LCMV GP-pseudotyped VSV-based systems for treatment of malignant glioma

Malignant glioma is the most frequent primary brain tumor and still has a very poor prognosis despite advances in neurosurgical resection and adjuvant radio- and chemotherapy. A promising new approach is the use of vesicular stomatitis virus (VSV)-based systems for glioma-targeted oncolytic virotherapy and/or gene therapy. To improve glioma specificity and to abrogate the VSV G-mediated VSV-inherent neurotropism, we pseudotyped VSV with the LCMV glycoprotein (LCMV GP). Retargeting to glioma cells while sparing healthy neurons was successfully achieved in vitro with a panel of different brain tumor cell lines in comparison to primary neurons. Furthermore, we investigated different systems to address viral spread and microdistribution of LCMV GP-pseudotyped VSV within the tumor. Besides the generation of a replication-competent LCMV GP pseudotype rVSV(GP) as a pure virotherapy approach, we were able to show that tumor-infiltrating adult stem cells can be used as a delivery system and packaging cell line for non-cytopathic, replication-deficient VSV vectors encoding the HSV-TK as suicide gene. Efficacy of rVSVAG-TK(GP) producing progenitor cells in mediating tumor killing after gancidovir treatment was shown in vitro in a G62 spheroid model. If the reduced neurotoxicity can be confirmed in our current studies in vivo, rVSV(GP) would be an extremely promising candidate for oncolytic virotherapy of brain cancer.