期刊
NATURE MEDICINE
卷 26, 期 5, 页码 720-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-020-0827-2
关键词
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资金
- National Institutes of Health [R01CA148699, R01CA159859, U54 CA232568-01]
- Pediatric Brain Tumour Foundation
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Cure Search Foundation
- b.r.a.i.n.child
- Meagan's Walk
- SWIFTY Foundation
- Brain Tumour Charity
- Genome Canada
- Genome BC
- Genome Quebec
- Ontario Research Fund
- Worldwide Cancer Research
- V-Foundation for Cancer Research
- Ontario Institute for Cancer Research - Government of Ontario
- Canadian Cancer Society Research Institute Impact grant
- Cancer Research UK Brain Tumour Award
- Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant by the Government of Canada through Genome Canada [SU2C-AACR-DT1113]
- SU2C Canada Cancer Stem Cell Dream Team Research Funding by the Government of Canada through Genome Canada [SU2C-AACR-DT-19-15]
- Government of Ontario
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
- SU2C St. Baldrick's Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113]
- Brain Canada NeuroDevNet
Intraventricularly delivered monovalent and trivalent CAR T cells exhibit greater therapeutic efficacy as compared with intravenously delivered CAR T cells in medulloblastoma xenograft mouse models and show potency in ependymoma xenograft mouse models. Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor alpha 2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor alpha 2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
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