Abstract P4-04-03: Targeting of phosphatidylserine by monoclonal antibodies augments the activity of immune checkpoint inhibitor PD-1/PD-L1 therapy in murine breast tumors

Abstract

Abstract Phosphatidylserine (PS) is a phospholipid that typically resides in the inner leaflet of the plasma membrane in many types of cells, including both tumor and tumor associated endothelial cells. Conditions that cause cellular stress, including those that occur from oxygen radicals, hypoxia, irradiation, and chemotherapy, cause a dramatic shift in PS localization. This change in localization results in PS shifting to the outer plasma membrane, allowing its recognition by components of the tumor microenvironment. Recognition of PS promotes an immunosuppressive environment that encourages tumor growth, in part by promoting the recruitment of myeloid derived suppressor cells, immature dendritic cells, and M2-like macrophages, in addition to inducing production of anti-inflammatory cytokines. Currently the chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapies to treat patients with solid tumors in multiple late-stage clinical trials, where it is believe to help augment the efficacy of chemotherapeutics by blockade of PS-mediated immunosuppression and triggering an Fc-FcR mediated pro-inflammatory response in the tumor microenvironment. While the results with PS targeting therapies with chemotherapeutics are encouraging, the effectiveness of PS targeting therapies in conjunction with therapies towards immune checkpoint regulators remains largely unknown. To better understand the role of PS-targeting in breast cancers, and its effectiveness when used in combination with checkpoint inhibitors, immune competent mice harboring either EMT-6 or E0771 breast tumors were utilized. Treatments comprised PS targeting antibodies and an anti-PD1 antibody (to interrupt the PD-1/PD-L1 signaling axis) either alone or in combination with each other, and the effect on tumor growth and immune suppression determined. In both models, which showed differential sensitivity to therapy, the inclusion of PS targeting antibodies with the checkpoint blocker antibody had a significantly greater anti-tumor response than either single agent alone. Citation Format: Gray M, Gong J, Nguyen V, Hutchins J, Freimark B. Targeting of phosphatidylserine by monoclonal antibodies augments the activity of immune checkpoint inhibitor PD-1/PD-L1 therapy in murine breast tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-03.