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.


CONCLUSIONS
The significant antitumor effects both in vivo and in vitro demonstrate the potential of multiepitope peptide-loaded VLPs as a vaccine against HCC.
Ding
Fei-Xiang
FX
Department of Medical Genetics, The Second Military Medical University, Shanghai, People's Republic of China.
Wang
Fang
F
Lu
Yi-Ming
YM
Li
Ka
K
Wang
Kai-Hui
KH
He
Xiao-Wen
XW
Sun
Shu-Han
SH
D019264:Adoptive Transfer; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000821:virology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D017325:Hepatitis B Vaccines / Q000096:biosynthesis*; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D055550:Protein Stability; D015534:Trans-Activators / Q000276:immunology*; D014611:Vaccination; D022223:Vaccines, Subunit / Q000096:biosynthesis; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D017325:Hepatitis B Vaccines; D015534:Trans-Activators; D022223:Vaccines, Subunit; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein