Abstract IA19: Response and resistance PD-1 pathway blockade

Abstract

Abstract Melanoma is a genetically complex cancer harboring a multitude of somatic mutations for potential targeting by the immune system. However, melanoma cells can co-opt normal immune tolerance mechanisms to evade elimination. The immunoglobulin-like molecule PD-L1 (B7-H1), expressed by many melanomas in situ, creates a protective shield against immune attack. PD-L1 is a ligand for the programmed death-1 (PD-1) receptor expressed on activated T and B cells, and it delivers an inhibitory signal to suppress antitumor immunity. Blocking the PD-1:PD-L1 interaction can rejuvenate anti-melanoma immunity and mediate tumor regression. Multicenter clinical trials of blocking antibodies against PD-1 (nivolumab, pembrolizumab) or PD-L1 (BMS-936559, MPDL3280A, MEDI4736) have been undertaken. In an early phase trial of biweekly nivolumab administration, durable objective tumor regressions and disease stabilization were observed among 31% and 7%, respectively, of 107 patients with advanced treatment-refractory melanoma. Median overall survival in this trial was 17 months. Partial tumor regressions that are durable and persist after drug discontinuation suggest that PD-1 blockade can reset the balance between the immune system and melanoma. In some patients, “mixed” tumor regressions or initial disease progression followed by regression suggest that tumor lesions separated anatomically or chronologically may be immunologically heterogeneous. Durable objective tumor regressions reported in clinical trials of various antibodies blocking the PD-1 and PD-L1 immune checkpoints validate the importance of targeting this pathway in melanoma therapy. Ongoing investigations into pharmacodynamics and potential biomarkers of response are designed to reveal the basis for immunological heterogeneity among different patients, and among diverse tumor sites in individual patients, to enable the optimal clinical development of these drugs. Supported by research grants from Bristol-Myers Squibb, the National Institutes of Health, Stand Up 2 Cancer, the Barney Family Foundation, the Laverna Hahn Charitable Trust, Moving for Melanoma of Delaware, and the Melanoma Research Alliance. Citation Format: Suzanne L. Topalian. Response and resistance PD-1 pathway blockade. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA19.