Efficacy with a replication-selective adenovirus plus cisplatin-based chemotherapy: Dependence on sequencing but not p53 functional status or route of administration

Replication-selective adenoviruses are being developed as novel anticancer therapeutics. Clinical trials with dl 1520, an E1B-M-r 55,000 gene-deleted adenovirus (ONYX-015), have demonstrated selective viral replication and bi ological activity in head and neck and ovarian carcinomas, but durable obje ctive responses mere not demonstrated. However, clinical results suggested potentially synergistic interactions with platinum-containing chemotherapy. To better characterize and optimize this interaction, we carried out combi ned modality treatment with ONYX-015 and cisplatin-based chemotherapy in th ree nude mouse-human tumor xenograft models with differing tumor locations or p53 functional status. Superior efficacy was demonstrated with combinati on therapy over either agent alone in all three models, independent of the route of ONYX-015 administration (intratumoral or i.p.). Virus replication was not demonstrably inhibited by cisplatin plus 5-fluorouracil chemotherap y, To assess the role of p53 function or cisplatin resistance in this inter action, we treated ovarian carcinomas that were matched except for p53 func tional status (A2780, A2780/CP70). Combination therapy led to improved surv ival over either agent alone in both the p53(-) and the p53(+) carcinomatos is models. Efficacy was highly dependent on the sequencing of the agents; t reatment with ONYX-015 prior to, or simultaneously with, chemotherapy was s ignificantly superior to chemotherapy followed by ONYX-015. These results s upport further evaluation of replication-selective adenoviruses and cisplat in-based chemotherapy in clinical trials.