TY  - JOUR
AU  - Theruvath, Johanna
AU  - Sotillo, Elena
AU  - Mount, Christopher W
AU  - Graef, Claus Moritz
AU  - Delaidelli, Alberto
AU  - Heitzeneder, Sabine
AU  - Labanieh, Louai
AU  - Dhingra, Shaurya
AU  - Leruste, Amaury
AU  - Majzner, Robbie G
AU  - Xu, Peng
AU  - Mueller, Sabine
AU  - Yecies, Derek W
AU  - Finetti, Martina A
AU  - Williamson, Daniel
AU  - Johann, Pascal D
AU  - Kool, Marcel
AU  - Pfister, Stefan
AU  - Hasselblatt, Martin
AU  - Frühwald, Michael C
AU  - Delattre, Olivier
AU  - Surdez, Didier
AU  - Bourdeaut, Franck
AU  - Puget, Stephanie
AU  - Zaidi, Sakina
AU  - Mitra, Siddhartha S
AU  - Cheshier, Samuel
AU  - Sorensen, Poul H
AU  - Monje, Michelle
AU  - Mackall, Crystal L
TI  - Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.
JO  - Nature medicine
VL  - 26
IS  - 5
SN  - 1546-170X
CY  - New York, NY
PB  - Nature America Inc.
M1  - DKFZ-2020-00900
SP  - 712-719
PY  - 2020
N1  - 2020 May;26(5):712-719
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32341579
DO  - DOI:10.1038/s41591-020-0821-8
UR  - https://inrepo02.dkfz.de/record/154632
ER  -