Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform
Open Access
- 16 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Immunology Research
- Vol. 8 (5), 672-684
- https://doi.org/10.1158/2326-6066.CIR-19-0745
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.Other Versions
Funding Information
- Parker Foundation (NA)
- Functional Genomics Initiative at MSKK
- HHS | NIH | National Cancer Institute (F30CA200327)
- HHS | NIH | National Institute of General Medical Sciences (T32GM07739)
- HHS | NIH | National Cancer Institute (RO1CA55349)
- HHS | NIH | National Cancer Institute (P01CA23766)
- HHS | NIH | National Cancer Institute (P30 CA008748)
- Deutsche Forschungsgemeinschaft (KL 3118/1-1)
- Damon Runyon Cancer Research Foundation (Damon Runyon Clinical Investigator Award)
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