Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors

Sharareh Gholamin, Siddhartha S. Mitra, Abdullah H. Feroze, Jie Liu, Suzana A. Kahn, Michael Zhang, Rogelio Esparza, Chase Richard, Vijay Ramaswamy, Marc Remke, Anne K. Volkmer, Stephen Willingham, Anitha Ponnuswami, Aaron McCarty, Patricia Lovelace, Theresa A. Storm, Simone Schubert, Gregor Hutter, Cyndhavi Narayanan, Pauline ChuEric H. Raabe, Griffith Harsh, Michael D. Taylor, Michelle Monje, Yoon-Jae Cho, Ravi Majeti, Jens P. Volkmer, Paul G. Fisher, Gerald Grant, Gary K. Steinberg, Hannes Vogel, Michael Edwards, Irving L. Weissman, Samuel H. Cheshier

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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. 2017

Original languageEnglish (US)
Article numbereaaf2968
JournalScience Translational Medicine
Volume9
Issue number381
DOIs
StatePublished - Mar 15 2017

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gholamin, S., Mitra, S. S., Feroze, A. H., Liu, J., Kahn, S. A., Zhang, M., Esparza, R., Richard, C., Ramaswamy, V., Remke, M., Volkmer, A. K., Willingham, S., Ponnuswami, A., McCarty, A., Lovelace, P., Storm, T. A., Schubert, S., Hutter, G., Narayanan, C., ... Cheshier, S. H. (2017). Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Science Translational Medicine, 9(381), [eaaf2968]. https://doi.org/10.1126/scitranslmed.aaf2968