by Douglas W. Loe, PhD, MBA
Chemotherapy has always and continues to be our first line of defense, but is not for the faint of heart. Some form of chemotherapy is still routinely prescribed for most types of the disease. The treatment works by targeting fast-growing cells, like those typically found in rapidly growing tumors. But while chemotherapy can shrink tumors, they often grow back and become resistant, or refractory to the treatment.
To combat this resistance, chemotherapy is now often used in combination with other treatments that have different mechanisms for attacking and killing cancer cells. Doctors must be cautious when combining treatments to ensure that the regimen does not become too toxic for patients to tolerate. The goal is to introduce drugs that can be used synergistically with chemotherapy to not only extend life, but to improve quality of life while undergoing treatment.
One approach that has proven quite promising is known as oncolytic virotherapeutics. Here, viruses are harnessed to infect, multiply within and subsequently lyse cancer cells; the virus targets tumors without affecting normal tissue.
Several types of oncolytic viruses have been developed to date. These include the adenovirus, the Newcastle-disease virus, and poxviruses (vaccinia virus), the most advanced of which is probably Jennerex’s JX-594 that performed well in Phase II liver cancer testing and is partnered with French biotechnology firm Transgene. The herpes simplex virus is also under consideration as an oncolytic virus; many engineered versions are in clinical trials for the treatment of patients with cancer, the most advanced of which is OncoVEX, developed by BioVex (now part of Amgen) and currently undergoing Phase III testing in melanoma and head & neck cancer. Picornaviruses and vesicular stomatitis virus are two other varieties in earlier-stage trials.
Finally, we come to what some consider the most promising form of oncolytic virus: the reovirus. This virus preferentially replicates in cancer cells that feature a common mutation known as an “activated Ras pathway,” while sparing normal cells. This makes it intrinsically tumor selective without the need for any genetic manipulation.
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 12 having been exposed and up to 100% testing positive by adulthood. Tumors bearing an activated Ras pathway cannot activate the anti-viral response mediated by the host cellular protein, 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. When normal cells are infected with reovirus, the immune system can neutralize the virus. 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.
While it has been demonstrated in animal studies that reovirus is capable of treating metastatic cancer in immunocompetent mice, it has also been shown that reovirus used in conjunction with immunosuppressive 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.
Calgary-based Oncolytics Biotech Inc. has developed a biologic agent, Reolysin, from naturally occurring reovirus. The virus has demonstrated impressive results in clinical trials on its own, but particularly in combination with certain chemotherapeutics. In preclinical studies in a wide variety of cancer cell lines, investigators found that when used together, reovirus and chemotherapy resulted in more efficient and synergistic anti-cancer activity than when each agent was used on its own.
These combinations are showing extremely good results in human trials, particularly in refractory head and neck cancer patients. Many head and 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.
It is difficult to provide a crystal-clear economic forecast for oncolytic viruses. However, demand for new and effective agents in oncology remains strong, giving us confidence that Reolysin could be similarly embraced if it performs well in Phase III testing. Global oncology-focused pharmaceutical firms may be keen to partner with Oncolytics once Reolysin Phase III head and neck cancer data are available, if not before, and capital markets are exhibiting optimism in Reolysin’s medical prospects.
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.
# # # #About the author:
Douglas W. Loe, Ph.D, MBA, is a consistently topped ranked healthcare and biotechnology analyst. Doug holds a MBA from Queen’s University and a Ph.D in biochemistry from the University of Guelph, working in the area of cancer chemotherapy and multidrug resistance, followed by post-doctoral training at the Queen’s University Cancer Research Institute. During his scientific career, he published multiple abstracts, peer-reviewed manuscripts and reviews related to P-glycoprotein and MRP-mediated multidrug resistance. He has covered Canadian biotech since 2000, initially as part of the research team at Yorkton Securities (now Macquarie Capital Markets), and has been with Versant since Fall 2002 where he covers a broad spectrum of drug development, medical technology, and healthcare services firms. He can be reached at [email protected]. Versant Partners is a member of the Canadian Investor Protection Fund (CIPF).
RSS