{"doi":"10.1200/jco.2009.26.7609","title":"Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates","abstract":"<h4>Purpose</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.","journal":"Journal of Clinical Oncology","year":2010,"id":6452,"datarank":15.659850197635887,"base_score":7.979681302387741,"endowment":7.979681302387741,"self_citation_contribution":1.1969521953581612,"citation_network_contribution":14.462898002277726,"self_endowment_contribution":1.1969521953581612,"citer_contribution":14.462898002277726,"corpus_percentile":85.6,"corpus_rank":2479,"citation_count":2920,"citer_count":159,"citers_with_citation_signal":159,"citers_with_endowment":159,"datacite_reuse_total":0,"is_dataset":false,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2010-07-01","authors":[{"id":59423,"name":"Charles G. 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