CALGARY, Alberta—Immunotherapies have gone past being a buzzword to taking the spotlight as rising stars in the pharmaceutical industry as companies work to harness the immune system in hopes of more effective treatments and long-lasting responses, and one of the leading targets of interest in this field is PD-1. By expressing PD-1 and its ligand, PD-L1, tumors are able to cloak themselves to avoid detection by the immune system.
Oncolytics Biotech, which is seeking to combine immunotherapy with standard cancer-fighting agents, is one of the many companies exploring this approach, and is doing so by boosting the therapeutic activity of anti-PD-1 inhibitors.
Oncolytics’ cornerstone in this is its lead compound Reolysin, a proprietary formulation of the human reovirus, based on research conducted by its chief operating officer, Dr. Matt Coffey. Reovirus, or respiratory enteric orphan virus, is a non-pathogenic virus widely found in the environment. In addition to alerting the immune system to the presence of cancer cells, it is also capable of selectively infecting and destroying cancer cells. While normal cells activate an antiviral response upon infection with reovirus, certain mutations in cancer cells render them unable to launch an antiviral response.
As explained on Oncolytics’ website, “Activating mutations of Ras and mutations along the Ras pathway occur in approximately two-thirds of all tumors. Tumors bearing an activated Ras pathway are deficient in their ability to activate an anti-viral response mediated by the host cellular protein, PKR. Since PKR is responsible for preventing reovirus replication, tumor cells that lack the activity of PKR are susceptible to reovirus infection and eventual cell death. As normal cells do not possess Ras activation, these cells are able to thwart reovirus infection by the activity of PKR. In a tumor cell with an activated Ras pathway, the reovirus is able to freely replicate and kill the host tumor cell. Progeny virus particles are then able to infect and kill surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until there are no longer any tumor cells carrying an activated Ras pathway available.”
Oncolytics is currently combining Reolysin with a variety of cancer-fighting agents, including PD-1 inhibitors. PD-1 inhibitors remove PD-1’s ability to hide from the immune system, and, paradoxically, says Dr. Brad Thompson, president and CEO of Oncolytics, “the more PD-1 and PD-L1 that’s around, the better those drugs work; so the better that the tumor is at hiding itself, it actually makes those drugs work better.” Reolysin increases the amount of PD-1 and PD-L1 that are produced, he explains, allowing such drugs to work better.
In clinical studies, Reolysin was found to induce up-regulation of PD-1 and PD-L1 in patients with primary glioblastomas or brain metastases. A single-arm clinical study combining Reolysin with gemcitabine in patients with advanced pancreatic cancer showed that patients receiving the combination therapy saw a median overall survival of 10.2 months, and one- and two-year survival rates of 45 and 24 percent, respectively. Additionally, in a poster presentation at the 2015 AACR Annual Meeting, Oncolytics showed that in immune-competent mouse models of B16 melanoma, combining reovirus with PD-1 blockade offers significant survival benefit by boosting tumor-specific natural killer responses and attenuating tumor-specific immunosuppression. The combination also offered enhanced survival times compared to intratumoral reovirus by itself, with 40 percent of mice being cured long-term.
Oncolytics has received an Orphan Drug Designation for Reolysin for the treatment of gastric cancers from the U.S. Food and Drug Administration, and Orphan Drug Designation from the European Medicines Agency for the treatment of pancreatic cancer.
Moving forward, Oncolytics intends to continue pursuing the combination of Reolysin with gemcitabine in pancreatic cancer. Thompson says the company will also investigate Reolysin in combination with GM-CSF, a drug that boosts the immune system by increasing the white blood cell count after chemotherapy, in pediatric brain cancer patients. The same combination will also be explored in a pair of cancer studies in the United Kingdom. Oncolytics will look into Reolysin’s potential when combined with checkpoint inhibitors later this year in melanoma and pancreatic cancer.
“I would expect that based on the trends that we’re seeing, immunotherapies could easily be anywhere between a third and 50 percent of the pharmaceutical sales in oncology within 10 years. It’s the biggest change in oncology that I’ve seen in my lifetime,” says Thompson of the potential in this field. “I mean, it’s critical. It’s really the first big leap forward, a real quantum improvement in cancer care that we’ve seen just in employing the immune system, and there’s of course a half-a-dozen different ways you can do that. I think there’s probably a dozen companies, along with us, that are incorporating the immune approach in with their existing approach of using those drugs for treating cancer, so it’s not only important to Oncolytics, but important to most of the companies that are in the industry.”