期刊
NATURE MEDICINE
卷 26, 期 5, 页码 712-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-020-0821-8
关键词
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资金
- German Cancer Aid (Deutsche Krebshilfe) [P-91650709]
- St Baldrick's/Stand Up To Cancer Pediatric Dream Team Translational Cancer Research Grant
- Parker Institute for Cancer Immunotherapy
- Virginia and D.K. Ludwig Fund for Cancer Research
- National Cancer Institute [5P30CA12443]
- Be Brooks Brave Fund St. Baldrick's Scholar Award
- Nuovo-Soldati Foundation
- ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Sante/National Alliance for the Life Sciences and Health) within the framework of the French Cancer Plan
- INSTINCT network program grant
- The Brain Tumour Charity
- Great Ormond Street Hospital Children's Charity
- Children with Cancer UK [16/193]
- Ligue Nationale Contre le Cancer
- ERA-NET TRANSCAN (JTC 2014) [TRAN201501238]
- TRANSCAN JTC 2017 [TRANS201801292]
- ITCC-P4 project [H2020-lMI2-JTl-201 5-07, 116064]
- St Baldrick's Foundation
- Interdisziplinare Zentrum fur Klinische Forschung Munster [Ha3/017/20]
- Deutsche Forschungsgemeinschaft (DFG) [HA 3060/8-1]
- DFG [1516/4-1]
- Tashia and John Morgridge Endowed Postdoctoral Fellowship from the Child Health Research Institute at Lucile Packard Children's Hospital
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [R25NS065741]
- Ludwig Cancer Center, Department of Neurosurgery at Stanford University
- Huntsman Cancer Institute, Department of Neurosurgery, University of Utah
- Ty Louis Campbell St. Baldrick's Foundation Scholar
- Kathryn S.R. Lowry Endowed Chari in Neurosurgery
- Siebel Scholars Award
- The Andrew McDonough B+ (Be Positive) Foundation
- The Morgan Adams Brain Tumor Foundation
- American Cancer Society Institutional Research Grant
- Plachy-Rubin foundation
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months(1,2). We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. (3,4)), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT(5,6), B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies. CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models.
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