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

Abstract

13139 HSV in which ICP34.5 is deleted directs tumour selective cell lysis and has proven safe in Phase I clinical trials. To produce oncolytic HSV with enhanced anti-tumour properties, we have deleted ICP34.5 from a clinical isolate of HSV-1, which enhances the tumour cell killing capabilities of the virus, deleted ICP47 (which blocks antigen presentation), and inserted the gene encoding GM-CSF. This aimed to maximize anti-tumour immune responses following intra-tumoural injection and provide an in situ, patient-specific, anti-tumour vaccine, combined with oncolysis. In vivo, both injected and non-injected tumours could be cured and animals were then protected against tumour cell challenge. A Phase I clinical trial with the virus (OncoVEXGM-CSF) has been conducted including patients with cutaneous or sub-cutaneous deposits of a number of tumour types (Lead Investigator: Professor Charles Coombes, Hammersmith Hospital, London). This demonstrated the virus to have a good safety profile, the main side effects being ‘flu-like symptoms, similar to those which have previously been observed with other oncolytic products. Virus replication and GM-CSF expression was demonstrated together with inflammation, flattening and necrosis of 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 biopsies, this correlated with areas of staining for HSV, suggesting the virus had caused the effect. Following this promising data, Phase II studies are underway in multiple tumour types. In addition to OncoVEXGM-CSF, further versions of OncoVEX 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 tumour control. Each of these have shown promising results in pre-clinical tumour models, including in combination with chemotherapy and radiotherapy where benefits which are at least additive have been demonstrated. [Table: see text]