Glioblastoma is the most frequent and most malignant
primary brain tumor with a poor prognosis. The translation of therapeutic strategies for
glioblastoma from the experimental phase into the clinic has been limited by insufficient animal models, which lack important features of human
tumors. Lentiviral gene therapy is an attractive therapeutic option for human
glioblastoma, which we validated in a clinically relevant animal model.
METHODOLOGY/PRINCIPAL FINDINGS: We used a rodent xenograft model that recapitulates the invasive and angiogenic features of human
glioblastoma to analyze the transduction pattern and therapeutic efficacy of lentiviral pseudotyped vectors. Both, lymphocytic choriomeningitis virus
glycoprotein (LCMV-GP) and
vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentiviral vectors very efficiently transduced human
glioblastoma cells in vitro and in vivo. In contrast, pseudotyped gammaretroviral vectors, similar to those evaluated for clinical
therapy of
glioblastoma, showed inefficient gene transfer in vitro and in vivo. Both pseudotyped lentiviral vectors transduced
cancer stem-like cells characterized by their CD133-,
nestin- and SOX2-expression, the ability to form spheroids in neural stem cell medium and to express astrocytic and neuronal
differentiation markers under serum conditions. In a therapeutic approach using the suicide gene herpes simplex virus
thymidine kinase (HSV-1-tk) fused to eGFP, both lentiviral vectors mediated a complete remission of solid
tumors as seen on MRI resulting in a highly significant survival benefit (p<0.001) compared to control groups. In all recurrent
tumors, surviving eGFP-positive
tumor cells were found, advocating
prodrug application for several cycles to even enhance and prolong the
therapeutic effect.
CONCLUSIONS/SIGNIFICANCE: In conclusion, lentiviral pseudotyped vectors are promising candidates for gene therapy of
glioma in patients. The inefficient gene delivery by gammaretroviral vectors is in line with the results obtained in clinical
therapy for GBM and thus confirms the high reproducibility of the invasive
glioma animal model for translational research.