DNA fusion vaccine designs to induce tumor-lytic CD8+ T-cell attack via the immunodominant cysteine-containing epitope of NY-ESO 1

Authors

  • Juan Campos-Perez,

    1. Genetic Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Search for more papers by this author
  • Jason Rice,

    1. Genetic Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Search for more papers by this author
  • David Escors,

    1. Department of Immunology and Molecular Pathology, Windeyer Institute, University College, London, United Kingdom
    2. Biomedical Research Centre, Pamplona, Navarre, Spain
    Search for more papers by this author
  • Mary Collins,

    1. Department of Immunology and Molecular Pathology, Windeyer Institute, University College, London, United Kingdom
    Search for more papers by this author
  • Alex Paterson,

    1. Genetic Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Search for more papers by this author
  • Natalia Savelyeva,

    Corresponding author
    • Genetic Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Search for more papers by this author
    • N.S. and F.K.S. are joint senior authors

  • Freda K. Stevenson

    1. Genetic Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
    Search for more papers by this author
    • N.S. and F.K.S. are joint senior authors


Correspondence to: Dr. Natalia Savelyeva, Genetic Vaccine Group, Cancer Sciences Unit, Southampton General Hospital, Southampton SO16 6YD, United Kingdom, Fax: +44-2380-795152, E-mail: ns1@soton.ac.uk

Abstract

The cancer/testis antigen NY-ESO-1 contains an immunodominant HLA-A2-binding peptide (SLLMWITQC), designated S9C, an attractive target for vaccination against several human cancers. As cysteine contains a reactive [BOND]SH, the oxidation status of exogenous synthetic peptide is uncertain. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to tumor-derived peptide sequences (p.DOM-peptide), placed at the C-terminus for optimal immunogenicity. In a “humanized” HLA-A2 preclinical model, p.DOM-S9C primed S9C-specific CD8+ T cells more effectively than adjuvanted synthetic peptide. A DNA vaccine encoding the full NY-ESO-1 sequence alone induced only weak S9C-specific responses, amplified by addition of DOM sequence. The analog peptide (SLLMWITQL) also primed peptide-specific CD8+ T cells, again increased by DNA delivery. Importantly, T cells induced by S9C-encoding DNA vaccines killed tumor cells expressing endogenous NY-ESO-1. Only a fraction of T cells induced by the S9L-encoding DNA vaccines was able to recognize S9C and kill tumor cells. These data indicate that DNA vaccines mimic posttranslational modifications of [BOND]SH-containing peptides expressed by tumor cells. Instability of synthetic peptides and the potential dangers of analog peptides contrast with the ability of DNA vaccines to induce high levels of tumor-lytic peptide-specific CD8+ T cells. These findings encourage clinical exploration of this vaccine strategy to target NY-ESO-1.

Ancillary