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

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 chromosome, including in pre-clinical 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 first-in-human clinical trial of Cas9-engineered T cells, ¹ dramatically reduced

SUBMITTER: Tsuchida CA 

PROVIDER: S-EPMC10055432 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature