期刊
CANCER DISCOVERY
卷 8, 期 8, 页码 958-971出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-1319
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资金
- NIH [5P01 CA0237669-38, 5P01 CA190174-02, 1P50 CA192937-01A1]
- Carson Family Charitable Trust
- Emerald Foundation
- Mr. and Mrs. Goodwyn Commonwealth Fund
- Annual Terry Fox Run for Cancer Research by the Canada Club of New York, Kate's Team
- William Laurence and Blanche Hughes Foundation
- Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center
- Juno Therapeutics
- Lake Road Foundation
- Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748]
- Parker Institute for Cancer Immunotherapy Pilot Grant
- American Society of Clinical Oncology
- American Society of Hematology
- Leukemia and Lymphoma Society
- National Comprehensive Cancer Center
CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. 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-cerebrospinal 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-specific 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. 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. (c) 2018 AACR.
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