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In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R\/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5\u2009years after infusion. We show that long-lived CAR-T cells developed a CD4\/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4\/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.<\/jats:p>","DOI":"10.1038\/s41591-023-02415-3","type":"journal-article","created":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T20:02:01Z","timestamp":1688587321000},"page":"1700-1709","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia"],"prefix":"10.1038","volume":"29","author":[{"given":"Nathaniel D.","family":"Anderson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Birch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2783-8482","authenticated-orcid":false,"given":"Theo","family":"Accogli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4120-343X","authenticated-orcid":false,"given":"Ignacio","family":"Criado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Khabirova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0240-0684","authenticated-orcid":false,"given":"Conor","family":"Parks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvette","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0937-5290","authenticated-orcid":false,"given":"Matthew D.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6063-0659","authenticated-orcid":false,"given":"Tarryn","family":"Porter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Albon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilyana","family":"Popova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Lopes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6046-8428","authenticated-orcid":false,"given":"Robert","family":"Wynn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Hough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satyen H.","family":"Gohil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Pule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0480-3911","authenticated-orcid":false,"given":"Persis J.","family":"Amrolia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6600-7665","authenticated-orcid":false,"given":"Sam","family":"Behjati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1555-2946","authenticated-orcid":false,"given":"Sara","family":"Ghorashian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,6]]},"reference":[{"key":"2415_CR1","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1200\/JCO.19.01086","volume":"38","author":"KW Maloney","year":"2020","unstructured":"Maloney, K. 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S.G., M.A.P. and P.J.A. have patent rights for CAT CAR in targeting CD19 and may receive royalties from Autolus Therapeutics PLC (patent application: World Intellectual Property Organization, WO 2016\/139487 Al). N.D.A., S.B. and S.G. have filed a patent application related to the use of a transcriptional signature to determine a persistence phenotype in CAR-T cells. The remaining authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}