Regression of human mammary adenocarcinoma by systemic administration of arecombinant gene encoding the hFlex-TRAIL fusion protein

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, i s a new member of the TNF family. It can specifically induce apoptosis in a variety of human tumors. To investigate the possibility of employing the T RAIL gene for systemic cancer therapy, we constructed a recombinant gene en coding the soluble form of the human Flt3L gene (h Flex) at the 5' end and the human TRAIL gene at the 3' end. Such design allows the TRAIL gene produ ct to be secreted into the body circulation. We have also demonstrated that the addition of an isoleucine zipper to the N-terminal of TRAIL greatly en hanced the trimerization of the fusion protein and dramatically increased i ts anti-tumor activity. The fusion protein reached the level of 16-38 mug/m l in the serum after a single administration of the recombinant gene by hyd rodynamic-based gene delivery in mice. A high level of the fusion protein c orrelated with the regression of a human breast tumor established in SCID m ice. No apparent toxicity was observed in the SCID mouse model. In addition , the fusion protein caused an expansion of the dendritic cell population i n the C57BL/6 recipient mice, indicating that the hFlex component of the fu sion protein was functional. Thus, the hFlex-TRAIL fusion protein may provi de a novel approach, with the possible involvement of dendritic cell-mediat ed anti-cancer immunity, for the treatment of TRAIL-sensitive tumors.