Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant

Exp Dermatol. 2001 Jun;10(3):161-7. doi: 10.1034/j.1600-0625.2001.010003161.x.

Abstract

The rapidly increasing incidence and mortality rate of malignant melanoma, together with the lack of efficient treatment of the late stages, makes it a serious threat to public health. Innovative new treatments are needed. The proteins of the ras-family of proto-oncogenes, functioning as relay switches for signalling pathways between cell surface and nucleus, are involved in cell proliferation, differentiation, apoptosis and transformation. If over-expressed or mutated they can induce and/or maintain a transformed state of a cell. Codon 61 mutations of N-ras seem to be involved in melanoma development on sun exposed sites. In order to induce an immune response towards mutated N-ras proteins we performed a phase 1 feasibility study. Ten melanoma patients were immunized intradermally 6 times with N-ras peptides (residue 49-73) with 4 codon 61 mutations using GM-CSF as adjuvant. HLA typing was not used as an inclusion criterion. Eight patients responded with strong delayed type hypersensitivity reactions. In 2 of the patients an in vitro response to the vaccine could also be detected. The specificity of the reaction could be confirmed by cloning of peptide-specific CD4 positive T cells from peripheral blood of the patients. Intradermal injection of ras peptides using GM-CSF as adjuvant is simple to perform and seems to be efficient in inducing cellular immune responses. Since a majority of the patients showed positive skin reactions and 2 of the patients analysed showed a T-helper response to this melanoma specific antigen, these promiscuous HLA class II binding mutant ras peptides may be candidates for inclusion into vaccine cocktails containing various established CTL epitopes.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Adult
  • Aged
  • Antibody Formation
  • Cell Division / drug effects
  • Clone Cells / pathology
  • Feasibility Studies
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / administration & dosage*
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Hypersensitivity, Delayed / immunology
  • Injections, Intradermal
  • Male
  • Melanoma / immunology*
  • Melanoma / pathology
  • Middle Aged
  • Mutation / immunology
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / immunology
  • Proto-Oncogene Proteins p21(ras) / administration & dosage*
  • Proto-Oncogene Proteins p21(ras) / immunology
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • T-Lymphocytes / immunology
  • Vaccination

Substances

  • Adjuvants, Immunologic
  • Peptide Fragments
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)