Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model

Abstract

Using a novel orthotopic MBT-2 murine bladder tumor model, we evaluated the feasibility of intravesical gene therapy utilizing a cationic liposome, DMRIE/DOPE. Superficial bladder tumors were consistently established by intravesical instillation of 5 x 105 MBT-2 cells in syngeneic C3H female mice. In situ gene transfer to bladder tumors was accomplished via intravesical instillation of plasmid DNA/DMRIE/DOPE lipoplex. β-Galactosidase (β-gal) gene expression was preferentially evident in bladder tumors and was present for at least 7 days after a single 30 min in situ transfection. Murine interleukin-2 (IL-2) gene was used for treatment of 3-day-old pre-established bladder tumors. Forty percent of animals treated with IL-2 gene were completely free of tumors by 60 days following the initial tumor implantation, while all control groups treated with β-gal gene died. Those animals initially cured of pre-established tumors were completely resistant to a subsequent tumor re-challenge and their splenocyte-derived cytotoxic T lymphocytes were shown to be specific to MBT-2 cells, indicating that immunological memory against MBT-2 tumors was elicited by the treatment. These results demonstrate the possibility of an effective clinical application of this in situ intravesical IL-2 gene delivery system to high-risk superficial bladder tumors, obviating a need for tumor procurement and ex vivo gene transfer.