Department of Neurological Surgery, Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, California.
Department of Neurology, Pediatrics, and Neurological Surgery and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
Neuro Oncol. 2018 Nov 12;20(12):1606-1615. doi: 10.1093/neuonc/noy089.
Oncolytic measles virus (MV) is effective in xenograft models of many tumor types in immune-compromised mice. However, no murine cell line exists that is tumorigenic, grows in immune-competent mice, and is killed by MV. The lack of such a model prevents an examination of the effect of the immune system on MV oncotherapy.
Cerebellar stem cells from human CD46-transgenic immunocompetent mice were transduced to express Sendai virus C-protein, murine C-Myc, and Gfi1b proteins. The resultant cells were injected into the brain of NSG mice, and a cell line, called CSCG, was prepared from the resulting tumor.
CSCG cells are highly proliferative, and express stem cell markers. These cells are permissive for replication of MV and are killed by the virus in a dose- and time-dependent manner. CSCG cells form aggressive tumors that morphologically resemble medulloblastoma when injected into the brains of immune-competent mice. On the molecular level, CSCG tumors overexpress natriuretic peptide receptor 3 and gamma-aminobutyric acid type A receptor alpha 5, markers of Group 3 medulloblastoma. A single intratumoral injection of MV‒green fluorescent protein resulted in complete tumor regression and prolonged survival of animals compared with treatments with phosphate buffered saline (P = 0.0018) or heat-inactivated MV (P = 0.0027).
This immune-competent model provides the first platform to test therapeutic regimens of oncolytic MV for Group 3 medulloblastoma in the presence of anti-measles immunity. The strategy presented here can be used to make MV-sensitive murine models of any human tumor for which the driving mutations are known.
溶瘤麻疹病毒（MV）在免疫功能低下的小鼠多种肿瘤异种移植模型中均有效。然而，不存在能在免疫功能正常的小鼠中致瘤、生长并被 MV 杀死的鼠细胞系。缺乏这种模型会阻碍对免疫系统对 MV 肿瘤治疗作用的研究。
将人 CD46 转基因免疫功能正常小鼠的小脑干细胞转导以表达仙台病毒 C 蛋白、鼠 C-Myc 和 Gfi1b 蛋白。将所得细胞注射到 NSG 小鼠的脑内，从所得肿瘤中制备出细胞系，称为 CSCG。
CSCG 细胞增殖活跃，表达干细胞标志物。这些细胞允许 MV 复制，并以剂量和时间依赖的方式被病毒杀死。CSCG 细胞形成侵袭性肿瘤，当注入免疫功能正常的小鼠脑内时，其形态类似于髓母细胞瘤。在分子水平上，CSCG 肿瘤过度表达利钠肽受体 3 和γ-氨基丁酸 A 型受体α5，这是 3 组髓母细胞瘤的标志物。与磷酸盐缓冲盐水（P = 0.0018）或热灭活 MV（P = 0.0027）治疗相比，单次肿瘤内注射 MV-绿色荧光蛋白可导致完全肿瘤消退和动物存活时间延长。
该免疫功能正常的模型首次为在抗麻疹免疫存在的情况下测试溶瘤 MV 治疗 3 组髓母细胞瘤的治疗方案提供了平台。这里提出的策略可用于构建任何已知驱动突变的人类肿瘤的 MV 敏感的鼠模型。
