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Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.
- Source :
-
Nature medicine [Nat Med] 2020 May; Vol. 26 (5), pp. 712-719. Date of Electronic Publication: 2020 Apr 27. - Publication Year :
- 2020
-
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 months <superscript>1,2</superscript> . We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. <superscript>3,4</superscript> ), 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 <superscript>5,6</superscript> , 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.
- Subjects :
- Adult
Animals
Brain drug effects
Brain immunology
Brain pathology
Brain Neoplasms immunology
Brain Neoplasms pathology
Cells, Cultured
Child, Preschool
Female
Fetus pathology
Humans
Infant
Injections, Intraventricular
Mice
Mice, Inbred NOD
Mice, SCID
Receptors, Chimeric Antigen administration & dosage
Receptors, Chimeric Antigen genetics
Receptors, Chimeric Antigen immunology
Rhabdoid Tumor immunology
Rhabdoid Tumor pathology
T-Lymphocytes immunology
T-Lymphocytes metabolism
T-Lymphocytes transplantation
Teratoma immunology
Teratoma pathology
Xenograft Model Antitumor Assays
B7 Antigens immunology
Brain Neoplasms therapy
Cancer Vaccines administration & dosage
Immunotherapy, Adoptive methods
Rhabdoid Tumor therapy
Teratoma therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 26
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 32341579
- Full Text :
- https://doi.org/10.1038/s41591-020-0821-8