TUESDAY, Feb. 8, 2022 — A genetically modified herpes virus appears to deliver a “one-two punch” to the rare and deadly form of brain cancer that killed U.S. Sen. John McCain, new findings show.
Glioblastoma brain tumors are a cancer nightmare, with an average survival of 12 to 15 months from initial diagnosis and four to six months after recurrence, researchers say. McCain died in August 2018, one year after doctors discovered he had the aggressive cancer.
“Despite 50 to 60 years of research and advances in surgery, chemotherapy and radiation, we haven’t pushed the needle much at all in terms of survival,” said senior researcher Dr. James Markert, chairman of neurosurgery at the University of Alabama at Birmingham’s Heersink School of Medicine. “Only 5% to 10% of patients live longer than five years. It’s almost universally fatal.”
It’s been known that G207 directly attacks and kills brain tumor cells, Markert said.
“There’s something different about tumor cells’ defense against viruses, so that the changes in the DNA that kept the virus from being infectious in normal human cells weren’t present in the tumor cells,” he said. “As a result, the virus became selective for infecting and killing tumor cells.”
Now it turns out the virus has another trick up its sleeve — it robs glioblastoma of its ability to evade detection by the immune system. Highlighted by the virus, the brain cancer comes under attack from the body’s natural defenses.
“It became apparent to us there was a really one-two punch,” Markert said. “The virus was invoking an immune response against the tumor as a secondary kind of anti-tumor response produced by the infection.”
Results from a phase 1B clinical trial involving six adult glioblastoma patients with recurring or progressing tumors provided Markert and his team with a new understanding of how the modified herpes virus attacks the cancer.
In the trial, patients had their glioblastomas surgically removed, and then most underwent radiation and chemotherapy.
The herpes virus was then injected directly into the site of their tumors.
A few days after the virus treatment, researchers drew genetic material from the treated tumors so they could better understand what happens inside the cancer as G207 attacks.
Untreated glioblastoma cells typically contain no genetic evidence of any immune response. “The tumor actually produces a number of factors to discourage the immune system from attacking it. It’s trying to act as a stealth invader as best it can,” Markert said.
But after treatment with G207, the tumors “are teeming with immune cells,” he said. The viral infection appears to produce a “danger signal” that directs the immune system’s attention to the cancer.
“In studying the genes associated with survival, [the researchers] found it was related to immune cell activation, turning on the body’s immune system to help fight the cancer,” said Dr. William Cance, chief medical and scientific officer for the American Cancer Society. “It gives us hope we can turn the immune system against these deadly brain tumors.”
Further analysis revealed about 500 genes that are significantly associated with patient survival after G207 treatment, and about half are related to immune response, Markert said.
“We hope that information is going to predict who are going to be the people who will respond really well, and who might need another treatment,” he said.
Five ongoing clinical trials are using genetically engineered herpes viruses to attack tumors of the brain and spinal cord, researchers said.
Trials have shown that the herpes virus treatment produces general but not uniform improvements in overall survival, researchers noted. For example, two of 36 glioblastoma patients treated with G207 in phase 1 trials had long-term survival of more than five and seven years.
In the most recent trial, the G207 virus kept four of 11 pediatric patients alive 18 months following treatment, Markert noted. Those results were published last spring in the New England Journal of Medicine.
“It turns out children do even better with the virus,” Markert said. “We think it’s because their immune systems might be stronger and their tumors are a bit more sensitive to the virus.”
Plans are underway to start a phase 2 study though a pediatric brain tumor consortium, Markert said.
“The frustrating thing about glioblastoma is that there are very limited therapies that have very limited efficacy. We need novel approaches to treat brain tumors like this,” said Cance, who wasn’t part of the new study.
He said the new paper provides a clearer explanation of how the virus therapy works, and who might best benefit from it.
“Hopefully, as they learn what predicts response, they’ll be able to be more selective with the patients who receive it,” Cance said.
Since glioblastoma is a rare disease, Markert said researchers hope to persuade the U.S. Food and Drug Administration to allow accelerated approval of G207.
This wouldn’t be the first FDA-approved herpes treatment for cancer, Markert noted. In 2015, the agency approved Imlygic, an Amgen-produced treatment for melanoma that also uses a modified herpes simplex virus.
“Melanoma, it turns out, is very responsive to immunotherapies, and so it’s quite logical that the virus would help put things over the top and produce a good immune response against a cancer that’s already susceptible to this kind of thing,” Markert said. “Glioblastoma is much more of a tough nut to crack.”
- James Markert, MD, MPH, chairman, neurosurgery, Heersink School of Medicine, University of Alabama at Birmingham
- William Cance, MD, chief medical and scientific officer, American Cancer Society
- Clinical Cancer Research, Feb. 1, 2022
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Posted February 2022