ANALYSIS, DESIGN, MODELS
By Darshak Bhatt
Prof. C.A.H.H. Daemen
Prof. R. Chammas
Dr. C.I. Oyarce Díaz
Dr. L. Nogueira de Sousa Andrade
PhD research performed at the University of Groningen and the University of Sao Paulo.
The deliberate use of viruses as oncolytic (cancer killing) agents has become evident since initial observations tracing back to the early 20th century. However, clinical use of therapeutic viruses requires them to be safe and effective. In this thesis, we analyzed, designed and modeled strategies to improve oncolytic virotherapy with a focus on genetically engineering Semliki Forest virus.
First, we evaluated clinical evidence on the use of virotherapy, revealing the potential of genetically modified viruses to enhance safety and tumor immunogenicity, while highlighting the need for controlled studies to validate efficacy. Subsequently, we designed Semliki Forest virus-based replicon particles, capable of a single round of infection and encode immunogenic cytokines. Using various tumor-immune co-culture assays we demonstrate that these oncolytic viruses strongly boost the recruitment and activation of immune cells. Notably, we observed that infection by oncolytic viruses counteracts the immuno-suppressive nature of tumor extracellular vesicles, as a relatively unexplored mechanism of virotherapy mediated immune-activation.
Next, we analyzed literature to understand various cellular and systemic mechanisms used by tumor, stromal and immune cells that undermine oncolytic virotherapy. To explore the spatiotemporal dynamics of virotherapy in presence of infection-resistant tumor cells and the resulting immune responses, we employed a computational modeling approach. Here, we show that even in few numbers, infection-resistant tumor and stromal cells impede tumor eradication by oncolytic viruses. Moreover, we demonstrate that highly effective inflammatory molecules released by infected cells, spreading rapidly are required for optimal anticancer T cell cytotoxicity throughout the tumor, resulting in tumor eradication.