%0 Journal Article
%A Theruvath, Johanna
%A Sotillo, Elena
%A Mount, Christopher W
%A Graef, Claus Moritz
%A Delaidelli, Alberto
%A Heitzeneder, Sabine
%A Labanieh, Louai
%A Dhingra, Shaurya
%A Leruste, Amaury
%A Majzner, Robbie G
%A Xu, Peng
%A Mueller, Sabine
%A Yecies, Derek W
%A Finetti, Martina A
%A Williamson, Daniel
%A Johann, Pascal D
%A Kool, Marcel
%A Pfister, Stefan
%A Hasselblatt, Martin
%A Frühwald, Michael C
%A Delattre, Olivier
%A Surdez, Didier
%A Bourdeaut, Franck
%A Puget, Stephanie
%A Zaidi, Sakina
%A Mitra, Siddhartha S
%A Cheshier, Samuel
%A Sorensen, Poul H
%A Monje, Michelle
%A Mackall, Crystal L
%T Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.
%J Nature medicine
%V 26
%N 5
%@ 1546-170X
%C New York, NY
%I Nature America Inc.
%M DKFZ-2020-00900
%P 712-719
%D 2020
%Z 2020 May;26(5):712-719
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:32341579
%R 10.1038/s41591-020-0821-8
%U https://inrepo02.dkfz.de/record/154632