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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, Jamie H D; Eyquem, Justin; Fraietta, Joseph A; June, Carl H; Chang, Howard Y; Ye, Chun Jimmie; Doudna, Jennifer A.
Afiliación
  • Tsuchida CA; University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, Berkeley, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
  • Brandes N; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Bueno R; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Trinidad M; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
  • Mazumder T; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Yu B; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA.
  • Hwang B; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Chang C; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Parker
  • Liu J; University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, Berkeley, Berkeley, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • Sun Y; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Hopkins CR; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, Univers
  • Parker KR; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
  • Qi Y; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Hofman L; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Graduate School of Life Sciences, Utrecht University, Utrecht, the Netherlands.
  • Satpathy AT; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Stadtmauer EA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Cate JHD; Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laborato
  • Eyquem J; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
  • Fraietta JA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, Univers
  • June CH; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, Univers
  • Chang HY; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
  • Ye CJ; University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, Berkeley, Berkeley, CA, USA; Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Parker Institute fo
  • Doudna JA; University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, Berkeley, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Gladstone-UCSF Institute of Genomic Immunology,
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.
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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
Texto completo
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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