title: Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant.
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.
authors.affiliation: Dermatological Clinic, Inselspital, University of Berne, Switzerland. re.hunger@gmx.net
authors.forename: R E
authors.initials: RE
authors.lastname: Hunger
authors.forename: C U
authors.initials: CU
authors.lastname: Brand
authors.forename: M
authors.initials: M
authors.lastname: Streit
authors.forename: J A
authors.initials: JA
authors.lastname: Eriksen
authors.forename: M K
authors.initials: MK
authors.lastname: Gjertsen
authors.forename: I
authors.initials: I
authors.lastname: Saeterdal
authors.forename: L R
authors.initials: LR
authors.lastname: Braathen
authors.forename: G
authors.initials: G
authors.lastname: Gaudernack
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000917:Antibody Formation; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells / Q000473:pathology; D005240:Feasibility Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007271:Injections, Intradermal; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology; D016283:Proto-Oncogene Proteins p21(ras) / Q000008:administration & dosage* / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D010446:Peptide Fragments; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)