Ping-pong dual CAR T cells: antigen-specific peripheral expansion of dual-targeted CAR T cells boosts antitumor immunity against solid tumors 2126

Abstract Description Chimeric Antigen Receptor (CAR) T cell therapy has shown promise in treating hematological cancers but faces challenges in solid tumors, particularly in expanding and persisting in the periphery. To address this, we designed a dual-targeted CAR T cell against peripheral B cells (anti-CD19) and solid tumor antigen (anti-mesothelin, MSLN) to maintain MSLN CAR T cell fitness and increase antitumor efficacy. We first assessed our technology in immunocompetent C57BL/6 mice where we established two syngeneic flank tumor models of pancreatic ductal adenocarcinoma (PDAC), ranging in immunogenicity, as well as an additional solid-tumor antigen model. Ultimately, we find enhanced B cell driven expansion in the blood, increased antitumor efficacy, and higher levels of early activation without increasing downstream exhaustion or toxicity compared to single CAR T cells. We have also identified the importance of B cell driven responses and alternative mechanisms of trafficking, likely owing to antigen engagement in the spleen. We have further translated our findings into human CAR T cells in NOD scid gamma (NSG) mice through the development of a novel model for CD19? B cells in the periphery. Together our work suggests that dual-targeted CAR T cells are a successful strategy to enhance CAR T cell expansion in the periphery and increase antitumor efficacy in both syngeneic and humanized models of PDAC and beyond. Funding Sources Supported by the NSF Graduate Research Fellowship Program, Patel Family Fellowship, as well as the Muriel Joan Drew Hege Fund. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)