دورية أكاديمية
Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells.
| العنوان: | Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells. |
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| المؤلفون: | 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 Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., 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, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., 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 Laboratory, Berkeley, CA, USA., 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, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., 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, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., 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 for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. Electronic address: jimmie.ye@ucsf.edu., 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, San Francisco, CA, USA; 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 Laboratory, Berkeley, CA, USA; Department of Chemistry, University of California Berkeley, Berkeley, CA, USA; Howard Hughes Medical Institute, University of California Berkeley, Berkeley, CA, USA. Electronic address: doudna@berkeley.edu. |
| المصدر: | Cell [Cell] 2023 Oct 12; Vol. 186 (21), pp. 4567-4582.e20. Date of Electronic Publication: 2023 Oct 03. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cambridge, Ma : Cell Press Original Publication: Cambridge, MIT Press. |
| مواضيع طبية MeSH: | CRISPR-Cas Systems*/genetics , Gene Editing*/methods , T-Lymphocytes* , Chromosome Aberrations*, Humans ; Chromosomes ; DNA Damage ; Clinical Trials as Topic |
| مستخلص: | 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. Competing Interests: Declaration of interests C.A.T., J.A.D., and the Regents of the University of California have patents pending or issued related to the use of CRISPR genome editing technologies. R.B. is an employee of BioMarin Pharmaceutical Inc., J.L. is an employee of Altos Labs, and K.R.P. is a co-founder and employee of Cartography Biosciences. A.T.S. is a co-founder of Immunai and Cartography Biosciences. A.T.S. has received research support from Arsenal Biosciences, Allogene Therapeutics, and 10x Genomics. J.H.D.C. is a co-founder of Initial Therapeutics. J.E. is a co-founder of Mnemo Therapeutics, a scientific advisory board member of Cytovia Therapeutics, and a consultant for Casdin Capital, Resolution Therapeutics, IndeeLabs, and Treefrog Therapeutics. J.E. has received research support from Cytovia Therapeutics, Mnemo Therapeutics, and Takeda Pharmaceutical Company. J.A.F. has received research support from Tmunity. C.H.J. and the University of Pennsylvania have patents pending or issued related to the use of gene modification in T cells for adoptive T cell therapy. C.H.J. is a co-founder of Tmunity. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, and Orbital Therapeutics, and an advisor to 10x Genomics, Arsenal Biosciences, Chroma Medicine, Spring Discovery, and Vida Ventures. C.J.Y. is a co-founder of Survey Genomics, and a scientific advisory board member of Related Sciences and Immunai. C.J.Y. is a consultant for Maze Therapeutics, TReX Bio, ImYoo, and Santa Ana Bio. C.J.Y. has received research support from the Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, Genentech, BioLegend, ScaleBio, and Illumina. J.A.D. is a co-founder of Editas Medicine, Intellia Therapeutics, Caribou Biosciences, Mammoth Biosciences, and Scribe Therapeutics, and a scientific advisory board member of Intellia Therapeutics, Caribou Biosciences, Mammoth Biosciences, Scribe Therapeutics, Vertex Pharmaceuticals, Felix Biosciences, The Column Group, Inari, and Isomorphic Labs. J.A.D. is the Chief Science Advisor at Sixth Street and a Director at Johnson & Johnson, Tempus, and Altos Labs. J.A.D. has sponsored research projects through Apple Tree Partners, Genentech, and Roche. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| التعليقات: | Update of: bioRxiv. 2023 Mar 22;:. (PMID: 36993359) |
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| معلومات مُعتمدة: | RM1 HG007735 United States HG NHGRI NIH HHS; T32 GM067547 United States GM NIGMS NIH HHS; RM1 HG009490 United States HG NHGRI NIH HHS; United States HHMI Howard Hughes Medical Institute; U01 AI142817 United States AI NIAID NIH HHS; R01 AR071522 United States AR NIAMS NIH HHS; R35 CA209919 United States CA NCI NIH HHS; R01 GM065050 United States GM NIGMS NIH HHS; F31 HL156468 United States HL NHLBI NIH HHS; R01 AI136972 United States AI NIAID NIH HHS; R01 HG011239 United States HG NHGRI NIH HHS |
| فهرسة مساهمة: | Keywords: CAR T cells; CRISPR screen; CRISPR-Cas9; DNA repair; T cells; aneuploidy; chromosome loss; clinical trial; genome editing; immunoengineering |
| سلسلة جزيئية: | ClinicalTrials.gov NCT03399448 |
| تواريخ الأحداث: | Date Created: 20231005 Date Completed: 20231103 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC10664023 |
| DOI: | 10.1016/j.cell.2023.08.041 |
| PMID: | 37794590 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1097-4172 |
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| DOI: | 10.1016/j.cell.2023.08.041 |