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

mBio (Nov 2018)

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

Affiliations

Qi Chen: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
Jin Wu: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
Qing Ye: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
Feng Ma: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Qian Zhu: Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
Yan Wu: Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
Chao Shan: 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
Xuping Xie: 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
Dapei Li: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Xiaoyan Zhan: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
Chunfeng Li: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
Xiao-Feng Li: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
Xiaoling Qin: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
Tongyan Zhao: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
Haitao Wu: Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
Pei-Yong Shi: 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
Jianghong Man: State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China
Cheng-Feng Qin: State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China

DOI: https://doi.org/10.1128/mBio.01683-18
Journal volume & issue: Vol. 9, no. 5

Abstract

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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.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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