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Lookup NU author(s): Dr Martina Finetti, Dr Daniel Williamson
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Research, 2020.
For re-use rights please refer to the publisher's terms and conditions.
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.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 months1,2. 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 ATRT5,6, 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.
Author(s): Theruvath J, Sotillo E, Mount CW, Graef CM, Delaidelli A, Heitzeneder S, Labanieh L, Dhingra S, Leruste A, Majzner RG, Xu P, Mueller S, Yecies DW, Finetti MA, Williamson D, Johann PD, Kool M, Pfister S, Hasselblatt M, Fruhwald MC, Delattre O, Surdez D, Bourdeaut F, Puget S, Zaidi S, Mitra SS, Cheshier S, Sorensen PH, Monje M, Mackall CL
Publication type: Article
Publication status: Published
Journal: Nature Medicine
Year: 2020
Volume: 26
Pages: 712-719
Print publication date: 01/05/2020
Online publication date: 27/04/2020
Acceptance date: 06/03/2020
Date deposited: 06/06/2020
ISSN (print): 1078-8956
ISSN (electronic): 1546-170X
Publisher: Nature Research
URL: https://doi.org/10.1038/s41591-020-0821-8
DOI: 10.1038/s41591-020-0821-8
PubMed id: 32341579
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