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

Nat Biotechnol. 2013 Jan;31(1):71-5. doi: 10.1038/nbt.2459. Epub 2012 Dec 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens / immunology*
  • Combinatorial Chemistry Techniques*
  • Humans
  • Neoplasms / immunology*
  • Signal Transduction*
  • T-Lymphocytes / immunology*


  • Antigens