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Cancer Immunology Research
Cancer Immunology Research
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Research Articles

Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform

Ron S. Gejman, Heather F. Jones, Martin G. Klatt, Aaron Y. Chang, Claire Y. Oh, Smita S. Chandran, Tatiana Korontsvit, Viktoriya Zakahleva, Tao Dao, Christopher A. Klebanoff and David A. Scheinberg
Ron S. Gejman
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
2Tri-Institutional MD-PhD Program (Memorial Sloan Kettering Cancer Center, Rockefeller University, Weill Cornell Medical College), New York, New York.
3Weill Cornell Medicine, New York, New York.
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  • ORCID record for Ron S. Gejman
  • For correspondence: ron.gejman@gmail.com scheinbd@mskcc.org
Heather F. Jones
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
3Weill Cornell Medicine, New York, New York.
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Martin G. Klatt
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
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Aaron Y. Chang
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
3Weill Cornell Medicine, New York, New York.
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Claire Y. Oh
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
3Weill Cornell Medicine, New York, New York.
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Smita S. Chandran
4Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
5Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York.
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Tatiana Korontsvit
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
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  • ORCID record for Tatiana Korontsvit
Viktoriya Zakahleva
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
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Tao Dao
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
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Christopher A. Klebanoff
3Weill Cornell Medicine, New York, New York.
4Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
5Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York.
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David A. Scheinberg
1Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
3Weill Cornell Medicine, New York, New York.
5Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: ron.gejman@gmail.com scheinbd@mskcc.org
DOI: 10.1158/2326-6066.CIR-19-0745 Published May 2020
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Abstract

T-cell receptor (TCR)–based therapeutic cells and agents have emerged as a new class of effective cancer therapies. These therapies work on cells that express intracellular cancer-associated proteins by targeting peptides displayed on MHC receptors. However, cross-reactivities of these agents to off-target cells and tissues have resulted in serious, sometimes fatal, adverse events. We have developed a high-throughput genetic platform (termed “PresentER”) that encodes MHC-I peptide minigenes for functional immunologic assays and determines the reactivities of TCR-like therapeutic agents against large libraries of MHC-I ligands. In this article, we demonstrated that PresentER could be used to identify the on-and-off targets of T cells and TCR-mimic (TCRm) antibodies using in vitro coculture assays or binding assays. We found dozens of MHC-I ligands that were cross-reactive with two TCRm antibodies and two native TCRs and that were not easily predictable by other methods.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:672–84

  • Received September 29, 2019.
  • Revision received November 28, 2019.
  • Accepted March 10, 2020.
  • Published first March 17, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (5)
May 2020
Volume 8, Issue 5
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Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform
Ron S. Gejman, Heather F. Jones, Martin G. Klatt, Aaron Y. Chang, Claire Y. Oh, Smita S. Chandran, Tatiana Korontsvit, Viktoriya Zakahleva, Tao Dao, Christopher A. Klebanoff and David A. Scheinberg
Cancer Immunol Res May 1 2020 (8) (5) 672-684; DOI: 10.1158/2326-6066.CIR-19-0745

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Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform
Ron S. Gejman, Heather F. Jones, Martin G. Klatt, Aaron Y. Chang, Claire Y. Oh, Smita S. Chandran, Tatiana Korontsvit, Viktoriya Zakahleva, Tao Dao, Christopher A. Klebanoff and David A. Scheinberg
Cancer Immunol Res May 1 2020 (8) (5) 672-684; DOI: 10.1158/2326-6066.CIR-19-0745
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