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
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.
