SUN-339 External Beam Radiation Therapy Improves TGFB1-Induced Mesenchymal Stem Cell-Mediated NIS Gene (131)I Therapy

The sodium iodide symporter (NIS) is the operational molecule that has allowed the efficient treatment of thyroid malignancies by the administration of (131)I for over 70 years. Various vector-driven approaches are currently under investigation to introduce the NIS gene into non-thyroidal tumors in order to more broadly apply this effective anticancer therapy. One such system makes use of genetically engineered mesenchymal stem cells (MSC) as therapy vehicles for the delivery of NIS into solid tumors. MSCs show an innate ability to home to and invade tumor environments in response to the danger signals and inflammatory cytokines produced by the tumor milieu. We and others have demonstrated that tissue or signal-specific gene promoters are able to enhance the specificity of MSC-mediated NIS transgene expression in tumors. External beam radiation therapy (EBRT), a standard principal therapeutic modality for the treatment of cancer, results in tissue damage and hence enhanced recruitment of NIS-expressing MSCs into human hepatocellular carcinoma (HuH7). At the same time, the tumor-associated cytokine TGFB1 is strongly upregulated in HuH7 tumors in response to radiation pretreatment. In the current study, we show that combining EBRT with MSC-based NIS-mediated (131)I therapy dramatically enhances therapeutic efficacy when a synthetic TGFB1-inducible SMAD-responsive promoter, as opposed to a constitutive CMV-promoter, is used to drive NIS expression in MSCs. It is thought that the remarkable therapeutic effect seen is linked to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based NIS expression within the tumor milieu.