The effects of oncolytic Maraba virus (MG1) in advanced non-small cell lung cancer

Abstract

Lung cancer is responsible for the highest cancer mortality worldwide. The prognosis for patients with advanced disease remains poor with five-year overall survival of <10%, highlighting the urgent unmet need for novel treatments. Oncolytic viruses (OV) are a promising form of IO that has demonstrated selective infection, replication and killing of tumour cells, as well as subsequent activation of anti-tumour immunity. Maraba virus, MG1, is one such OV that is currently being investigated in phase I/II clinical trials as part of a "prime-boost" cancer vaccine. This thesis explores the anti-cancer effects of clinical-grade Maraba virus (MG1) in a panel of lung cancer cell lines in vitro and then also in vivo in an immunocompetent murine lung cancer model. The ability of MG1 to reach the tumour, replicate within it and exert anti-tumour benefits with systemic, as opposed to intratumoural, administration in vivo was investigated. Moreover, the ability of MG1 infection to reduce immunogenic cell death in lung cancer cell lines and the changes in the tumour immune microenvironment in vivo was examined. Finally, as the current body of evidence suggests that OVs often have limited efficacy as single agents, the potential synergistic enhancement of MG1 virotherapy in combination with other standard modalities of treatment was investigated. The results discussed here show that oncolytic Maraba virus was able to selectively infect, replicate inside and kill non-small cell lung cancer cells, both in vitro and in vivo. Furthermore, in vivo, the virus retained its tumour tropism properties even after systemic delivery and replicated to doses that were comparable to intratumoural delivered MG1, despite the development of anti-viral neutralising antibodies rising in parallel with viral replication in treatment-naive mice. Finally, MG1 was shown to inhibit tumour growth delay in a murine kung cancer model, likely due to stimulation of anti-tumoural innate immune effects.