Reovirus - possible therapy of cancer

Abstract

Oncolytic viruses infect, replicate in, and eventually lyse tumor cells but spare normal ones. In addition to direct lysis, a result of viral replicative cycle, viruses also mediate tumor cell destruction by inducing nonspecific and specific antitumor immunity. Some viruses express proteins that are cytotoxic to tumor cells. Viruses recognized as oncolytic agents can therefore be divided into three categories: 1/ naturally occurring viruses (e.g. Newcastle disease virus, vesicular stomatitis virus, autonomous parvoviruses, some measles virus strains, reovirus) that selectively replicate in tumor cells, in some instances owing to their relative resistance to interferon action; 2/ virus mutants in which some genes essential for replication in normal cells but evitable in cancer cells have been deleted (e.g.adenovirus ONYX 015 that replicates only in cells with defected p53 or herpes virus G207 which exacts the presence of ribonucleotide reductase); 3/ virus mutants modified by the introduction of tissue-specific transcriptional elements that drive viral genes (e.g.adenovirus CV706 that has PSA restricted expression of E1A and E1B and adenovirus adMycTK that binds selectively on myc protein). Reovirus is prevalent in the human population but not associated with any known human disease. Studies have shown that reovirus multiplicate preferentially in tumor cells with activated gene of ras family or ras-signaling pathway while sparing normal cells. Activated ras or its pathway could be found in as many as 60-80% of human malignancies. In our studies we used cell lines that demonstrably express activated ras. We showed the cytopathic effect of reovirus (serotype 3 strain Dearing) on medulloblastoma cell lines and compared it with its acting on normal human fibroblasts. Oncolytics Biotech Inc. is currently guiding three Phase I or Phase I/II Reolysin studies, and has completed two clinical studies and concluded enrolment in a third one.