Tseng SY, Otsuji M, Gorski K, et al. nonCsmall-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, Rabbit polyclonal to ABCA13 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer had received antiCPD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with nonCsmall-cell lung cancer, STA-21 and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including nonCsmall-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.) Passive cancer immunotherapy that uses tumor-targeted monoclonal antibodies has achieved broad therapeutic efficacy.1 However, T-cell directed immunotherapy has been less successful.2 Despite the large number of tumor antigens induced by genetic and epigenetic changes found in STA-21 all cancers, tumors resist immune attack by inducing tolerance among tumor-specific T cells and by expressing ligands that engage inhibitory receptors and dampen T-cell STA-21 functions within the tumor microenvironment.3 Preclinical STA-21 and clinical data show that antibody blockade of these immune checkpoints can significantly enhance antitumor immunity.4 Cytotoxic T-lymphocyteCassociated antigen 4 (CTLA-4), an inhibitory receptor that down-modulates the initial stages of T-cell activation, was the first clinically validated checkpoint pathway target.5C9 Antagonist antiCCTLA-4 monoclonal antibodies mediate tumor regression, most notably in patients with melanoma, but are accompanied by frequent immune-related adverse events. Ipilimumab (Yervoy, Bristol-Myers Squibb), an antiCCTLA-4 antibody, was recently approved for the treatment of patients with stage IV melanoma on the basis of a randomized phase 3 trial that showed prolongation of overall survival.9 Programmed death 1 (PD-1) protein is another T-cell coinhibitory receptor with a structure similar to that of CTLA-4 but with a distinct biologic function and ligand specificity.10,11 PD-1 has two known ligands, PD-L1 (B7-H1)12,13 and PD-L2 (B7-DC).14,15 In contrast to CTLA-4 ligands, CD80 (B7-1) and CD86 (B7-2), PD-L1 is selectively expressed on many tumors16C18 and on cells within the tumor microenvironment in response to inflammatory stimuli.19 Blockade of the interaction between PD-1 and PD-L1 potentiates immune responses in vitro20 and mediates preclinical antitumor activity.16,17 PD-L1 is the primary PD-1 ligand that is up-regulated in solid tumors, where it can inhibit cytokine production and the cytolytic activity of PD-1+, tumor-infiltrating CD4+ and CD8+ T cells.16,21,22 These properties make PD-L1 a potentially promising target for cancer immunotherapy. BMS-936559 is a high-affinity, fully human, PD-L1Cspecific, IgG4 (S228P) monoclonal antibody that inhibits the binding of PD-L1 to both PD-1 and CD80. Additional characterization of this antiCPD-L1 antibody is presented in the study protocol, available with the full text of this article at NEJM.org. In this report, we present clinical evidence regarding the safety, clinical activity, and pharmacokinetic and pharmacodynamic effects of antiCPD-L1 antibody in patients with selected advanced cancers. METHODS STUDY DESIGN The primary objective of this phase 1 study was to assess the safety and adverse-event profiles of antiCPD-L1 antibody in patients with selected advanced cancers. Secondary objectives included assessment of the antitumor activity of the antibody and its pharmacokinetics. Pharmacodynamic measures were included as exploratory objectives. (Additional information is provided in the study protocol and in a detailed statistical analysis plan and the Methods section in the Supplementary Appendix, available at NEJM.org.) PATIENTS Patients were required to have documented.