Myd88/Cd40 Enhanced Cd19-Specific Car-T Cells Maintain Therapeutic Efficacy Following Resolution Of Cytokine-Related Toxicity Using Inducible Caspase-9

Introduction: The efficacy of chimeric antigen receptor-modified T cells (CAR-T) targeting CD19+ leukemias and lymphomas is dependent on their in vivo expansion following adoptive transfer. Additional genetic augmentations to improve CAR-T expansion may improve therapeutic efficacy but risks increasing CAR-T toxicity. Here, we demonstrate that a highly active CD19-specific CAR-T cell constitutively expressing a MyD88/CD40 (MC) costimulatory fusion protein and the inducible caspase-9 (iC9) safety switch, is effective at eliminating tumors but induces acute cytokine-related toxicity in animal models. This toxicity, however, can be resolved by administration of rimiducid to induce partial CAR-T apoptosis preserving long-term anti-tumor effects.