Polymer Coated Vaccinia Virus for Enhanced Blood Stream Stability

Viruses are commonly used in medical treatments as vectors for drug delivery and more recently, as therapeutics for targeted cancer treatment either via cell destruction or by stimulating an immune-response against the cancer cells. Oncolytic viruses can selectively infect cancer cells over normal cells and then self-amplify within those target cells. It is this selectivity and ability to replicate which makes the use of oncolytic viruses in cancer treatment so revelatory. Recent success using herpes simplex virus, vaccinia virus and adenovirus, in clinical trials for cancer treatment, has led to increased clinical and commercial interest in virotherapy. However, there are still important challenges to overcome before using viruses as therapeutic agents in cancer treatment becomes a standard approach.
Firstly, there is the challenge of delivering the virus via the bloodstream so that all the distant sites of cancer deposition can be reached. When injected into the body, viruses are recognised as xenogens and are attacked and cleared from the body before they are able to reach the desired location(s). This immune clearance impedes the efficiency of the oncolytic virus. If the virus does manage to reach the tumour site, it then needs to have maintained a sufficient level of activity to then infect and kill cancer cells. This leads to the second challenge; the virus needs to be stable in the blood and retain a high level of infectivity. Thirdly, tumours are high pressure environments with dense disorganised collections of cells. This means they have no convective flow passing through them, making it difficult for particulates such as viruses to delivery into and penetration throughout the whole tumour. There may need to be mechanisms in place to help the virus continue to propagate until the entire tumour has been eradicated. This proposal will investigate ways in which vaccinia virus could be adapted and used in combination with mechanical stimuli to provide an approach which can overcome these three limiting barriers. Ultimately we hope the approach will create an extremely selective and powerful strategy for using oncolytic virus.

Vaccinia virus has been used to treat hundreds of patients in late stage clinical trials but is only effective when delivered by intratumoural injection. Providing better circulation kinetics and better tumour uptake following intravenous injection will widen the number of patients that can be treated with this vector. The quick and efficient life cycle of vaccinia virus means it rapidly destroys the cells it infects and leads to it spreading efficiently between cancer cells. This is ideal in cancer treatment, where cells are densely packed. A common concern with virotherapy is that viruses can cause serious illness. The vaccinia virus is derived from the pox-virus family and was used in the 1970 immunity program which lead to world-wide eradication of small pox. It therefore has an extensive well defined safety profile. Vaccinia virus only replicates in the cytoplasm of host cells, outside the nucleus, and therefore has very few interactions with host cellular proteins. This allows for rapid replication and production of extracellular enveloped virions, the type of virion responsible for its cell to cell spread, which are unaffected by the negative effects of host cell defences. In order to increase the utility of vaccinia virus, it is important to alter its appearance to the immune system of the host so as to allow its transportation to the tumour site.
As a DPhil student within Dr Carlisle's group I will be investigating the polymer coated vaccinia virus and the mechanisms which can be used to enhance its tumour delivery.