Subunit peptide cancer vaccines targeting activating mutations of the p21 ras proto-oncogene.

Abstract

Activating mutations of the p21 ras proto-oncogene are involved in the development of many common malignancies. Because activating mutations are limited in number, occur within otherwise completely conserved regions, and can be expressed by premalignant lesions, ras is an attractive target for subunit peptide vaccine approaches. Several studies in transplantable tumor models support the possibility that protection against tumors bearing activated ras can be achieved using peptide-based immunogens. We have identified an autochthonous tumor model, A/J mouse lung, which parallels human tumors in the progression of proliferative lesions from premalignant to malignant and which is a very sensitive in vivo system for the detection of activated ras. Although T-cells recognizing a number of activating substitutions can be elicited in this model, peptide immunogens corresponding to the most commonly observed activating mutations are weakly immunogenic. We have engineered a chimeric immunogen incorporating a promiscuous T-cell epitope to enhance the immunogenicity of an oligopeptide corresponding to a weakly immunogenic substitution. These and other challenges associated with developing subunit peptide vaccines to prevent tumors bearing activated ras are discussed.