Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate.
Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate.
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用寨卡病毒减毒活疫苗候选药物治疗人类胶质母细胞瘤。
DOI：
10.1128/mbio.01683-18
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发表时间：
2018-09-18
期刊：
影响因子：
6.4
通讯作者：
Qin CF
中科院分区：
文献类型：
--
作者：
Chen Q;Wu J;Ye Q;Ma F;Zhu Q;Wu Y;Shan C;Xie X;Li D;Zhan X;Li C;Li XF;Qin X;Zhao T;Wu H;Shi PY;Man J;Qin CF
胶质母细胞瘤（GBM）是最致命的脑肿瘤类型，目前无法治愈，因为传统治疗方法包括手术切除肿瘤的主要部分和针对残余肿瘤细胞的放疗和化疗，其复发率很高。这些治疗的失败主要是由于胶质瘤干细胞（GSCs）的细胞亚群的存在，这种细胞亚群对放疗和化疗具有抗性，能够自我更新和致瘤性。由于寨卡病毒（ZIKV）对感染gsc具有溶瘤性，我们在人gsc衍生的原位模型中测试了一种用于治疗人GBM的减毒活疫苗候选疫苗（ZIKV- lav）。我们的研究结果表明，ZIKV-LAV通过选择性杀死肿瘤内的GSCs，保持了对胶质母细胞瘤的良好疗效。此外，ZIKV-LAV在治疗动物脑内注射时表现出极好的安全性。ZIKV-LAV的安全性及其对人GSCs的有效性之间的良好平衡表明，它是与当前治疗方案联合治疗GBM的潜在候选者。胶质母细胞瘤（GBM）是最致命的脑肿瘤类型，胶质瘤干细胞（GSCs）有助于肿瘤复发和治疗抵抗。因此，针对GSCs的溶瘤病毒可能有助于改善GBM的治疗。由于寨卡病毒（ZIKV）具有感染gsc的溶瘤性，我们在gsc衍生的原位模型中研究了ZIKV减毒活疫苗候选（ZIKV- lav）治疗人GBM的安全性和有效性。鼠脑内注射ZIKV-LAV未引起神经系统症状或行为异常。ZIKV-LAV的神经毒力比许可的日本脑炎病毒LAV 14-14-2更弱，强调了ZIKV-LAV治疗潜在GBM的优越安全性。重要的是，ZIKV-LAV通过选择性杀死肿瘤内的GSCs，显著降低了脑瘤内的生长，延长了动物的生存时间。在机制上，ZIKV感染引发抗病毒免疫、炎症和GSC凋亡。总之，这些结果进一步支持ZIKV-LAV用于GBM治疗的临床开发。
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 chemotherapy 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 chemotherapy 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 intracerebral injection 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. Glioblastoma (GBM) is the deadliest type of brain tumor, and glioma stem cells (GSCs) contribute to tumor recurrence and therapeutic resistance. Thus, an oncolytic virus targeting GSCs may be useful for improving GBM treatment. Because Zika virus (ZIKV) has an 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. Intracerebral injection 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 survival by 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.