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 liver. 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 × 10 6 cells) were injected intraperitoneally on day 0 into BD-IX rats. On day 10, TK − cells (3 × 10 6 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 ± 0.7g; n = 6) ( P <0.05). The volume of TK − tumors in the liver was significantly lower in GCV-treated rats with TK + peritoneal tumors (12.5 ± 8.3 mm 3) compared to rats with TK − peritoneal tumors (96.7 ± 18.1 mm 3) ( 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 include enhanced immunologic responses against disseminated disease.