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

Authors

  • Yuan Hong,

    1. Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Augusta, GA
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  • Yibing Peng,

    1. Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Augusta, GA
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  • Z. Sheng Guo,

    1. Department of Surgery, and University of Pittsburgh Cancer Institute, Pittsburgh, PA
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  • Jose Guevara-Patino,

    1. Depart of Surgery, Cardinal Bernardin Cancer Center, Loyola University, Maywood, IL
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  • Junfeng Pang,

    1. Department of Radiology and Molecular Chaperone Biology, Georgia Regents University Cancer Center, Medical College of Georgia, Augusta, GA
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  • Lisa H. Butterfield,

    1. Department of Medicine, Surgery, and Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA
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  • Nahid F. Mivechi,

    1. Department of Radiology and Molecular Chaperone Biology, Georgia Regents University Cancer Center, Medical College of Georgia, Augusta, GA
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  • David H. Munn,

    1. Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Augusta, GA
    2. Department of Pediatrics, Medical College of Georgia, Augusta, GA
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  • David L. Bartlett,

    1. Department of Surgery, and University of Pittsburgh Cancer Institute, Pittsburgh, PA
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  • Yukai He

    Corresponding author
    1. Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Augusta, GA
    2. Department of Medicine, Medical College of Georgia, Augusta, GA
    • Address reprint requests to: Dr. Yukai He, Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, CN-4150, 1410 Laney Walker Blvd., Augusta, GA 30912. E-mail: yhe@gru.edu; fax: 706-721-1670.

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  • Potential conflict of interest: Dr. Munn consults for, received grants from, and owns stock in NewLink Genetics.

  • 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).

Abstract

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)

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