Therapeutischer Effekt des Gentransfers von Flt3-Ligand beim experimentellen Pankreaskarzinom

Abstract

Purpose: Flt3 is an important receptor expressed on the cell membrane of immature antigen presenting cells. The binding of Flt3 to its ligand (Flt3L) activates the proliferation of these cells. This mechanism is currently being evaluated in the therapy of malignant tumors. The aim of the present study was to study the effect of Flt3L gene transfer on the immune response and tumor growth in experimental pancreatic cancer. Methods: The efficacy of the transfection technique (LakZ) was proven in vitro and in vivo. Tumor induction was achieved in 20 Lewis rats by a subcutaneous inoculation of rat pancreatic tumor cells (DSL6A). The animals were allocated into 3 groups: control, mock-treatment, treatment with Flt3L-plasmid. The therapy was started after the tumor reached a diameter of 5–8 mm. The plasmid (10 µg, 20 µl) was injected intratumorally 3 times/week. The duration of therapy was 2 weeks. The total observation time was 6 weeks. Tumor volume, number of responders, leukocyte markers, lymphocyte infiltration, tumor proliferation and tumor vessel density were measured. Results: There were no significant differences in any parameter between control and mock-treatment groups. The tumor volume was significantly lower in the Flt3L-group in week 1 and week 2. The number of responders was significantly higher in the Flt3L-group compared with control and mock-treatment. The number of CD80+ positive monocytes in the spleen was significantly higher after Flt3L gene transfer. There were no differences of infiltrating lymphocytes, proliferation and tumor blood vessels between the groups. Conclusion: Intratumoral gene transfer of Flt3L caused an increase of CD80 positive cells and a moderate reduction of tumor growth. This improvement of local tumor control in the first weeks could be explained by an increase of antigen presentation.