A tumour-killing virus can hide from the immune system and avoid being destroyed by “hitchhiking” on the back of blood cells.
Reoviridae, or the reovirus, refers to a family of viruses whose name is derived from ‘respiratory enteric orphan viruses’ – ‘orphaned’ initially as they were not associated with any known disease. 4 of the 9 genera can infect humans and animals, although currently known effects are generally limited to stomach upsets and colds in children.
Exploiting the Reovirus’ Oncolytic Properties
The reovirus has more recently been shown to have oncolytic, i.e. cancer-killing, properties. They were found to infect and kill certain cancerous cells while leaving the surrounding tissue unharmed. It was found that the reovirus replicates specifically in tumour cells. Initial experiments on mice, however, suggested that the reovirus could not circulate and survive in the blood due to its destruction by the immune system. This would imply that the reovirus would only work if injected directly into tumours, a barrier to their widespread use.
The Hitchhiker’s Guide to the Tumour
A very recent study at the University of Leeds looked at 10 people with bowel cancer that has spread to the liver. The patients in the study were all due for surgery to have their tumours removed. In the three weeks prior to surgery they were given up to five doses of the experimental reovirus treatment.
Liver tissue was examined following surgery. The virus was found specifically in the tumour and not healthy tissue. It was shown that the virus is able to escape from the immune system by hiding in the blood. It was found in blood cells but not liquid blood plasma, suggesting that the virus attaches itself to blood cells. By hitchhiking its way along the blood canals, the virus is able to avoid being detected by the immune system. How clever!
Prof Alan Melcher, from the University of Leeds, said the virus was “even cleverer” than previously thought. “By piggybacking on blood cells, the virus is managing to hide from the body’s natural immune response and reach its target intact.” The researchers referred to this as ‘hitchhiking’.These new findings suggest that the reovirus could be injected directly into the blood for the potential treatment of certain cancers.
Reolysin: Phase III Clinical Trial In Progress
Oncolytics Biotech Inc., a Canadian biotech company has developed proprietary formulation of the human reovirus (‘proprietary’ meaning the company does not have to disclose the exact formula). Their lead product, REOLYSIN® is currently in late stage (Phase III) clinical testing in head and neck cancers.
The reovirus replicates specifically in tumor cells that have a constitutively activated Ras pathway. Ras proteins belong to a class of protein called small GTPase that are involved in transmitting signals within cells. The cellular signal transduction under their control results in the switching on of genes involved in cell growth, differentiation and survival. Mutations in ras genes can lead to the production of permanently activated Ras proteins. Because this can result in increased cell growth and division, Ras signaling is implicated in cancer. Indeed, Ras is the most common oncogene in human cancer. Such mutations and mutations along the Ras pathway occur in approximately two-thirds of all tumors.
Oncolytic Biotech Inc. explains: “Tumors bearing an activated Ras pathway are deficient in their ability to activate an anti-viral response mediated by the host cellular protein, PKR. Since PKR is responsible for preventing reovirus replication, tumor cells that lack the activity of PKR are susceptible to reovirus infection and eventual cell death.” [see image below, taken from Ocolytic Biotech Inc. website]
The Implications are HUGE
Research now should focus on understanding why the reovirus affects only cancer cells and not healthy tissue; i.e. why cancer cells are more susceptible to infection? Another exciting venture has been the research of genetically modified viruses for cancer treatment. At the University of Ottawa, scientists have engineered a poxvirus (i.e. a virus that can infect both vertebrates and invertebrates) for cancer-selective replication. They used this poxvirus as a means for the intravenous delivery and expression of transgenes in tumours. One such engineered oncolytic poxvirus has been shown to selectively infect, replicate and express transgene products in cancer tissue after intravenous infusion. Normal cells were unaffected.
In 2010, the direct medical costs associated with cancer exceeded $125 billion. The American Cancer Society estimates that this year, 1.6 million new cancer cases will be diagnosed and that more than 1,500 people a day are dying from the disease in the US alone. A big problem in cancer therapy is the rejection of medications by the body. Modified viruses hold the promise of a new platform technology for the direct and effective manipulation of tumour cells.