REPEATED INTRANASAL APPLICATION OF NEURAL STEM CELL-MEDIATED ENZYM/PRODRUG THERAPY USING A NOVEL HSV-THYMIDINE KINASE VARIANT IMPROVES THERAPEUTIC EFFICIENCY IN AN INTRACRANIAL GLIOBLASTOMA MODEL

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Abstract

BACKGROUND: Neural stem cells (NSCs) have an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive gliomas. We have recently introduced the concept of intranasal application of NSCs as a noninvasive and direct alternative delivery method for glioma-targeting NSCs. Here, we demonstrate that the repeated non-invasive intranasal administration of tumor-targeting NSC is able to deliver a novel suicide gene (TK.007) to intracerebrally growing human glioblastoma xenografts. METHODS: Murine NSC were genetically modified to stably express a novel, codon-optimized HSVtk(A168H) mutant (TK.007). The biological activity of the NSC-mediated TK.007/ganciclovir (GCV) system was assessed in cell survival and bystander assays using various human glioma cell lines. Therapeutic effects of intratumoral and intranasal NSC-TK007 applications alone and the sequential combinations of both was tested using an intracranial U87 human glioblastoma model in nude mice. All animals received 50 mg/kg GCV i.p. for five consecutive days. In all experiments two control groups received either NaCl instead of GCV or NSC containing the control vector instead of NSC-TK.007. Therapeutic efficiency was determined by assessment of tumor size by 7T MR-imaging and by establishment of Kaplan-Meier survival curves. RESULTS: Cell survival and bystander assays confirmed the GCV catalytic activity of NSC-expressed TK007 in a GCV dose dependent manner and a significant bystander effect at 12.5% of cells. Tumor targeted migration was demonstrated by intravital imaging of luciferase-expressing NSC. In glioma-bearing mice a single intratumoral application of NSC-TK007 followed by systemic prodrug application of GCV lead to a significant tumor growth inhibition of 72% versus the control groups at day 22 and translated in a prolonged survival time. Mice recieving a cyclic intranasal application of NSC-TK.007 alone displayed a signifcant longer survival than the controls. This effect was significantly enhanced when cyclic intranasal NSC-TK.007 therapy was preceded by a single intratumoral application of NSC-TK007 and led to a significant tumor growth inhibition of >95% and improved survival time. CONCLUSIONS: Our data demonstrates that the NSC-mediated TK.007/GCV therapy, which is based on the clinically most widely used suicide system to date, is safe, nontoxic, and effective in glioblastoma-bearing mice. Most importantly, our findings establish that the intranasal application of therapeutically-modified NSC is a safe and non-invasive application method which allows a chronic treatment during the disease course. SECONDARY CATEGORY: Clinical Neuro-Oncology.

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