Herpes simplex virus thymidine kinase/ganciclovir-mediated killing of tumor cell induces tumor-specific cytotoxic T cells in mice.

Transfer of the herpes simplex virus thymidine kinase (HSV-TK) gene into cancer cells followed by treatment with ganciclovir (GCV) is an attractive strategy of cancer gene transfer. HSV-TK-transduced cells are efficiently killed by the direct cytotoxic effect of GCV-triphosphate, which is generated by HSV-TK from GCV. In addition, the bystander effect kills adjacent nontransduced tumor cells, although this mechanism is not fully understood. We addressed whether the systemic immune response is involved in tumor regression in vivo. Renca cells, from a renal carcinoma cell line transduced with a retroviral vector bearing the HSV-TK gene driven by the cytomegalovirus early promoter, were inoculated into BALB/c mice. After complete regression of inoculated tumors with GCV treatment, the animals were challenged with nontransduced tumor cells. Rejection or significant growth inhibition of challenged tumor cells was observed. In these animals, tumor-specific cytotoxic T cells were efficiently induced. CD8+ cells appeared to be a main component in this cytotoxic T cell fraction. Expression of class I major histocompatibility complex antigens increased in HSV-TK+ cells treated with GCV. These results suggest that suicide gene therapy may be useful not only for short-term tumor regression mediated by direct cell killing and bystander effect, but also, due to the vaccination effect, may be an aid in long-term tumor regression and prevention of recurrence.