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

CC Kloss, M Condomines, M Cartellieri… - Nature …, 2013 - nature.com
CC Kloss, M Condomines, M Cartellieri, M Bachmann, M Sadelain
Nature biotechnology, 2013nature.com
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 …
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.
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