Lu Dong-Dong, Zhang Xi-Ran

Unresectable hepatocellular carcinoma (HCC) lacks effective therapy and entails very poor prognosis. To investigate the possibility of employing new methods in the treatment of liver cancer we have explored a gene-therapeutic approach to stimulate antitumor immunity by adenoviral-mediated transfer of 4-1BB ligand to treat HCC in rats. In vitro infection of a rat HCC cell line (McA-RH7777) with adenoviral vector expressing 4-1BB ligand (AdCMVm 4-1BBL) induced 4-1BBL expression in a dose-dependent manner. Expression of 4-1BBL in McA-RH7777 cells did not alter their growth rate in vitro, but it abrogated their tumorigenicity when 4-1BBL expressing cells were implanted into the liver of syngenic Buffalo rats. In vivo gene therapy of established orthotopic HCC nodules (6.5 mm in diameter) in Buffalo rats by intratumoral injection of AdCMVm 4-1BBL vector led to complete tumor eradication and long-term survival in 69.5% of treated animals. Therapy with AdCMVm 4-1BBL induced strong lymphocytic infiltration of the tumor tissue and increased apoptosis of malignant cells. The observed antitumor effect was mediated by CD8+T cells and was associated with increased interleukin (IL)-12 serum levels and enhanced natural killer (NK) activity. Animals that eliminated the tumor after in vivo gene therapy developed protective antitumor immunity being resistant to rechallenge with neoplastic cells. Toxicity of the therapy with AdCMVm 4-1BBL was slight, with only a transient increase in the level of serum transaminases and minor lymphocyte infiltration of normal liver tissue. These data demonstrate that intratumoral administration of AdCMVm 4-1BBL may provide an efficient and safe treatment for HCC.

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