CD28- and 4-1BB-based CAR-T cell therapy for solid tumors: insights from an Immunocompetent Mouse Model 4361

Abstract Description Chimeric antigen receptor-engineered T (CAR-T) cells have shown remarkable success in hematologic malignancies but limited efficacy in solid tumors. Xenograft models are commonly used for preclinical CAR-T studies, but immunocompetent models better reflect the complex immune interactions in solid tumor settings. Using a C57BL/6 mouse model of B16F10 melanoma, we evaluated syngeneic CAR-T cells with CD28 (28z) or 4-1BB (BBz) costimulatory domains. We conducted a comprehensive comparison of these constructs, focusing on transcriptional profiles, differentiation phenotypes, effector functions, trafficking kinetics to tumor and lymphoid tissues, and pharmacodynamic characteristics. Transcriptomic analyses revealed that 28z CAR-T cells upregulated effector-related genes, while BBz CAR-T cells expressed more division-related genes, consistent across human and mouse CAR-T cells. In tumor-bearing mice, CAR-T cells peaked in the blood at day 7 post-infusion and diminished by day 21, mirroring clinical observations in solid tumor trials. Importantly, we identified significant differences between 28z and BBz CAR-T cells in polyfunctionality, trafficking dynamics, and inflammatory cytokine/chemokine profiles in plasma. Our study highlights the relevance of immunocompetent models for CAR-T therapy in solid tumors and provides insights into the distinct characteristics of CD28- and 4-1BB-based CAR-T cells, aiding in the design of more effective therapies for solid tumors. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)