TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation.
Mühlgrabner V., Peters T., Velasco Cárdenas RM-H., Salzer B., Göhring J., Plach A., Höhrhan M., Perez ID., Goncalves VDR., Farfán JS., Lehner M., Stockinger H., Schamel WW., Schober K., Busch DH., Hudecek M., Dushek O., Minguet S., Platzer R., Huppa JB.
Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)-modified T cells and call for alternative antigen receptor designs for effective T cell-based cancer immunotherapy. Here, we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousandfold. TCC-based antigen recognition occurred without adverse nonspecific signaling, which is typically observed in CAR-T cells, and did not depend-unlike sensitized peptide/MHC detection by conventional T cells-on CD4 or CD8 coreceptor engagement. TCC-endowed signaling properties may prove critical when targeting antigens in low abundance and aiming for a durable anticancer response.