Large genomic deletions of a novel oncolytic Vaccinia Virus increase anti-tumour immunogenicity
Adrian Pelin1,2, Fabrice LeBoeuf1,2, Brian A. Keller1,2, Marie-Claude Bourgeois-Daigneault1,2, Dominic Roy1,2, Jiahu Wang1,2 and John C. Bell1,2
1Faculty of Medicine, University of Ottawa, Ottawa, Canada; 2Centre for Innovative Cancer Research, Ottawa Hospital Research Institute
The heterogeneous nature of cancer cells helps explain why chemotherapy treatments, which typically have a single molecular target, often fail to improve patient survival. An alternative treatment is the use of oncolytic viruses which are able to control tumour growth through multiple different mechanisms. We have previously shown that Pexa-Vec (formerly JX-594), a Vaccinia virus (VacV) based oncolytic agent can be safely administered to cancer patients.
We believe a successful 2nd generation VacV-based oncolytic will be able to replicate faster in the tumour and have greater immunostimulatory properties. To this end, we compared five common wild-type strains of VacV in co-infection experiments both in vitro and in vivo and analyzed the output by next generation sequencing. Our results show the Copenhagen strain replicates fastest, making up to 90% of the final viral population in cancer cell lines.
Given Copenhagen’s promising “oncolytic engine”, we sought to focus on a second critical therapeutic attribute of an ideal oncolytic: the ability to stimulate anti-tumour immunity. We have identified several VacV-Copenhagen clones with large genomic deletions of immunosuppressive and anti-apoptotic activities. Interestingly, these deletions do not hinder the replication kinetics of the virus. In fact, these deleted viruses kill cancer cells much faster with up to 6 times more tumour cell death. Finally, using an infected cell vaccine platform these viruses induced better anti-tumour immune control leading to longer survival times in an aggressive orthotopic murine melanoma model (*p < 0.01).
This research increases our understanding of VacV biology and will allow the bioengineering of a novel immunotherapeutic for our fight against cancer.