IMMU-72. Locoregionally delivered PD-1 blockade augments B7-H3 targeting CAR T cell efficacy in models of glioblastoma

Glioblastoma (GBM) is the most lethal primary brain tumor in adults presenting with a 95% five-year mortality rate. Due to high relapse rates, GBM remains a major unmet clinical need for new treatment approaches. An innovative approach to target GBM is the administration of chimeric antigen receptor (CAR) T cells to treat relapsed/refractory disease. In this study we identified B7-H3 as an optimal target antigen for CAR T cell therapy of GBM, and developed a novel B7-H3 targeting CAR T cell. These CAR T cells demonstrated robust, antigen-specific cytolysis and cytokine production, while demonstrating low tonic signaling and preservation of a stem/naïve cell phenotype. Using multiple orthotopic xenograft models of GBM we show that a single intravenous administration of B7-H3 targeted CAR T cells confers tumor control, and long-term survival. We identified upregulation of T cell inhibitory ligands PD-L1 and PD-L2 as a mechanism of resistance to CAR T cell therapy. Accordingly, we modified our B7-H3 targeting CAR T cells to secrete a PD-1 blocking scFv downstream of the CAR. Using this armored approach, we further demonstrated that concomitant PD-1 blockade through secretion of a PD-1 blocking scFv by CAR T cells augments the antitumor capabilities of B7-H3-targeting CAR T cells. This was demonstrated through increased infiltration of the adoptively transferred T cells into tumors and improved effector function which conferred durable, long-term remissions in a disease-relevant model of GBM. Together, these data demonstrate B7-H3 targeting CAR T cells armored with concomitant PD-1 blockade are a safe and efficient method for improving the antitumor capacity of B7-H3 targeting CAR T cells in the context of GBM.