Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells

Tsuchida, Connor A.; Brandes, Nadav; Bueno, Raymund; Trinidad, Marena; Mazumder, Thomas; Yu, Bingfei; Hwang, Byungjin; Chang, Christopher; Liu, Jamin; Sun, Yang; Hopkins, Caitlin R.; Parker, Kevin R.; Qi, Yanyan; Hofman, Laura; Satpathy, Ansuman T.; Stadtmauer, Edward A.; Cate, J.H.D.; Eyquem, Justin; Fraietta, Joseph A.; June, Carl H.; Chang, Howard Y.; Ye, Chun; Doudna, Jennifer A.

doi:10.1016/j.cell.2023.08.041

articleCellOct 1, 2023HYBRID OA

Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells

CAConnor A. Tsuchida NBNadav Brandes RBRaymund Bueno MTMarena Trinidad TMThomas Mazumder

University of California, San Francisco · Innovative Genomics Institute · +10 more institutions

PubMed

Indexed incrossrefpubmed

Abstract

CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome remains a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that chromosome loss was generalizable across the genome and resulted in partial and entire loss of the targeted chromosome, including in preclinical chimeric antigen receptor T cells. T cells with chromosome loss persisted for weeks in culture, implying the potential to interfere with clinical use. A modified cell manufacturing process, employed in our…

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Topics & keywords

Topics

Keywords

CRISPR
Genome editing
Biology
Cas9
Chimeric antigen receptor
Chromosome
Chromosome engineering
Genetics

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