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Efficacy with a replication-selective adenovirus plus cisplatin-based chemotherapy: dependence on sequencing but not
Abstract:
Replication-selective adenoviruses are being developed as novel anticancer therapeutics. Clinical trials with dl 1520, an E1B-Mr 55,000 gene-deleted adenovirus (ONYX-015), have demonstrated selective viral replication and biological activity in head and neck and ovarian carcinomas, but durable objective responses were not demonstrated. However, clinical results suggested potentially synergistic interactions with platinum-containing chemotherapy. To better characterize and optimize this interaction, we carried out combined modality treatment with ONYX-015 and cisplatin-based chemotherapy in three nude mouse-human tumor xenograft models with differing tumor locations or p53 functional status. Superior efficacy was demonstrated with combination 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 chemotherapy. To assess the role of p53 function or cisplatin resistance in this interaction, we treated ovarian carcinomas that were matched except for p53 functional status (A2780, A2780/CP70). Combination therapy led to improved survival over either agent alone in both the p53(-) and the p53(+) carcinomatosis models. Efficacy was highly dependent on the sequencing of the agents; treatment with ONYX-015 prior to, or simultaneously with, chemotherapy was significantly superior to chemotherapy followed by ONYX-015. These results support further evaluation of replication-selective adenoviruses and cisplatin-based chemotherapy in clinical trials.
Insights
Combining ONYX-015 (a replication-selective adenovirus) with cisplatin chemotherapy shows superior efficacy in preclinical cancer models. Optimal results were achieved when the adenovirus was administered before or concurrently with chemotherapy.
Area of Science:
- Oncology
- Virology
- Gene Therapy
Background:
- Replication-selective adenoviruses are emerging anticancer therapeutics.
- ONYX-015 (dl 1520) shows activity in certain carcinomas but lacks durable responses.
- Clinical data suggest synergy between ONYX-015 and platinum chemotherapy.
Purpose of the Study:
- To investigate the combined efficacy of ONYX-015 and cisplatin-based chemotherapy.
- To evaluate the impact of p53 functional status and treatment sequencing on combination therapy outcomes.
Main Methods:
- Utilized three nude mouse-human tumor xenograft models with varying tumor characteristics.
- Assessed combination therapy with ONYX-015 and cisplatin +/- 5-fluorouracil.
- Compared different administration routes and sequences of ONYX-015 and chemotherapy.
Main Results:
- Combination therapy demonstrated superior efficacy compared to monotherapy across all models.
- Efficacy was independent of ONYX-015 administration route (intratumoral or i.p.).
- Sequential administration of ONYX-015 before or concurrently with chemotherapy yielded significantly better outcomes.
Conclusions:
- Combined modality treatment with ONYX-015 and cisplatin-based chemotherapy is a promising strategy.
- Treatment sequencing is critical for maximizing therapeutic benefit.
- Further clinical evaluation of this combination therapy is warranted.