TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation
Peters, T.; Muehlgrabner, V.; Velasco Cardenas, R. M. H.; Platzer, R.; Gohring, J.; Salzer, B.; Plach, A.; Hoehrhan, M.; Doel-Perez, I.; Goncalves, V. D. R.; Farfan, J. S.; Lehner, M.; Stockinger, H.; Schamel, W. W.; Schober, K.; Busch, D. H.; Hudecek, M.; Dushek, O.; Minguet, S.; Huppa, J. B.
Show abstract
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 thousand-fold. TCC-based antigen recognition occurred without adverse non-specific 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 anti-cancer response.
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