Division of Pediatric Neurosurgery, Department of Neurosurgery, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Ludwig Cancer Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sci Transl Med. 2017 Mar 15;9(381). doi: 10.1126/scitranslmed.aaf2968.
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.
在缺乏有效治疗方法的情况下，儿科恶性原发性脑肿瘤的发病率和死亡率仍然很高。通过阻断抗吞噬性 CD47-SIRPα 相互作用来利用抗 CD47 抗体介导巨噬细胞吞噬肿瘤细胞，在各种人类恶性肿瘤的临床前异种移植中显示出了希望。我们证明了一种人源化抗 CD47 抗体 Hu5F9-G4 对五种侵袭性和病因不同的儿科脑肿瘤的影响：3 组髓母细胞瘤（原发性和转移性）、非典型畸胎样横纹肌样肿瘤、原始神经外胚层肿瘤、小儿神经胶质瘤和弥漫性内在脑桥神经胶质瘤。Hu5F9-G4 在患者来源的原位异种移植模型中表现出了体外和体内的治疗效果。脑室内给予 Hu5F9-G4 进一步增强了其对播散性髓母细胞瘤脑膜疾病的活性。值得注意的是，Hu5F9-G4 在体外和体内对正常人类神经细胞的活性很小，在免疫活性同种异体神经胶质瘤模型中也重复了这一现象。因此，Hu5F9-G4 是一种潜在的安全有效的治疗多种儿科中枢神经系统恶性肿瘤的药物。
