Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells.
Cell
; 186(21): 4567-4582.e20, 2023 10 12.
Article
en En
| MEDLINE
| ID: mdl-37794590
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 first-in-human clinical trial of Cas9-engineered T cells (NCT03399448), 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Aberraciones Cromosómicas
/
Sistemas CRISPR-Cas
/
Edición Génica
Tipo de estudio:
Guideline
Límite:
Humans
Idioma:
En
Revista:
Cell
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos