Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellularcarcinoma leads to tumor regression in mice

Background & Aims: alpha-Fetoprotein (AFP) is a tumor-associated protein th at is frequently expressed at high levels in hepatocellular carcinoma (HCC) . The aim of the study was to characterize self-reactive cytotoxic T lympho cytes (CTLs) directed against murine AFP (mAFP) after DNA-based immunizatio n in mice, Methods: To study CTL responses, mAFP-expressing recombinant vac cinia viruses were generated. An HCC tumor model was established in C57L/J mice by injection of syngeneic endogenously mAFP-expressing Hepa1-6 cells. Results: Gene gun and intramuscular coimmunizations of DNA expression vecto rs encoding mAFP with plasmids encoding murine interleukin (IL)-12, granulo cyte-macrophage colony-stimulating factor, or IL-18 induced weak CTL activi ty against mAFP in different mouse strains. Some mice developed anti-mAFP a ntibody responses, suggesting breaking of immunologic ignorance, No hepatoc yte damage was detectable despite low-level endogenous hepatic mAFP express ion. Therapeutic immunizations of mice bearing mAFP-expressing murine HCCs induced partial regression of tumors. A significant survival benefit was ob served in mice immunized with mAFP expression vector DNA but not in untreat ed mice or in mice immunized with mock/cytokine plasmid DNA, Conclusions: T he data show that AFP may be used as a potential self tumor antigen to indu ce CTL and CD4(+) T cell-mediated regression of AFP-expressing HCC by DNA-b ased immunization.