It took at least 10 years for the poliovirus PVSPIRO, first created by Dr. Matthias Gromeier, of Duke, to be ready for a clinical trial.
The idea: Use the poliovirus to help treat recurrent glioblastoma, a deadly cancer with very few effective treatments and a short survival length. People diagnosed with the grade IV malignant glioma, on average, have a survival of less than 20 months. It’s less than a year if the cancer is recurrent, meaning it returns after surgery, chemotherapy and radiation, according to a new study published in The New England Journal of Medicine.
“This is a very, very serious condition where we really have no effective treatment at this point, so we’re very excited that we had extraordinary survival in a portion of patients with our therapy,” Gromeier said.
Researchers at Duke University gave 61 patients the poliovirus. At the end of the trial, the survival rate at two and three years was 21 percent, with some patients living more than 57 months after given the experimental treatment.
But it wasn’t just survival that the researchers saw, Gromeier said — they also saw that patients had a good quality of life throughout the additional time they received.
“A successful trial means that our patients will live longer and have high quality as sustained long-term survival,” he said.
Gromeier said that he first found the poliovirus used to treat the recurrent glioblastoma in 1994. The cancer cells being targeted have a receptor on them called the CD155 receptor. The poliovirus that was used targets this receptor.
It doesn’t just kill the cancer cells, he said. It also increases the immune response so that the body can fight the cancer itself.
But to get to the point where the 61 patients could be given the poliovirus, the researchers needed a place that could create the virus. They turned to the National Cancer Institute, which in turn, contracted the manufacturing of the virus to the Frederick National Laboratory for Cancer Research.
The process started in 2002, said Trevor Broadt, director of quality control of the Biopharmaceutical Development Program at the Frederick National Laboratory.
The poliovirus that Gromeier created was a construct. It isn’t found in nature. So there were many safety concerns and a lot of questions that had to be addressed before it could be used in the trial, Broadt said.
“This was a challenge for us because it represented essentially a new class of potential therapeutic products,” Broadt said. “Obviously, people have been getting vaccine-based poliovirus for quite some time. This was a completely different construct even though it was based on the vaccine strain.”
The first patient material, or the virus that could be given to people in the trial, was created in 2009.
One of the other reasons for the length of time was the amount that needed to be manufactured and the purity at which it needed to be, said Anthony Welch, a project officer at the National Cancer Institute’s division of cancer treatment and diagnosis.
They needed a million times more virus than what would actually be given, Welch said. And they also needed much more and a much higher purity than the poliovirus that was given in the vaccine against the paralyzing disease, Broadt said.
Because polio can be such a devastating disease, there were safety concerns. The Food and Drug Administration needed to ensure that the created virus wouldn’t infect those other than the intended targets, including those creating the virus and those who would be in contact with the patients, Broadt said.
According to the published study, there was no autoimmune reactions due to the poliovirus.
Replicating the poliovirus was also a challenge, Broadt said, due to the process by which it was created.
“It’s a somewhat unique process,” he said.
After they figured out manufacturing challenges, the testing issues came. The FDA required that the virus be tested in non-human primates as well as mice. Those studies were done by an outside company.
Once it was approved and could be given to a patient, the virus was injected directly into the brain over a period of time.
Although the trial has been considered successful, the FNL is no longer making the poliovirus. That’s been transferred to a commercial company, which often happens after the FNL creates or replicates a drug or virus, Welch said.
It allows the FNL researchers to move on to the next challenge. Currently, they are focusing on personalized medicine, which is a new trend in medicine focusing on more customizable treatments based on the disease and a person’s genetic makeup.
For Gromeier and Duke, the use of the poliovirus is expanding, both outside of glioblastoma and outside of Duke. The trial will be done at other hospitals for replication, Gromeier said.
This therapy is being used with other cancers like melanoma, after all other treatments have failed. There’s a possibility it can also be used in triple negative breast cancer, he said.
The endpoint of a trial like this is overall survival. And Gromeier is already looking at ways to use the poliovirus to better treat the cancer, such as treating people earlier.
The current trial will also go on to phase 2 and phase 3 trials, if successful.
“Every clinical trial is just the trial before the next one,” Gromeier said.