Preclinical evaluation of the oncolytic effect of recombinant, suicide gene-armed measles vaccine virus (MeV)-vectors on cholangiocarcinoma cells

Introduction: Today, cholangiocarcinoma (CC) only is curable in early stages by complete surgical resection. Therapeutics employing new methods of action are desperately needed. Virotherapeutic viruses 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 yeast uracil phospho¬ribosyltransferase which converts the prodrug 5-Fluorocytosine to 5-Fluorouracile (approved chemo¬therapeutic) and subsequently to 5-FUMP (toxic metabolite)) was evaluated 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 cyto¬toxicity assays. MeV-SCD replicates in all three cell lines to a comparable extend. Partial resistance to MeV infection was shown 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 and a prolonged median survival compared to medium control. A second animal experiment employing an enhanced MeV vector in a HuCCT1 xenograft model is currently underway and shows very promising results so far.

Perspectives: In vitro, MeV shows very encouraging characteristics as a novel therapeutic agent to CC. Consequently, testing of combination treatment approaches with radiation and chemo-therapeutics is in progress in our laboratory.

Cholangiocarcinoma - Measles - Virotherapy