The deliberate use of viruses as oncolytic (cancer killing) agents has become evident since initial observations tracing back to the early 20th century. This thesis explores strategies to enhance oncolytic virotherapy, focusing on genetically engineered Semliki Forest virus. We first reviewed clinical data showing that modified viruses can improve safety and tumor immunogenicity, though more controlled trials are needed. We then developed Semliki Forest virus replicon particles designed to infect once and deliver cytokines that activate immune responses. In vitro tumor-immune models confirmed these particles recruit and stimulate immune cells, and counteract the immunosuppressive effects of tumor-derived vesicles.
To understand obstacles to effective therapy, we reviewed mechanisms by which tumors resist viral infection. Using computational modeling, we showed that even a small number of infection-resistant cells can hinder viral efficacy. We further demonstrated that rapid diffusion of inflammatory signals from infected cells is essential for robust T cell activation and complete tumor clearance.