Improved Tumor Specificity of Mesothelin (MSLN)-specific Killer Immunoglobulin Receptor (KIR)-based Chimeric Antigen Receptor (CAR) T cell therapy SynKIR-110 3562

Abstract Description MSLN is highly expressed in solid tumors but weakly in few normal tissues, making it a promising target for CAR T cell therapy. Early MSLN CAR T trials using the SS1 anti-MSLN binder with 41BB-CD3z showed clinical safety, but lacked efficacy. A recent report describing patient lung toxicity with a MSLN CAR T using a different binder underscores the urgent need for safer CAR T with enhanced tumor specificity. We previously developed a KIR-CAR, SynKIR-110 comprised of a split-chain design: a SS1 MSLN binding domain, and DAP12 T cell activation domain. This design mimics natural multichain immunoreceptors and demonstrates greater potency vs CD3z-based CAR T in vivo. To investigate SynKIR-110 tumor specificity we compared it to the clinically tested SS1-41BBz. T cells were stimulated with MSLN-positive (MSLN+) or negative (MSLN-) targets. T cell growth, phenotype, co-culture cytokines, and longitudinal tumor lysis were assessed. SynKIR-110 showed 4-fold higher growth, 4-fold lower CAR MFI expression and 6-fold lower 41BB+% vs SS1-41BBz at baseline. Both eliminated MSLN+ targets similarly. However, SS1-41BBz also showed higher basal killing and secreted higher cytokine levels upon MSLN- target co-culture, while SynKIR-110 did not. Overall SynKIR-110 demonstrates improved tumor specificity without the constitutive activation seen in SS1-41BBz. Further studies will explore the molecular pathways linked to enhanced tumor specificity, potency and exhaustion resistance of SynKIR-110. Funding Sources Verismo Therapeutics Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)