1. An engineering strategy to target activated EGFR with CAR T cells.
- Author
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Dobersberger M, Sumesgutner D, Zajc CU, Salzer B, Laurent E, Emminger D, Sylvander E, Lehner E, Teufl M, Seigner J, Bobbili MR, Kunert R, Lehner M, and Traxlmayr MW
- Subjects
- Humans, Immunotherapy, Adoptive methods, Animals, Neoplasms immunology, Neoplasms therapy, Cell Line, Tumor, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, Mice, ErbB Receptors immunology, ErbB Receptors metabolism, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Chimeric antigen receptor (CAR) T cells have shown remarkable response rates in hematological malignancies. In contrast, CAR T cell treatment of solid tumors is associated with several challenges, in particular the expression of most tumor-associated antigens at lower levels in vital organs, resulting in on-target/off-tumor toxicities. Thus, innovative approaches to improve the tumor specificity of CAR T cells are urgently needed. Based on the observation that many human solid tumors activate epidermal growth factor receptor (EGFR) on their surface through secretion of EGFR ligands, we developed an engineering strategy for CAR-binding domains specifically directed against the ligand-activated conformation of EGFR. We show, in several experimental systems, that the generated binding domains indeed enable CAR T cells to distinguish between active and inactive EGFR. We anticipate that this engineering concept will be an important step forward to improve the tumor specificity of CAR T cells directed against EGFR-positive solid cancers., Competing Interests: Declaration of interests M.L. and M.W.T. receive funding from Miltenyi Biotec., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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