Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.

Autor: Theruvath J; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Sotillo E; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Mount CW; Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA., Graef CM; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Delaidelli A; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada., Heitzeneder S; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Labanieh L; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.; Department of Bioengineering, Stanford University, Stanford, CA, USA., Dhingra S; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Leruste A; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Majzner RG; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Xu P; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Mueller S; Department of Neurology, University of California San Francisco, San Francisco, CA, USA.; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Yecies DW; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA., Finetti MA; Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK., Williamson D; Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK., Johann PD; Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Kool M; Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany., Pfister S; Hopp Children's Cancer Center Heidelberg, Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany.; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Hasselblatt M; Institute of Neuropathology, Münster University Hospital, Münster, Germany., Frühwald MC; University Children's Hospital Augsburg, Swabian Children's Cancer Center, Augsburg, Germany.; EU-RHAB Registry Center, Augsburg, Germany., Delattre O; Paris Sciences Lettres Research University, INSERM U830, Paris, France.; Paris Sciences Lettres Research University, SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France., Surdez D; Paris Sciences Lettres Research University, INSERM U830, Paris, France.; Paris Sciences Lettres Research University, SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France., Bourdeaut F; Paris Sciences Lettres Research University, INSERM U830, Paris, France.; Paris Sciences Lettres Research University, SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France., Puget S; Paris University, Necker-Enfants Malades Hospital, Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Paris, France., Zaidi S; Paris Sciences Lettres Research University, INSERM U830, Paris, France.; Paris Sciences Lettres Research University, SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, Paris, France., Mitra SS; Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Cheshier S; Division of Pediatric Neurosurgery, Department of Neurosurgery, Primary Children's Hospital and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Sorensen PH; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada., Monje M; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.; Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.; Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Institute for Stem Cell and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA., Mackall CL; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2020 May; Vol. 26 (5), pp. 712-719. Date of Electronic Publication: 2020 Apr 27.
DOI: 10.1038/s41591-020-0821-8
Abstrakt: 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 1,2 . 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 ATRT 5,6 , 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.
Databáze: MEDLINE