{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:24:43Z","timestamp":1790677483276,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"CERCA Programme\/Generalitat de Catalunya"},{"name":"Health Department PERIS","award":["#SLT\/002\/16\/00374"],"award-info":[{"award-number":["#SLT\/002\/16\/00374"]}]},{"name":"AGAUR-project","award":["2017SGR1080"],"award-info":[{"award-number":["2017SGR1080"]}]},{"name":"MCI\/AEI\/ERDF","award":["RTI2018-094049-B-I00"],"award-info":[{"award-number":["RTI2018-094049-B-I00"]}]},{"name":"ERC EPIPHARM"},{"DOI":"10.13039\/100008050","name":"Cellex Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010434","name":"\u201cla Caixa\u201d Foundation","doi-asserted-by":"publisher","award":["LCF\/PR\/GN18\/51140001"],"award-info":[{"award-number":["LCF\/PR\/GN18\/51140001"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010434","name":"\u201cla Caixa\u201d Foundation","doi-asserted-by":"publisher","award":["LCF\/PR\/GN18\/50310007"],"award-info":[{"award-number":["LCF\/PR\/GN18\/50310007"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010434","name":"\u201cla Caixa\u201d Foundation","doi-asserted-by":"publisher","award":["RF-2016\u201302364388"],"award-info":[{"award-number":["RF-2016\u201302364388"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Accelerator Award\u2014Cancer Research","award":["UK\/AIRC\u2014INCAR"],"award-info":[{"award-number":["UK\/AIRC\u2014INCAR"]}]},{"name":"Associazione Italiana Ricerca per la Ricerca sul Cancro (AIRC) Project 5","award":["9962"],"award-info":[{"award-number":["9962"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n\u2009=\u200979), which was associated with CR (Fisher exact test, P\u2009&amp;lt;\u2009.001) and enhanced event-free survival (hazard ratio\u2009[HR] =\u20090.36; 95% confidence interval\u2009[CI] =\u20090.19 to 0.70; P\u2009=\u2009.002; log-rank P\u2009=\u2009.003) and overall survival (HR\u2009=\u20090.45; 95% CI\u2009=\u20090.20 to 0.99; P\u2009=\u2009.047; log-rank P\u2009=\u2009.04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n\u2009=\u200935), where it was associated with CR (Fisher exact test, P\u2009&amp;lt;\u2009.001) and enhanced overall survival (HR\u2009=\u20090.31; 95% CI\u2009=\u20090.11 to 0.84; P\u2009=\u2009.02; log-rank P\u2009=\u2009.02).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jnci\/djab194","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T19:20:08Z","timestamp":1632338408000},"page":"436-445","source":"Crossref","is-referenced-by-count":61,"title":["Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies"],"prefix":"10.1093","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5021-6916","authenticated-orcid":false,"given":"Carlos A","family":"Garcia-Prieto","sequence":"first","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"},{"name":"Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1858-7076","authenticated-orcid":false,"given":"Lorea","family":"Villanueva","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8700-2540","authenticated-orcid":false,"given":"Alberto","family":"Bueno-Costa","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4077-5137","authenticated-orcid":false,"given":"Veronica","family":"Davalos","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Europa Azucena","family":"Gonz\u00e1lez-Navarro","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Clinic, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-1648","authenticated-orcid":false,"given":"Manel","family":"Juan","sequence":"additional","affiliation":[{"name":"Department of Immunology, Hospital Clinic, Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1lvaro","family":"Urbano-Ispizua","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Department of Hematology, University of Barcelona (UB), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5157-4376","authenticated-orcid":false,"given":"Julio","family":"Delgado","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Cancer (CIBERONC), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4699-6862","authenticated-orcid":false,"given":"Valent\u00edn","family":"Ortiz-Maldonado","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-3465","authenticated-orcid":false,"given":"Francesca","family":"del Bufalo","sequence":"additional","affiliation":[{"name":"Department of Paediatric 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5277-8998","authenticated-orcid":false,"given":"Matilde","family":"Sinibaldi","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology and Oncology, Cell and Gene Therapy, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6656-957X","authenticated-orcid":false,"given":"Marta","family":"Soler","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8488-5306","authenticated-orcid":false,"given":"Manuel","family":"Castro de Moura","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4084-6815","authenticated-orcid":false,"given":"Gerardo","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2736-5758","authenticated-orcid":false,"given":"Rocio G","family":"Urdinguio","sequence":"additional","affiliation":[{"name":"Nanomaterials and Nanotechnology Research Center (CINNCSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Department of Organisms and Systems Biology (BOS), University of Oviedo, Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3792-4085","authenticated-orcid":false,"given":"Agustin F","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Nanomaterials and Nanotechnology Research Center (CINNCSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Department of Organisms and Systems Biology (BOS), University of Oviedo, Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8450-2603","authenticated-orcid":false,"given":"Mario F","family":"Fraga","sequence":"additional","affiliation":[{"name":"Nanomaterials and Nanotechnology Research Center (CINNCSIC), Health Research Institute of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), Department of Organisms and Systems Biology (BOS), University of Oviedo, Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Bar","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amilia","family":"Meir","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orit","family":"Itzhaki","sequence":"additional","affiliation":[{"name":"Ella Lemelbaum Institute for Immuno Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal J","family":"Besser","sequence":"additional","affiliation":[{"name":"Ella Lemelbaum Institute for Immuno Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel"},{"name":"Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Avigdor","sequence":"additional","affiliation":[{"name":"Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"name":"Institute of Hematology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1411-8942","authenticated-orcid":false,"given":"Elad","family":"Jacoby","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel"},{"name":"Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-6093","authenticated-orcid":false,"given":"Manel","family":"Esteller","sequence":"additional","affiliation":[{"name":"Cancer and Leukemia Epigenetics and Biology Program (PEBCL), Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Cancer (CIBERONC), Madrid, Spain"},{"name":"Institucio Catalana de Recerca i Estudis Avan\u00e7ats (ICREA), Barcelona, Spain"},{"name":"Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"issue":"2","key":"2022030807392418200_djab194-B1","doi-asserted-by":"crossref","first-page":"e104","DOI":"10.1016\/S1470-2045(19)30729-6","article-title":"CAR T-cell product performance in 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