Poliovirus can attach to a receptor found on the surface of almost all solid tumor cancer cells
Researchers engineered a safe version of the poliovirus to inject into tumors
There’s a surprising upside to the virus that causes polio disease, new research indicates.
An engineered version of poliovirus improved the overall survival rate of patients with a lethal form of brain cancer, according to results from a phase one clinical trial. Among 61 patients with recurrent glioblastoma who received the experimental therapy, 21% will survive for three years or longer, compared with just 4% of patients treated with multiple sessions of chemotherapy, the current standard therapy.
“This is only the first step, and it’s opening the door to multiple new trials,” said Dr. Matthias Gromeier, a co-author of the study and a professor of neurosurgery at the Duke University School of Medicine.
In the next few weeks, the researchers will begin clinical trials on patients with melanoma skin cancer and breast cancer, explained Dr. Darell D. Bigner, a co-author of the study, a professor of pathology and emeritus director of The Preston Robert Tisch Brain Tumor Center at Duke University. “We are encouraged and eager to continue with the additional studies that are already underway or planned.”
The research represents an 18-year collaboration with the National Cancer Institute and the US Food and Drug Administration. The safety trial results were simultaneously presented Tuesday at the 22nd International Conference on Brain Tumor Research and Therapy in Norway and published in the New England Journal of Medicine.
Virtues of a virus
Poliovirus can attach to a receptor on the surface of glioblastoma cancer cells, as well as the surface of cells that make up most solid tumors.
“Our strategy did not start out with the intent to use poliovirus in cancer immunotherapy. Rather, Dr. Gromeier made a series of research observations over many years,” said Dr. Annick Desjardins, a co-author of the study and an associate professor of neurology and neurosurgery at Duke.
Gromeier discovered that a receptor for poliovirus was “virtually universally expressed on cancerous cells of most tumors,” Desjardins said. Burkitt’s lymphoma is the only solid tumor that lacks this poliovirus receptor, a key to the door allowing the virus to enter and kill cancer cells.
To create a cancer immunotherapy based on Gromeier’s discovery, the researchers swapped out the genetic sequence that allows poliovirus to reproduce in normal cells and replaced it with DNA code taken from rhinovirus, the cause of the common cold.
This was a “safety measure,” Desjardins explained, so the new engineered virus could not damage neurons and cause polio. However, the genetic modification does not prevent the hybrid virus from replicating inside cancer cells, a process that releases toxins which destroy cancer cells.
After conducting animal experiments with the engineered poliovirus, the researchers enrolled and treated human patients diagnosed with glioblastoma beginning in 2012.
Treatment starts with an implanted catheter in a patient’s brain, Desjardins said. Next, the engineered poliovirus is infused directly into the tumor through the catheter. Once the total 6½ hours of infusion are completed, the catheter is removed.
At higher dosages of the experimental therapy, some of the patients experienced severe inflammation, which resulted in seizures, cognitive difficulties (including confusion and language difficulties) and other side effects such as nausea. The research team restricted itself to lower-than-hoped doses, yet they still witnessed noteworthy effects.
Overall average survival time for the 61 patients who received the experimental therapy was 12.5 months, compared with 11.3 months for a control group of matched patients who received standard treatment (chemotherapy).
Some of the poliovirus therapy patients have shown – and continue to show – remarkable resilience: One who began treatment at age 20 and another who began at age 60 have remained alive for more than 69 months – nearly six years – and are still alive today, according to the authors of the study.
“The two longest surviving patients have actually recurred and been retreated,” Bigner said. “With chemotherapy, once patients fail, they are resistant, and they don’t respond.”
Getting a positive response to a therapy after cancer reappears is “extremely unusual,” he said, adding that in these patients, cancer may be “converted” into a chronic disease. “Whenever they recur, we’ll just treat them again,” Bigner said.
Overall, 21% of the poliovirus patients should remain alive three years after treatment, compared with just 4% of the control patients, statistical analysis suggests.
“We are presently enrolling in a phase two trial combining the genetically modified poliovirus with one dose of chemotherapy,” Desjardins said. “We are also enrolling on a trial for pediatric brain tumor patients.” Because it is easier to infuse a therapy into tumors anywhere other than the brain, the researchers expect better results when they use this treatment on other forms of cancer, she said.
“Patients receiving the poliovirus therapy have had surprising and promising clinical outcomes,” said Dr. Bryan Choi, a fellow in the Cellular Immunotherapy Program at Massachusetts General Hospital Cancer Center and the Department of Neurosurgery at Harvard Medical School. “It will be critical to support the study of this treatment and other immune-based approaches for glioblastoma in larger, randomized clinical trials.”
Choi, who was not involved in the new study but who has published research on the topic, said that “the poliovirus, which otherwise causes a horrible disease that we’ve sought to eradicate for over half a century, has now been re-engineered to instead target and attack another deadly disease, in this case glioblastoma, which is the worst form of brain cancer.”
“Perhaps the most promising aspect is the ability for this modified virus to not only directly kill brain cancer cells but to release tumor antigens,” Choi said. Antigens are toxins that unleash the body’s immune reponse. “The immune system then recognizes these antigens and can mount a potent secondary assault on the remaining tumor,” he said.
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“It’s truly astounding that a scourge of the last century has reemerged through scientific innovation to offer so many people hope,” Choi said.
More succinctly, Bigner said: “I have never seen anything like that in my 50 years of cancer research.”