Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma.

Abstract

UNLABELLED:

Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared-self/tumor antigens that are only able to induce weak immune responses. In this study we investigated whether the HCC-associated self/tumor antigen of alpha-fetoprotein (AFP) could be engineered to create an effective vaccine to break immune tolerance and potently activate CD8 T cells to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. We found that the approach of computer-guided methodical epitope-optimization created a highly immunogenic AFP and that immunization with lentivector expressing the epitope-optimized AFP, but not wild-type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only cross-recognized short synthetic wild-type AFP peptides, but also recognized and killed tumor cells expressing wild-type AFP protein. Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. In addition, prime-boost immunization with the optimized AFP significantly increased the frequency of AFP-specific memory CD8 T cells in the liver that were highly effective against emerging HCC tumor cells, further enhancing the tumor prevention of carcinogen-induced autochthonous HCC.

CONCLUSIONS:

Epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. Our study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild-type AFP.

• Authors: Yuan Hong, Yibing Peng, Z Sheng Guo, Jose Guevara-Patino, Junfeng Pang, Lisa H Butterfield, Nahid F Mivechi, David H Munn, David L Bartlett, Yukai He
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 59 Issue 4 Pg. 1448-58 (Apr 2014) ISSN: 1527-3350 [Electronic] United States
• PMID: 24122861 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Association for the Study of Liver Diseases.

Chemical References

• Cancer Vaccines
• Carcinogens
• Epitopes
• alpha-Fetoproteins

Topics

• Animals
• CD8-Positive T-Lymphocytes (pathology)
• Cancer Vaccines (therapeutic use)
• Carcinogens
• Carcinoma, Hepatocellular (chemically induced, immunology, prevention & control)
• Disease Models, Animal
• Epitopes
• Immune Tolerance (physiology)
• Liver Neoplasms (chemically induced, immunology, prevention & control)
• Male
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Treatment Outcome
• alpha-Fetoproteins (genetics)