Developing a Novel Pharmacoviral Anti-Cancer Strategy Combining Targeted Immunotherapy and Oncolytic Rhabdovirus VSV∆51

Abstract

Oncolytic viruses (OVs) are attenuated viruses that have been engineered to selectively infect and kill cancer cells. OVs exert anti-tumour effects through different mechanisms that reprogram the tumour microenvironment and stimulate anti-tumour immunity. While OVs can treat many cancers, a major challenge is heterogeneity of treatment responses and tumour resistance to OV infection. To address this hurdle, the Diallo lab identified several compounds, termed viral enhancers, that improve cancer-selective OV infection and spread. These small molecules belong to multiple pharmacologic classes which impair cancer cell antiviral responses. Of note is the class of microtubule destabilizing agents (MDA), a mainstay of conventional antineoplastic chemotherapy. Although we have proven these compounds significantly improve OV efficiency, the cytotoxicity of MDAs urges improved targeting and safety. My thesis therefore centers on antibody-drug conjugate (ADC) technology which was used to deliver viral enhancing payloads to specific antigen-expressing cancer cells in combination with oncolytic vesicular stomatitis virus (VSVΔ51). We demonstrated that the clinically-approved anti-HER2 ADC, trastuzumab emtansine (T-DM1, Kadcyla®) synergizes with VSVΔ51 in HER2-positive tumours to improve overall survival and reduce tumour burden (Chapter 2). Kadcyla® consists of anti-HER2 antibody trastuzumab conjugated to a potent, viral-sensitizing MDA. To assess this pharmacoviral strategy in vivo, we engineered a novel immune-competent mouse model of human HER2+ cancer (Chapter 3). To address the issue of tumour resistance against antibody therapy through antigen absence, we designed a VSVΔ51 variant encoding the epitope of Kadcyla®: VSVΔ51-HER2T. This virus can deliver this antigen to the surface of infected cells to sensitize HER2-negative tumours to HER2-targeted therapies, including ADCs and T-cell engagers (Chapter 4). This strategy operates in a tumour agnostic fashion, independently of endogenous expression of the target antigen. Overall, we showcased the compatibility of VSV with multiple targeted combination strategies. We moreover demonstrated the efficacy of these rationally-designed combinations in multiple pre-clinical models, including in vivo disease models and ex vivo patient specimens. Importantly, our strategies culminate in a pan-cancer therapeutic approach that aims to break down clinical barriers to access to targeted therapies.