Modulation of TCR stimulation and pifithrin-α improves the genomic safety profile of CRISPR-engineered human T cells.

Autor:	Ursch LT; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany., Müschen JS; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany., Ritter J; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany., Klermund J; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, 79106 Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, 79106 Freiburg, Germany., Bernard BE; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany., Kolb S; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany., Warmuth L; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany., Andrieux G; Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Miller G; Core Facility Statistical Consulting, Helmholtz Zentrum München, 85764 Neuherberg, Germany., Jiménez-Muñoz M; Core Facility Statistical Consulting, Helmholtz Zentrum München, 85764 Neuherberg, Germany., Theis FJ; Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany; School of Computing, Information and Technology, Technical University of Munich, 85748 Garching, Germany., Boerries M; Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, 79106 Freiburg, Germany., Busch DH; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany; German Center for Infection Research, Deutsches Zentrum für Infektionsforschung (DZIF), Partner Site Munich, 81675 Munich, Germany., Cathomen T; Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, 79106 Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, 79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Schumann K; Technical University of Munich (TUM), School of Medicine and Health, Department of Preclinical Medicine, Institute for Medical Microbiology, Immunology and Hygiene, 81675 Munich, Germany; TUM, Institute for Advanced Study, 85748 Garching, Germany. Electronic address: kathrin.schumann@tum.de.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Dec 17; Vol. 5 (12), pp. 101846. Date of Electronic Publication: 2024 Dec 04.
DOI:	10.1016/j.xcrm.2024.101846
Abstrakt:	CRISPR-engineered chimeric antigen receptor (CAR) T cells are at the forefront of novel cancer treatments. However, several reports describe the occurrence of CRISPR-induced chromosomal aberrations. So far, measures to increase the genomic safety of T cell products focused mainly on the components of the CRISPR-Cas9 system and less on T cell-intrinsic features, such as their massive expansion after T cell receptor (TCR) stimulation. Here, we describe driving forces of indel formation in primary human T cells. Increased T cell activation and proliferation speed correlate with larger deletions. Editing of non-activated T cells reduces the risk of large deletions with the downside of reduced knockout efficiencies. Alternatively, the addition of the small-molecule pifithrin-α limits large deletions, chromosomal translocations, and aneuploidy in a p53-independent manner while maintaining the functionality of CRISPR-engineered T cells, including CAR T cells. Controlling T cell activation and pifithrin-α treatment are easily implementable strategies to improve the genomic integrity of CRISPR-engineered T cells. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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