@article{c27b0e3c80c04144a9c2807ff5b35f17,
title = "Treatment of human glioblastoma with a live attenuated Zika virus vaccine candidate",
abstract = "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. 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 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.",
keywords = "Anticancer therapy, Glioblastoma, Vaccine, Zika virus",
author = "Qi Chen and Jin Wu and Qing Ye and Feng Ma and Qian Zhu and Yan Wu and Chao Shan and Xuping Xie and Dapei Li and Xiaoyan Zhan and Chunfeng Li and Li, {Xiao Feng} and Xiaoling Qin and Tongyang Zhao and Haitao Wu and Shi, {Pei Yong} and Jianghong Man and Qin, {Cheng Feng}",
note = "Funding Information: We thank Jeremy Rich (University of California, San Diego) for providing the GSCs used in this study and Zhongping Chen (Sun Yat-sen University) for the helpful discussions. This work was supported by the National Key Research and Development Project of China (no. 2016YFD0500304), the National Natural Science Foundation (NSFC) of China (no. 31870912, no. 31770190, U170220023, no. 81661148054, no. 81572889, no. 31522029, and no. 31670883), the National Science and Technology Major Project of China (no. 2018ZX09711003 and no. 2017ZX10304402), the CAMS Initiative for Innovative Medicine (no. 2016-I2M-1-005), and the Beijing Municipal Science and Technology Commission (Z161100000216154). The laboratory of C.-F.Q. was supported by the Excellent Young Scientist Program (no. 81522025), the Innovative Research Group (no. 81621005) from NSFC, and a Newton Advanced Fellowship from the U.K. Academy of Medical Sciences. The laboratory of P.-Y.S. was supported by the University of Texas STARs Award, a CDC grant for the Western Gulf Center of Excellence for Vector-Borne Diseases, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, UTMB CTSA UL1TR-001439, and NIH grant AI127744. Funding Information: This work was supported by the National Key Research and Development Project of China (no. 2016YFD0500304), the National Natural Science Foundation (NSFC) of China (no. 31870912, no. 31770190, U170220023, no. 81661148054, no. 81572889, no. 31522029, and no. 31670883), the National Science and Technology Major Project of China (no. 2018ZX09711003 and no. 2017ZX10304402), the CAMS Initiative for Innovative Medicine (no. 2016-I2M-1-005), and the Beijing Municipal Science and Technology Commission (Z161100000216154). The laboratory of C.-F.Q. was supported by the Excellent Young Scientist Program (no. 81522025), the Innovative Research Group (no. 81621005) from NSFC, and a Newton Advanced Fellowship from the U.K. Academy of Medical Sciences. The laboratory of P.-Y.S. was supported by the University of Texas STARs Award, a CDC grant for the Western Gulf Center of Excellence for Vector-Borne Diseases, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, UTMB CTSA UL1TR-001439, and NIH grant AI127744. Publisher Copyright: {\textcopyright} 2018 Chen et al.",
year = "2018",
month = sep,
day = "1",
doi = "10.1128/mBio.01683-18",
language = "English (US)",
volume = "9",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "5",
}