Multiepitope Peptide-Loaded Virus-Like Particles as a Vaccine Against Hepatitis B Virus-Related Hepatocellular Carcinoma

To develop a hepatitis B virus (HBV) therapeutic vaccine that can induce a broad but specific immune response and significant antitumor effects both in vivo and in vitro, we inserted HBV X protein (HBx)-derived epitopes HBX(52-60), HBx((92-100)), and HBx((115-123)); a novel subdominant cytolytic T lymphocyte (CTL) epitope HBx((140-148)); and the universal T helper epitope pan human leukocyte antigen DR-binding epitope into HBV core protein to form multiepitope peptide-loaded virus-like particles (VLPs). CTL responses against epitope-loaded VLPs were elicited by priming with VLP-pulsed dendritic cells in both HLA-A*0201 transgenic (Tg) mice and peripheral blood lymphocytes from HLA-A2(+)/HBx(+) HBV-infected hepatocellular carcinoma (HCC) patients. The multiepitope peptide-loaded VLPs demonstrated significantly higher immunogenicity in Tg mice than any single responsive epitope. Significant antitumor effects were demonstrated both with primary cultured autologous HCC cells in vitro and tumor-bearing Tg mice in vivo in an HLA-A2-restricted and epitope-specific fashion. Conclusion: The significant antitumor effects both in vivo and in vitro demonstrate the potential of multiepitope peptide-loaded VLPs as a vaccine against HCC. (HEPATOLOGY 2009;49:1492-1502.)