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.

• Authors: 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
• Journal: mBio (mBio) Vol. 9 Issue 5 (09 18 2018) ISSN: 2150-7511 [Electronic] United States
• PMID: 30228241 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright © 2018 Chen et al.

Chemical References

• Vaccines, Attenuated

Topics

• 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, virology)
• Oncolytic Virotherapy
• Oncolytic Viruses
• Vaccines, Attenuated (immunology, therapeutic use)
• Vero Cells
• Viral Tropism
• Xenograft Model Antitumor Assays
• Zika Virus