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...

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Veröffentlicht in:Nature biotechnology 2013-01, Vol.31 (1), p.71-75
Hauptverfasser: Kloss, Christopher C, Condomines, Maud, Cartellieri, Marc, Bachmann, Michael, Sadelain, Michel
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Sprache:eng
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Zusammenfassung: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 antigen 1 , 2 , 3 . However, few truly tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell–mediated damage 4 , 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.
ISSN:1087-0156
1546-1696
DOI:10.1038/nbt.2459