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Antisense TGF-ß2 Immunotherapy for Hepatocellular Carcinoma: Treatment in a Rat Tumor Model

From the Department of Surgery (MM, BK, LD, DKI), UCLA Medical Center, UCLA School of Medicine, Los Angeles, California, and the Department of Surgery, Division of Transplantation (LM, RA, DKI), UC Irvine Medical Center, Orange, California.

Correspondence: Address correspondence and reprint requests to: Dr. David K. Imagawa, UC Irvine Medical Center, Dept. of Surgery, Div. of Transplantation, Bldg 26, Room 1001, Route 81, 101 The City Drive, Orange, CA 92868-3298; Fax: 714-456-8796; E-mail: dkimagaw{at}uci.edu

BACKGROUND: The overexpression of transforming growth factor-beta (TGF-ß) in hepatocellular carcinoma (HCC) appears to induce immunosuppression toward the tumor cells.

METHODS: A rat HCC cell line, Morris hepatoma rat cell line (MRH)-7777 (MRH), was transfected with antisense TGF-ß2 in pCEP-4 vector and used as immunotherapy against the development of wild-type tumors. An enzyme-linked immunosorbent assay (ELISA) confirmed that TGF-ß2 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-ß2 modified).

RESULTS: 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-ß 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.

CONCLUSIONS: These results demonstrate the successful treatment of HCC tumors in rats by a HCC vaccine genetically altered with antisense TGF-ß2. Decreased production of TGF-ß in HCC vaccine enhances immunogenicity against wild-type HCC tumor cells.

Key Words: TGF-ß— • Hepatocellular carcinoma— • Antisense— • Gene therapy.

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