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TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation.

Vanessa MühlgrabnerTimo PetersRubí M-H Velasco CárdenasBenjamin SalzerJanett GöhringAngelika PlachMaria HöhrhanIago Doel PerezVasco Dos Reis GonçalvesJesús Siller FarfánManfred LehnerHannes StockingerWolfgang W A SchamelKilian SchoberDirk H BuschMichael HudecekOmer DushekSusana MinguetRené PlatzerJohannes B Huppa
Published in: Science advances (2024)
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.
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