Immune-dependent distant bystander effect after adenovirus-mediated suicide gene transfer in a rat model of liver colorectal metastasis

Gene transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene se nsitizes tumor cells to the toxic effect of ganciclovir (GCV). The toxic ef fect of GCV extends to nontransduced surrounding cells by a metabolic proce ss known as the bystander effect. A distant bystander effect, which involve s anatomically separated tumors, has been reported in vivo. Our aim was to evaluate and characterize such distant effect in a rat model of colorectal tumors implanted in the liver using adenovirus to carry the HSV-tk gene. Tw o colorectal tumors were implanted in two distinct liver lobes of the liver . One of the tumor was transduced with an adenoviral vector containing HSV- tk gene. The volumes of the tumors were monitored after GCV treatment. Impl ication of the immune system was studied histologically and after in vivo m anipulations. After GCV administration, the nontransduced distant tumor reg ressed partially or completely in the experimental group. Immunohistochemic al analysis revealed the presence of CD8(+) lymphocytes in the distant lesi on. HSV-tk/GCV-induced immune response against tumors was evidenced by an a doptive transfer assay (Winn assay) and the distant bystander effect was bl unted after CD8(+) lymphocytes depletion. However, the survival rates for t reated animals were not improved. These findings demonstrate that an immune -mediated effective distant bystander effect can be obtained after limited adenoviral-mediated transfer of the HSV-tk gene.