Now researchers at Yale University have found that a virus that's in the same family as rabies effectively kills an aggressive form of human brain cancer in mice. Using time-lapse laser imaging, the team watched vesicular stomatitis virus (VSV) rapidly home in on brain tumors, selectively killing cancerous cells in its path, while leaving healthy tissue intact. What's more, Anthony Van den Pol, lead researcher and professor of neurosurgery and neurobiology at Yale, says that VSV is able to self-replicate and produce secondary lines of defense.
"A metastasizing tumor is fairly mobile, and a surgeon's knife can't get out all of the cells," says Van den Pol. "A virus might be able to do that, because as a virus kills a tumor cell, it could also replicate, and you could end up with a therapy that's self-amplifying."
In the past few years, scientists have looked to viruses as potential allies in fighting cancer. Researchers at the Mayo Clinic are engineering the measles virus to combat multiple myeloma, a cancer of the bone marrow. And while various groups have seen limited results after injecting herpes and polio-related viruses directly into brain tumors in mice, Van den Pol wanted to find a more effective cancer-killing strain.
His search for a virus candidate began six years ago, when he and his colleagues tested the effect of different viruses on brain tumors in culture. Repeatedly, VSV came out "at the top of the heap." The team grew the virus through many generations, isolating strains that infected cancer cells quickly while having a slow effect on healthy cells. The researchers recently ran the most effective strain through a number of tests in live mice, and they've published their results in a recent issue of the Journal of Neuroscience.
In its experiment, the team transplanted glioblastoma--the most common and aggressive form of human brain cancer--into the brains of mice. Prior to transplantation, researchers genetically engineered the tumor cells to express a red marker, which, once inside the brain, would show up in laser microscopy scans. Similarly, Van den Pol inserted a green marker in VSV cells and injected the virus intravenously through the tail. Within a few days, researchers observed that the green virus found its way to the brain and selectively infiltrated red tumor masses and individual tumor cells, while avoiding normal cells. Van den Pol says that as the virus infects tumors, cancerous cells start to turn green, swelling up until they eventually burst.
"It's like a balloon," says Van den Pol. "If you keep blowing air into it, it explodes. The carcass is still there, but it's no longer a balloon. And these are basically dead cells, unable to divide anymore or survive as intact cells."
It's not yet clear why VSV is such an effective tumor killer, although Van den Pol has several theories. One possible explanation may involve a tumor's weak vascular system. Vessels that supply blood to tumors tend to be leaky, allowing a virus traveling through the bloodstream to cross an otherwise impermeable barrier into the brain, directly into a tumor.
Van den Pol says that VSV may also target cancer cells because of inherent defects in a tumor's immune system. Typically, in the presence of a virus, normal cells launch an immune response by producing interferon, proteins that prevent viral infection in healthy cells. Tumors lack such strong viral defenses, providing an easy target for viruses.
There are several considerations that the team will have to face before moving to clinical trials. In its tests, the team observed live scans of the virus over a few days before sacrificing the animals for closer study. It remains to be seen how the virus will act on the brain over a longer timescale.
Additionally, the researchers used immuno-compromised mice. While these mice are still able to produce interferon as a local cellular defense, they have a weakened systemic immune system--one that's unable to produce B and T cells that would otherwise destroy viruses. Van den Pol explains that such a weakened system allowed the team to insert transplanted human tumors in mice without their being rejected. However, in order to test the virus as an effective therapy, the team will have to make sure that a normal immune system doesn't stamp out the virus before it has a chance to act on tumors.
"What usually happens with most of these tests is, you have a nice animal model where the virus spreads through the tumor," says Samuel Rabkin, associate virologist in the department of neurosurgery at Massachusetts General Hospital. "In more-realistic models, the host may have a response to the virus that limits the effect."