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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 (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). Art. No. eaaf2968. ISSN 1946-6234. https://resolver.caltech.edu/CaltechAUTHORS:20170324-102505296

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/scitranslmed.aaf2968DOIArticle
http://stm.sciencemag.org/content/9/381/eaaf2968PublisherArticle
http://www.sciencetranslationalmedicine.org/cgi/content/full/9/381/eaaf2968/DC1PublisherSupplementary Materials
Additional Information:© 2017 American Association for the Advancement of Science. Submitted 31 October 2014; Resubmitted 25 January 2016; Accepted 7 December 2016; Published 15 March 2017. We thank J. Marcellus and M. Coburn at the Stanford University Department of Neurosurgery Brain Bank and J. Bueno and C. Cuevas at the Stanford University Tissue Bank for collection and acquisition of freshly resected tumor samples. We thank M. Lim of the Department of Neurosurgery at Johns Hopkins School of Medicine for the GL261 mouse glioma cell line. We also thank Y.-J.C. from the Oregon Health & Science University for providing us with primary patient MB and ATRT samples and D. Bigner for cell lines D283 and D425. We are grateful to the surgical support staff at the Lucile Packard Children’s Hospital for their vital role in providing us with timely support for tissue acquisition. We thank the members of the Weissman and Cheshier laboratories for their help during various experiments and M. Alvarez and the staff of the Stanford University Veterinary Service Center for their help with animal husbandry. We would also like to acknowledge and thank C. J. Christensen for editing the manuscript. We especially acknowledge the patients and their parents for their consent for tissue donation for research. This study was supported by the Price Family Charitable Fund, the Stanford Center for Children’s Brain Tumors (to S.G., S.S.M., M.M., M.E., and S.H.C.), the St. Baldrick’s Foundation, the American Brain Tumor Association (to S.H.C.), the Seibel Scholars Award from the Siebel Stem Cell Institute (to S.S.M.), the Pew Latin American Fellows (to S.A.K.), the Deutsche Forschungsgemeinschaft (VO 1976/1 to A.K.V.), the National Institute of Neurological Disorders and Stroke (NINDS K08NS070926 to M.M.), the National Cancer Institute Core Grant to the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (P30 CA006973 to E.H.R.), the McKenna Claire Foundation (to M.M.), the Matthew Larson Foundation (to E.H.R. and M.M.), the California Institute for Regenerative Medicine (CIRM RB4-06093 and RN3- 06510 to M.M. and DR3-06965 to R.M. and I.L.W.), the Alex’s Lemonade Stand Foundation (to M.M.), The Cure Starts Now Foundation (to M.M.), the Lyla Nsouli Foundation (to M.M.), the Dylan Jewett, Connor Johnson, Zoey Ganesh, Dylan Frick, Abigail Jensen, Wayland Villars, and Jennifer Kranz Memorial Funds (to M.M.), the Virginia and D. K. Ludwig Fund for Cancer Research (to M.M., R.M., I.L.W., and S.H.C.), the Lucile Packard Foundation for Children’s Health, Child Health Research Institute at the Stanford University (NIH-NCATS-CTSA UL1 TR001085), the Tashia and John Morgridge Endowed Pediatric Faculty Scholar and Fellowships Awards (to S.H.C.), and the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases (to M.M.). M.R. received a postdoctoral fellowship from the Dr. Mildred Scheel Foundation/German Cancer Aid. Y.-J.C. is supported by the Ericksen Family Endowed Professorship for Research (Oregon Health & Science University), the St. Baldrick’s “Miracles for Michael” Scholar Award, and NIH U01-CA176287. E.H.R. is a St. Baldrick’s Scholar. S.H.C. is the Ty Louis Campbell Foundation St. Baldrick’s Scholar recipient. S.H.C. received gifts from G. Landegger, R. McDowell, V. McDowell, C. Comey, J. Huang, C. Fisher, and J. Fisher. Author Contributions: S.G., S.S.M., I.L.W., and S.H.C. conceived the project and wrote the manuscript. J.L., S.W., J.P.V., R.M., and I.L.W. developed and characterized Hu5F9-G4. S.G., S.S.M., S.H.C., E.H.R., M.M., Y.-J.C., S.S., and A.P. generated and provided patient-derived pediatric brain tumor cells. S.G., S.S.M., C.R., and M.Z. performed phagocytosis assays. S.G., A.H.F., S.A.K., and R.E. performed in vivo experiments. G.H. supervised the brain tumor bank. S.S.M., A.M., T.A.S., A.K.V., S.W., and P.L. provided the animals, reagents, and technical support. S.H.C., G.G., G.K.S., M.E., and P.G.F. provided primary patient samples, V.R., M.R., and M.D.T. provided and analyzed gene array expression data. S.G. and P.C. carried out IHC analysis. S.G. and C.N. collected and analyzed data on blood and CSFs. H.V. contributed to tissue analysis. Competing interests: I.L.W. and R.M. are coinventors on multiple patents regarding CD47 antibody targeting that have been licensed to Forty Seven Inc. They serve on the board of directors and as consultants and have equity ownership. J.L. and J.P.V. are coinventors on multiple patents regarding CD47 antibody targeting that have been licensed to Forty Seven Inc. They are employees at Forty Seven Inc. and have equity ownership. Data and materials availability: The data sets used in this study are available at http://hgserver1.amc.nl/cgi-bin/r2/main.cgi?&species=hs.
Funders:
Funding AgencyGrant Number
Price Family Charitable FundUNSPECIFIED
Stanford Center for Children’s Brain TumorsUNSPECIFIED
St. Baldrick’s FoundationUNSPECIFIED
American Brain Tumor AssociationUNSPECIFIED
Siebel Stem Cell InstituteUNSPECIFIED
Pew Latin American Fellows ProgramUNSPECIFIED
Deutsche ForschungsgemeinschaftVO 1976/1
National Institute of Neurological Disorders and StrokeK08NS070926
NIHP30 CA006973
National Cancer InstituteUNSPECIFIED
McKenna Claire FoundationUNSPECIFIED
Matthew Larson FoundationUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)RB4-06093
California Institute for Regenerative Medicine (CIRM)RN3- 06510
California Institute for Regenerative Medicine (CIRM)DR3-06965
Alex’s Lemonade Stand FoundationUNSPECIFIED
The Cure Starts Now FoundationUNSPECIFIED
Lyla Nsouli FoundationUNSPECIFIED
Dylan Jewett Memorial FundUNSPECIFIED
Connor Johnson Memorial FundUNSPECIFIED
Zoey Ganesh Memorial FundUNSPECIFIED
Dylan Frick Memorial FundUNSPECIFIED
Abigail Jensen Memorial FundUNSPECIFIED
Wayland Villars Memorial FundUNSPECIFIED
Jennifer Kranz Memorial FundUNSPECIFIED
Virginia and D. K. Ludwig Fund for Cancer ResearchUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
NIHUL1 TR001085
Tashia and John Morgridge Endowed Pediatric Faculty Scholar AwardUNSPECIFIED
Anne T. and Robert M. Bass Endowed Faculty ScholarshipUNSPECIFIED
Dr. Mildred Scheel FoundationUNSPECIFIED
German Cancer AidUNSPECIFIED
Oregon Health and Science UniversityUNSPECIFIED
St. Baldrick’s “Miracles for Michael” Scholar AwardUNSPECIFIED
NIHU01-CA176287
Ty Louis Campbell FoundationUNSPECIFIED
Issue or Number:381
Record Number:CaltechAUTHORS:20170324-102505296
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170324-102505296
Official Citation:Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors BY 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 CHU, ERIC H. RAABE, GRIFFITH HARSH IV, 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 SCIENCE TRANSLATIONAL MEDICINE 15 Mar 2017: Vol. 9, Issue 381, eaaf2968 DOI: 10.1126/scitranslmed.aaf2968
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:75387
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:24 Mar 2017 18:06
Last Modified:03 Oct 2019 16:49

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