Optimization and individualization of sodium iodide symporter (NIS)-based gene therapy in glioblastoma based on characterization of tumor heterogeneity and tumor micromilieus
Within the SFB 824 (Imaging for Selection, Monitoring and Individualization of Cancer Therapies; Coordinator: Prof. Dr. M. Schwaiger, Klinikum rechts der Isar, TU München; www.sfb824.de we have evaluated targeted polyplexes and genetically engineered mesenchymal stem cells (eMSCs) as vehicles for the tumor-selective delivery of the sodium iodide symporter (NIS) gene in advanced tumor models. Tumor-selective NIS transgene induction followed by effective 131I therapy was demonstrated in pancreatic adenocarcinoma, colon cancer liver metastases and orthotopic liver cancer mouse models either by engineering MSCs to express NIS under control of gene promoters activated by tumor microenvironment-enhanced signals (e.g. RANTES and HIF), or by polyplexes designed to target tumor-surface markers (e.g. EGFR and c-MET). Based on its dual function as reporter and therapy gene, NIS was highly effective for the therapeutic application of 131I, and allowed detailed non-invasive in vivo tracking of eMSCs and polymers by 123I-scintigraphy/SPECT and 124I-PET imaging. The synthesis of a novel PET tracer for NIS imaging, 18F-tetrafluoroborate (18F-TFB), was improved providing significantly enhanced imaging quality.
As an essential step towards clinical application, in the current funding period we are building on and expanding these studies to the optimization and individualization of NIS-based gene therapy for glioblastoma multiforme (GBM), as a clinically highly relevant tumor with urgent need for novel therapy approaches