Grant: CIHR Fellowship

Engineered oncolytic viruses (OVs) are a novel class of anti-cancer bio-therapeutics shown to preferentially replicate in the tumor microenvironment, lyse cancer cells and release neoantigens. Vaccinia virus-derived OVs have advanced to Phase III clinical trials; however, patients have presented with off-target replication of the virus in normal tissues, including the development of pox lesions on their skin. As tumor selectivity is critical to OV success, I hypothesize that the rational deletion of Vaccinia genes will restrict viral replication to cancer cells. Because cancer cells are thought to be more deficient in their antiviral response compared to normal cells, I will probe the function of different Vaccinia proteins during the infection of cancer, normal and immune cells. By looking at protein-protein interactions I will be able to determine which Vaccinia genes target the antiviral pathway and whether this happens in cancer cells, healthy cells or both. Meanwhile, I will evaluate whether the deletion of these viral genes increases immune activation. Vaccinia deleted genes that show a phenotype of immune activation will have their interacting host-factors knocked out using CRISPR/Cas9 in primary immune cells. This will reveal novel Vaccinia-Host interactions which are immune suppressing, enriching our understanding of Vaccinia biology and immunology. Finally, I will create novel candidates for cancer virotherapy by deleting multiple Vaccinia genes which have a minimal function in cancer cells compared to healthy cells and are immune suppressing. I will evaluate these candidate OVs for cancer selectivity, ability to kill cancer cells and immune activation.