Yale School of Medicine's scientific community is always pushing the boundaries. That is what a world-class research institution does. Ultimately, people are the beneficiaries.
Here is one example: Ebola. You might think that nothing good could come from this virus, which killed thousands and spread fear and panic across the globe in 2014. But as deadly as it is, Ebola and a similar virus endemic to West Africa known as Lassa fever virus have the potential to do some serious good.
Scientists led by Anthony N. Van den Pol, PhD, a professor of neurosurgery, have found that genetically modified viruses containing genes from Ebola or Lassa fever viruses have a key distinction from the real-world diseases that cause human misery. When combined with genetic material from another virus, Ebola and Lassa can help target and kill brain cancer cells.
“In their natural state, these viruses bind to a lot of different tissues,” says Dr. van den Pol. “That’s one of the reasons they’re so dangerous—and also why they may have the potential to treat different types of cancer.”
While the Ebola and Lassa fever viruses that occur in nature attack the body’s internal organs, overwhelm the immune system and cause often-fatal internal bleeding, the lab-created hybrid viruses “appear very safe and don’t cause lethal effects,” Dr. van den Pol says. Their only target is cancer cells, specifically those in the most deadly type of brain tumor, glioblastoma.
The cancer-virus link
We usually think about how viruses may cause cancer, not cure it. Viruses ranging from human papilloma virus (HPV) to Epstein-Barr to hepatitis B and C have all been found to increase a patient’s likelihood of developing certain cancers. But as Dr. van den Pol and colleagues have found the opposite effect may also be possible.
Dr. van den Pol’s lab at Yale Medicine’s Department of Neurosurgery is one of the leading centers internationally that is investigating the use of tumor-killing viruses to cure brain cancer. Dr. van den Pol has been researching and testing such viruses for about 15 years. His goal is to find an effective treatment for glioblastoma, a type of fast-growing and especially deadly brain tumor that afflicts more than 10,000 people a year.
Today, patients with glioblastoma undergo neurosurgery to remove all or part of the tumor and receive radiation and chemotherapy. “The problem is, in the long run, the brain tumor can recur,” Dr. van den Pol says.
As a glioblastoma expands, it compresses surrounding tissue. After a diagnosis, people generally survive for about 14 months. “Even a great neurosurgeon can have trouble eliminating all the cancer cells because they’ve migrated away from the main body of the tumor into the brain,” says Dr. van den Pol. “That’s where the virus might be able to help out—by going after the remaining tumor cells.”
For decades, scientists have tested the ability of many types of viruses to successfully target and kill cancer cells. The goal: to identify viruses that destroy cancerous tumors without also devastating healthy cells nearby.
This has proved to be a difficult task. For example, previous lab tests have found that a virus in the rabies family known as vesicular stomatitis virus (VSV) is very good at targeting and killing brain tumors. But along with killing the tumor, VSV may also infect healthy brain tissue, which can lead to serious neurological problems or even death.
Turning a killer into a cure
Dr. Van den Pol and his team worked with a virus in which a crucial gene from VSV is deleted, then replaced with a gene from one of five other viruses that affect animals and humans. The five viruses are Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, Ebola virus and Lassa virus. The next step was to see whether those lab-created hybrid bugs would retain the ability to obliterate brain cancer cells, with less collateral damage to the brain overall.
(The scientists do not handle the deadly viruses in the lab but instead use genetic sequences from these known killers.)
In the first part of the experiment, researchers transplanted human brain tumor cells into the brains of laboratory mice and rats. A control group of the rodents, which were not injected with any of the hybrid viruses, died about a month later from complications caused by their brain tumors. Of the mice injected with a hybrid virus, those treated with the hybrid Ebola-VSV and Lassa-VSV viruses fared the best.
Dr. Van den Pol’s team found that the Ebola-VSV hybrid virus infected the animals’ brain tumors and killed cancer cells and left healthy brain cells largely unharmed. In the end, mice and rats treated with Ebola-VSV lived a week or two longer than the control rodents, which received no treatment. “The virus selectively infects the tumor, but the virus doesn’t get the job done,” Dr. van den Pol says. “It increases lifespan, but it doesn’t cure the disease.”
More promising was the Lassa-VSV hybrid. It not only infected the tumors and killed cancer cells, but it kept attacking until the tumor was destroyed. As with the Ebola hybrid, Lassa-VSV also did not appear to infect and damage healthy cells. The mice in this group survived the brain tumor and did not seem to suffer any side effects. “They survived for a long time, at least as long as we’ve watched them, which is close to 100 days," Dr. van den Pol says, adding that little trace of the tumor or virus could be detected at that point. “In addition to directly killing the glioblastoma cells, the virus may also enhance an immune response directed against the tumor,” he explained. The Yale Medicine team’s results were published in the Journal of Virology in July 2015.
The finding that Ebola-VSV and Lassa-VSV not only killed brain tumor cells, but also had little to no effect on healthy cells was crucial. “We don’t want to waste time working with something that could make a human sick, or make an animal sick in a test,” Dr. van den Pol says. “We want viruses that selectively infect the cancer cells and either do not at all, or very minimally, infect normal cells.” The modified Ebola-VSV and Lassa-VSV viruses appear to do just that, at least in the brains of mice that have cancerous tumors.
Hope for human trials
So far, Dr. van den Pol’s lab has only tested the hybrid viruses only in animals. To move to human trials, Yale scientists need approval from the U.S. Food and Drug Administration, which governs drug testing in human patients. The first step would be to have a “clinical grade” version of the virus, one that is pure enough for use in human subjects (Animal testing can be done with a less-pure “laboratory grade” version). By Dr. van den Pol’s estimate, creating a clinical-grade Lassa-VSV virus would cost about $750,000.. He is hopeful that if the money can be raised, human testing will not be far off.
In the meantime, he and his team continue to lead the way in using tumor-killing viruses to cure difficult-to-treat brain tumors. In this quest, they arehelped along by a multidisciplinary team of experts at Yale Medicine—from neurosurgeons who routinely treat brain tumors, to virologists who consult on the workings of viruses in general, to clinicians at the Cancer Center who are devoted to treating and curing different kinds of cancer.
If they get the green light for a clinical trial, the Yale scientists will begin by administering a very low dose of the virus to patients who have not had success with other treatments for their glioblastoma. “We don’t yet know, in the long run, if it will work as well in humans,” Dr. van den Pol says. Glioblastomas have a variety of genetic mutations—some of which may not be susceptible to the virus, he explains. “We hope the Lassa-VSV virus will attack a substantial number of glioblastomas.”
For now, he says, it’s a reason to be hopeful. “We need to try something different,” he says. “And this is one thing that’s different.”