Preclinical development of HIvax: Human survivin highly immunogenic vaccines

Hum Vaccin Immunother. 2015;11(7):1585-95. doi: 10.1080/21645515.2015.1050572.

Abstract

Our previous work involved the development of a recombinant fowlpox virus encoding survivin (FP-surv) vaccine that was evaluated for efficacy in mesothelioma mouse models. Results showed that FP-surv vaccination generated significant immune responses, which led to delayed tumor growth and improved animal survival. We have extended those previous findings in the current study, which involves the pre-clinical development of an optimized version of FP-surv designed for human immunization (HIvax). Survivin-derived peptides for the most common haplotypes in the human population were identified and their immunogenicity confirmed in co-culture experiments using dendritic cells and T cells isolated from healthy donors. Peptides confirmed to induce CD8(+) and CD4(+) T cells activation in humans were then included in 2 transgenes optimized for presentation of processed peptides on MHC-I (HIvax1) and MHC-II (HIvax2). Fowlpox vectors expressing the HIvax transgenes were then generated and their efficacy was evaluated with subsequent co-culture experiments to measure interferon-γ and granzyme B secretion. In these experiments, both antigen specific CD4(+) and CD8(+) T cells were activated by HIvax vaccines with resultant cytotoxic activity against survivin-overexpressing mesothelioma cancer cells. These results provide a rationale for clinical testing of HIvax1 and HIvax2 vaccines in patients with survivin-expressing cancers.

Keywords: EpiMatrix; T-Lymphocytes; cancer vaccines; fowlpox; immunodominant epitopes; mesothelioma; tregitopes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody Formation
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / genetics*
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Genetic Vectors
  • Granzymes / immunology
  • Granzymes / metabolism
  • Humans
  • Immunization
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / isolation & purification
  • Inhibitor of Apoptosis Proteins / genetics*
  • Inhibitor of Apoptosis Proteins / immunology*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Lymphocyte Activation
  • Mesothelioma
  • Survivin
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / immunology
  • Transgenes

Substances

  • BIRC5 protein, human
  • Cancer Vaccines
  • Immunodominant Epitopes
  • Inhibitor of Apoptosis Proteins
  • Survivin
  • Interferon-gamma
  • Granzymes