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

1] Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA. [2] Biochemistry, Cell, and Molecular Biology Program, Weill Cornell Graduate School for Medical Sciences, Cornell University, New York, New York, USA.
Nature Biotechnology (Impact Factor: 39.08). 12/2012; DOI: 10.1038/nbt.2459
Source: PubMed

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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