***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: 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 . ) Therapies that target the programmed death-1 ( PD-1 ) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types . One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 lig and ( PD-L1 ) and its ligation to PD-1 on antigen-specific CD8 + T cells ( termed adaptive immune resistance ) . Here we show that pre-existing CD8 + T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy . We analysed sample s from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy ( pembrolizumab )  using quantitative immunohistochemistry , quantitative multiplex immunofluorescence , and next-generation sequencing for T-cell antigen receptors ( TCRs ) . In serially sample d tumours , patients responding to treatment showed proliferation of intratumoral CD8 + T cells that directly correlated with radiographic reduction in tumour size . Pre-treatment sample s obtained from responding patients showed higher numbers of CD8- , PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours , with close proximity between PD-1 and PD-L1 , and a more clonal TCR repertoire . Using multivariate analysis , we established a predictive model based on CD8 expression at the invasive margin and vali date d the model in an independent cohort of 15 patients . Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8 + T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance BACKGROUND & AIMS Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 ( CTLA-4 ) , an inhibitory co-receptor that interferes with T cell activation and proliferation . The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma ( HCC ) and chronic hepatitis C virus ( HCV ) infection ; and to study the safety of its administration to cirrhotic patients . METHODS Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity . Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response . Most patients were in the advanced stage and 43 % had an altered liver function ( Child-Pugh class B ) . RESULTS A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events . Some patients had a transient albeit intense elevation of transaminases after the first dose , but not following subsequent cycles . Partial response rate was 17.6 % and disease control rate was 76.4 % . Time to progression was 6.48 months ( 95 % CI 3.95 - 9.14 ) . A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy , particularly in those patients with a more prominent drop in viral load . This antiviral effect was associated with an enhanced specific anti-HCV immune response . CONCLUSIONS Tremelimumab safety profile and antitumor and antiviral activity , in patients with advanced HCC developed on HCV-induced liver cirrhosis , support further investigation Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab . In the single-arm , phase II KEYNOTE-055 study , we evaluated pembrolizumab , an anti-programmed death 1 receptor antibody , in this platinum- and cetuximab-pretreated population with poor prognosis . Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment . Patients received pembrolizumab 200 mg every 3 weeks . Imaging was performed every 6 to 9 weeks . Primary end points : overall response rate ( Response Evaluation Criteria in Solid Tumors v1.1 , central review ) and safety . Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death lig and 1 ( PD-L1 ) expression and human papillomavirus ( HPV ) status . Results Among 171 patients treated , 75 % received two or more prior lines of therapy for metastatic disease , 82 % were PD-L1 positive , and 22 % were HPV positive . At the time of analysis , 109 patients ( 64 % ) experienced a treatment-related adverse event ; 26 patients ( 15 % ) experienced a grade ≥ 3 event . Seven patients ( 4 % ) discontinued treatment , and one died of treatment-related adverse events . Overall response rate was 16 % ( 95 % CI , 11 % to 23 % ) , with a median duration of response of 8 months ( range , 2 + to 12 + months ) ; 75 % of responses were ongoing at the time of analysis . Response rates were similar in all HPV and PD-L1 subgroups . Median progression-free survival was 2.1 months , and median overall survival was 8 months . Conclusion Pembrolizumab exhibited clinical ly meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab BACKGROUND & AIMS Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4 ) on the surface of activated T lymphocytes . Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma ( HCC ) . This study aim ed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation . METHODS Thirty-two patients with HCC were enrolled : male : female : 28:4 ; median age : 62 ( range 36 - 76 ) . Patients were given tremelimumab at two dose levels ( 3.5 and 10mg/kg i.v . ) every 4weeks for 6 doses , followed by 3-monthly infusions until off-treatment criteria were met . On day 36 , patients underwent subtotal radiofrequency ablation or chemoablation . Staging was performed by contrast-enhanced CT or MRI scan every 8weeks . RESULTS No dose-limiting toxicities were encountered . The most common toxicity was pruritus . Of the 19 evaluable patients , five ( 26.3 % ; 95 % CI : 9.1 - 51.2 % ) achieved a confirmed partial response . Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load . Six-week tumor biopsies showed a clear increase in CD8 + T cells in patients showing a clinical benefit only . Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1 % and 33.1 % respectively , with median time to tumor progression of 7.4months ( 95 % CI 4.7 to 19.4months ) . Median overall survival was 12.3months ( 95 % CI 9.3 to 15.4months ) . CONCLUSIONS Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC , and leads to the accumulation of intratumoral CD8 + T cells . Positive clinical activity was seen , with a possible surrogate reduction in HCV viral load . LAY SUMMARY Studies have shown that the killing of tumors by direct methods ( known as ablation ) can result in the immune system being activated or switched on . The immune system could potentially also recognize and kill the cancer that is left behind . There are new drugs available known as immune checkpoint inhibitors which could enhance this effect . Here , we test one of these drugs ( tremelimumab ) together with ablation . CLINICAL TRIAL NUMBER Clinical Trials.gov : NCT01853618 BACKGROUND Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab ( an anti-PD-1 antibody ) plus ipilimumab ( an anti-CTLA-4 antibody ) compared with ipilimumab alone . We report 2-year overall survival data from a r and omised controlled trial assessing this treatment in previously untreated advanced melanoma . METHODS In this multicentre , double-blind , r and omised , controlled , phase 2 trial ( CheckMate 069 ) we recruited patients from 19 specialist cancer centres in two countries ( France and the USA ) . Eligible patients were aged 18 years or older with previously untreated , unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 . Patients were r and omly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo , every 3 weeks for four doses . Subsequently , patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity , whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase . R and omisation was done via an interactive voice response system with a permuted block schedule ( block size of six ) and stratification by BRAF mutation status . The study funder , patients , investigators , and study site staff were masked to treatment assignment . The primary endpoint , which has been reported previously , was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response . Overall survival was an exploratory endpoint and is reported in this Article . Efficacy analyses were done on the intention-to-treat population , whereas safety was assessed in all treated patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT01927419 , and is ongoing but no longer enrolling patients . FINDINGS Between Sept 16 , 2013 , and Feb 6 , 2014 , we screened 179 patients and enrolled 142 , r and omly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone . In each treatment group , one patient no longer met the study criteria following r and omisation and thus did not receive study drug . At a median follow-up of 24·5 months ( IQR 9·1 - 25·7 ) , 2-year overall survival was 63·8 % ( 95 % CI 53· 
    Output:
    
The main treatment‐related adverse events for ipilimumab were skin , gastrointestinal , and renal toxicities .
Nivolumab had a narrow and mild toxicity spectrum , mainly causing endocrine toxicities .
Integrated evidence from the pooled incidences , subgroup , and sensitivity analyses implied that nivolumab is the best option in terms of safety , especially for the treatment of lung cancer .
Compared with other ICI drugs used to treat cancer , atezolizumab had the best safety profile in general , and nivolumab had the best safety profile in lung cancer when taking an integrated approach .