 29 % ) melanoma patients , circulating TAA-specific T cells were detectable prior to immunizations . No significant changes in the frequency and specificity were found during the treatment period in all patients . Presence of circulating TAA-specific T cells was not correlated with survival ( log rank , P=0.215 ) . Inside melanoma tissue , TAA-specific TIL could be detected in 75 % of 16 available tumor sample s. In case of detectable TAA-specific TIL , median survival was 22.5 months compared to median survival of 4.5 months in case of absence of TAA-specific T cells ( log rank , P=0.0094 ) . In none of the patients , TAA-specific T cells were found both in tumor tissue and blood at the same time . Conclusions : These data suggest that the presence of TAA-specific TILs forms a prognostic factor , predicting improved survival in advanced-stage melanoma patients . The absence of TAA-specific T cells in the circulation suggests that homing of the tumor-specific T cell population to the tumor site contributes to the effectiveness of antitumor immunity 2510 Background : Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma and renal cancer that is associated with inflammatory-type adverse events termed immune breakthrough events ( IBEs ) . METHODS 25 patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times injected subcutaneously with Ipilimumab at 3 mg/kg intravenously every eight weeks for 12 months . The primary endpoints were toxicity and the achievement of a 40 % rate of tolerable IBEs , and 20 % or less rate of intolerable adverse events . Immune responses measured by ELISPOT and peptide-tetramer assays , and time to relapse were also assessed . The three melanoma peptides differed from wild type by one amino acid modification to increase HLA binding , and were administered at 1000 mcg/dose each . RESULTS Median age was 55 , with 13 men and 12 women . 15 patients had stage IV , and 10 had stage IIIC resected disease . Thus far , 12/25 ( 48 % ) patients had grade s 2 - 3 IBEs ; 5 ( 20 % ) were dose limiting ; 7 had GI toxicity , of which 2 were dose limiting ; four had skin toxicity , of which 2 were dose limiting ; one patient had hypopituitarism , which was also dose limiting . No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids . Serologic assays of IBD-related microbial and auto-antibodies showed that seven of eight patients tested had increases in ANCA IgG or I2 IgA , and 5/8 had increases in ASCA IgA. Four of 25 patients have relapsed with a median of 10 months of follow-up . Two were again rendered NED surgically . The two remaining patients were treated with biochemotherapy , with one CR and one PR . All 25 patients are alive , one with disease . No patient with grade 2 - 3 IBEs has relapsed . ELISPOT assays showed that 10/11 patients tested responded in fresh P BMC to MART-1 and gp100 . CONCLUSIONS These data suggest that IBEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab at 3 mg/kg with a peptide vaccine , and support testing the current regimen in a larger r and omized trial . [ Table : see text ] Background Cytotoxic T lymphocyte – associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens . We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade . The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti – CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes . In this study , we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus , interleukin (IL)-2 , in patients with metastatic melanoma . Methods Thirty-six patients received anti – CTLA-4 antibody  every 3 weeks . Three patients per cohort received doses of .1 , .3 , 1.0 , and 2.0 mg/kg . Twenty-four patients received 3.0 mg/kg . All patients received IL-2 therapy ( 720,000 IU/kg every 8 hours to a maximum of 15 doses ) . Results Eight patients ( 22 % ) experienced objective tumor responses ( three complete and five partial ) , including metastases in the lungs , lymph nodes , mediastinum , and subcutaneous tissues . Six of the eight patients have ongoing objective responses at 11 to 19 months . Five patients ( 14 % ) developed grade III/IV autoimmune toxicities secondary to anti – CTLA-4 administration , including four patients with enterocolitis and one with arthritis and uveitis . Conclusions There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration , because the 22 % objective response rate is that expected from the sum of these two agents administered alone . Durable cancer regressions were seen in patients treated with this combination PURPOSE Cytotoxic T lymphocyte-associated antigen 4 ( CTLA4 ) blockade with CP-675,206 , a fully human anti-CTLA4 monoclonal antibody , may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans . A phase I trial was conducted to test the safety of CP-675,206 . PATIENTS AND METHODS Thirty-nine patients with solid malignancies ( melanoma , n = 34 ; renal cell , n = 4 ; colon , n = 1 ) received an intravenous ( IV ) infusion of CP-675,206 at seven dose levels . The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose . RESULTS Dose-limiting toxicities and autoimmune phenomena included diarrhea , dermatitis , vitiligo , panhypopituitarism and hyperthyroidism . Two patients experienced complete responses ( maintained for 34 + and 25 + months ) , and there were two partial responses ( 26 + and 25 + months ) among 29 patients with measurable melanoma . There have been no relapses thus far after objective response to therapy . Four other patients had stable disease at end of study evaluation ( 16 , 7 , 7 , and 4 months ) . Additionally , five patients had extended periods without disease progression ( 36 + , 35 + , 26 + , 24 + , and 23 + months ) after local treatment of progressive metastases . Longer systemic exposure to CP-675,206  achieved in higher dose cohorts predicted for a higher probability of response . CONCLUSION CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg , result ing in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma 
    Output:
    
Available clinical data suggest that anti-CTLA-4 mAbs are very different from traditional mAbs , chemotherapies , and immunotherapies in terms of patterns of response , duration of response , and adverse event profile .