DNA fusion gene vaccines induce cytotoxic T-cell attack on naturally processed peptides of human prostate-specific membrane antigen

Eur J Immunol. 2011 Aug;41(8):2447-56. doi: 10.1002/eji.201141518. Epub 2011 Jul 4.

Abstract

For long-term attack on tumor cells in patients with prostate cancer, induction of cytolytic T cells is desirable. Several lineage-specific target proteins are known and algorithms have identified candidate MHC class I-binding peptides, particularly for HLA-A*0201. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to candidate tumor-derived peptide sequences. Using three separate peptide sequences from prostate-specific membrane antigen (PSMA) (peptides PSMA(27) , PSMA(663) , and PSMA(711) ), this vaccine design induced high levels of CD8(+) T cells against each peptide in a HLA-A(*) 0201 preclinical model. In contrast, the full-length PSMA sequence containing all three epitopes was poorly immunogenic. Induced T cells were cytotoxic against peptide-loaded tumor cells, but only those against PSMA(27) or PSMA(663) peptides, and not PSMA(711) , were able to kill tumor cells expressing endogenous PSMA. Cytotoxicity was also evident in vivo. The preclinical model provides a powerful tool for generating CD8(+) T cells able to predict whether target cells can process and present peptides, essential for planning peptide vaccine-based clinical trials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Surface / chemistry
  • Antigens, Surface / genetics
  • Antigens, Surface / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes, T-Lymphocyte / immunology
  • Glutamate Carboxypeptidase II / chemistry
  • Glutamate Carboxypeptidase II / genetics
  • Glutamate Carboxypeptidase II / immunology*
  • HLA-A Antigens / immunology
  • HLA-A2 Antigen
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Peptides / genetics
  • Peptides / immunology*
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • Tetanus Toxin / genetics
  • Tetanus Toxin / immunology
  • Vaccination / methods
  • Vaccines, DNA / administration & dosage
  • Vaccines, DNA / genetics
  • Vaccines, DNA / immunology*

Substances

  • Antigens, Surface
  • Cancer Vaccines
  • Epitopes, T-Lymphocyte
  • HLA-A Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Peptides
  • Recombinant Fusion Proteins
  • Tetanus Toxin
  • Vaccines, DNA
  • Interferon-gamma
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II