An Anti-CD47 Antibody Is Effective in Pediatric Brain Tumor Models

Malignant pediatric brain tumors are associated with tumor immune resistance and immune escape. The cell surface protein CD47 has been shown to promote evasion of innate immune surveillance in multiple tumor types, making it a potential therapeutic target. CD47 binds to and activates SIRPα on the surface of myeloid cells, thereby inhibiting the phagocytic activity of macrophages. Thus, blocking the CD47–SIRPα interaction may promote selective phagocytosis of cancer cells. Gholamin, Mitra, and colleagues evaluated a humanized anti-CD47 antibody, Hu5F9-G4, in pediatric brain tumor models. In group 3 medulloblastoma orthotopic xenografts, Hu5F9-G4 suppressed the growth of primary tumors as well as leptomeningeal and spinal metastases and extended survival. Further, Hu5F9-G4–treated tumors displayed enhanced macrophage recruitment and a higher frequency of intratumor macrophages. Hu5F9-G4 was detected in the cerebrospinal fluid, demonstrating that it penetrated the blood–brain barrier, and exhibited no toxicity against nonmalignant neural cells, supporting further investigation for the treatment of patients with brain tumors. In addition to medulloblastoma, Hu5F9-G4 induced tumor cell phagocytosis and inhibited tumor growth in pediatric atypical teratoid rhabdoid tumor (ATRT), primitive neuroectodermal tumor (PNET), pediatric glioblastoma (pGBM), and diffuse intrinsic pontine glioma (DIPG) patient-derived xenografts (PDX). An anti-mouse CD47 antibody was tested to evaluate the safety and efficacy of targeting the CD47–SIRPα interaction in mice with an intact immune system. The anti-CD47 antibody inhibited the growth of a mouse glioma allograft and exhibited no toxicity in normal brain tissue, suggesting that CD47–SIRPα disruption may be safe and effective in an immunocompetent host. Collectively, these findings indicate that CD47 blockade with Hu5F9-G4 has antitumor activity without toxicity to normal neural cells in PDX models of pediatric medulloblastoma, ATRT, PNET, pGBM, and DIPG. These results support further investigation of anti-CD47 therapies for the treatment of pediatric brain tumors and central nervous system (CNS) metastases.

Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, et al. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med 2017;9:eaaf2968.

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