Cancer gene therapy with HSV-tk/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo

To examine the immunological mechanisms involved in cancer gene therapy usi ng the herpes simplex virus thymidine kinase (HSV-rk) gene and ganciclovir (GCV), murine hepatocellular carcinoma (HCC) cells, BNLIME A.7R.I, were tra nsduced retrovirally with the HSV-tk gene. HSV-tk-transduced cells exhibite d a more than 2,000-fold higher sensitivity to GCV compared with untransduc ed parental cells. When HSV-tk-transduced HCG cells were mixed with parenta l cells at a 50% ratio and implanted subcutaneously into immunocompetent sy ngeneic mice, complete inhibition of tumor formation was achieved by GCV tr eatment. Conversely, no significant inhibitory effects on tumor formation w ere observed in athymic nude mice. When established solid tumors in immunoc ompetent mice containing HSV-tk-transduced cells at an only 5% ratio were t reated with GCV, marked infiltration by lymphocytes including CD4(+) and CD 8(+) ones, and apoptotic death of tumor cells were induced, and significant reduction or even complete regression of tumors was achieved. Furthermore, such cured mice rejected rechallenge with parental HCC cells into the cont raflank regions. Our results indicate that cancer gene therapy with the HSV -tk/GCV system can indeed induce efficient antitumor effects and protective immunity in immunocompetent mice but not in nude mice, indicating that T-c ell-mediated immune responses may be a critical factor for achieving succes sful gene therapy against cancer using the HSV-tk/GCV system. (C) 1999 Wile y-Liss, Inc.