Mutant ras epitopes as targets for cancer vaccines.

The ras p21 proto-oncogenes (ie, K-ras, H-ras, N-ras) encode a family of proteins vital to cellular signaling and function. Point mutations in these genes have been found in a wide diversity of human cancers, suggesting a strong association in the development of the malignant phenotype. Although the precise mechanisms leading to tumorigenesis are not fully understood, it has been proposed that point mutations in the ras p21 proto-oncogenes contribute to the transformation process through constitutive transduction of growth-promoting signals. These oncoproteins are distinct from normal ras p21 in both DNA and protein sequences at specific sites, typically positions 12, 13, 59, or 61. A large frequency of human cancers harbor point mutations in the ras gene at codon 12, where the normal Gly residue is substituted with either a Val, Asp or Cys residue. From an immunologic perspective, these "neo-determinants" may now represent unique and highly specific epitopes for T cell (CD4+ and/or CD8+) recognition in cancer immunotherapy. Evaluation of point-mutated ras as a T-cell epitope could be determined biologically with short synthetic peptides that precisely mimic those altered sites. Several laboratories have established approaches in both murine and human systems to evaluate the point-mutated ras p21 oncogene product as a potential tumor-specific target and characterization of the resulting cellular immune responses. It has been demonstrated that (1) active immunization of mice with the appropriate mutant protein or peptides leads to the production of cytotoxic CD4+ (Th1 subtype) or CD8+ T lymphocytes, which mediate MHC-restricted, antigen-specific lysis of tumor cells in vitro bearing endogenous mutant ras epitopes; and (2) in vitro stimulation of human lymphocytes from some normal individuals or carcinoma patients with mutant ras peptides results in the expansion of CD4+ and CD8+ precursors, which may exhibit cytotoxicity against autologous or MHC-matched, antigen-bearing target cells. Taken collectively, these preclinical findings provide the rationale for the development of potential immunotherapies directed against point-mutated ras oncogene products.