OncoVEXGM-CSF is a second generation oncolytic HSV expressing GM-CSF. Deletion of ICP34.5 provides tumor selectivity, a modification extensively studied elsewhere. Compared to previous oncolytic HSV, oncolytic potency is increased using a clinical virus strain with greater lytic capabilities than previous laboratory strains, and by expressing US11 as an IE rather than an L gene. Immune stimulation is improved by deleting ICP47, which blocks antigen presentation, and expression of GM-CSF. Following intra-tumoral injection, OncoVEXGM-CSF is, therefore, intended to stimulate a GM-CSF-enhanced immune response to tumor antigens released by oncolysis. This aims to treat metastatic disease and reduce tumor recurrence. A Phase I/II clinical trial in 26 evaluable patients enrolled with cutaneous, sub-cutaneous or nodal deposits of melanoma (8), breast (13), head and neck (3), and colon cancer (2) has now been completed. Nine patients were HSV seronegative and 17 seropositive. Patients received single doses of 106, 107 or 108 pfu/ml of OncoVEXGM-CSF, the volume depending on the size of the tumor, followed by a multi-dosing phase of 3 injections using a number of regimens. Overall the most common side effects were transient grade I/II pyrexia and flu-like symptoms and inflammation at injected sites. These effects were more marked and/or extensive at higher doses and in patients who were HSV sero-negative at first dosing, including one Grade III pyrexia. This led to the development of a tolerising regimen of one 106 pfu/ml dose followed by two 108 pfu/ml doses 2-3 weeks later. The only serum biochemical change was one transient Grade II transaminitis. Viral DNA was detected transiently in the blood of 10 patients and virus at the injected site of 3 patients. Dose related GM-CSF expression was detected in injected tumors by RT-PCR. GM-CSF by ELISA was also detected at low levels in serum from some patients which was more evident following multiple doses. Tumor necrosis was evident clinically and/or by histology in biopsies taken ∼2 weeks after the final dose in the majority of patients. In some cases necrosis was considerable, albeit pre-injection biopsies were not available. Infiltration of T cells and macrophages possibly indicative of an anti-tumor immune response was also observed. In two cases both injected tumors and tumors nearby flattened, and in some cases non-contiguous tumor deposits became mildly inflamed. There were no obvious differences in the effects on the different tumor types. In conclusion, OncoVEXGM-CSF has been well tolerated and evidence of biological activity observed, including virus replication, tumor necrosis, and GM-CSF expression. Following this promising data, OncoVEXGM-CSF is now in Phase II development in a number of tumor types.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]