Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade
We previously published about this research in a story titled “Zika Virus Destroyed Glioblastoma in Mice” which can be found here. The study was originally published in the research journal JCI Insight. You can view the full text of the study here.
This research team was associated with and supported by the Washington University School of Medicine in St. Louis.
Zika virus is a name that raises alarm bells for most people that have heard of it, and for good reason. Though first isolated in Uganda in 1947, Zika is probably best remembered in recent memory for triggering an epidemic lasting from April 2015 to November 2016, with the virus ultimately spreading throughout much of North and South America. The virus causes Zika fever, which generally produces mild symptoms, such as rash, fever, joint pain, and red eyes that usually resolve without issue; however, it became notorious for causing birth defects when pregnant mothers were infected, such as microcephaly.
A vaccine for Zika may be available in the not so distant future, but the team of scientists in this study may have found an astonishing medical use for the virus: as part of an immunotherapy treatment for glioblastoma, the most widespread and deadly form of brain cancer in adults. Now I know we talked about brain tumors last week in this series, but this study was just too interesting to pass up…so bear with me.
This research was based on findings from an earlier study from 2017, which found that Zika virus could kill brain cancer stem cells, which are known for being very treatment-resistant. Other research has demonstrated that Zika could prevent death in a glioma mouse model. In this study, the scientists sought to understand the impact of Zika on glioblastoma and how it could play a role in treatment.
The mouse study found that the Zika virus was effective because it could draw immune cells to the site of the cancer tumor. Glioblastoma creates a surrounding that wards off immune cells and suppresses the immune response, meaning that PD-1 inhibitors, a class of immunotherapy used in other cancers, are ineffective. The scientists hoped that by combining the action of a PD-1 inhibitor, which activates the immune cells, and Zika, which previously had the effect of drawing immune cells to the area, they could find an effective approach.
Once again using mouse models, the researchers introduced the Zika virus into the tumor environment. They found, as before, that the virus increased the presence of immune system cells in the area. More specifically the numbers of CD8+ T-cells greatly increased. They also treated other mice with a PD-1 inhibitor. In both of these groups, the survival rate increased from around 30 percent to around 60 percent. However, another group of mice was treated with both Zika and PD-1; in this group, the survival benefit was around 90 percent.
The scientists found that the increase of CD8+ T-cells brought about by Zika was the key mechanism to its efficacy. They also tested the effect in a model of relapsed disease by reintroducing cancer cells in survivor mice that had been treated with Zika. These mice saw better survival times compared to a control group, suggesting the potential for long-term benefit.
Ultimately, the findings indicate that Zika virus, when modified into an immune-sensitized strain in particular, could be a useful therapy for glioblastoma, particularly when combined with immunotherapy such as a PD-1 inhibitor.
Glioblastoma is a rare brain cancer. It is also the most aggressive cancer to originate in the brain. It is characterized by its rapid progression and poor response to most treatments. In most cases, the cause of glioblastoma is not known. A small number of cases evolve from another type of tumor called an astrocytoma. Risk factors for glioblastoma include genetic disorders such as Turcot syndrome and neurofibromatosis, exposure to pesticides, smoking, and a career in petroleum refining or rubber manufacture. Symptoms of glioblastoma include personality changes, headaches, memory loss, seizures, vomiting, and nausea; patients may lose consciousness in late stages. Treatment approaches include anticonvulsants, steroids, chemotherapy, radiation, and surgery. While a small number of patients can survive for several years, treatment is often ineffective, with the tumor relapsing quickly. The five-year survival rate is only three percent. To learn more about glioblastoma, click here.
Why Does it Matter?
Glioblastoma, in the vast majority of cases, is effectively a death sentence for the majority of patients. Survival after diagnosis is only around 14 months, so making progress in treatment outcomes for this disease is an urgent unmet medical need. While it is definitely unusual for a virus responsible for an epidemic to be used for the treatment of another disease, desperate situations can sometimes call for desperate measures.
As it stands, the findings from this study could lead to a modified Zika virus playing an important role in improving prognosis in glioblastoma. However, with the use of a potentially pathogenic virus, safety concerns will be paramount. Future research will have to focus on what it will take for Zika to be used in treatment safely.
“By using Zika virus, we’re revving up the immune system to respond to an otherwise ineffective immunotherapy. This also sets the stage to prevent recurrence, allowing us to overcome two major barriers to effective treatment.” – Milan. G. Chheda, MD, co-senior author