Oncolytic virotherapy for nasopharyngeal cancer

Abstract

Objectives. To evaluate the oncolytic potential of a replication‐selective mutant adenovirus (VAI‐deleted adenovirus) in an established EBV‐positive cancer cell line and to develop a new regime to enhance the potency of the virus by combination with additional agents.Methods. In vitro (cytotoxicity) assays to determine cell survival were performed to assess the viral potency of replicating adenovirus (wild‐type and the VAI‐deleted mutant) in established EBV‐negative and EBV‐positive cancer cell lines. Various drugs including a histone deacetylase inhibitor (HDACi), phenylbutyrate and standard chemotherapeutic agents used in nasopharyngeal cancer (cisplatin, 5‐fluorouracil and paclitaxel) were evaluated for their cytotoxic effect on these tumour cells. Subsequent experiments were performed to determine whether addition of these increased the anti‐tumour efficacy of the VAI‐deleted adenovirus and/or lowered the required viral dose. Sequencing studies with the virus and drugs were carried out to determine the most synergistic combination causing cytotoxicity. Viral infectivity and replication studies with and without HDACi were also undertaken.Results. The mutant adenovirus was found to be more potent than the wild‐type virus against the EBV‐positive cells. Combination with various therapeutic agents (phenylbutyrate, cisplatin, 5‐fluorouracil and paclitaxel) results in lowering of the virus dose and a synergistic effect. Sequencing of drug followed by virus achieves the best results. There was no significant change in infectivity or replication with addition of the HDACi.Conclusion. Combination of the VAI‐deleted adenovirus with agents already in clinical use results in synergy. In vivo and thereafter translational studies would enable the clinical application of such treatment for EBV‐associated tumours.Reference 1 Wang, Y., et al. (2005) Virus‐associated RNA I‐deleted adenovirus, a potential oncolytic agent targeting EBV‐associated tumors. Cancer Res. 65, 523–531