Effective gene therapy for liver tumors with intra-arterial injection of IL-12 gene-engineered fibroblasts (Preliminary study)

Interleukin-12 (IL-12) mediates potent anti-tumor effects in animal models. However, this cytokine has shown dose-dependent toxicity in human clinical trials. We report here preliminary results of gene therapy with IL- 12 in a rat liver metastasis model. Intra-arterial injection of gene- engineered fibroblasts into liver should yield a high amount of IL-12 at tumor site without systemic toxicity. Syngeneic breast cancer cells (MADB106) were injected into liver via portal vein in Fisher rat. On the seventh day, gene-engineered fibroblasts with IL-12 (CRIP-IL12), which produced not only IL-12 protein but also IL-12 retrovirus, were injected via the gastro- duodenal artery (GDA). On the twenty-first day, rats were sacrificed and liver weight and tumor number were examined. As controls, lac-Z gene- transduced fibroblasts (CRIP-lacZ) and saline (HBSS) were injected. Intra- arterial injection of CRIP-IL12 showed significantly better anti-tumor effects than controls in liver weight and tumor numbers. In livers treated with CRIP-lacZ or HBSS, tumor nodules fused with each other to form large lesions and replaced most normal liver tissue. Intra-arterial injection of CRIP-IL12 caused a marked reduction in the number of identifiable metastases with little disturbance in normal liver. Furthermore, intra-arterial injection of CRIP-IL12 showed better anti-tumor effects than subcutaneous injection of the same cells, which reflects the systemic effects of CRIP- IL12. Intra-arterial injection of IL-12 gene-engineered fibroblasts into liver is a promising and effective therapy for multiple liver tumors without systemic toxicity.