Journal Article

DKFZ-2020-00900

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Theruvath, J. ; Sotillo, E. ; Mount, C. W. ; Graef, C. M. ; Delaidelli, A. ; Heitzeneder, S. ; Labanieh, L. ; Dhingra, S. ; Leruste, A. ; Majzner, R. G. ; Xu, P. ; Mueller, S. ; Yecies, D. W. ; Finetti, M. A. ; Williamson, D. ; Johann, P. D.DKFZ* ; Kool, M.DKFZ* ; Pfister, S.DKFZ* ; Hasselblatt, M. ; Frühwald, M. C. ; Delattre, O. ; Surdez, D. ; Bourdeaut, F. ; Puget, S. ; Zaidi, S. ; Mitra, S. S. ; Cheshier, S. ; Sorensen, P. H. ; Monje, M. ; Mackall, C. L.

2020
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/s41591-020-0821-8

Abstract: 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.

Note: 2020 May;26(5):712-719

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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