Abstract

Systemic delivery of oncolytic viruses has remained a substantial challenge for the field. Sequestration of virus particles by the reticular endothelial system together with neutralising antibodies and complement take a heavy toll on administered dose. A number of different strategies have been proposed or have been attempted in the clinics or pre-clinically including cell-based delivery, dose scheduling and vector modification. We have focused on using a group B oncolytic virus, Enadenotucirev (formerly called ColoAd1), that retains activity in human blood and can be produced in sufficient quantities to allow repeated administration of a ‘breakthrough dose’. A breakthrough dose is the amount of virus required to saturate neutralisation or unwanted interactions with blood components. Dose scheduling and optimisation of infusion rates can then be used to manipulate clearance by the innate immune system and maximise the number of viable virus particles in the blood stream in order to achieve tumour delivery. In clinical trials we are able to show that a data driven optimisation of virus kinetics can achieve convincing delivery to tumours and expression of virus late proteins. This data validates the utility of Enadenotucirev as an oncolytic product candidate and provides a strong platform for next generation agents expressing therapeutic biologicals.