Interleukin-6-controlled, mesenchymal stem cell-based sodium/iodide symporter gene therapy improves survival of glioblastoma-bearing mice

Carolin Kitzberger, Khuram Shehzad, Volker Morath, Rebekka Spellerberg, Julius Ranke, Katja Steiger, Roland E. Kälin, Gabriele Multhoff, Matthias Eiber, Franz Schilling, Rainer Glass, Wolfgang A. Weber, Ernst Wagner, Peter J. Nelson, Christine Spitzweg

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

New treatment strategies are urgently needed for glioblastoma (GBM)—a tumor resistant to standard-of-care treatment with a high risk of recurrence and extremely poor prognosis. Based on their intrinsic tumor tropism, adoptively applied mesenchymal stem cells (MSCs) can be harnessed to deliver the theranostic sodium/iodide symporter (NIS) deep into the tumor microenvironment. Interleukin-6 (IL-6) is a multifunctional, highly expressed cytokine in the GBM microenvironment including recruited MSCs. MSCs engineered to drive NIS expression in response to IL-6 promoter activation offer the possibility of a new tumor-targeted gene therapy approach of GBM. Therefore, MSCs were stably transfected with an NIS-expressing plasmid controlled by the human IL-6 promoter (IL-6-NIS-MSCs) and systemically applied in mice carrying orthotopic GBM. Enhanced radiotracer uptake by 18F-Tetrafluoroborate-PET/magnetic resonance imaging (MRI) was detected in tumors after IL-6-NIS-MSC application as compared with mice that received wild-type MSCs. Ex vivo analysis of tumors and non-target organs showed tumor-specific NIS protein expression. Subsequent 131I therapy after IL-6-NIS-MSC application resulted in significantly delayed tumor growth assessed by MRI and improved median survival up to 60% of GBM-bearing mice as compared with controls. In conclusion, the application of MSC-mediated NIS gene therapy focusing on IL-6 biology-induced NIS transgene expression represents a promising approach for GBM treatment.

Original languageEnglish
Pages (from-to)238-253
Number of pages16
JournalMolecular Therapy - Oncolytics
Volume30
DOIs
StatePublished - 21 Sep 2023
Externally publishedYes

Keywords

  • NIS
  • PET imaging
  • gene therapy
  • glioblastoma
  • interleukin-6 promoter
  • mesenchymal stem cells
  • sodium/iodide symporter

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