1. Preclinical evaluation of a novel CAR-T therapy utilizing a scFv antibody highly specific to MAGE-A4 p230-239 /HLA-A∗02:01 complex.
- Author
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Wang L, Matsumoto M, Akahori Y, Seo N, Shirakura K, Kato T, Katsumoto Y, Miyahara Y, and Shiku H
- Subjects
- Mice, Animals, Humans, T-Lymphocytes, HLA-A Antigens, Immunotherapy, Adoptive, Single-Chain Antibodies genetics, Receptors, Chimeric Antigen genetics, Neoplasms
- Abstract
Despite the revolutionary success of chimeric antigen receptor (CAR)-T therapy for hematological malignancies, successful CAR-T therapies for solid tumors remain limited. One major obstacle is the scarcity of tumor-specific cell-surface molecules. One potential solution to overcome this barrier is to utilize antibodies that recognize peptide/major histocompatibility complex (MHCs) in a T cell receptor (TCR)-like fashion, allowing CAR-T cells to recognize intracellular tumor antigens. This study reports a highly specific single-chain variable fragment (scFv) antibody against the MAGE-A4
p230-239 /human leukocyte antigen (HLA)-A∗02:01 complex (MAGE-A4 pMHC), screened from a human scFv phage display library. Indeed, retroviral vectors encoding CAR, utilizing this scFv antibody as a recognition component, efficiently recognized and lysed MAGA-A4+ tumor cells in an HLA-A∗02:01-restricted manner. Additionally, the adoptive transfer of T cells modified by the CAR-containing glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related receptor (GITR) intracellular domain (ICD), but not CD28 or 4-1BB ICD, significantly suppressed the growth of MAGE-A4+ HLA-A∗02:01+ tumors in an immunocompromised mouse model. Of note, a comprehensive analysis revealed that a broad range of amino acid sequences of the MAGE-A4p230-239 peptide were critical for the recognition of MAGE-A4 pMHC by these CAR-T cells, and no cross-reactivity to analogous peptides was observed. Thus, MAGE-A4-targeted CAR-T therapy using this scFv antibody may be a promising and safe treatment for solid tumors., Competing Interests: Declaration of interests M.M. and Y.K. are employees of Sony Group Corporation, which collaborated in the development of a closed-cell isolation system. The Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, is an endowment department supported by a grant from T cell Nouveau., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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