Lung cancer remains the leading cause of cancer death worldwide. Mutations in KRAS are detected in up to 30% of lung cancer cases, about 80% of which occur in codon 12, yet no effective therapies specifically targeting mutant KRAS have been developed. Boosting the host immune response to cancer cells by vaccinating against defined tumor-associated antigens (TAAs) as a means of treating established tumors or preventing the development of tumors in high risk individuals such as current or former smokers is an area of intense research. The present study evaluated both immunogenicity and anti-tumor efficacy of a newly formulated multipeptide (peptides 15-17 amino acids long) vaccine targeting multiple epitopes of the KRAS molecule in a mouse model of KRAS-driven lung tumor. Vaccination was performed in the prevention setting in a transgenic mouse model, where mutated mouse Kras (G12D) is conditionally over-expressed in the lungs of mice using a CCSP promoter. A multi-score prediction algorithm was used to identify likely immunogenic epitopes in the KRAS protein sequence. The identified peptides were synthesized and screened in naïve mice for immunogenicity. The formulated vaccine contained the top four peptides, which elicited the strongest immunologic response and showed 100% sequence homology between human and mouse. The multipeptide KRAS vaccine was then tested in an inducible CCSP-TetO-KRASG12D mouse model, where the vaccines mixed with the Freund’s adjuvant or adjuvant alone were administered prior to activating the mutant KRAS protein. Our results show the KRAS peptide vaccine exhibited striking efficacy, reducing tumor number and tumor burden by >80% when compared with adjuvant alone. Splenocytes collected from vaccinated animals at the end of the study showed a robust immunologic response to the immunizing peptides. Furthermore, in vitro stimulation of these splenocytes by the vaccine peptides resulted in the secretion of cytokines indicative of Th1 (interferon gamma) and Th17 (IL17) responses but with minimal secretion of Th2 related cytokines e.g. IL3 and IL4. In the draining lymph nodes from vaccinated mice rejecting tumors, there was a substantial increase in CD4 cells but a limited increase in CD8 cells. In summary, the multipeptide KRAS vaccine was immunogenic and efficacious in the primary prevention of KRAS-induced lung cancer in mice, indicating that the approach can potentially be used for the prevention of KRAS-driven cancers either alone or in combination with other modalities.
Citation Format: Jing Pan, Qi Zhang, Shizuko Sei, Robert H. Shoemaker, Ronald A. Lubet, Yian Wang, Ming You. Immunoprevention of KRAS-driven lung adenocarcinoma by a multi-peptide KRAS vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1698. doi:10.1158/1538-7445.AM2017-1698