Improvement of Oncolytic Viral Therapy Through Transgenic Delivery of Constitutively Active EPAC

Abstract

Oncolytic viruses (OVs) are designed to selectively infect and kill cancer cells, while also initiating any anti-tumor immunity. They can be engineered to express therapeutic transgenes that improve their ability to spread through the tumor microenvironment or improve their oncolytic activity. In this thesis, I develop a collection of Vaccinia OVs that express the exchange protein activated by cAMP (EPAC) as a therapeutic payload to enhance virus spread in tumours. I show that poxviruses expressing constitutively active forms of EPAC improve viral spread in vitro in both cellular monolayers, Transwell assays and 3D tumour spheroids. In addition, the EPAC viruses decrease tumour growth and increase survival in mice with MC38 tumours. We also explore the combination of these viruses with the EPAC inhibitor ESI-09, which has anti-metastatic properties and which we show can inhibit B16 metastasis to the lungs following surgery resection. Our study shows that the Vaccinia virus expressing active EPAC shows promise as a potential cancer therapeutic.