Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate

Qi Chen; Jin Wu; Qing Ye; Feng Ma; Qian Zhu; Yan Wu; Chao Shan; Xuping Xie; Dapei Li; Xiaoyan Zhan; Chunfeng Li; Xiao-Feng Li; Xiaoling Qin; Tongyan Zhao; Haitao Wu; Pei-Yong Shi; Jianghong Man; Cheng-Feng Qin

doi:10.1128/mBio.01683-18

Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate

mBio. 2018 Sep 18;9(5):e01683-18. doi: 10.1128/mBio.01683-18.

Authors

Qi Chen^#¹, Jin Wu^#^{2

3}, Qing Ye^#^{1

4}, Feng Ma^#^{5

6}, Qian Zhu⁷, Yan Wu⁷, Chao Shan⁸, Xuping Xie⁸, Dapei Li^{5

6}, Xiaoyan Zhan², Chunfeng Li^{1

5

6}, Xiao-Feng Li¹, Xiaoling Qin¹, Tongyan Zhao¹, Haitao Wu⁷, Pei-Yong Shi⁹, Jianghong Man¹⁰, Cheng-Feng Qin¹¹

Affiliations

¹ State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China.
² State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
³ Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Institute of Environmental Medicine, Academy of Military Medical Sciences, Tianjin, China.
⁴ Guangzhou No.8 People's Hospital, Guangzhou Medical University, Guangzhou, China.
⁵ Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
⁶ Suzhou Institute of Systems Medicine, Suzhou, China.
⁷ Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China.
⁸ Department of Biochemistry and Molecular Biology, Department of Pharmacology and Toxicology, Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, USA.
⁹ Department of Biochemistry and Molecular Biology, Department of Pharmacology and Toxicology, Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas, USA peshi@utmb.edu jhman@ncba.ac.cn qincf@bmi.ac.cn.
¹⁰ State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China peshi@utmb.edu jhman@ncba.ac.cn qincf@bmi.ac.cn.
¹¹ State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China peshi@utmb.edu jhman@ncba.ac.cn qincf@bmi.ac.cn.

^# Contributed equally.

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: Zika virus; anticancer therapy; glioblastoma; vaccine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Apoptosis
Brain Neoplasms / therapy*
Chlorocebus aethiops
Female
Glioblastoma / therapy*
Humans
Inflammation
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Neoplastic Stem Cells / pathology
Neoplastic Stem Cells / virology
Oncolytic Virotherapy*
Oncolytic Viruses
Vaccines, Attenuated / immunology
Vaccines, Attenuated / therapeutic use
Vero Cells
Viral Tropism
Xenograft Model Antitumor Assays
Zika Virus

Substances

Vaccines, Attenuated

Abstract

Publication types

MeSH terms

Substances

Grants and funding