New research shows that the oncolytic reovirus, which kills cancer cells by replication within the cell, may also have the potential to prime the immune system to mount a defense against cancer cells
PARIS, FranceNew research shows that the oncolytic reovirus, which kills cancer cells by replication within the cell, may also have the potential to prime the immune system to mount a defense against cancer cells (see image on page 1). "Reovirus holds promise as a cytotoxic agent and in immunotherapy approaches against cancer," Alan Melcher, MD, of the Cancer Research UK Clinical Centre, Leeds, and his colleagues said in a poster presentation at the 1st Joint Meeting of European National Societies of Immunology (PD-3890). "Reovirus immune activation may support priming of innate (and adaptive) antitumor immunity."
How Reovirus Works
Reovirus (respiratory enteric orphan virus) is found naturally in sewage and water supplies, and by adulthood, most people have been exposed. However, the disease is nonpathogenic.
The reovirus specifically targets tumor cells containing an active form of Ras, a genetic mutation found in more than two-thirds of all human cancers but not in normal cells. Tumors bearing an activated Ras pathway are deficient in their ability to activate the antiviral response mediated by the host cellular protein PKR, making them susceptible to reovirus replication. Normal cells lack Ras and are able to stop reovirus infection through normal PKR activity, but in tumor cells with an activated Ras pathway, reovirus is able to replicate freely and eventually kill the host tumor cells.
As cell death occurs, progeny virus particles are then free to infect surrounding cancer cells, a cycle of infection, replication, and cell death that is repeated until there are no longer any tumor cells carrying an activated Ras pathway.
Immune System Activation
In Dr. Melcher's experiments, incubation of reovirus with human dendritic cells led to signs of immune system activation, including the release of cytokines and enhancement of natural killer (NK) and T cell activity. Moreover, reovirus did not induce either productive infection or death in dendritic cells. The study showed that dendritic cell activation by reovirus is dependent on PKR, p38, NFκB, and MEK signaling.
Oncolytics Biotech Inc. (Calgary, Alberta, Canada) is currently conducting phase I and II trials of Reolysin, its oncolytic virus therapy based on wildtype reovirus. In these early-phase trials in patients with advanced cancers, Reolysin has been well tolerated and has shown antitumor activity, the company said.
In a phase II trial in the United Kingdom, Reolysin will be administered intratumorally in combination with low-dose radiation in patients with advanced cancers. In a phase I/II study at the University of Alabama at Birmingham, the agent is being tested as intravenous monotherapy in patients with recurrent malignant gliomas. Oncolytics also has signed a collaborative agreement with the NCI to conduct multiple clinical trial with Reolysin, possibly in patients with melanoma or ovarian cancer.
"We've understood the mechanism of action of reovirus replication in cancer for a number of years," said Dr. Matthew Coffey, chief scientific officer at Oncolytics, "but we also observed that often tumors continued to shrink after the virus was gone." He noted that Dr. Melcher's immunologic work now suggests that reovirus exposure is "educating" the immune system to recognize and kill the same cancer cells that are attacked by reovirus. "If you can teach the immune system to recognize cancer cells, it may be possible to fight off the disease for much longer than we originally anticipated," Dr. Coffey said.