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Long terminal repeat CRISPR-CAR-coupled "Universal" T cells mediate potent anti-leukemic effects
DC Field | Value | Language |
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dc.contributor.author | Georgiadis, Christos | - |
dc.contributor.author | Preece, Roland | - |
dc.contributor.author | Nickolay, Lauren | - |
dc.contributor.author | Etuk, Aniekan | - |
dc.contributor.author | Petrova, Anastasia | - |
dc.contributor.author | Ladon, Dariusz | - |
dc.contributor.author | Danyi, Alexandra | - |
dc.contributor.author | Humphryes-Kirilov, Neil | - |
dc.contributor.author | Ajetunmobi, Ayokunmi | - |
dc.contributor.author | Kim, Daesik | - |
dc.contributor.author | Kim, Jin-Soo | - |
dc.contributor.author | Qasim, Waseem | - |
dc.date.accessioned | 2020-04-27T13:00:14Z | - |
dc.date.available | 2020-04-27T13:00:14Z | - |
dc.date.created | 2019-08-16 | - |
dc.date.created | 2019-08-16 | - |
dc.date.created | 2019-08-16 | - |
dc.date.issued | 2018-05 | - |
dc.identifier.citation | Molecular Therapy, Vol.26 No.5, pp.1215-1227 | - |
dc.identifier.issn | 1525-0016 | - |
dc.identifier.other | 81106 | - |
dc.identifier.uri | https://hdl.handle.net/10371/165704 | - |
dc.description.abstract | Gene editing can be used to overcome allo-recognition, which otherwise limits allogeneic T cell therapies. Initial proof-of-concept applications have included generation of such "universal" T cells expressing chimeric antigen receptors (CARs) against CD19 target antigens combined with transient expression of DNA-targeting nucleases to disrupt the T cell receptor alpha constant chain (TRAC). Although relatively efficient, transgene expression and editing effects were unlinked, yields variable, and resulting T cell populations heterogeneous, complicating dosing strategies. We describe a self-inactivating lentiviral "terminal" vector platform coupling CAR expression with CRISPR/Cas9 effects through incorporation of an sgRNA element into the Delta U3 3' long terminal repeat (LTR). Following reverse transcription and duplication of the hybrid Delta U3-sgRNA, delivery of Cas9 mRNA resulted in targeted TRAC locus cleavage and allowed the enrichment of highly homogeneous (> 96%) CAR(+) (> 99%) TCR- populations by automated magnetic separation. Molecular analyses, including NGS, WGS, and Digenome-seq, verified on-target specificity with no evidence of predicted off-target events. Robust anti-leukemic effects were demonstrated in humanized immunodeficient mice and were sustained longer than by conventional CAR(+)TCR(+) T cells. Terminal-TRAC (TT) CAR T cells offer the possibility of a pre-manufactured, non-HLA-matched CAR cell therapy and will be evaluated in phase 1 trials against B cell malignancies shortly. | - |
dc.language | 영어 | - |
dc.publisher | Nature Publishing Group | - |
dc.title | Long terminal repeat CRISPR-CAR-coupled "Universal" T cells mediate potent anti-leukemic effects | - |
dc.type | Article | - |
dc.contributor.AlternativeAuthor | 김진수 | - |
dc.identifier.doi | 10.1016/j.ymthe.2018.02.025 | - |
dc.citation.journaltitle | Molecular Therapy | - |
dc.identifier.wosid | 000431485300008 | - |
dc.identifier.scopusid | 2-s2.0-85044601637 | - |
dc.citation.endpage | 1227 | - |
dc.citation.number | 5 | - |
dc.citation.startpage | 1215 | - |
dc.citation.volume | 26 | - |
dc.identifier.sci | 000431485300008 | - |
dc.description.isOpenAccess | Y | - |
dc.contributor.affiliatedAuthor | Kim, Jin-Soo | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordPlus | GENOME EDITING SPECIFICITY | - |
dc.subject.keywordPlus | CHIMERIC-ANTIGEN-RECEPTOR | - |
dc.subject.keywordPlus | GENE-EXPRESSION | - |
dc.subject.keywordPlus | DIGENOME-SEQ | - |
dc.subject.keywordPlus | NUCLEASES | - |
dc.subject.keywordPlus | RNA | - |
dc.subject.keywordPlus | TRANSDUCTION | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | PROMOTER | - |
dc.subject.keywordPlus | CLEAVAGE | - |
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