Abstract:
Cholangiocarcinoma is curable only in its early stages by complete surgical resection. Thus, in advanced disease stages in which a complete removal of the tumour mass is no longer possible and palliative chemotherapy only achieves modest success, therapeutics employing new methods of action are needed. Oncolytic viruses employed in clinical studies have been shown to preferentially infect cancer cells. Beyond that, virotherapeutic cell killing can be enhanced by virus-based expression of suicide genes that convert non-toxic prodrugs into toxic reagents.
The aim of this thesis was to evaluate an oncolytic measles vaccine virus expressing SuperCD, a fusion protein of yeast cytosine deaminase and yeast uracil phosphoribosyltransferase that converts the prodrug 5-fluorocytosine to 5-fluorouracil, an approved chemotherapeutic. This vector was evaluated using three different human cholangiocarcinoma cell lines.
In vitro, all cholangiocarcinoma cell lines were found to be permissive to MeV infection. Partial blocking of MeV-mediated oncolysis could be overcome by utilisation of the SuperCD transgene together with administration of the prodrug 5- fluorocytosine.
In vivo, intratumoural application of SuperCD-armed measles vaccine virus to- gether with a systemic 5-fluorocytosine treatment showed a significant reduc- tion in tumour size in a TFK-1 xenograft mouse model when compared with virus-only treatment. In a second animal experiment employing a HuCCT1 xenograft tumour model, an enhanced SuperCD-armed MeV vector, in which the SuperCD transgene was expressed from a different genomic position, not only led to reduced tumour volumes, but also to a significant survival benefit.
These highly interesting results pave the way to a first phase I trial employing our virotherapeutic vector (MeV ld-SCD) plus oral application of 5-FC in patients with advanced, non-resectable cholangiocarcinoma.
