title: Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells.
abstract: Current T-cell engineering approaches redirect patient T cells to tumors by transducing them with antigen-specific T-cell receptors (TCRs) or chimeric antigen receptors (CARs) that target a single antigen. However, few truly tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell-mediated damage. Here we present a strategy to render T cells specific for a tumor in the absence of a truly tumor-restricted antigen. T cells are transduced with both a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen. Using the prostate tumor antigens PSMA and PSCA, we show that co-transduced T cells destroy tumors that express both antigens but do not affect tumors expressing either antigen alone. This 'tumor-sensing' strategy may help broaden the applicability and avoid some of the side effects of targeted T-cell therapies.
authors.affiliation: Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Kloss
authors.forename: Maud
authors.initials: M
authors.lastname: Condomines
authors.forename: Marc
authors.initials: M
authors.lastname: Cartellieri
authors.forename: Michael
authors.initials: M
authors.lastname: Bachmann
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D000941:Antigens / Q000276:immunology*; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D009369:Neoplasms / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens