{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:45:49Z","timestamp":1793148349813,"version":"4.5.0"},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T00:00:00Z","timestamp":1672617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.<\/jats:p>","DOI":"10.1093\/jnen\/nlac121","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T14:38:31Z","timestamp":1672670311000},"page":"160-168","source":"Crossref","is-referenced-by-count":11,"title":["Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma"],"prefix":"10.1093","volume":"82","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2280-5905","authenticated-orcid":false,"given":"Esther H","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman S","family":"Ahmadian","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushma N","family":"Bharadwaj","sequence":"additional","affiliation":[{"name":"Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine , Stanford, California, USA"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lehi","family":"Acosta-Alvarez","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary D","family":"Threlkeld","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J","family":"Frank","sequence":"additional","affiliation":[{"name":"Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine , Stanford, California, USA"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B","family":"Miklos","sequence":"additional","affiliation":[{"name":"Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine , Stanford, California, USA"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Monje","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine , Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,2]]},"reference":[{"key":"2024032523500453900_nlac121-B1","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1056\/NEJMoa1707447","article-title":"Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma","volume":"377","author":"Neelapu","year":"2017","journal-title":"N Engl J Med"},{"key":"2024032523500453900_nlac121-B2","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1056\/NEJMoa1914347","article-title":"KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma","volume":"382","author":"Wang","year":"2020","journal-title":"N Engl J Med"},{"key":"2024032523500453900_nlac121-B3","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S0140-6736(21)00933-8","article-title":"Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b\/2 open-label study","volume":"398","author":"Berdeja","year":"2021","journal-title":"Lancet"},{"key":"2024032523500453900_nlac121-B4","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1200\/EDBK_238691","article-title":"The other side of CAR T-cell therapy: Cytokine release syndrome, neurologic toxicity, and financial burden","volume":"39","author":"Santomasso","year":"2019","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"2024032523500453900_nlac121-B5","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1093\/brain\/awz053","article-title":"Neurological toxicities associated with chimeric antigen receptor T-cell therapy","volume":"142","author":"Rubin","year":"2019","journal-title":"Brain"},{"key":"2024032523500453900_nlac121-B6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1097\/PPO.0000000000000377","article-title":"Management of T-cell engaging immunotherapy complications","volume":"25","author":"Varadarajan","year":"2019","journal-title":"Cancer J"},{"key":"2024032523500453900_nlac121-B7","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","article-title":"ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells","volume":"25","author":"Lee","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"2024032523500453900_nlac121-B8","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1001\/jamaneurol.2020.2703","article-title":"Clinical predictors of neurotoxicity after chimeric antigen receptor T-cell therapy","volume":"77","author":"Rubin","year":"2020","journal-title":"JAMA Neurol"},{"key":"2024032523500453900_nlac121-B9","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1158\/2159-8290.CD-17-0698","article-title":"Endothelial activation and blood\u2013brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T","volume":"7","author":"Gust","year":"2017","journal-title":"Cancer Discov"},{"key":"2024032523500453900_nlac121-B10","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/ana.25502","article-title":"Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy","volume":"86","author":"Gust","year":"2019","journal-title":"Ann Neurol"},{"key":"2024032523500453900_nlac121-B11","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1093\/jnen\/nly064","article-title":"Neuropathology of a case with fatal CAR T-cell-associated cerebral edema","volume":"77","author":"Torre","year":"2018","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523500453900_nlac121-B12","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1093\/jnen\/nlaa099","article-title":"Multifocal necrotizing leukoencephalopathy with preferential microglia toxicity in a patient treated with chimeric antigen receptor T-cells and review of the literature","volume":"79","author":"Marker","year":"2020","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024032523500453900_nlac121-B13","doi-asserted-by":"crossref","first-page":"e533","DOI":"10.1097\/HS9.0000000000000533","article-title":"Clinicopathologic findings in fatal neurotoxicity after adoptive immunotherapy with CD19-directed CAR T-cells","volume":"5","author":"Karschnia","year":"2021","journal-title":"Hemasphere"},{"key":"2024032523500453900_nlac121-B14","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.cell.2018.10.049","article-title":"Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment","volume":"176","author":"Gibson","year":"2019","journal-title":"Cell"},{"key":"2024032523500453900_nlac121-B15","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.cell.2020.08.022","article-title":"Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for article single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies","volume":"183","author":"Parker","year":"2020","journal-title":"Cell"},{"key":"2024032523500453900_nlac121-B16","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1440-1789.2008.00945.x","article-title":"Methotrexate-related leukoencephalopathy without radiation therapy: Distribution of brain lesions and pathological heterogeneity on two autopsy cases","volume":"29","author":"Matsubayashi","year":"2009","journal-title":"Neuropathology"},{"key":"2024032523500453900_nlac121-B17","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ejca.2020.11.021","article-title":"Fatal neurotoxicity after chimeric antigen receptor T-cell therapy: An unexpected case of fludarabine-associated progressive leukoencephalopathy","volume":"144","author":"Winter","year":"2021","journal-title":"Eur J Cancer"}],"container-title":["Journal of Neuropathology &amp; Experimental Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/82\/2\/160\/52172863\/nlac121.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/82\/2\/160\/52172863\/nlac121.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:35:25Z","timestamp":1711413325000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jnen\/article\/82\/2\/160\/6967050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,2]]},"references-count":17,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1,2]]},"published-print":{"date-parts":[[2023,1,20]]}},"URL":"https:\/\/doi.org\/10.1093\/jnen\/nlac121","relation":{},"ISSN":["0022-3069","1554-6578"],"issn-type":[{"value":"0022-3069","type":"print"},{"value":"1554-6578","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2023,1,2]]}}}