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Subunit peptide cancer vaccines targeting activating mutations of the p21 ras proto-oncogene
P L Triozzi1, G D Stoner, P T Kaumaya
1Division of Hematology/Oncology, Ohio State University Medical Center, Columbus, USA.
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.
Insights
Targeting Ras mutations with peptide vaccines shows promise for cancer prevention. Enhancing immunogenicity of Ras peptide vaccines is crucial for effective tumor protection against common malignancies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Activating mutations in the p21 ras proto-oncogene drive many common cancers.
- Ras mutations are conserved and present in premalignant lesions, making them ideal targets for peptide vaccines.
- Previous studies suggest peptide immunogens can protect against Ras-mutated tumors.
Purpose of the Study:
- To evaluate the potential of subunit peptide vaccines targeting Ras mutations for cancer prevention.
- To investigate the immunogenicity of Ras peptides in a relevant autochthonous tumor model.
- To engineer enhanced immunogens for weakly immunogenic Ras mutations.
Main Methods:
- Utilized an A/J mouse lung tumor model that mimics human tumor progression.
- Assessed T-cell responses to various activating Ras substitutions.
- Developed a chimeric immunogen by incorporating a promiscuous T-cell epitope to boost immunogenicity.
Main Results:
- Identified a sensitive in vivo model for detecting activated Ras.
- Observed that common Ras mutation peptides are weakly immunogenic.
- Successfully engineered a chimeric immunogen to enhance peptide immunogenicity.
Conclusions:
- Ras is a viable target for subunit peptide vaccines in cancer prevention.
- Enhancing the immunogenicity of Ras peptide immunogens is critical for vaccine efficacy.
- Further development is needed to overcome challenges in creating effective Ras-targeted peptide vaccines.