P08.42 Long-term treatment with Valganciclovir improves lentiviral suicide gene therapy for glioblastoma

Abstract

Previously we have shown that lentiviral vector mediated herpes simplex virus thymidine kinase (HSV-Tk) / ganciclovir (GCV) therapy is a very promising therapeutic option for GBM treatment. However, after long-term remission, tumor recurrence was observed in treated animals and interestingly a fraction of recurrent glioma cells expressed HSV-Tk. We hypothesized that short-term GCV treatment, which is used in clinical trials for suicide gene therapy of GBM, fails to eliminate a fraction of glioma cells which are slow-proliferating; thus, a longer period of prodrug administration might provide a better outcome. Here, we compared long-term treatment with the prodrug valganciclovir (valGCV), which is tailored for oral administration, to short-term treatment with GCV within the context of suicide gene therapy for experimental GBM. After orthotopic implantation of patient derived GBM spheroids and visible tumor growth on MRI, we injected lentiviral vectors expressing TK.007, a highly active mutant of HSV-tk. Animals were treated with either short-term GCV (3 weeks) or long-term valGCV (3 months). Although both treatment groups showed remission and subsequent tumor recurrence, animals in the valGCV treatment group survived significantly longer and had a longer recurrence-free time period. When analyzing the recurrent tumors, we observed that these were more invasive and less angiogenic compared to primary tumors in the control groups. Furthermore, recurrent tumors showed upregulation of tyrosine kinase receptor expression, in particular EGFR. These results open up the possibility for a combination treatment of lentiviral suicide gene therapy with tyrosine kinase receptor inhibitors in the future.