Oncolytic measles virus-loaded human bone marrow-derived mesenchymal stem cells as systemic cancer therapeutic agents for human hepatocellular carcinoma

摘要

Hepatocellular carcinoma (HCC) represents one of the major global health concerns affecting both developing and developed nations. Though currently hepatectomy and orthotopic liver transplantation could provide a potentially curative treatment for HCC, only a small proportion of patients will be eligible for these treatments since HCC is often detected at an advanced stage. Additionally, the observed cure rates for these treatments are elusive due to the high incidence of recurrence and salvage therapies for recurrent disease are not curative. Hence, the development of innovative therapeutic platforms for clinical applications is urgently needed. An emerging cancer therapeutic tool is the mesenchymal stem cell (MSC)-based therapy. MSC is a potentially good candidate due to its ability to target tumor cells and integrating into the stroma. Their easiness of expansion in culture is an additional advantage. Recently oncolytic measles viruses (MV) have been demonstrated to have potent oncolytic activity against several types of human cancers and their toxicity has also been reported to be minimal. Oncolytic MV targets CD46+ cells. MV uses the hemagglutinin envelope glycoprotein to infect cancer cells via the cellular CD46 receptor and the fusion envelope glycoprotein to trigger fusion of the viral cell membranes for virus entry. Expression of these fusogenic hemagglutinin and fusion proteins on surfaces of virus-infected cells results in massive intercellular fusion with uninfected neighbouring CD46+ to generate the characteristic MVinduced cytopathic effects of syncytia formation. We have demonstrated that most of the human HCC tested are CD46+. We are therefore exploiting the ability of the Edmonston vaccine lineage of MV as a CD46+-selective oncolytic agent for HCC cancer therapy. In this presentation, the homing ability of MSC was investigated in an orthotopic human HCC xenograft model. Results showed that systemic delivery of oncolytic MV-loaded human bone marrow (BM)- derived MSC preferentially home at tumor sites and the overexpression of CD46 on cell surfaces of human HCC cells resulted in the preferential killing of the tumor cells. Pre-existing antiviral antibodies in cancer patients can potentially neutralize the MV and decrease its antitumor potency. Hence, the ability of the BM-derived MSC to protect the “naked” MV viruses from antibody neutralization is also being investigated