title: Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.
abstract: Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.|Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sharareh
authors.identifier: 0000-0001-7759-0780
authors.initials: S
authors.lastname: Gholamin
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA. smitra@stanford.edu cheshier@stanford.edu.|Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Siddhartha S
authors.identifier: 0000-0002-1829-7856
authors.initials: SS
authors.lastname: Mitra
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Abdullah H
authors.identifier: 0000-0002-7761-6765
authors.initials: AH
authors.lastname: Feroze
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.|Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Suzana A
authors.identifier: 0000-0002-5058-1144
authors.initials: SA
authors.lastname: Kahn
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael
authors.identifier: 0000-0002-7067-0689
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rogelio
authors.identifier: 0000-0003-0833-2715
authors.initials: R
authors.lastname: Esparza
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Chase
authors.initials: C
authors.lastname: Richard
authors.affiliation: Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.|Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.|Department of Gynecology and Obstetrics, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Anne K
authors.identifier: 0000-0002-1774-7974
authors.initials: AK
authors.lastname: Volkmer
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Willingham
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Anitha
authors.identifier: 0000-0003-3555-9448
authors.initials: A
authors.lastname: Ponnuswami
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: McCarty
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lovelace
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Theresa A
authors.identifier: 0000-0002-2307-9714
authors.initials: TA
authors.lastname: Storm
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Schubert
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Gregor
authors.identifier: 0000-0002-7570-3902
authors.initials: G
authors.lastname: Hutter
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Cyndhavi
authors.identifier: 0000-0001-8662-599X
authors.initials: C
authors.lastname: Narayanan
authors.affiliation: Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chu
authors.affiliation: Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Eric H
authors.identifier: 0000-0002-9368-7037
authors.initials: EH
authors.lastname: Raabe
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Griffith
authors.initials: G
authors.lastname: Harsh
authors.affiliation: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.|Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Monje
authors.affiliation: Department of Pediatrics and Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97231, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.|Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Majeti
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jens P
authors.initials: JP
authors.lastname: Volkmer
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Paul G
authors.identifier: 0000-0002-1196-1590
authors.initials: PG
authors.lastname: Fisher
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Gerald
authors.identifier: 0000-0002-2651-4603
authors.initials: G
authors.lastname: Grant
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
authors.affiliation: Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Edwards
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.|Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA. smitra@stanford.edu cheshier@stanford.edu.|Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Samuel H
authors.identifier: 0000-0003-4983-6610
authors.initials: SH
authors.lastname: Cheshier
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051928:CD47 Antigen / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004195:Disease Models, Animal; D006801:Humans; D007121:Immunocompetence; D007276:Injections, Intraventricular; D008527:Medulloblastoma / Q000188:drug therapy / Q000473:pathology; D008577:Meningeal Neoplasms / Q000473:pathology / Q000556:secondary; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010587:Phagocytosis / Q000187:drug effects; D011971:Receptors, Immunologic / Q000378:metabolism*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000943:Antigens, Differentiation; D051928:CD47 Antigen; C497894:CD47 protein, human; D011971:Receptors, Immunologic; C501920:SIRPA protein, human