Enhancement of immune checkpoint PD-1 blockade efficacy in ovarian cancer

Abstract Introduction Advanced stage ovarian cancer is often asymptomatic and only twenty percent of patients with this diagnosis have a survival duration of five years. Immune checkpoint molecule programmed cell death-1 (PD-1) and its ligand, PD-L1, limit T cell immune responses, and thus are immunosuppressive. Clinical trials using anti-PD-1 or anti-PD-L1 antibody treatment has resulted in objective response rates (ORR) in only 10-15% of ovarian cancer patients. Our ultimate goal is to improve this outcome. Recepteur d'origine nantais (RON) is a c-Met related tyrosine kinase which binds to macrophage stimulatory protein (MSP). RON is expressed by myeloid suppressor cells and tumor cells. Inhibition of RON/ MSP ligation upregulates STAT-1 and IL-12 in macrophages, driving IFN-γ production in CD8+T cells and might potentiate the efficacy of anti-PD-1 antibody treatment. Objectives and Methods We hypothesize that combination therapy of anti-PD-1 blocking antibody which restores T cell proliferative and cytotoxic functions, combined with therapy targeting other suppressive pathways, will concomitantly overcome multiple immune suppressive mechanisms, and prevent ovarian cancer in mice. In a pilot study, ovarian cancer was induced in female C57BL/6 (H-2Kb) mice (Jackson Laboratories) at 8 weeks old, by intraperitoneal (I.P.) injection of 1 x 106 ID8-RFP ovarian tumor cells in 5 mice/ group. We determined the efficacy of anti-PD-1 antibody (RMP1-14, BioXCell; 200ug/ dose, 0.5 ml vol. I.P., 4 doses) given alone or with a RON inhibitor, BMS-777607 (each dose 50 mg/ kg body weight, 20 doses orally over 5 weeks; Selleck Chemicals). Mice were euthanized at about day 70 when control mice with disease had extended abdomens. Results Treatment of mice with an anti-PD-1 blocking antibody combined with a RON inhibitor resulted in disease improvement in 5/5 mice. The average volume of ascites recovered from 5 combination treated mice was 1.62 ml (2/5 mice had no ascites) compared with 6.64 ml from the corresponding control (a 4-fold reduction in ascites with combination treatment). There was an average 2 fold reduction in ascites volume in anti-PD-1 antibody treated mice in comparison with IgG controls (4.14 ml versus 8.62 ml). BMS-777607 treatment (vs vehicle) did not significantly alter ascites volume. Flow cytometry evaluation of spleen cells showed that in the combination treated mouse group, there was an increase in the average percentage of CD3 (combined treatment group 26.7 vs control 8.5%), CD4 (10.6 vs control 5.0%) and CD8 T cells (10.6 vs control 2.7%). We are investigating changes in immune responses genes in RNA of intestines and livers. Conclusions Anti-PD-1 antibody treatment is effective in treating ovarian cancer in mice, but treatment with this agent combined with RON/ c-Met inhibitor, BMS-777607 is superior to either single therapy. Combination treatment with these 2 agents holds promise as a novel therapeutic approach for ovarian cancer. Citation Format: Maureen Drakes, Swati Mehrotra, Ronald Potkul, Yueying Liu, M. Sharon Stack, Patrick Stiff. Enhancement of immune checkpoint PD-1 blockade efficacy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1688.