Zika virus vaccine used to battle brain cancer

Scientists at Singapore’s Duke-NUS Medical School have found a way to use the Zika virus to destroy brain cancer cells and inhibit tumour growth, while sparing healthy cells. Their findings, published in the Journal of Translational Medicine, potentially offer a new treatment alternative for brain cancer patients who currently have a poor prognosis.

Glioblastoma multiforme is the most common malignant brain cancer, with more than 300,000 patients diagnosed annually worldwide. Survival rates for such patients are poor (around 15 months), mainly due to high incidence of tumour recurrence and limited treatment options. For such patients, oncolytic virotherapy — or the use of engineered viruses to infect and kill cancer cells — may address the current therapeutic challenges. Zika virus is one such option in early development.

The Duke-NUS team sought to investigate Zika virus live-attenuated vaccine (ZIKV-LAV) strains, which are ‘weakened’ viruses with limited ability to infect healthy cells but can still grow rapidly and spread within a tumour mass. The team discovered that these strains target rapidly proliferating cells over mature cells, making them ideal for targeting fast-growing cancerous cells in the adult brain.

“We selected Zika virus because it naturally infects rapidly multiplying cells in the brain, allowing us to reach cancer cells that are traditionally difficult to target,” said Dr Carla Bianca Luena Victorio, first author of the team’s study. “Our ZIKV-LAV strains also replicate themselves in brain cancer cells, making this a living therapy that can spread and attack neighbouring diseased cells.”

Victorio and her team determined that ZIKV-LAV strains were highly effective in infecting cancer cells as these viruses bind to proteins that are present in high levels only in cancer cells and not in healthy cells. Upon infecting a cancer cell, these virus strains hijack the cell’s resources to reproduce, ultimately killing the cell. As the cancer cell’s protective membrane ruptures upon death, it releases its contents, including virus progeny that can infect and kill neighbouring cancer cells. In addition, some cellular proteins released from the infected cells can activate an immune response to further inhibit tumour growth.

Through their experiments, the team observed that infection from ZIKV-LAV strains caused 65–90% of glioblastoma multiforme tumour cells to die. While the ZIKV-LAV strains also infected 9–20% of cells from blood vessels in the brain, the infection did not kill these healthy cells. In contrast, the original parent Zika virus strain killed up to 50% of healthy brain cells.

The scientists also discovered that the ZIKV-LAV strains were not able to reproduce well even when they managed to infect healthy cells; the amount of virus measured in healthy brain cells infected with ZIKV-LAV was only 0.36 to 9 times higher than before infection. In contrast, the amount of virus in brain cancer cells infected with ZIKV-LAV was 100 to a billion times higher than before infection. This further illustrates that conditions in cancer cells are significantly more conducive for virus reproduction than in normal cells.

“We hope to present the Zika virus in a new light by highlighting its potential to kill cancer cells,” said Assistant Professor Ann-Marie Chacko, senior author on the paper. “When a live virus is attenuated, such that it is safe and effective to fight infectious diseases, it can be beneficial to human health — not just as a vaccine but also as a potent tumour-eradicating agent.”

The live attenuated virus strains were originally developed as a vaccine by Professor Ooi Eng Eong’s group at Duke-NUS. As a control, the virus strains were also tested on brain neurons or nerve cells that had been cultivated from human stem cells. This provides a reliable screening tool to assess the safety and efficacy of using the virus as therapy in human cells.

Chacko’s group is improving these and other Zika virus strains to increase their potency in killing not only brain cancer cells, but other types of cancer cells as well, while making them safer for use in patients. They are also modifying the virus so it can be imaged non-invasively after it has been injected into a patient; this will allow doctors to monitor where the virus goes in the patient and how long it is functional in the tumour. To this end, the group is exploring commercialising their virus strains as both a Zika vaccine and treatment for brain cancer, and potentially other cancers as well.

Top image caption: Professor Ooi Eng Eong, Dr Carla Bianca Luena Victorio, Assistant Professor Alfred Sun and Assistant Professor Ann-Marie Chacko with a culture of their Zika vaccine strains.