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In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood\u2013cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system\u2013specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.<\/jats:p>\n                  <jats:p>Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958\u201371. \u00a92018 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 899<\/jats:p>","DOI":"10.1158\/2159-8290.cd-17-1319","type":"journal-article","created":{"date-parts":[[2018,6,7]],"date-time":"2018-06-07T11:00:07Z","timestamp":1528369207000},"page":"958-971","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":877,"title":["Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia"],"prefix":"10.1158","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9423-4059","authenticated-orcid":false,"given":"Bianca D.","family":"Santomasso","sequence":"first","affiliation":[{"name":"1Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"2Parker Institute for Cancer Immunotherapy, San Francisco, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae H.","family":"Park","sequence":"additional","affiliation":[{"name":"3Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"4Department of Medicine, Joan and Sanford Weill Medical College of Cornell University, New York, New York."},{"name":"5Center for Cellular Therapy, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"6Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darin","family":"Salloum","sequence":"additional","affiliation":[{"name":"7Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Riviere","sequence":"additional","affiliation":[{"name":"6Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Flynn","sequence":"additional","affiliation":[{"name":"9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Mead","sequence":"additional","affiliation":[{"name":"10Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Halton","sequence":"additional","affiliation":[{"name":"5Center for Cellular Therapy, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"11Department of Nursing, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuyan","family":"Wang","sequence":"additional","affiliation":[{"name":"6Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Senechal","sequence":"additional","affiliation":[{"name":"6Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"8Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence","family":"Purdon","sequence":"additional","affiliation":[{"name":"5Center for Cellular Therapy, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin R.","family":"Cross","sequence":"additional","affiliation":[{"name":"12Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"12Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behroze","family":"Vachha","sequence":"additional","affiliation":[{"name":"13Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"DeAngelis","sequence":"additional","affiliation":[{"name":"1Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Li","sequence":"additional","affiliation":[{"name":"14Juno Therapeutics, Seattle, 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