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

被引：350

作者：

Gholamin, Sharareh ^{[1
,2
,3
,17
]}

Mitra, Siddhartha S. ^{[1
,2
,3
]}

Feroze, Abdullah H. ^{[1
,18
]}

Liu, Jie ^{[4
,19
]}

Kahn, Suzana A. ^{[1
,2
,3
]}

Zhang, Michael ^{[1
]}

Esparza, Rogelio ^{[1
]}

Richard, Chase ^{[1
,20
]}

Ramaswamy, Vijay ^{[5
,6
]}

Remke, Marc ^{[5
,6
,7
]}

Volkmer, Anne K. ^{[2
,3
,8
]}

Willingham, Stephen ^{[2
,3
,21
]}

Ponnuswami, Anitha ^{[9
]}

McCarty, Aaron ^{[2
,3
]}

Lovelace, Patricia ^{[2
,3
]}

Storm, Theresa A. ^{[2
,3
]}

Schubert, Simone ^{[9
]}

Hutter, Gregor ^{[1
,22
]}

Narayanan, Cyndhavi ^{[4
]}

Chu, Pauline ^{[10
]}

Raabe, Eric H. ^{[11
]}

Harsh, Griffith ^{[12
]}

Taylor, Michael D. ^{[6
]}

Monje, Michelle ^{[1
,2
,3
,9
]}

Cho, Yoon-Jae ^{[13
,14
]}

Majeti, Ravi ^{[2
,3
,4
]}

Volkmer, Jens P. ^{[2
,3
,19
]}

Fisher, Paul G. ^{[9
]}

Grant, Gerald ^{[1
]}

Steinberg, Gary K. ^{[12
]}

Vogel, Hannes ^{[15
,16
]}

Edwards, Michael ^{[1
]}

Weissman, Irving L. ^{[2
,3
,15
,16
]}

Cheshier, Samuel H. ^{[1
,2
,3
]}

机构：

[1] Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Div Pediat Neurosurg,Dept Neurosurg, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Stanford Ludwig Canc Ctr, Stanford, CA 94305 USA

[4] Stanford Univ, Sch Med, Dept Med, Div Hematol, Stanford, CA 94305 USA

[5] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada

[6] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Div Neurosurg, Toronto, ON M5G 1X8, Canada

[7] Heinrich Heine Univ, German Consortium Translat Canc Res, Div Pediat Neurooncol, D-40225 Dusseldorf, Germany

[8] Univ Dusseldorf, Dept Gynecol & Obstet, D-40225 Dusseldorf, Germany

[9] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[10] Stanford Univ, Sch Med, Dept Comparat Med, Stanford, CA 94305 USA

[11] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Div Pediat Oncol, Baltimore, MD 21287 USA

[12] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA

[13] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97231 USA

[14] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97231 USA

[15] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[16] Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA

[17] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91106 USA

[18] Univ Washington, Med Ctr, Dept Neurol Surg, 325 9th Ave,Campus Box 359924, Seattle, WA 98104 USA

[19] Forty Seven Inc, Menlo Pk, CA 94025 USA

[20] Univ Penn, Perelman Sch Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[21] Corvus Pharmaceut, Burlingame, CA 94010 USA

[22] Univ Basel Hosp, Dept Neurosurg, Spitalstr 21, CH-4031 Basel, Switzerland

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 381期

关键词：

CANCER STEM-CELLS; MEDULLOBLASTOMA SUBGROUPS; THERAPEUTIC TARGET; APOPTOTIC CELLS; SOLID TUMORS; SIRP-ALPHA; CD47; PROTEIN; EPENDYMOMA; EXPRESSION;

D O I：

10.1126/scitranslmed.aaf2968

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-SIRPa 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.

引用

页数：13

共 56 条

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