Designing and building oncolytic viruses

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

As might be expected, proponents of a given OV are typically able to advance strong arguments to support their choice of platform, emphasizing unique features such as replication kinetics, genome plasticity, targetability, seroprevalence and stability that may lead to superior oncolysis. However, it is too early to determine which unique viral characteristics will be the critical drivers of clinical success for a given cancer type. Reverse genetics systems are available for virtually all virus families, and the rules of engagement for new virus creation are well established. In general, the most effective strategy is to combine rational design with evolution, allowing each engineered virus to mutate and fully adapt to its intended target cells after it has been rescued. Biosafety oversight is in place at all academic centers responsibly engaging in virus engineering activities, and it is now a relatively straightforward matter to generate and test new virus configurations using what now amounts to the world's best lego set. Viral gene and noncoding sequences can be modified in a variety of ways to add or eliminate functions and nonviral genes or noncoding regulatory elements, whether synthetic or naturally occurring, can be added into viral genomes to confer additional desirable properties. The overarching engineering goal for the oncolytic virotherapy field is to generate viruses that can be efficiently delivered to disseminated tumors in the body where they will spread and selectively kill both infected and uninfected tumor cells, without causing collateral damage and posing no risk of transmission to the population.