Oncolytic Viruses: Novel Cancer Therapeutics Current cancer therapies for metastatic disease have limited efficacy and high toxicity and thus novel approaches to treatment are sought. Viruses have many characteristics which make them desirable as a therapeutic strategy for the treatment of cancer including their ability to infect cells and replicate, induce cell death, release viral particles and spread through human tissues. We have shown that a variety of viruses selectively replicate in and kill human cancer cell lines, primary patient samples and purge contaminated bone marrow of leukemic cells. Although the mechanisms of preferential oncolytic activity are incompletely understood, our hypothesis is that during tumor evolution, genetic abnormalities accumulate that, while providing malignancies a growth/survival advantage, also compromise the antiviral program of tumour cells. One cytokine pathway that seems to be frequently defective in tumour cell lines is the interferon signaling cascade. In particular, mutants of Rhabdovirus and Orthopoxviruses which strongly induce interferon expression are safe anti-cancer therapeutics in a variety of animal tumour models. We are optimizing and selecting for virus strains with improved efficacy. We are carrying out a detailed analysis of the behavior of tumour microenvironment cells during oncolytic virus therapy. In particular we have shown in both mouse models and samples taken from patients undergoing OV therapy that our viruses can infect and disrupt tumour vasculature. The affect of OV therapy on all aspects of tumour microenvironment (e.g. support cells, immune infiltrates) is under investigation