OR35-5 Stromal targeting of sodium iodide symporter using mesenchymal stem cells allows radioiodine imaging and therapy of hepatic colon cancer metastases

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR35-Neoplasia of Endocrine Tissues
Bench to Bedside
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 122 (Moscone Center)
Kerstin Knoop*1, Nathalie Schwenk1, Patrick Dolp1, Michael Johannes Willhauck1, Christoph Zischek1, Guido Böning1, Heidrun Zankl1, Marcus Hacker1, Burkhard Göke1, Ernst Wagner2, Peter J Nelson1 and Christine Spitzweg1
1University Hospital of Munich, Munich, Germany, 2Ludwigs-Maximilians-University, Munich, Germany
The tumor-homing property of mesenchymal stem cells (MSC) has lead to their use as delivery vehicles for therapeutic genes. The application of the sodium iodide symporter (NIS) as reporter and therapy gene allows non-invasive imaging of MSC biodistribution and functional transgene expression by 123I-scintigraphy or PET-imaging, as well as therapeutic application of 131I or 188Re. Based on the critical role of the chemokine RANTES/CCL5 secreted by MSCs in the course of tumor stroma recruitment and differentiation into cancer associated fibroblasts, use of the RANTES/CCL5 promoter should allow tumor stroma-targeted expression of NIS after MSC-mediated delivery.

In the current study we stably transfected human MSCs with NIS driven by the CCL5 promoter (RANTES-NIS-MSC). Human colon carcinoma cells LS174t were injected into the spleen of nude mice, which resulted in induction of multifocal liver metastases. We investigated distribution and recruitment of RANTES-NIS-MSCs in liver metastases by 123I-scintigraphy and 124I-PET imaging and ex vivoanalyses after systemic tail vein injections of RANTES-NIS-MSCs.

Five days after intrasplenic tumor cell injection 5x105 RANTES-NIS-MSCs were injected via the tail vein three times in four-day-intervals followed by radionuclide application 48h later. 123I-scintigraphy and biodistribution studies as well as 124I-PET imaging revealed active MSC recruitment and CCL5 promoter activation in the multifocal liver lesions in 70% of mice as shown by tumor-selective iodide accumulation. After i.v. injection of wild-type-MSCs no significant iodide accumulation in liver metastases was observed. Immunofluorescence and real-time PCR analyses confirmed selective MSC recruitment and RANTES/CCL5-promoter activation in the stroma of liver metastases, while healthy liver tissue and non-target organs did not show MSC recruitment. Administration of two therapeutic doses of 131I (55.5 MBq) in RANTES-NIS-MSC treated mice resulted in improved survival.

Taken together, our results convincingly demonstrate selective recruitment of MSCs stably expressing NIS driven by the RANTES/CCL5-promoter into liver metastases resulting in induction of tumor-specific iodide accumulation and a therapeutic effect of 131I, opening the exciting prospect of NIS-mediated radionuclide therapy of metastatic cancers after MSC-mediated gene delivery.

Nothing to Disclose: KK, NS, PD, MJW, CZ, GB, HZ, MH, BG, EW, PJN, CS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm