胶质母细胞瘤是人类肿瘤中恶性程度最高的肿瘤之一，患者平均生存期只有14个月左右，常规的治疗后患者复发率几乎达到100％。近日，军事医学研究院秦成峰研究员与国家生物医学分析中心满江红研究员、美国德克萨斯大学史佩勇教授联合攻关等联合攻关，成功将寨卡病毒疫苗株开发为新型溶瘤病毒，为胶质母细胞瘤的临床治疗开辟了新的方向。相关研究以Treatment of Human Glioblastoma with a Live Attenuated Zika VirusVaccine Candidate”为题于2018年9月18日在线发表于美国微生物学会权威期刊mBio上。
FIG1 Characterization of the safety profile of ZIKV-LAV upon intracerebral administration in mice 2、减毒寨卡病毒疫苗株的溶瘤效果分析。研究人员在体内外模型中评估了寨卡疫苗株对胶质瘤干细胞的溶瘤活性。正在细胞水平的体外模型研究结果发现，寨卡疫苗株可高效感染胶质瘤干细胞，并快速诱导大量细胞死亡，阻止肿瘤球形成。更重要的是，寨卡疫苗株仅对胶质瘤干细胞表现出较高的杀伤效果，对分化后的胶质瘤细胞感染率非常低，能够有效避免“误伤”正常脑细胞（图2）。
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FIG2 ZIKV-LAV preferentially infects and kills GSCs and impairs tumorsphere formation 3、减毒寨卡病毒疫苗株体内的溶瘤效果分析。进一步的，研究人员建立了基于病人来源的胶质瘤干细胞的小鼠模型，并通过模拟肿瘤复发的程序进行治疗。结果发现，与对照组小鼠相比，治疗组小鼠脑内胶质瘤干细胞数量大幅减少，同一时间点胶质瘤干细胞比例仅为对照组一半左右更为重要的是，寨卡疫苗治疗组小鼠不仅脑内肿瘤发生时间明显延后，而且生存周期显著延长，显示出了优越的临床转化应用前景（图3，图4）。 。
Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute totumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) hasan oncolytic tropism for infecting GSCs, we investigated the safety and efficacy of a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a GSC-derived orthotopic model. Intracere bralinjection of ZIKV-LAV into mice caused no neurological symptoms or behavioral abnormalities. The neurovirulence of ZIKV-LAV was more attenuated than that of the licensed Japanese encephalitis virus LAV 14-14-2, underlining the superior safety of ZIKV-LAV for potential GBM treatment. Importantly, ZIKV-LAV significantly reduced intracerebral tumor growth and prolonged animal survivalby selectively killing GSCs within the tumor. Mechanistically, ZIKV infection elicited antiviral immunity, inflammation, and GSC apoptosis. Together, these results further support the clinical development of ZIKV-LAV for GBM therapy.
【IMPORTANCE】Glioblastoma (GBM), the deadliest type of brain tumor, is currently incurable because of its high recurrence rate after traditional treatments, including surgery to remove the main part of the tumor and radiation and chemo therapy to target residual tumor cells. These treatments fail mainly due to the presence of a cell subpopulation called glioma stem cells (GSCs), which are resistant to radiation and chemo therapy and capable of self-renewal and tumorigenicity. Because Zika virus (ZIKV) has an oncolytic tropism for infecting GSCs, we tested a live attenuated ZIKV vaccine candidate (ZIKV-LAV) for the treatment of human GBM in a human GSC-derived orthotopic model. Our results showed that ZIKV-LAV retained good efficacy against glioblastoma by selectively killing GSCs within the tumor. In addition, ZIKV-LAV exhibited an excellent safety profile upon intracerebralin jection into the treated animals. The good balance between the safety of ZIKV-LAV and its efficacy against human GSCs suggests that it is a potential candidate for combination with the current treatment regimen for GBM therapy.
参考文献：
1. Qi Chen, Jin Wu,Qing Ye, Feng Ma, Qian Zhu, Yan Wu, Chao Shan, Xuping Xie, Dapei Li, XiaoyanZhan, Chunfeng Li, Xiao-Feng Li, Xiaoling Qin, Tongyang Zhao, Haitao Wu,Pei-Yong Shi, Jianghong Man, Cheng-Feng Qin. Treatment of Human Glioblastomawith a Live Attenuated Zika Virus Vaccine Candidate.
DOI:10.1128/mBio.01683-18
https://mbio.asm.org/content/9/5/e01683-18
2. China Daily：Zikavaccine shows promise for treating deadly brain cancer寨卡疫苗有望治疗致命脑癌
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