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

• DOI: 10.1126/sciadv.adj4632
• Publication Date: 2024-09-04T18:00:13Z
• Authors: Vanessa Mühlgrabner; Timo Peters; Rubí M.-H. Velasc...; Benjamin Salzer; Janett Göhring; Angelika Plach; Maria Höhrhan; Iago Doel Perez; Vasco Dos Reis Go...; Jesús Siller Farfán; Manfred Lehner; Hannes Stockinger; Wolfgang W. Schamel; Kilian Schober; Dirk H. Busch; Michael Hudecek; Omer Dushek; Susana Minguet; René Platzer; Johannes B. Huppa
• Keywords: Cancer Research; Receptors, Chimeric Antigen; CD3 Complex; T-Lymphocytes; Cell Line, Tumor; Receptors, Antigen, T-Cell; 610; Humans; Biomedicine and Life Sciences; Lymphocyte Activation; Immunotherapy, Adoptive; Signal Transduction; 3. Good health

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.