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

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 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.

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Figure 1: Dual chimeric receptor-mediated activation and costimulation of human T cells facilitates robust cytotoxicity, proliferation and tumor eradication.
Figure 2: Reducing CAR mediated activation signals restricts T-cell activity to tumors expressing both antigens upon combinatorial antigen recognition.
Figure 3: Concept of combinatorial antigen recognition and balanced signaling for selective tumor eradication.

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Acknowledgements

We thank I. Riviere for reviewing the manuscript and J. Plotkin and G. Gunset for outstanding technical assistance. Our work is supported by Department of Defense Prostate Cancer Training Award PC101964 (C.C.K.), the Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, the Major Family Fund for Cancer Research at Memorial Sloan-Kettering, the support of Mr. and Mrs. Joel S. Mallah, and Mr. Lewis Sanders.

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C.C.K. designed and performed experiments, analyzed data, and wrote the manuscript. M. Condomines contributed reagents, performed experiments, interpreted results and reviewed the manuscript. M. Cartellieri contributed reagents and performed experiments. M.B. contributed reagents and designed experiments. M.S. designed experiments, analyzed data, interpreted results and wrote the paper.

Corresponding author

Correspondence to Michel Sadelain.

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The authors declare no competing financial interests.

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Kloss, C., Condomines, M., Cartellieri, M. et al. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol 31, 71–75 (2013). https://doi.org/10.1038/nbt.2459

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