Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity.
Kondo T., Bourassa FXP., Achar S., DuSold J., Céspedes PF., Ando M., Dwivedi A., Moraly J., Chien C., Majdoul S., Kenet AL., Wahlsten M., Kvalvaag A., Jenkins E., Kim SP., Ade CM., Yu Z., Gaud G., Davila M., Love P., Yang JC., Dustin ML., Altan-Bonnet G., François P., Taylor N.
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.