A novel armed oncolytic measles vaccine virus for the treatment of cholangiocarcinoma

Introduction: Up to now, cholangiocarcinoma (CC) only is curable in early stages by complete surgical resection. Therapeutics employing new methods of action are desperately needed. Virotherapeutic viruses, which are already employed in clinical studies, spread preferentially in cancer cells and virus-mediated cell killing can be enhanced by expression of suicide genes.

Methods: A measles vaccine virus (MeV) vector (Schwarz strain) expressing SCD (fusion protein of yeast cytosine deaminase and uracil phosphoribosyltransferase which converts the prodrug 5-Fluorocytosine to 5-Fluorouracil (approved chemotherapeutic) and subsequently to 5-FUMP (toxic metabolite)) was evaluated in vivo and in vitro using three cholangiocarcinoma cell lines (RBE, TFK, and HuCCT1).

Results: In vitro, all CC cell lines were found to be permissive to MeV infection as shown by growth curves, western blotting, and cytotoxicity assays. MeV-SCD replicates in all three cell lines to a comparable extent. Partial resistance to MeV infection was demonstrated to be overcome by employment of the SCD transgene and administration of 5-FC. As shown by cytotoxicity assays, infection of HuCCT1 cells in vitro by MeV-SCD together with application of 5-FC significantly decreases cell survival from 87.7±3% (virus only) to 4.4±2% (virus + prodrug). In vivo, intratumoral application of MeV-SCD in a TFK-1 xenograft mouse model showed a significant reduction in tumor size. In a second animal experiment employing a HuCCT1 xenograft tumor model, an enhanced SCD-armed MeV vector not only led to reduced tumor volumes, but also to a significant survival benefit.

Conclusion: Our preclinical data on SCD-armed MeV demonstrate very encouraging characteristics for usage as a novel therapeutic agent against cholangiocarcinoma.