Injecting Genetically Modified Zika Virus into the Brain to Treat Deadly Brain Tumors

Recently, researchers from Oregon Health and Science University and Washington University in St. Louis published a research paper titled "Intracranial injection of genetically modified, mosquito non-transmissible Zika virus: Safety in primates and ramifications for brain tumor therapy" in the Cell sub-journal, Cell Reports Medicine.

Glioblastoma (GBM) is an aggressive brain tumor with a median survival period of less than 21 months. Immune checkpoint inhibitors, peptide vaccines, and dendritic cell vaccines have not shown significant benefits in clinical trials. Over the past two decades, the standard of care for glioblastoma has remained largely unchanged, including surgery, radiation therapy, chemotherapy, and more recently, anti-mitotic Tumor Treating Fields.

Glioblastoma typically recurs within 6 months even after maximum treatment, posing a significant clinical challenge. A highly heterogeneous subpopulation of glioblastoma stem cells (GSCs) is resistant to standard therapies and may be the underlying driver of recurrence. Furthermore, its tumor microenvironment (TME) is strongly immunosuppressive and lacks anti-tumor immune cells. Therefore, new therapeutic strategies are needed to address these challenges.

Oncolytic viruses can infect and destroy tumor cells, offering a potential treatment for glioblastoma. A range of viruses, including H-1 parvovirus, reovirus, measles virus, Newcastle disease virus, vaccinia virus, poliovirus, adenovirus, herpes simplex virus, retrovirus, myxoma virus, and vesicular stomatitis virus, have been or are being studied as oncolytic virus therapies for GBM. However, these viruses do not exclusively infect glioblastoma stem cells, and to date, no virus has been successfully developed for widespread clinical application.

Zika virus (ZIKV)-based oncolytic therapy is unique in that it specifically targets glioblastoma stem cells, shrinking tumor volume and extending survival in various mouse models of glioma.

Although Zika virus causes congenital brain abnormalities in fetuses of infected mothers, it rarely infects the brains of adults. The research team demonstrated that ZIKV does not infect adult brain tissue samples from epilepsy surgeries but specifically infects SOX2+ glioblastoma stem cells from human glioblastoma slices. Additionally, in mice, intratumoral oncolytic Zika virus treatment enhanced the effects of systemic antibody-mediated PD-1 blockade.

Glioblastoma is an incurable brain tumor. ZIKV has the ability to specifically kill glioblastoma stem cells, which are responsible for treatment resistance. In mouse models of glioblastoma, Zika virus also triggers an anti-tumor inflammatory response and prolongs survival.

To support the clinical development of oncolytic Zika virus therapy and address safety concerns regarding intratumoral treatment, the research team modified the 3'untranslated region (3'UTR) of the Zika virus genome by deleting 10 nucleotides—Δ10 3'-UTR ZIKV. This elimination removes the possibility of the virus countering the innate antiviral immune response, and the modified virus cannot be transmitted by mosquitoes.

Figure 1. Viral RNA and infectious virus levels in rhesus macaque brains 14 days after intracranial injection of Δ10 3'-UTR ZIKV. (Hirsch A J, et al., 2025).

To further evaluate its safety, the research team injected Δ10 3'-UTR ZIKV into the brains of tumor-free rhesus macaques. Following injection, these primates showed no signs of clinical disease. Histologically, as expected, the Zika virus infection triggered mild inflammation that subsided within two weeks. After 14 days, no infectious virus was detected in the brain or any other organs. These findings support the safety of using Δ10 3'-UTR ZIKV in the brain and, combined with previous data, advance its clinical translation as an oncolytic and immunomodulatory therapy for glioblastoma.