MSC AS CARRIER CELLS FOR A RHABDOVIRUS-BASED ONCOLYTIC VIROTHERAPY OF OVARIAN CANCER

Ovarian Cancer is one of the leading causes of death from gynecological malignancies in the western world. A promising new approach is the vesicular stomatitis virus (VSV)-based oncolytic virotherapy as VSV is one of the most potent oncolytic viruses and there is no pre-existing antiviral immunity in the human population. However, VSV's glycoprotein-mediated inherent neurotoxicity has hindered clinical development so far. Furthermore, delivery of virus to disseminated tumor cells and infiltration of solid tumor tissue has to be optimized. To abrogate VSV's neurotoxicity, we pseudotyped VSV with the non-neurotropic glycoprotein of the lymphocytic choriomeningitis virus (LCMV-GP). Oncolytic potency was tested in cancer cell cultures and xenograft mouse models. Furthermore, toxicity was evaluated in tumor-bearing immunocompromized NOD/SCID mice. VSV-GP exhibited a more than 10ˆ6-fold higher LD50 compared to VSV wild-type upon intracranial injection in mouse brain, and the maximum tolerated dose was 10ˆ6 fold higher for VSV-GP upon intratumoral injection in immunocompromized mice. Furthermore, effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell cultures. Accordingly, intratumoral injection of VSV-GP into ovarian cancer s.c. xenografts led to tumor remission in all animals. Relapsing tumors were still susceptible to VSV-GP mediated oncolysis. To improve delivery of VSV-GP to distant tumor sides and to circumvent recognition of the virus by the host immune system, we use mesenchymal stem cells (MSC) as carrier cells. MSC were shown to be effective carrier cells for VSV-GP as they can be infected easily and virus replicates to high titers. The results of our in vitro and in vivo studies demonstrate that LCMV GP-pseudotyped VSV exhibits a highly beneficial toxicity and efficacy profile in ovarian cancer, which can be further optimized using MSC as carrier cells.