The authors note that there are critical safety issues associated with the injection of ZIKV into the brain. It is determined that necessary adaptations of the virus must be achieved in order to ensure its effectiveness as an oncolytic virus for the treatment of GBM. In order to address the safety concerns associated with the use of ZIKV as a oncolytic virus, the researchers have developed a genetically modified live attenuated ZIKV vaccine (ZIKV-LAV). In order to establish the efficacy of the ZIKV-LAV, the researchers conducted tests to address the safety of intracerebral injection, evaluation in vivo efficacy, and define the oncolytic mechanism in regards to the potential treatment of GBM.
In order to address the areas of concern identified by the researchers, ZIKV-LAV was injected into mice. The intracerebral injection allowed for the examination of the impact of ZIKV-LAV on the neurological condition of the test mice. The results of the research were then discussed in detail throughout the remainder of the report, with reference to the significance of the findings of the study. The results of this study build upon previous research conducted by the authors.
The first major finding of the study concerned the safety of ZIKV-LAV intracerebral injection in test mice. It was found that intracerebral injection posed no major health risks in multiple mice models. Intracranial injection of 10,000 PFU of ZIKV-LAV as well as wild-type ZIKV into 3-week-old BALB/c nude mice was conducted. In addition to these injections, a control injection was established employing c commonly employed clinical JEV-LAV injection.
The injection of ZIKV-LAV did not lead to morbidity, mortality, or weight loss in any of the test mice. Additionally, no pathological adaptations were observed in the brains of the mice injected with ZIKV-LAV. Furthermore, no viral RNAs were observed in organs outside of the brain. The authors note that the pathological results observed in the study may be been impacted by the presence of limited inflammation in the test mice as a result of the lack of T cells.
A concern was noted in regards to the potential for behavioral change resulting from the presence of ZIKV in multiple animal models. It order to address this concern, the researchers monitored the behavior of the test mice in order to determine the behavioral adaptations that may result from injection of ZIKV-LAV. This observation revealed no major behavioral adaptations during the observation period.
The second major finding of the study concerns the prolonged life of the mice that received the intracerebral injection of ZIKV-LAV. Clinical treatment was mimicked through the injection of GSCs and ZIKV-LAV in order to determine the efficacy of the ZIKV-LAV in a clinical setting. Those mice implanted with GCSs developed fast progressing tumors and died shortly after injection. In comparison, those mice that received the intracerebral injection of ZIKV-LAV experienced delayed tumor growth. Survival timetables were significantly extended for those mice that received the ZIKV-LAV injection.
The ZIKV-LAV injection was also shown to exhibit tumoricidal characteristics. These characteristics were identified by the researchers as the third major finding of the study. Isolation of GBM bulk cells was conducted in test mice, and ZIKV-LAV was employed in order to determine the impact of the injection on the cells. It was shown that this injection had significant oncolytic effects.
The fourth major finding of the study consisted of the identification of the preferential targeting of GSCs by ZIKV-LAV. The ZIKV-LAV injection was shown to effectively destroy GSCs in test mice. The specific targeting of GSCs by the ZIKV-LAV injection further expanded the potential efficacy of ZIKV-LAV as an oncolytic option for the future treatment of GBM in human patients.
The fifth and final major finding of the study consisted of the identification of antiviral immunity and inflammation in GSCs developed through the presence of ZIKV. The researchers employed transcriptome sequencing (RNA-seq) in order to show that ZIKV infection caused a generally observable antiviral immune response and inflammation in GSCs within infected mice. These results signify the importance of cytokine responses and interferon signaling in the oncolytic effects of ZIKV in the study.
The results observed by the researchers revealed that ZIKV-LAV may in fact offer a potential means of reducing the progression of GBM through the destruction of GSCs in those patients experiencing tumor growth. Furthermore, the safety of this ZIKV-LAV injection was demonstrated in the mice tests. Specifically, it was shown that the injection did not have a negative impact on neurological health or behavior.
Chen Q, Wu J, Ye Q, Ma F, Zhu Q, Wu Y, Shan C, Xie X, Li D, Zhan X, Li C, Li X-F, Qin X, Zhao T, Wu H, Shi P-Y, Man J, Qin C-F. 2018. Treatment of human glioblastoma with a live attenuated Zika virus vaccine candidate. mBio 9:e01683-18. https://doi.org/10.1128/mBio .01683-18.