Antisense TGF-beta2 immunotherapy for hepatocellular carcinoma: treatment in a rat tumor model.

Abstract

The overexpression of transforming growth factor-beta (TGF-beta) in hepatocellular carcinoma (HCC) appears to induce immunosuppression toward the tumor cells. A rat HCC cell line, Morris hepatoma rat cell line (MRH)-7777 (MRH), was transfected with antisense TGF-beta2 in pCEP-4 vector and used as immunotherapy against the development of wild-type tumors. An enzyme-linked immunosorbent assay (ELISA) confirmed that TGF-beta2 production was markedly lower for antisense modified cells as compared to wild-type tumor cells. Tumors were initiated by injecting MRH cells into the flanks of Buffalo rats. This was followed by biweekly vaccinations with irradiated MRH cells (unmodified, pCEP-4 alone, or antisense TGF-beta2 modified). In the group that received irradiated MRH unmodified cells, 55% of rats died from tumor burden, and 36% developed tumor regression. In the group that received irradiated MRH cells modified with pCEP-4 vector alone, 50% died from tumors and 33% had spontaneous regression. In animals treated with pCEP-4/TGF-beta antisense modified cells, none developed tumors. Cell-mediated cytotoxicity assays demonstrated a twofold increase in lytic activity in the effector cells of the animals treated with antisense modified cells. These results demonstrate the successful treatment of HCC tumors in rats by a HCC vaccine genetically altered with antisense TGF-beta2. Decreased production of TGF-beta in HCC vaccine enhances immunogenicity against wild-type HCC tumor cells.