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Cancer-Killing Viruses Employ Multiple Mechanisms

The search for safe, effective cancer therapies has led numerous academic and industrial research groups to investigate oncolytic, or cancer-killing viruses//. Oncolytic viruses which include the naturally occurring reovirus, infect cancer cells while sparing healthy tissues. Once inside the tumor cell, the viruses produce thousands of copies of themselves, causing tumor cells to burst. After tumor cells die, viruses clear rapidly from the body without harming the patient.

More recently however, it has been discovered that the reovirus may also have the potential to prime the body’s own immune system to mount a defense against cancer cells. Oncolytics Biotech Inc., a company developing an oncolytic virus treatment based on the reovirus, believes that in addition to directly killing cancer cells, oncolytic viruses may induce a powerful, long-lasting immune response that continues to shrink tumors for weeks or months after the virus is gone. This complementary tumor-killing mechanism is based on the virus acting on specific immune system cells.

The immune system is composed of three “layers” or mechanisms that protect humans from disease. The first line of defense, the skin and mucous membranes, acts as a physical barrier. The second layer is the innate immune system, a broad-acting, short-term, non-specific immune response to pathogens such as bacteria or viruses. Microbes that evade the innate system encounter a third layer of protection; a second, more powerful immune mechanism called the adaptive immune response. Through adaptive immunity, populations of white blood cells known as lymphocytes – B cells and T cells – mount a powerful, highly specific immune system attack on specific pathogens. The adaptive immune responses to virus and bacterial infections, for example, are quite different.

The immune system also protects humans from cancer. In the case of the reovirus, researchers believe the key is the interaction between innat e and adaptive immune responses, specifically communication between dendritic and natural killer cells (part of innate immunity) and certain types of T cells (from the adaptive immune system).

“We’ve understood the mechanism of action of reovirus replication in cancer for a number of years,” explains Dr. Matt Coffey, Chief Scientific Officer at Oncolytics, “but we also observed that often tumors continued to shrink after the virus was gone.” 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.”

Reovirus is an oncolytic virus that specifically targets tumor cells containing an active form of ras, a genetic mutation found in many types of cancer but not in normal cells. Because of the reovirus genetic makeup, it also appears to activate an immune response that spells double trouble for cancer cells.

Researchers hypothesized that reovirus activation of dendritic cells, which are key to early detection of infection (through the innate immune response), may “instruct” cells belonging to the adaptive immune response, namely natural killer cells and T cells, to attack the tumor even after the virus no longer remains in the body.

Experiments at respected institutions such as St. James University Hospital in Leeds and the Mayo Clinic in Rochester suggest that incubation of reovirus with human dendritic cells led to well-known signs of immune system activation. One of these is the release of cancer-fighting chemicals known as cytokines. Moreover, reovirus did not induce either productive infection (which generates many thousands of copies of the virus) or death in dendritic cells. In other words, although the dendritic cells were technically infected with reovirus, they did not suffer the same fate as cancer cells. In fact, infection actually stimulated the cells to a higher level of cancer-fighting immune activation, as well as priming the cancer-killing ability of natural killer cells and T cells.

These experiments indicate that in addition to killing cancer cells by invading them, the reovirus may support early, innate anti-tumor immunity as well as longer-lasting adaptive immunity against cancer. Discovery of the “immune connection” has lead to a more complete picture of how oncolytic viruses kill cancer cells. If scientists can enhance the anti-tumor immune response, they may be able to make reovirus therapy more effective.

“These results are exciting as they suggest that in addition to directly killing cancer cells in the short term, the reovirus imparts an important cancer-killing ability to the body’s own immune system,” said Dr. Coffey.



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