A novel approach for image-guided 131 I therapy of pancreatic ductal adenocarcinoma using mesenchymal stem cell-mediated NIS gene delivery

Christina Schug, Aayush Gupta, Sarah Urnauer, Katja Steiger, Phyllis Fung Yi Cheung, Christian Neander, Konstantinos Savvatakis, Kathrin A. Schmohl, Marija Trajkovic-Arsic, Nathalie Schwenk, Markus Schwaiger, Peter J. Nelson, Jens T. Siveke, Christine Spitzweg

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The sodium iodide symporter (SLC5A5/NIS) as theranostic gene would allow for non-invasive imaging of functional NIS expression and therapeutic radioiodine application. Genetically engineered mesenchymal stem cells (MSC), based on their tumor-homing abilities, show great promise as tumor-selective NIS gene delivery vehicles for non-thyroidal tumors. As a next step towards clinical application, tumor specificity and efficacy of MSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Syngeneic murine MSCs were stably transfected with a NIS-expressing plasmid driven by the CMV-promoter (NIS-MSC). In vivo 123 I-scintigraphy and 124 I-PET revealed significant perchlorate-sensitive NIS-mediated radioiodide accumulation in PDAC after systemic injection of NIS-MSCs. Active MSC recruitment into the tumor stroma was confirmed using NIS immunohistochemistry (IHC). A therapeutic strategy, consisting of three cycles of systemic MSC-mediated NIS delivery, followed by 131 I application, resulted in a significant delay and reduction in tumor growth as compared to controls. Furthermore, IHC analysis of a-SMA and Ki67 revealed differences in the amount and behavior of activated fibroblasts in tumors of mice injected with NIS-MSCs as compared with saline-treated mice. Taken together, MSCs as NIS gene delivery vehicles in this advanced endogenous PDAC mouse model demonstrated high stromal targeting of NIS by selective recruitment of NIS-MSCs after systemic application resulting in an impressive 131 I therapeutic effect. Implications: These data expand the prospect of MSC-mediated radioiodine imaging-guided therapy of pancreatic cancer using the sodium iodide symporter as a theranostic gene in a clinical setting.

Original languageEnglish
Pages (from-to)310-320
Number of pages11
JournalMolecular Cancer Research
Volume17
Issue number1
DOIs
StatePublished - 1 Jan 2019
Externally publishedYes

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