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

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. Th e proteins of the vas-family of proto-oncogenes, functioning as relay switc hes for signalling pathways between cell surface and nucleus, are involved in cell proliferation, differentiation, apoptosis and transformation. If ov er-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 dev elopment on sun exposed sites, In order to induce an immune response toward s mutated N-ras proteins we performed a phase 1 feasibility study. Ten mela noma patients were immunized intradermally 6 times with N-ras peptides (res idue 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 stron g delayed type hypersensitivity reactions. In 2 of the patients an in vitro response to the vaccine could also be detected. The specificity of the rea ction could be confirmed by cloning of peptide-specific CD4 positive T cell s from peripheral blood of the patients. Intradermal injection of vas pepti des 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 sh owed positive skin reactions and 2 of the patients analysed showed a T-help er 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.