A phase I vaccine trial with peptides reflecting ras oncogene mutations ofsolid tumors

Mutations in the ras genes occur in 20% of all human cancers. These genes, in turn, produce mutated proteins that are unique to cancer cells, renderin g them distinguishable from normal cells by the immune system. Thus, mutate d Ras proteins may form potential targets for immune therapy. We conducted a phase I/pilot clinical trial in patients with advanced cancers to test th e toxicity and the ability to induce an immune response by vaccination with 13-mer mutated Ras peptides reflecting codon 12 mutations. These peptides corresponded to each of the patient's own tumor Ras mutation. Patients were vaccinated monthly x 3 subcutaneously with the specific Ras peptide along with Deter adjuvant (RiBi ImmunoChem Research, Inc., Hamilton, MT, U.S.A.) at one of five different peptide dose levels (100, 500, 1,000, 1,500, and 5 ,000 mu g). Three out of 10 evaluable patients generated a mutant Ras speci fic CD4+ and/or CD8+ T-cell immune response. The CD8+ cytotoxic cells speci fic for Gly to Val mutation at codon 12 were capable of lysing an HLA-A2-ma tched tumor cell line carrying the corresponding mutant but not the wild-ty pe ras gene. The treatment has been well tolerated with no evidence of seri ous acute or delayed systemic side effects on any of the five dose levels. We demonstrated that we can generate in cancer patients specific T-lymphocy te responses that detect single amino acid differences in Ras oncoproteins. Neither the immune responses nor the minor side effects seen were found to be dose dependent. This approach may provide a unique opportunity for gene rating a tumor-directed therapy. Also, in vitro stimulation of these cells with the corresponding peptide generated specific T-cell lines that could b e used for adoptive immune therapy.