Potential conflict of interest: Dr. Munn consults for, received grants from, and owns stock in NewLink Genetics.
Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma
Article first published online: 18 FEB 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 4, pages 1448–1458, April 2014
How to Cite
Hong, Y., Peng, Y., Guo, Z. S., Guevara-Patino, J., Pang, J., Butterfield, L. H., Mivechi, N. F., Munn, D. H., Bartlett, D. L. and He, Y. (2014), Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology, 59: 1448–1458. doi: 10.1002/hep.26893
Research in this study was supported by the Distinguished Investigator Fund from Georgia Research Alliance to Yukai He and NIH CA112431 (DHM) and CA062130 (NFM).
- Issue published online: 24 MAR 2014
- Article first published online: 18 FEB 2014
- Accepted manuscript online: 12 OCT 2013 10:10AM EST
- Manuscript Accepted: 6 OCT 2013
- Manuscript Revised: 25 SEP 2013
- Manuscript Received: 8 AUG 2013
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. (Hepatology 2014;59:1448-1458)