Regression of established macroscopic liver metastases after in situ transduction of a suicide gene

Abstract

The herpes simplex virus type 1 thymidine kinase (HSV1-TK) converts nontoxic nucleoside analogs such as ganciclovir into phosphorylated compounds that act as chain terminators and specifically kill dividing cells. This property could be exploited for the treatment of tumors that are made up of rapidly dividing cells invading a nonproliferating tissue. For this purpose, specific expression of the suicide gene into dividing tumor cells can be further targeted by using retroviral-mediated gene transfer. We investigated whether the direct intratumoral transduction of a suicide gene might induce the elimination of malignant solid tumors. Rats with established macroscopic liver metastases were given an intratumoral injection of packaging cells producing either HSV1-TK- or lacZ-expressing recombinant retroviral particles. All rats were next treated with ganciclovir. A dramatic regression of the tumor volume was observed in the HSV1-TK-treated animals. The residual tumors were mostly made up of a massive fibrotic reaction, with the mean cancer cell mass being reduced approximately 60-fold compared to controls. In some animals, the residual tumors were devoid of cancer cells. This treatment efficacy appears in part due to a "bystander effect" in which phosphorylated ganciclovir could be transferred from cell to cell and to an active local immune reaction evidenced by massive infiltration of the tumors by macrophages and both CD4+ and CD8+ lymphocytes. This efficient therapeutic approach might be an ultimate treatment for disseminated liver metastases in humans and could also be applied to treatment of a large variety of solid tumors.