Mesenchymal Stem Cell-mediated Image-guided Sodium Iodide Symporter (NIS) Gene Therapy Improves Survival of Glioblastoma-bearing Mice


 Purpose:Mesenchymal stem cells (MSCs) have emerged as cellular-based vehicles for the delivery of therapeutic genes in cancer therapy based on their inherent tumor homing capability. As theranostic gene, the sodium iodide symporter (NIS) represents a successful target for non-invasive radionuclide-based imaging and therapy. In this study, we applied genetically engineered MSCs for tumor-targeted NIS gene transfer in experimental glioblastoma (GBM) – a tumor with an extremely poor prognosis. Experimental Design:A syngeneic, immunocompetent GL261 GBM mouse model was established by subcutaneous and orthotopic implantation. Further, a subcutaneous xenograft U87 model was used. Bone marrow-derived MSCs were stably transfected with a NIS-expressing plasmid driven by the constitutively active CMV-promoter (NIS-MSCs). After multiple or single intravenous injection of NIS-MSCs, tumoral iodide uptake was monitored in vivo using 123I-scintigraphy or 124I-PET. Following validation of functional NIS expression, a therapy trial with 131I was performed based on the most optimal application regime as seen by 124I-PET imaging in the orthotopic approach. Results:A robust tumoral NIS-specific radionuclide accumulation was observed after NIS-MSC and radioiodide application by NIS-mediated imaging. NIS immunofluorescence staining of GBM and non-target tissues showed tumor-selective MSC homing along with NIS expression. Application of therapeutically effective 131I led to significantly delayed tumor growth and prolonged median survival after NIS-MSC treatment as compared to controls. Conclusions:A strong tumor-selective recruitment of systemically applied MSCs into GBM was found using NIS as reporter gene followed by successful therapeutic application of radioiodide demonstrating the potential use of NIS-based MSCs as therapy vehicles as a new GBM therapy approach.