Modified versions of viruses could be the key to curing the deadliest forms of brain cancer.
Are herpes and polio the future of brain cancer treatment?
For more than 100 years, doctors and scientists have been trying to harness the power of viruses to do good. In promising new research, viruses are now being put to work against the deadliest and most common form of brain cancer: glioblastoma multiforme.
Patients diagnosed with glioblastoma typically survive an average of 15 months. The difficulty of surgical interventions, problematic biological mechanisms in the brain, and the complex structure of the tumors themselves make the diagnosis a death sentence.
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In a new study from researchers at the University of Alabama at Birmingham, scientists used a genetically modified version of the herpes virus (the same one that causes cold sores) known as G207 to treat glioblastoma in six pediatric patients.
The results, they say, are encouraging.
“Thus far, we have found that the virus is safe and tolerable when given alone, and we are seeing evidence suggestive of tumor killing in most of the children treated,” Dr. Gregory Friedman, the lead author and associate professor of pediatric hematology-oncology at UAB, told Healthline.
Additionally, they note that there were no observed dose-limiting toxicities or serious side effects. Of the six patients, five showed evidence of tumor killing. One continues to show response to the therapy without any other treatment after 18 months.
In the treatment, doctors use a catheter to inject G207 directly into the brain tumor. G207 isn’t just any herpes virus, though. It has been genetically modified to make it safe for normal cells but still capable of replicating in and killing cancer cells.
The effects of the virus on the cancer are twofold: It’s oncolytic (meaning it actually attacks cancer cells), and it’s immunologic (meaning it provokes a response from the immune system). Cancer cells are often able to avoid detection by immune system T cells. Thus the ability of the virus to alert the immune system to the presence of the cancer is invaluable.
The work is a culmination of over 20 years of research into genetically engineered oncolytic viruses by UAB researcher Dr. James Markert. He and his colleagues initially described their concept in 2001. They are now leading trials on a second-generation herpes virus called M032.
“There are a lot of advantages of using herpes virus as an oncolytic agent. It is a very well-studied virus. All of the essential and nonessential genes have been identified, and nonessential genes can be removed to make the virus safe for normal cells without removing the ability of the virus to infect and kill cancer cells,” said Friedman.
He added, “Another important advantage is the virus is very immunogenic and stimulates a robust immune response. As the immune cells are attracted to the area to remove the virus, they can recognize tumor proteins that are present from the virus lysing [destroying] tumor cells and can begin to attack the tumor.”
In another impressive study published this month in The New England Journal of Medicine, researchers used a genetically modified polio virus in a similar fashion.
In a cohort of 61 patients who failed to respond to other standard therapies, including radiation and chemotherapy, Duke University oncologists injected the virus, known as PVSRIPO, directly into glioblastoma tumors. The intervention drastically improved survival outcomes.
“What we were able to show was not only were we able to infect the tumor, but we were also able to trigger what we call a secondary immune response, reactivating the immune system of our patients against glioblastoma. That’s how we have the long-term survivors,” Dr. Annick Desjardins, lead study author and director of clinical research at Duke’s Preston Robert Tisch Brain Tumor Center, told Healthline.
Two years after receiving a dose of PVSRIPO, 21 percent of patients were still alive, compared to just 14 percent of the control group. After three years, the number of survivors continued to plateau at 21 percent, while only 4 percent in the control group survived.
“Really what we saw was that survival at the first year and a half, two years, the survival of the two groups was very similar. Then at two years, the curves split,” said Desjardins.
She explained the reason the patients become long-term survivors is that they are immunized after treatment, which basically means their immune system is trained in recognizing their tumor. “If the tumor wakes up again, the immune system can fight it.”
Among the cohort, there are now patients six years out from receiving the polio virus treatment that are still alive — well beyond the average 15-month survival rate.
However, oncolytic viral immunotherapy is still in an early stage of development as a treatment for brain cancer, with years of clinical trials to come. To date, only one of these therapies has been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment.
In 2015, the FDA approved the first-ever oncolytic viral immunotherapy, talimogene laherparepvec (Imlygic) for melanoma. Like the treatment being developed at UAB, Imlygic uses a genetically modified herpes virus.
Glioblastoma is a tricky and dangerous form of cancer that has thus far evaded standard courses of treatment for several reasons.
It’s location in the brain makes it exceedingly difficult to operate on and remove via physical surgical interventions. The brain’s own defense mechanism also makes it resistant to anticancer drugs.
The blood-brain barrier, a layer of specialized cells that separate the brain from the bloodstream, is the last line of defense between viruses and toxins. However, the barrier can also have the adverse effect of preventing anticancer drugs from reaching the brain or weakening their potency to a degree that they’re no longer effective.
Using a catheter to inject a virus directly into the tumor itself bypasses the defense of the blood-brain barrier.
The biological makeup of glioblastoma tumors is also problematic.
“It is a tumor that we call heterogeneous. If you look at the tumor, different parts of it will have different genetic mutations. So, treatments that are available for other types of cancer that have one main driver mutation, in glioblastoma it might only attack 10 percent of the cells,” said Desjardin.
Glioblastoma are also usually “cold,” meaning that they tend to be invisible to the immune system. Viral immunotherapies help to flip the switch on these tumors, allowing the immune system’s deadly T cells to target them.
Both Desjardin and Friedman are encouraged by their findings and are further pursuing the next stages of treatment.
“In the next part of the study, we are investigating the safety and tolerability of adding in a single low-dose of radiation within 24 hours of virus inoculation,” said Friedman. “Radiation can release tumor proteins leading to increased recruitment and function of T cells that can attack the tumor. As soon as this study is complete, we anticipate moving to a Phase 2 trial.”
Desjardins said they are currently examining how they can increase the survival percentage of those who receive the treatment and how more of the immune system can be activated to fight cancer.
“There are definite ways of doing that,” said Desjardins. “We’re just starting.”