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

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...

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Veröffentlicht in:Cancer immunology research 2020-05, Vol.8 (5), p.672-684
Hauptverfasser: Gejman, Ron S, Jones, Heather F, Klatt, Martin G, Chang, Aaron Y, Oh, Claire Y, Chandran, Smita S, Korontsvit, Tatiana, Zakahleva, Viktoriya, Dao, Tao, Klebanoff, Christopher A, Scheinberg, David A
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Sprache:eng
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Zusammenfassung: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 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.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-19-0745