The idea that viruses may be co-opted to do good rather than harm isn’t entirely new; researchers have been attempting to harness the power of viruses and bacteria for more than a century. Vaccines are the shining example of using bad bugs to do good in priming the immune system to fight disease.
But disease-causing viruses aren’t always easy to corral, and attempts to use them to activate the immune system against things other than fellow bacteria and viruses — including cancer, for example — have not been so successful. There is only one approved virus-based treatment for cancer, which uses herpes virus against melanoma.
In a new report published in the New England Journal of Medicine, however, scientists led by a team at Duke University report they may have trained another virus to target cancer, by using poliovirus to target brain tumors.
Dr. Darell Bigner, emeritus director of the Preston Robert Tisch Brain Tumor Center at Duke University Cancer Center, and his team engineered a poliovirus that was designed to target a difficult-to-treat brain cancer known as glioblastoma. Among a group of 61 people who had failed to respond to current therapies, which include radiation and chemotherapy, 21% who received the poliovirus treatment were alive after three years, compared to 4% who generally survive that long following standard therapy.
The virus-based therapy is the culmination of 20 years of work by Bigner’s colleague Dr. Matthias Gromeier, professor of neurosurgery at Duke, who engineered a poliovirus that could activate the immune system but not cause polio. He accomplished that by swapping out one of the poliovirus’ genes for a similar one found in the rhinovirus that causes the common cold. Poliovirus has evolved to become quite adept at infecting certain human cells, by targeting a molecular door on these cells known as CD155. This door, or receptor, is found on cells in the intestines, and in motor nerves in the spinal cord, which explains why poliovirus infection causes paralysis. (Poliovirus that infects intestinal, cells, however, often doesn’t cause serious health problems or even many noticeable symptoms.) It is also found on many solid tumors as well, including glioblastoma.
When Gromeier’s modified poliovirus infected these brain cancer cells, it began to kill some of them. But more importantly, the virus also recruited other immune system cells to launch an attack on the cancer cells. The poliovirus made these additional immune cells “extremely angry,” says Gromeier, which is a good thing for fighting the cancer — but only to a certain extent. An over-activated immune response can cause serious inflammation, and the researchers had to lower the initial dose of the virus therapy, which they injected directly into the tumors in the brain, several times before they found the right balance for an immune attack on the cancer.
As aggressive as that initial immune assault can be, however, it can dissipate just as quickly, when the virus starts to die off. Poliovirus is designed to infect cells and reproduce for a few weeks, and once the microbes have done their work in infecting cells, their anti-cancer effect wanes as well. But Bigner and his team are optimistic that they can address that potential shortcoming by taking advantage of other recent advances in immune-based therapies for cancer. They plan on combining their poliovirus treatment with so-called checkpoint inhibitors, which release the immune system to attack tumor cells with more abandon. (Normally the immune system is trained not to attack cancer cells, since they are not foreign intruders like bacteria or viruses, but the body’s own cells that grow out of control.) “It’s a very obvious combination strategy for us that we will pursue,” says Gromeier.
So far, Bigner says that eight of the 61 patients are what he considers long-term responders, who have survived longer on the virus-based therapy than they would have if they had received radiation and chemotherapy. Some of their tumors began growing again, but they were treated with another dose of the poliovirus therapy, and were able to stop the cancer from growing. Some were also treated with chemotherapy when the tumors began to grow again, and “many of them responded dramatically; their tumors fell apart,” says Bigner. His group is now conducting another trial to compare people who are treated with the poliovirus therapy alone, or with the poliovirus and a single dose of chemotherapy.
The people in the current study had all been treated with standard therapies and saw their cancer return, but Bigner hopes that the results lead to moving the virus-based immune therapy earlier in the disease, when people’s immune systems are stronger and better able to launch an effective attack against cancer. He is also encouraged that the strategy will work against other cancers as well, and plans to start studies with people diagnosed with melanoma and difficult-to-treat triple negative breast cancer. Animal studies hint that the virus could be used against pancreatic, prostate and stomach cancers, too.
“I’ve been doing this for 50 years and have never seen responses in a study like this,” says Bigner. “The results, in terms of long-term survival, are better than anything in the literature. And I think we can build on this.”