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.)