{"doi":"10.1101/2023.03.22.533709","title":"Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells","abstract":"Summary 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":389921,"datarank":0.7619504993609816,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.33696849775254906,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.33696849775254906,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":13,"citers_with_citation_signal":13,"citers_with_endowment":13,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":983466,"name":"Nadav Brandes","orcid":"0000-0002-0510-2546","position":1,"is_corresponding":false},{"id":24090,"name":"Raymund Bueno","orcid":"0000-0001-8534-9399","position":2,"is_corresponding":false},{"id":849169,"name":"Marena Trinidad","orcid":"0000-0001-7839-4642","position":3,"is_corresponding":false},{"id":1016246,"name":"Thomas Mazumder","orcid":"0000-0003-2427-2652","position":4,"is_corresponding":false},{"id":236071,"name":"Bingfei Yu","orcid":"0000-0001-5550-6701","position":5,"is_corresponding":false},{"id":654907,"name":"Byungjin Hwang","orcid":"0000-0002-7221-3641","position":6,"is_corresponding":false},{"id":1016247,"name":"Christopher Chang","orcid":"0000-0003-3124-8773","position":7,"is_corresponding":false},{"id":312357,"name":"Jamin Liu","orcid":"0000-0001-6386-3709","position":8,"is_corresponding":false},{"id":2816,"name":"Yang Sun","orcid":"0000-0002-9344-8060","position":9,"is_corresponding":false},{"id":1016248,"name":"Caitlin R. 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