Treatment of hepatocellular carcinoma with a novel suicide gene-expressing oncolytic measles vaccine virus

Introduction: Oncolytic viruses are promising agents under investigation as cancer therapeutics. These replication competent viruses selectively infect and kill cancer cells. However, early clinical results point out that oncolysis achieved by unmodified vectors seems to be not sufficiently effective. To enhance cell killing, oncolytic viruses can be engineered to express suicide genes which convert non-toxic substances (prodrugs) into toxic metabolites. Aims: Development of new anti-HCC regimens based on oncolytic measles vaccine virus (MeV) expressing optimized suicide genes. Methods: We have generated (i) MeV vectors expressing the suicide gene SCD (MeV-SCD), a fusion of cytosine deaminase and uracil phosphoribosyltransferase and (ii) a MeV vector expressing VP22SCD (MeV-VP22SCD) which is a fusion of SCD to the intercellular transport protein VP22. Different hepatoma cell lines were used to test the susceptibility to both, MeV oncolysis and the suicide gene therapy. Conversion of 5-FC to 5-FU (5-fluorouracil) was demonstrated by HPLC. Cell death pathways of the infected cells were examined. In addition to these in vitro experiments, we also tested the effect of MeV-SCD in vivo. Results: All cell lines were found to be susceptible to MeV. Cell killing was enhanced by treatment with 5-FC. Comparison of the different MeV vectors suggests that VP22 does not further enhance the bystander effect in the context of an oncolytic virus with fusogenic glycoproteins. Of note, survival of tumor bearing mice was significantly prolonged by combinatorial treatment with MeV-SCD + 5-FC. Conclusion: Oncolytic virotherapy represents a promising addition for multimodal oncological concepts. By employing the SCD/5-FC system in combination with cytolytic MeV vectors, partial resistances of HCC to oncolysis can be overcome and the efficiency of MeV-mediated oncolysis can be enhanced significantly. On this basis, clinical phase I/II trials are currently under development.