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Ursch, L.T.* ; Müschen, J.S.* ; Ritter, J.* ; Klermund, J.* ; Bernard, B.E.* ; Kolb, S.* ; Warmuth, L.* ; Andrieux, G.* ; Miller, G. ; Jiménez-Muñoz, M. ; Theis, F.J. ; Boerries, M.* ; Busch, D.H.* ; Cathomen, T.* ; Schumann, K.*

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

Cell Rep. Med. 5:101846 (2024)
Verlagsversion DOI PMC
Free journal
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Car T Cell Therapy ; Crispr Engineering ; T Cell Activation ; Aneuploidy ; Chromosomal Aberrations ; Genomic Integrity ; Human T cells ; Large Deletions ; Pifithrin-alpha ; Translocations; Protects Mice; P53; Inhibitor; Targets; Alpha; Dna; Apoptosis
ISSN (print) / ISBN 2666-3791
e-ISSN 2666-3791
Zeitschrift Cell Reports Medicine
Quellenangaben Band: 5, Heft: 12, Seiten: , Artikelnummer: 101846 Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CF Statistical Consulting (CF-STATCON)
Institute of Computational Biology (ICB)
Förderungen
Else Kroner-Fresenius-Stiftung
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
German Federal Ministry of Education and Research (BMBF) within the Medical Informatics Funding Scheme
Core Facility "CyTUM MIH"in cell sorting (DFG)