Efficacy of a replication-selective adenovirus against ovarian carcinomatosis is dependent on tumor burden, viral replication and p53 status

Intraperitoneal (i.p.) recurrence of cisplatin-refractory and p53 mutant ov arian cancer is a major clinical problem, despite surgery and chemotherapy. dl1520 (ONYX-015) is an E1B-55 kDa gene-deleted adenovirus engineered sele ctively to replicate in and destroy cancer cells lacking functional p53. Ho wever, a correlation between efficacy and p53 function has not been definit ively studied in vivo to date, and efficacy following ip. administration ha d not been previously described. We therefore carried out experiments to ad dress these issues in three nude mouse-human ovarian carcinomatosis xenogra ft models. Intraperitoneal treatment with dl1520 led to complete tumor erad ication and/or significantly improved survival in two p53(-) nude mouse-hum an ovarian tumor xenograft models. OVCAR3 ip. xenografts underwent complete regressions in 11 of 12 mice (versus one of seven controls; P = 0.001), wh ile mice bearing cisplatin-resistant A2780 tumors had significantly improve d survival versus controls (P = 0.05). In contrast, the A2780 p53(+) ovaria n cancer xenograft was resistant to dl1520. The efficacy of i.p. dl1520 in the p53(-) models correlated strongly with tumor burden present at the time of treatment initiation, and no efficacy was seen with non-replicating/UV- inactivated dl1520. Selectively replicating viruses such as dl1520 hold pro mise as i.p. therapies for p53-deficient and chemotherapy-resistant ovarian carcinomas. A phase I clinical trial of i.p. dl1520 (ONYX-015) is underway in patients with cisplatin-resistant ovarian carcinoma.