Specific elimination of tumor stem cells using oncolytic viruses

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Within tumor tissue a small fraction of cells has been demonstrated to behave like stem cells. These so called tumor stem cells have been described to reinitiate tumors and to even generate tumor vasculature. Surface markers such as CD133 are being used to identify and enrich tumor stem cells. CD133-positive tumor cells in hepatocellular cancer and glioblastoma are rare in tumor tissue but have a high potential for tumor initiation and were described to be resistant against radio- and chemotherapy. Anti-tumoral drugs targeted to tumor stem cells are therefore highly desirable.The applicants group has developed unique methods to achieve the retargeting of oncolytic viruses to any cell type and cellular surface receptor of choice. Towards the goals of this proposal, the applicants group generated for the first time an oncolytic virus that uses CD133 as receptor for cell entry. This virus termed MV-CD133 has been derived from measles virus (MV) and infects and lyses selectively CD133-positive tumor cells. Initial studies in mice carrying subcutaneously growing human hepatocellular carcinoma cells showed that MV-CD133 is able to exert a strong anti-tumoral effect. Notably, MV-CD133 reduced tumor growth more efficiently than the parental measles virus which is currently investigated in numerous clinical trials for the treatment of different tumor entities. This proposal aims at generating a novel anti-tumoral agent with absolute specificity for CD133-positive tumor cells. Based on the relevance of CD133 as marker for tumor stem cells, MV-CD133 may be the first oncolytic virus that selectively infects and kills tumor stem cells. By now, a tumor stem cell specific virus has not been described for any type of oncolytic virus. Based on preliminary data, we hypothesize that CD133-targeting enhances the anti-tumoral potential of oncolytic viruses for the treatment of hepatocellular cancer (HCC). Beyond HCC, we will explore the activity of MV-CD133 against glioblastoma for which CD133 has been suggested as tumor stem cell marker as well. To further enhance the oncolytic activity of MV-CD133 we will arm the virus with suicide genes and extend its tropism to CD133-negative tumor cells. The anti-tumoral efficacy of the viruses will be quantified in cell killing assays and by monitoring tumor growth in different mouse tumor models. Special emphasis will be put on the evaluation of primary tumor cells containing varying degrees of CD133-positive cells for their ability to form tumors and metastases when the CD133-positive cells in these samples have been infected by the virus. The activity of MV-CD133 will also be assessed in multi-focal tumor models which are more relevant for clinical applications. We expect from this project an improved understanding of the relevance of CD133 as marker of tumor stem cells as well as the basis for a novel innovative strategy in tumor therapy.