OncoVEX: A family of oncolytic herpes simplex viruses optimised for therapeutic use

2897 HSV in which the neurovirulence factor ICP34.5 is inactivated directs tumor selective cell lysis and has proven safe in the Phase I clinical studies conducted so far. To produce oncolytic HSV with enhanced anti-tumor properties, we have deleted ICP34.5 from a clinical isolate of HSV-1, which enhances the tumor cell killing capabilities of the virus, and also deleted ICP47 (which blocks antigen presentation in HSV infected cells) and inserted the gene encoding GM-CSF. This aimed to maximize anti-tumor immune responses following intra-tumoral injection and provide an in situ , patient-specific, anti-tumou vaccine, combined with oncolysis. In vivo , both injected and non-injected tumors could be cured with this virus and animals were then protected against further tumor cell challenge. Following this promising data a Phase I clinical trial with the virus (OncoVEX GM-CSF ) was conducted including patients with cutaneous or sub-cutaneous deposits of a number of tumor types (Lead Investigator: Professor Charles Coombes, Hammersmith Hospital, London). This demonstrated the virus to have a good safety profile, the main side effects observed being ‘flu-like symptoms, similar to those which have previously been observed with other oncolytic products and cancer vaccines, combined with evidence of biological activity including virus replication and GM-CSF expression. In addition inflammation, tumor flattening and necrosis was observed in injected lesions which was in some cases considerable and which was also in some cases observed in lesions which had not themselves been injected. In all cases where necrosis was observed in biopsy material, this correlated with areas of staining for HSV, suggesting the virus had caused the effect. Following this promising data, preparation for Phase II studies is underway. In addition to OncoVEX GM-CSF , further versions of the OncoVEX virus expressing other active genes have been constructed and tested in pre-clinical models. These include a virus expressing TNF, intended to be synergistic with radiotherapy, and versions of the virus expressing a pro-drug activating gene combined with the delivery of a fusogenic glycoprotein designed to maximize the properties of the virus for local tumor control. Each of these have shown promising results in pre-clinical tumor models, including in combination with chemotherapy and radiotherapy where benefits which are at least additive have been demonstrated.