Advanced-stage ovarian cancers are typically sensitive to initial platinum-based therapy, but most recur and eventually develop platinum resistance. Effective therapies for platinum-resistant disease are an unmet need. New data suggest that ofranergene obadenovec (VB-111), a novel viral gene therapy, is active in this context.

VB-111 consists of an adenoviral vector carrying a TNFR1–FAS chimeric death receptor transgene with a modified pre-endothelin 1 promoter that is activated specifically in angiogenic endothelial cells. This agent is postulated to abrogate tumour angiogenesis through TNF-induced, TNFR1–FAS-mediated endothelial cell death. The associated tumour cell death and antigen release, as well as the immune adjuvant effect of the virus itself, might also result in enhanced antitumour immunity.

In a phase I/II trial, 21 women with ovarian cancer refractory or resistant to platinum-based chemotherapy received paclitaxel plus up to seven doses of VB-111. The phase II expansion cohort comprising 17 women who received the optimally tolerated ‘therapeutic’ dose of VB-111 and paclitaxel had a median overall survival of 16.6 months, compared with 5.8 months in those who received sub-therapeutic doses in phase I of the study (P = 0.03). Among the phase II cohort, 58% of evaluable patients had GCIG CA-125 responses, with a median duration of 10 months, and 73% had RECIST disease control (partial responses in 13%). Biopsy samples obtained from two patients after one or two doses of VB-111 had regions of tumour cell apoptosis as well as increased CD8+ T cell and CD4+ T cell infiltration compared with control specimens from untreated patients.

Treatment was well tolerated, with no dose-limiting toxicities. The most common adverse events (AEs) were fatigue (in 52% of patients), nausea (52%), fever (48%), anaemia (38%), diarrhoea (33%) and headache (29%). Serious AEs were reported in 29% of patients and grade ≥3 AEs in 43%.

These findings warrant larger-cohort randomized controlled trials of VB-111.