Gene therapy by membrane-expressed superantigen for alpha-fetoprotein-producing hepatocellular carcinoma

Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant, which can stimulate T cells bearing certain T-cell receptor beta-chain variable regions, when bound to major histocompatibility complex II molecules. In vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells. In this study, we used SEA fused with CD80 transmembrane region (named as SEAtm) driven by alpha-fetoprotein (AFP) enhancer/promoter to reduce toxicity and to improve safety and efficiency in the application of SEA. We demonstrated that SEAtm by adenovirus from the AFP enhancer/promoter (AdAFPSEA) could be expressed on the surface of AFP-producing cell line Hepa1-6 instead of non-AFP-producing cell lines. Hepa1-6 infected by recombinant adenovirus stimulated proliferation of splenocytes and activated CD4(+) and CD8(+) T cells in vitro. After AdAFPSEA was injected into the subcutaneously established hepatoma in vivo, the expression of SEA was detected in tumor tissues, which subsequently induced tumor-specific cytotoxic T cells in spleen. Moreover, hepatocellular carcinoma (HCC) xenografts were suppressed by treatment with AdAFPSEA and the survival time of treated mice was prolonged. These findings suggest that membrane-expressed SEA by adenovirus from AdAFPSEA can generate stronger local and systemic antitumor responses against HCC.