Virotherapeutic treatment of cholangiocarcinoma using a novel armed oncolytic measles vaccine virus

Cholangiocarcinoma is curable only in early stages by complete surgical resection. Thus, in advanced disease stages in which a complete removal of the tumor mass is no longer possible and palliative chemotherapy only achieves modest success, therapeutics employing new methods of action are desperately needed. Oncolytic viruses employed in clinical studies have been shown to spread preferentially in cancer cells. Beyond that, virotherapeutic cell killing can be enhanced by virus-based expression of suicide genes. We engineered a measles vaccine virus (MeV) vector expressing SCD, a fusion protein of yeast cytosine deaminase and uracil phosphoribosyltransferase, which converts the prodrug 5-fluorocytosine (5-FC) to the chemotherapeutic compound 5-fluorouracil (5-FU) and subsequently to 5-fluorouracil monophosphate. In our study, this novel vector was evaluated using different human-derived cholangiocarcinoma cell lines. In vitro, all cholangiocarcinoma cell lines were found to be permissive to MeV infection. Partial blocking of MeV-mediated oncolysis due to primary resistance mechanisms often found inherently in tumor cells could be over come by employment of the SCD transgene together with administration of 5-FC. In vivo, intratumoral application of SCD-armed MeV together with a systemic 5-FC treatment showed a significant reduction in tumor size in a TFK-1 xenograft mouse model when compared to virus-only treatment. In a second animal experiment employing a HuCCT1 xenograft tumor model, an expression enhanced SCD-armed MeV vector, in which the transgene was expressed from genome position one, not only led to reduced tumor volumes, but also to a significant survival benefit. On basis of these encouraging preclinical data on employment of SCD-armed MeV for the virotherapeutic treatment of chemotherapy-resistant cholangiocarcinoma, a clinical virotherapy trial is set up currently.