Pre-conditioning radiation synergizes with IL2-superkine (Sup2) and IL33 armed CAR T cells to control solid tumor growth through increased CAR T cell engraftment and persistent effector activity 3584

Abstract Description Chimeric antigen receptor (CAR) T cells are highly effective against liquid tumors but have limited efficacy against solid tumors. We previously showed that melanoma-specific CAR T cells armed with IL2 superkine (Sup2) and alarmin IL33 substantially delay B16F10 tumor growth by augmenting endogenous tumor immunity. However, patients typically receive lymphodepleting regimens before CAR T cell therapy. To determine the effect of lymphodepletion, tumor-bearing mice were treated with 5gy total body irradiation prior to CAR T cell transfer. We found that radiation synergized with Sup2-IL-33 to substantially extend CAR T cell engraftment and tumor control. Depletion of Sup2-IL33 CAR T cells resulted in subsequent loss of tumor control, demonstrating that in contrast to immunocompetent mice, CAR persistence is necessary for durable tumor control. To understand how radiation alters CAR T cells, we characterized tumors and draining lymph nodes using flow cytometry and scRNAseq. Sup2-IL33 armed CAR T cells isolated from irradiated mice uniquely transitioned from a memory precursor effector cell (MPEC) to a short-lived effector cell (SLEC) phenotype. Sup2-IL33 and radiation resulted in higher CAR T cells expressing CD44 and PD1. Thus, in contrast to non-conditioned mice, tumor control is mediated by CAR T cells rather than host cells following lymphodepletion. Radiation synergized with Sup2-IL33 to increase CAR T cell engraftment, persistence and function. Funding Sources CA271553 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)