Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12

The use of gene therapy to enhance antitumor immunity has emerged as a prom ising procedure to fight cancer, In this study we have tested the ability o f an adenovirus carrying interleukin 12 (IL-12) gene (AdCMVIL-12) to elimin ate tumoral lesions in 3 animal models of orthotopic hepatocellular carcino ma (HCC). Intratumoral injection of AdCMVIL-12 in animals with a single big tumor nodule implanted in the liver resulted in significant inhibition of tumor growth in a dose-dependent manner. Fifty percent of animals that rece ived a dose of 5 x 10(9) plaque-forming units, showed complete regression o f the tumor 2 weeks after treatment. In animals with 2 independent tumor no dules in the left liver lobe, injection in only one of them of 5 x 10(9) pf u AdCMVIL-12 induced, 15 days after therapy, complete regression of 50% of treated tumors and also of 50% of untreated lesions, with 60% long-term sur vival, Rats that were tumor free after therapy with AdCMVIL-12 showed prote ction against tumor rechallenge. A group of rats received the carcinogen di ethylnitrosamine and developed multiple hepatic dysplasic nodules of 1 to 5 mm in diameter. These animals were treated by intrahepatic artery injectio n of either AdCMVIL-12 (4 x 10(9) pfu) or control vector, In this model AdC MVIL-12 induced complete tumor regression in 20% of treated rats and inhibi ted tumor growth in 60% of cases with an increase in rat survival. Activati on of natural killer (NK) cells and inhibition of angiogenesis were found t o be antitumor mechanisms set in motion by AdCMVIL-12, Our data indicate th at experimental HCC can be efficiently treated by intratumoral or intravasc ular injection of adenovirus expressing IL-12.