Abstract 4978: Targeting of phosphatidylserine by monoclonal antibodies enhances activity of immune checkpoint inhibitors in tumors

Abstract

Abstract Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed on tumor vascular endothelial cells (ECs) and tumor cells. PS exposure becomesenhanced in response to chemotherapy, irradiation, and oxidative stresses in the tumor microenvironment. PS exposure in tumors promotes an immunosuppressive microenvironment which includes the recruitment of myeloid derived suppressor cells (MDSCs), immature dendritic cells, and M2-like macrophages as well as the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumor cells and their secreted microparticles triggers an Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses the immunosuppressive PS meditated checkpoint, thereby enhancing anti-tumor immunity. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using multiple syngeneic tumors in immune competent mice, we demonstrate PS targeting antibodies enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation. Citation Format: Jian Gong, Van Nguyen, Shen Yin, Rich Archer, Jeff Hutchins, Bruce Freimark. Targeting of phosphatidylserine by monoclonal antibodies enhances activity of immune checkpoint inhibitors in tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4978. doi:10.1158/1538-7445.AM2014-4978