Development of systemic immunologic responses against hepatic metastases during gene therapy for peritoneal carcinomatosis with retroviral HS-tk and ganciclovir

Abstract

Gene therapy with retroviral mediated gene transfer of the herpes simplex thymidine kinase (HS-tk) gene into a tumor mass confers sensitivity of the tumor cells to ganciclovir (GCV). Tumor-specific immunologic responses may develop following treatment of the primary tumor with retroviral HS-tk and GCV. In the present study we assessed whether GCV treatment of HS-tk transduced colon cancer (TK⁺) implanted in the peritoneal cavity induced a systemic antitumor response that would inhibit growth of a second wild-type (TK⁻) tumor implanted in the live. DHDK12 rat colon cancer cells were transduced in vitro with the retroviral HS-tk vector and established as a permanent cell line (TK⁺ cells). TK⁺ or TK⁻ DHDK12 cells (6×10⁶ cells) were injected intraperitoneally on day 0 into BD-IX rats. On day 10, TK⁻ cells (3×10⁶ cells) were injected into the liver in all the groups. The animals were then treated with GCV (150 mg/kg) for 13 days. TK⁺ peritoneal tumors underwent significant regression during therapy with GCV (0.05±0.004 g; n=7) compared to wild-type (TK⁻) tumors (2.2±0.7 g; n=6) (P<0.05). The volume to TK⁻ tumors in the liver was significantly lower in GCV-treated rats with TK⁺ peritoneal tumors (12.5±8.3 mm³) compared to rats with TK⁻ peritoneal tumors (96.7±18.1 mm³) (P<0.05). Histology of the liver tumors in the TK⁺ groups showed a dense monocytic infiltrate with fibrosis and only occasional viable tumor cells. Gene therapy with retroviral HS-tk vectors may provide a novel approach to treatment of gastrointestinal cancer by both direct cytotoxicity and an indirect mechanism that may included enhanced immunologic responses against disseminated disease.