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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Antibodies, Monoclonal, Humanized
Brain Neoplasms
Anti-Idiotypic Antibodies
Pediatrics
Medulloblastoma
Heterografts
Glioma
Primitive Neuroectodermal Tumors
Cytophagocytosis
Neoplasms
Therapeutics
Glioblastoma
Allografts
Central Nervous System
Macrophages
Morbidity
Mortality
In Vitro Techniques

ASJC Scopus subject areas

  • Medicine(all)

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Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. / Gholamin, Sharareh; Mitra, Siddhartha S.; Feroze, Abdullah H.; Liu, Jie; Kahn, Suzana A.; Zhang, Michael; Esparza, Rogelio; Richard, Chase; Ramaswamy, Vijay; Remke, Marc; Volkmer, Anne K.; Willingham, Stephen; Ponnuswami, Anitha; McCarty, Aaron; Lovelace, Patricia; Storm, Theresa A.; Schubert, Simone; Hutter, Gregor; Narayanan, Cyndhavi; Chu, Pauline; Raabe, Eric H.; Harsh, Griffith; Taylor, Michael D.; Monje, Michelle; Cho, Yoon-Jae; Majeti, Ravi; Volkmer, Jens P.; Fisher, Paul G.; Grant, Gerald; Steinberg, Gary K.; Vogel, Hannes; Edwards, Michael; Weissman, Irving L.; Cheshier, Samuel H.

In: Science Translational Medicine, Vol. 9, No. 381, eaaf2968, 15.03.2017.

Research output: Contribution to journalArticle

Gholamin, S, Mitra, SS, Feroze, AH, Liu, J, Kahn, SA, Zhang, M, Esparza, R, Richard, C, Ramaswamy, V, Remke, M, Volkmer, AK, Willingham, S, Ponnuswami, A, McCarty, A, Lovelace, P, Storm, TA, Schubert, S, Hutter, G, Narayanan, C, Chu, P, Raabe, EH, Harsh, G, Taylor, MD, Monje, M, Cho, Y-J, Majeti, R, Volkmer, JP, Fisher, PG, Grant, G, Steinberg, GK, Vogel, H, Edwards, M, Weissman, IL & Cheshier, SH 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, vol. 9, no. 381, eaaf2968. https://doi.org/10.1126/scitranslmed.aaf2968
Gholamin, Sharareh ; Mitra, Siddhartha S. ; Feroze, Abdullah H. ; Liu, Jie ; Kahn, Suzana A. ; Zhang, Michael ; Esparza, Rogelio ; Richard, Chase ; Ramaswamy, Vijay ; Remke, Marc ; Volkmer, Anne K. ; Willingham, Stephen ; Ponnuswami, Anitha ; McCarty, Aaron ; Lovelace, Patricia ; Storm, Theresa A. ; Schubert, Simone ; Hutter, Gregor ; Narayanan, Cyndhavi ; Chu, Pauline ; Raabe, Eric H. ; Harsh, Griffith ; Taylor, Michael D. ; Monje, Michelle ; Cho, Yoon-Jae ; Majeti, Ravi ; Volkmer, Jens P. ; Fisher, Paul G. ; Grant, Gerald ; Steinberg, Gary K. ; Vogel, Hannes ; Edwards, Michael ; Weissman, Irving L. ; Cheshier, Samuel H. / Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. In: Science Translational Medicine. 2017 ; Vol. 9, No. 381.
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AU - Gholamin, Sharareh

AU - Mitra, Siddhartha S.

AU - Feroze, Abdullah H.

AU - Liu, Jie

AU - Kahn, Suzana A.

AU - Zhang, Michael

AU - Esparza, Rogelio

AU - Richard, Chase

AU - Ramaswamy, Vijay

AU - Remke, Marc

AU - Volkmer, Anne K.

AU - Willingham, Stephen

AU - Ponnuswami, Anitha

AU - McCarty, Aaron

AU - Lovelace, Patricia

AU - Storm, Theresa A.

AU - Schubert, Simone

AU - Hutter, Gregor

AU - Narayanan, Cyndhavi

AU - Chu, Pauline

AU - Raabe, Eric H.

AU - Harsh, Griffith

AU - Taylor, Michael D.

AU - Monje, Michelle

AU - Cho, Yoon-Jae

AU - Majeti, Ravi

AU - Volkmer, Jens P.

AU - Fisher, Paul G.

AU - Grant, Gerald

AU - Steinberg, Gary K.

AU - Vogel, Hannes

AU - Edwards, Michael

AU - Weissman, Irving L.

AU - Cheshier, Samuel H.

PY - 2017/3/15

Y1 - 2017/3/15

N2 - 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

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