Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells

To increase the tumor specificity of engineered T cells, Kloss et al. design an approach that relies on T cell recognition of two, rather than one, antigens. 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 antigen1,2,3. However, few truly tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell–mediated damage4,5,6,7. 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.