Opinion: Can viruses kill cancer?

Chemotherapy is not for the faint of heart, but it can kill many forms of cancer. But while chemotherapy can shrink tumors, they often grow back and become resistant, or refractory to the treatment.

A graphic is of reoviruses proliferating from cancer cells
Image: Oncolytics Biotech

To combat this resistance, doctors often cautiously combine chemotherapy with other treatments that have different mechanisms for attacking and killing cancer cells.One approach that has proven quite promising in clinical studies is known as oncolytic virotherapeutics. Here, viruses are harnessed to infect, multiply within, and subsequently lyse cancer cells -- all without affecting normal tissue. Several types of oncolytic viruses have been developed to date. The most clinically advanced poxvirus is probably JX-594 -- during a Phase II trial, 5 of 7 evaluable patients exhibited stable disease after taking JX-594 combined with the multikinase inhibitor Nexavar. A separate Phase III trial of the herpes virus OncoVEX GM-CSF found that 14 of 17 patients with head & neck cancer developed stable disease, and the same proportion of patients were alive and disease-free after more than two years of follow-up. Finally, we come to what some consider the most promising form of oncolytic virus: the reovirus. Reovirus is a virus with no known associated disease. It replicates in the cytoplasm and therefore does not integrate into the cell's DNA. Reovirus is found everywhere in nature and has been isolated from untreated sewage, river, and stagnant waters. Exposure to reovirus is common in humans, with half of all children by the age of twelve having been exposed and nearly 100 percent testing positive by adulthood. This virus preferentially replicates in cancer cells with an activated Ras pathway, while sparing normal cells. This makes it intrinsically tumor selective without the need for any genetic manipulation. Reovirus's selective targeting of transformed cancerous cells was described as far back as 1977 by University of Hawaii researchers but was specifically linked to activation of the oncogene Ras in a seminal 1998 Science paper published by University of Calgary researcher Patrick Lee, who found that activated Ras shuts down cellular pathways that would normally mount a response to viral challenge. Tumors bearing an activated Ras pathway cannot activate the anti-viral response mediated by the host cellular protein, double-stranded RNA protein kinase (PKR). Studies have shown that reovirus actively replicates in transformed cell lines with an active Ras signaling pathway, eventually killing the host cell and freeing the viral progeny that go on to infect and kill more Ras-activated tumor cells. But when normal cells are infected with reovirus, the immune system can neutralize the virus. This mechanism will target many -- if not most -- cancer cells. Approximately one-third of human cancers have activating mutations in the Ras gene itself, and it is possible that more than two-thirds of cancer cells have an activated Ras signaling pathway because of activating mutations in genes upstream or downstream of Ras. It has been demonstrated in animal studies that reovirus is capable of treating metastatic cancer in immunocompetent mice, and that reovirus used in conjunction with immunosuppressive or other cytotoxic drugs can effectively prolong animal survival. This supported the development of clinical protocols in which immune-suppressive drugs could be combined with a systemically administered reovirus in the treatment of cancer. The combination of reovirus with various chemotherapies in human colorectal cancer cell lines demonstrated synergistic cytotoxic activity. In addition to modulating the immune response, the use of chemotherapies along with reovirus treatment may enhance intratumoral spread of the virus, probably by mitigating any immune response to reovirus infection that the host or the tumor itself could mount. In fact, data from multiple preclinical and Phase I studies show that reovirus works particularly well in combination with microtubule-targeted taxanes like paclitaxel and DNA-targeted platinum drugs like carboplatin, and these agents are used in combination with a reovirus-based biologic agent in a pivotal Phase III head & neck cancer trial currently enrolling patients. Calgary-based Oncolytics Biotech has developed this biologic agent, Reolysin, from naturally occurring reovirus, and it is showing extremely good results in human trials. Many head & neck cancer patients treated with a combination of Reolysin and chemotherapy to date have experienced dramatic and prolonged tumor shrinkage, without increasing adverse side effects. Specifically, in a 31-patient open-label Phase I/II advanced cancer trial that included mostly head & neck cancer patients, 14 of the 19 evaluable patients exhibited either partial response (8) or stable disease (6) when treated with Reolysin-carboplatin-paclitaxel combination therapy, encouraging results when considering that most subjects were already refractory to alternative therapies. It is difficult to provide a crystal-clear economic forecast for oncolytic viruses. But it is telling that equity markets are exhibiting optimism in Reolysin's medical prospects by the magnitude of capital raised by the firm in recent years (over US$40 million since November 2009). As we have seen, there are a number of oncolytic viruses that have shown potential use in cancer treatment and demand for more effective agents is strong. Future research studies will give us an even clearer perspective on which, if any, of these viruses offer the most effective route toward a reliable and commercially viable complement to chemotherapy for oncologists and their patients.

Douglas W. Loe
Image: Versant Partners

linkurl:Douglas W. Loe,;http://www.versantpartners.com/en/bios/dloe.html PhD, MBA, is a healthcare and biotechnology analyst at Versant Partners, a member of the Canadian Investor Protection Fund (CIPF). Loe holds a PhD in biochemistry from the University of Guelph, working in the area of cancer chemotherapy and multidrug resistance, followed by postdoctoral training at the Queen's University Cancer Research Institute, in which he focused on P-glycoprotein and MRP-mediated multidrug resistance. He can be reached at linkurl:DLoe@versantpartners.com.;mailto:dloe@versantpartners.com Neither the author nor Versant Partners own shares in, or are financially compensated by, Oncolytics Biotech.
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[7th September 2009]