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Reoviruses as cancer therapeutics
CALGARY, Alberta—April 3, 2007—Expanding its portfolio of reovirus-based therapeutic applications, Oncolytics Biotech announced it was granted U.S. Patent 7,198,783—"Sensitization of Neoplastic Cells to Radiation Therapy with Reovirus"—which described a way to sensitize Ras-activated radiation-resistant cancer cells. According to company CSO Dr. Matt Coffey, the patent supports Oncolytics' ongoing Phase II trial of radiation-reovirus cotherapy.
Dozens of development-stage cancer drugs target extremely narrow, well-defined cellular pathways thought to be unique or essential to cancer. Similarly, genomics and proteomics research labs have identified hundreds of genes that confer susceptibility to specific types of cancer treatment or resistance to the most serious side effects.
The challenge is to discover and promote molecules that work safely within these patient populations, while providing concrete survival benefit. So far, the model for targeted therapies is to use them along with traditional cytotoxic agents and/or radiation, to improve the likelihood of an objective response.
Oncolytic viruses bridge the gap between established and emerging treatment regimes. Oncolytic viruses are targeted agents whose replication within tumors causes cancer cells to die. The promise of oncolytic viral therapy is the development of agents that act broadly against a range of cancer types, while simultaneously sparing patients from the most serious side effects of traditional therapy.
Medical case studies over the past century have described numerous spontaneous cancer remissions in late-stage disease following contraction of a known, or in some cases unknown, viral infection. In these cases, viruses are believed to have acted as agents that somehow preferentially selected tumor cells for their growth and replication, and as a consequence killed their host cell, but their true mechanisms have been largely unknown until the last decade or so.
The groundbreaking product in this category was ONYX-015, a modified adenovirus that normally infects the upper respiratory tract. This agent selectively replicates within, and kills cancer cells that lack a functioning p53 tumor suppressor gene. More than half of all cancers express this maladaptive alteration. ONYX-015 carries a "loss-of-function" mutation, meaning that unlike wild-type adenoviruses, it lacks a protein that binds to and inactivates p53 in cancer cells. Wild-type adenoviruses disable this gene before viral replication can occur. Thus, the ONYX-015 adenovirus infects and kills only cancer cells expressing the p53 abnormality, and leaves normal cells unaffected.
ONYX-015 was ultimately not pursued for approval in North America but it is now licensed for sale in China. Nevertheless, other oncolytic viruses are in various stages of clinical and preclinical testing. Preliminary results point to the promise of this approach to treating cancer.
In 2000, Canadian investigators reported some success in preclinical testing of vesicular stomatitis virus injected directly into mouse tumors. More recently, researchers at the Memorial Sloan Kettering Cancer Center in New York have tested a modified form of the herpes virus against a variety of tumor cell lines. While the natural form of herpes virus cause cold sores and other human ailments, the mutant strain used by the Sloan Kettering scientists replicates only inside cancer cells. Thus far, the modified virus was shown to be active against 110 tumor cell types, as well as in several animal models for cancer of the breast, thyroid, liver, and other organs.
Oncolytics' reovirus product, REOLYSIN, is based on research conducted in the 1990s at the University of Calgary. The reovirus replicates only in tumor cells possessing an activated pathway for Ras oncogenes, which play a role in more than two thirds of human cancers.
REOLYSIN represents a departure from most previously studied oncolytic viruses. First, the reovirus is not associated with any human disease, a fact that greatly expands opportunities to test and use it in humans. Second, the virus is unmodified in any way, naturally infecting cancer cells in its natural form. The reovirus particles also enter normal cells but cannot replicate in them.
The eventual impact of oncolytic viruses on cancer treatment is a story that waits to be told, which is precisely the position in which monoclonal antibodies found themselves 15 years ago. Thanks to a number of pioneering companies and academic researchers, oncologists have bought into the concept of monoclonals, which have been validated numerous times commercially. Oncolytic viruses have not yet reached that point, but we expect they will following larger Phase II and III trials.
New agents – and oncolytic viruses are no exception – will most likely enter clinical practice as adjunctive agents to conventional chemotherapy, radiation, or one or more targeted therapies. Although much remains to be learned about REOLYSIN and other oncolytic virus therapies, our clinical experience with these agents suggests that they can be readily combined with standard cancer therapies to produce additive efficacy.