Molecular therapy of maligngant glioma with lentiviral vectors and tumor infiltrating progenitor cells

The aim of the project is to establish a stable packaging cell line for lentiviral vectors based on bone marrow derived tumor infiltrating progenitor cells (BM-TIC) for the treatment of malignant glioma. In previous studies, we have shown that BM-TIC migr ate and distribute efficiently within malignant glioma. Furthermore, we demonstrated specific and efficient transduction of glioma cells by lentiviral vectors pseudotyped with the glycoprotein of the Lymphocytic choriomeningitis virus (LCMV-GP). The combi nation of these two effective systems should lead to an efficient distribution of vectors by migration of the therapautic cells and an efficient transduction of glioma cells with therapeutic genes. BM-TIC will be transduced with lentiviral genes and a ve ctor containing a marker gene. High-titre clones will be selected and tested in vivo for migration and transduction of glioma cells. A xenograft model for human glioma will be used, which is highly invasive and resembles glioblastoma in the patient. Ther eby the targeting of infiltrating tumor cells can be analyzed, which is clinically highly important as the infiltrating glioma cells are responsible for recurrent tumors. In a second step, we will analyze the efficiacy of the suicide gene HSV-tk, the immu ne stimulatory gene IL-12 and different si-RNA´s against tumor growth promoting genes in a combined approach. The most efficient combination of therapeutic genes will be introduced into the lentiviral packaging cell line and high titre clones will be sele cted. The final therapeutic cell line will be tested in vivo for therapeutic efficacy and toxicity to enter the clinical phase of development.