Grant: Master's Award: Canada Graduate Scholarships

Oncolytic viruses represent a promising and novel avenue in targeted cancer therapeutics. Their efficacy can be attributed to their ability to selectively replicate in malignant cells, resulting in cell death, while leaving normal tissue relatively unscathed. One of the main obstacles associated with this type of treatment is achieving efficient viral delivery. It is therefore necessary to conceal the virus from the immune system in order to prevent premature neutralization. Modified strains of vaccinia virus have produced encouraging success rates, while maintaining an excellent safety profile in preclinical models as well as clinical trials. Among the numerous advantages that vaccinia presents as an oncolytic virus is its ability to form both functionally and antigenically distinct progeny particles: the intracellular mature virus (IMV), the cell-associated enveloped virus (CEV) and the extracellular enveloped virus (EEV). The EEV travels in the blood to mediate long distance dissemination of the virus. This can be achieved since the outer membrane of the particle carries few viral proteins and some host cell surface proteins, including complement regulatory proteins. The proportion of IMV, CEV and EEV produced depends on the host cell line and the virus strain, however EEV represents a minor fraction of the total progeny. With the intention of creating an enhanced EEV forming 'stealth' oncolytic virus, we have introduced mutations into three different gene products of the vaccinia genome: A34R, A33R and B5R, all of which have been shown to increase the proportion of EEV progeny particles formed. Independently, these mutations have been extensively studied, however, the combination of EEV enhancing mutations have never been studied in this strain of virus for their impact on oncolytic efficacy. Ideally, we will be able to more effectively deliver virus to primary tumours as well as distal metastases.