Résumé
Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHATL8F/p53R175H) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.
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•TCRs impact CARs across a continuum of antigens, from antagonism to enhancement•Modeling of TCR/CAR crosstalk reveals ternary fuzzy logic in dual receptor activation•Fuzzy logic produces an antagonism-enforced braking system (AEBS) in CAR T cells•AEBS CAR T cells eradicate tumors with minimal toxicity against healthy human tissue
Robot-assisted analysis and theoretical modeling of TCR/CAR crosstalk enable the design of adoptive T cell therapies that maximize anti-tumor activity and minimize toxicity in healthy tissues.