Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.03.22.533709v1?rss=1

Authors: Tsuchida, C. A., Brandes, N., Bueno, R., Trinidad, M., Mazumder, T., Yu, B., Hwang, B., Chang, C., Liu, J., Sun, Y., Hopkins, C. R., Parker, K. R., Qi, Y., Satpathy, A., Stadtmauer, E., Cate, J. H. D., Eyquem, J., Fraietta, J. A., June, C. H., Chang, H. Y., Ye, C. J., Doudna, J. A.

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 chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with protection from chromosome loss observed in this protocol, suggesting both a mechanism and strategy for T cell engineering that mitigates this genotoxicity in the clinic.

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