COMBINATION SUICIDE AND CYTOKINE GENE-THERAPY FOR HEPATIC METASTASES OF COLON-CARCINOMA - SUSTAINED ANTITUMOR IMMUNITY PROLONGS ANIMAL SURVIVAL

The effectiveness of combination therapy using a suicide gene and cyto kine genes for the treatment of metastatic colon carcinoma in the mous e liver was investigated. Pre-established hepatic tumors treated with a recombinant adenoviral vector containing the herpes simplex virus th ymidine kinase gene (tk) exhibited substantial regression, although al l treated animals suffered from subsequent relapses. Although cotreatm ent with a mouse interleukin 2 (mIL-2)-containing adenoviral vector in duced an effective antitumor immune response, the immunity waned with time, and the treated animals eventually succumbed to hepatic tumor re lapse or distant metastases. In this study, mouse granulocyte macropha ge colony-stimulating factor (mGM-CSF) gene was tested for its ability to further enhance and prolong the antitumoral cellular immunity. A f raction of the animals treated with tk + mIL-2 + mGM-CSF developed lon g-term antitumor immunity and survived for more than 4 months without recurrence. This long-term antitumor immunity could be enhanced furthe r by subsequent ''vaccination'' with mIL-2-expressing parental tumor c ells. The results indicate that local expression of GM-CSF in the hepa tic tumors and prolonged mIL-2 expression are necessary to generate pe rsistent antitumor immunity that is essential for the prevention of tu mor recurrence and long-term animal survival.