Biology guided design of off-the-shelf CAR γδ T cells for the treatment of solid tumors 4680

Abstract Description Chimeric Antigen Receptor (CAR) T-cell therapy has achieved significant success in treating hematological malignancies. However, its efficacy against solid tumors remains suboptimal due to the immunosuppressive tumor microenvironment, metabolic restrictions, and the scarcity of tumor-specific antigens not expressed in vital tissues. Here, we demonstrate the effectiveness of a novel CAR T-cell platform utilizing cord blood-derived γδ T-cell subsets, which can be used allogeneically (“off-the-shelf”) and mimic populations commonly found in solid tumors. We employed single-chain variable fragment (scFv) sequences targeting transmembrane molecules expressed in metastatic small cell lung cancer and other tumors, but not in vital tissues like the lung, heart, kidney or brain. These target antigens were identified through a comprehensive proteogenomic approach. To overcome PD-1-driven inhibition and enhance metabolic reprogramming, we designed an innovative CD3ζ-less CAR architecture that outperforms conventional second-generation CARs. Our results show that γδ T cells, functioning as natural killers independent of MHC presentation, are superior to αβ T cells in this context. The new CAR architecture demonstrated enhanced tumor cell killing efficiency, providing a strong rationale for future clinical trials to optimize CAR T-cell therapy for the most common and aggressive human solid tumors. Funding Sources R01CA278907 (NCI), R01CA297896 (NCI), 2R01CA124515 (NCI), R21CA276205 (NCI) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)