***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 
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    Input: PURPOSE Programmed death-1 ( PD-1 ) , an inhibitory receptor expressed on activated T cells , may suppress antitumor immunity . This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity , pharmacodynamics , and immunologic correlates . PATIENTS AND METHODS Thirty-nine patients with advanced metastatic melanoma , colorectal cancer ( CRC ) , castrate-resistant prostate cancer , non-small-cell lung cancer ( NSCLC ) , or renal cell carcinoma ( RCC ) received a single intravenous infusion of  anti-PD-1 ( MDX-1106 ) in dose-escalating six-patient cohorts at 0.3 , 1 , 3 , or 10 mg/kg , followed by a 15-patient expansion cohort at 10 mg/kg . Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy . RESULTS Anti-PD-1 was well tolerated : one serious adverse event , inflammatory colitis , was observed in a patient with melanoma who received five doses at 1 mg/kg . One durable complete response ( CRC ) and two partial responses ( PRs ; melanoma , RCC ) were seen . Two additional patients ( melanoma , NSCLC ) had significant lesional tumor regressions not meeting PR criteria . The serum half-life of anti-PD-1 was 12 to 20 days . However , pharmacodynamics indicated a sustained mean occupancy of > 70 % of PD-1 molecules on circulating T cells > or = 2 months following infusion , regardless of dose . In nine patients examined , tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment . CONCLUSION Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity . Exploration of alternative dosing regimens and combinatorial therapies with vaccines , targeted therapies , and /or other checkpoint inhibitors is warranted BACKGROUND Blockade of programmed death 1 ( PD-1 ) , an inhibitory receptor expressed by T cells , can overcome immune resistance . We assessed the antitumor activity and safety of BMS-936558 , an antibody that specifically blocks PD-1 . METHODS We enrolled patients with advanced melanoma , non-small-cell lung cancer , castration-resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks . Response was assessed after each 8-week treatment cycle . Patients received up to 12 cycles until disease progression or a complete response occurred . RESULTS A total of 296 patients received treatment through February 24 , 2012 .  Grade 3 or 4 drug-related adverse events occurred in 14 % of patients ; there were three deaths from pulmonary toxicity . No maximum tolerated dose was defined . Adverse events consistent with immune-related causes were observed . Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , melanoma , or renal-cell cancer .  Cumulative response rates ( all doses ) were 18 % among patients with non-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with melanoma ( 26 of 94 patients ) , and 27 % among patients with renal-cell cancer ( 9 of 33 patients ) . Responses were durable ; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up . To assess the role of intratumoral PD-1 lig and ( PD-L1 ) expression in the modulation of the PD-1-PD-L1 pathway , immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients . Of 17 patients with PD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with PD-L1-positive tumors had an objective response ( P=0.006 ) . CONCLUSIONS Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer , melanoma , or renal-cell cancer ; the adverse-event profile does not appear to preclude its use . Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response . ( Funded by Bristol-Myers Squibb and others ; Clinical Trials.gov number , NCT00730639 . ) Purpose : To evaluate the safety , tolerability , pharmacokinetics , and pharmacodynamics of IMP321 , a recombinant soluble LAG-3Ig fusion protein which agonizes MHC class II – driven dendritic cell activation . Experimental Design : Patients with advanced renal cell carcinoma were treated with escalating doses of IMP321 s.c . Blood sample s were assayed to determine plasma pharmacokinetic parameters , detect human anti-IMP321 antibody formation , and determine long-lived CD8 T cell responses . Results : Twenty-one advanced renal cell carcinoma patients received 119 injections of IMP321 at doses ranging from 0.050 to 30 mg/injection s.c . biweekly for 6 injections . No clinical ly significant adverse events were observed . Good systemic exposure to the product was obtained following s.c . injections of doses above 6 mg . IMP321 induced both sustained CD8 T-cell activation and an increase in the percentage of long-lived effector-memory CD8 T cells in all patients at doses above 6 mg . Tumor growth was reduced and progression-free survival was better in those patients receiving higher doses ( > 6 mg ) of IMP321 : 7 of 8 evaluable patients treated at the higher doses experienced stable disease at 3 months compared with only 3 of 11 in the lower dose group ( P = 0.015 ) . Conclusion : The absence of toxicity and the demonstration of activity at doses above 6 mg warrant further disease-directed studies of IMP321 in combined regimens ( e.g. , chemoimmunotherapy ) . ( Clin Cancer Res 2009;15(19):6225–31 The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression . These changes distinguish cancer cells from their normal counterparts , allowing tumours to be recognized as foreign by the immune system . However , tumours are rarely rejected spontaneously , reflecting their ability to maintain an immunosuppressive microenvironment . Programmed death-lig and 1 ( PD-L1 ; also called B7-H1 or CD274 ) , which is expressed on many cancer and immune cells , plays an important part in blocking the ‘ cancer immunity cycle ’ by binding programmed death-1 ( PD-1 ) and B7.1 ( CD80 ) , both of which are negative regulators of T-lymphocyte activation . Binding of PD-L1 to its receptors suppresses T-cell migration , proliferation and secretion of cytotoxic mediators , and restricts tumour cell killing . The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections . Blocking PD-L1 should therefore enhance anticancer immunity , but little is known about predictive factors of efficacy . This study was design ed to evaluate the safety , activity and biomarkers of PD-L1  inhibition using the engineered humanized antibody MPDL3280A . Here we show that across multiple cancer types , responses ( as evaluated by Response Evaluation Criteria in Solid Tumours , version 1.1 ) were observed in patients with tumours expressing high levels of PD-L1 , especially when PD-L1 was expressed by tumour-infiltrating immune cells . Furthermore , responses were associated with T-helper type 1 ( TH1 ) gene expression , CTLA4 expression and the absence of fractalkine ( CX3CL1 ) in baseline tumour specimens . Together , these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1 , and is re-invigorated on antibody treatment CTL-associated antigen 4 ( CTLA4 ) is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells . CTLA4 blockade with antibody treatment has been shown to augment antitumor immunity in animal models and is being developed as a treatment for cancer patients . As has been seen in pre clinical models , combining CTLA4 blockade and granulocyte macrophage colony-stimulating factor (GM-CSF)-based immunotherapies can enhance the antitumor efficacy of this approach . We therefore examined whether CTLA4 blockade could be combined with GM-CSF administration . We treated 24 patients with metastatic , castration-resistant prostate cancer in a phase I trial where sequential cohorts were treated with increasing doses of ipilimumab , a fully human anti-CTLA4 antibody . Study subjects also received s.c . injections of GM-CSF at a fixed dose . Of the six patients treated at the highest dose level , three had confirmed PSA declines of > 50 % , including one patient that had a partial response in visceral metastases . Expansion of activated , circulating CD25(+ ) CD69(+ ) CD8(+ ) T cells occurred more frequently at higher doses of treatment and was greater in magnitude than was seen in patients who received the same doses of either ipilimumab or GM-CSF alone . By screening sera with protein arrays , we showed that our treatment can induce antibody responses to NY-ESO-1 . These results show that this combination immunotherapy can induce the expansion not only of activated effector CD8 T cells in vivo but also of T cells that are specific for known tumor-associated antigens from the endogenous immune repertoire Purpose : Cytotoxic T lymphocyte associated antigen ( CTLA-4 ) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies . Our group conducted the first preoperative clinical trial with the anti – CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder . Experimental Design : Six patients were treated with 3 mg/kg/dose of anti – CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody . Primary end points of the study were safety and immune monitoring . Results : Most drug-related adverse events consisted of grade 1/2 toxicities . All patients had measurable immunologic pharmacodynamic effects , consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation . To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti – CTLA-4 , a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival . Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells , sustained over a period of 12 weeks of therapy , correlates with increased likelihood of clinical benefit consisting of overall survival . Conclusions : Our trial shows that anti – CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses , which can efficiently guide the monitoring of patients treated in the metastatic disease setting . Clin Cancer Res ; 16(10 ) ; 2861–71 . © 2010 AACR Purpose : The interaction of programmed death-1 lig and ( PD-L1 ) with its receptor ( PD-1 ) on T cells inactivates antitumor immune responses . PD-L1 expression has been associated with poor outcomes in renal cell carcinoma ( RCC ) but has not been investigated in advanced RCC patients receiving VEGF-targeted therapy .  Experimental Design : Formalin-fixed paraffin-embedded specimens were collected at baseline from patients in the COMPARZ trial . Tumor cell PD-L1 expression by IHC was evaluated using H-score ( HS ) . Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages . Intratumor CD8-positive T cells were quantified morphometrically . Associations between biomarkers and survival were investigated using the log-rank test . Results : HS data were available from 453 of 1,110 patients . Sixty-four percent of patients had negative PD-L1 expression ( HS = 0 ) . Patients with HS > 55 ( n = 59 , 13 % ) had significantly shorter overall survival ( OS ) than those with HS ≤ 55 in both pazopanib and sunitinib arms ( median 15.1 vs. 35.6 and 15.3 vs. 27.8 months , respectively , P = 0.03 ) . In both arms , median OS was shortest in patients with HS > 55 and intratumor CD8-positive T-cell counts > 300 ( 9.6 and 11.9 months with pazopanib and sunitinib , respectively ) . Median OS in patients with HS ≤ 55 and CD8-positive T-cell counts ≤ 300 was 36.8 and 28.0 months with 
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Nevertheless , ipilimumab may significantly improve overall survival compared with placebo in subgroups of patients with favorable prognostic features .
Overall , immune-related effects such as colitis and dermatitis were common and well tolerated .
Our systematic review shows that antibodies blocking immune checkpoints offer interesting and long-lasting response rates in heavily pretreated patients with advanced urologic cancers .
More promising results are currently provided by anti-CTLA-4 antibodies in prostate cancer and by PD-1/PD-L1 inhibitors in renal cancer .
PATIENT SUMMARY Data from studies support the activity and safety of  immune checkpoint inhibitors  in urologic cancers , alone or in combination with conventional cancer therapies .
Encouraging data in other oncologic fields could translate into interesting responses in urological cancers