Abstract
Lung cancer remains the leading cause of cancer death worldwide. Mutations in KRAS are detected in up to 30% of lung cancer cases. No effective therapies specifically targeting mutant KRAS have been developed. Vaccination against KRAS mutants is one of the venues of active exploration. The present study evaluated both immunogenicity and antitumor efficacy of a newly formulated multipeptide vaccine targeting multiple epitopes of the KRAS molecule. The formulated vaccine contained top four peptides, which elicited the strongest immunologic response and showed 100% sequence homology between human and mouse. The multipeptide KRAS vaccine was tested in an inducible CCSP-TetO-KRASG12D mouse model, where the vaccine was administered prior to activating the mutant KRAS protein. 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 showed a robust immunologic response to the immunizing peptides. Furthermore, in vitro stimulation of these splenocytes by the vaccinated peptides resulted in the secretion of cytokines indicative of Th1 responses but with minimal secretion of Th2-related cytokines. The multipeptide KRAS vaccine was immunogenic and efficacious in the primary prevention of KRAS-induced lung cancer, indicating that the approach potentially can be used to prevent other KRAS-driven cancers, either alone or in combination with other modalities.
Highlights
Lung cancer, which has a low five-year survival rate, remains the leading cause of cancer death worldwide, with cases rising globally [1]
The present study evaluated both immunogenicity and antitumor efficacy of a newly formulated multipeptide vaccine targeting multiple epitopes of the Kirsten rat sarcoma viral oncogene homolog (KRAS) molecule
We demonstrate that the multipeptide KRAS vaccine is immunogenic and efficacious in the primary prevention of KRAS-induced lung cancer, indicating that the approach potentially can be used to prevent other KRAS-driven cancers, either alone or in combination with other modalities
Summary
Lung cancer, which has a low five-year survival rate, remains the leading cause of cancer death worldwide, with cases rising globally [1]. A number of genetic and epigenetic abnormalities are identified as essential drivers promoting tumor development [2, 3] This has facilitated the identification and characterization of potential tumor antigens that have become relevant targets for the development of cancer vaccines. Among the oncogenes in NSCLC (non-small cell lung cancer), mutations of the Kirsten rat sarcoma viral oncogene homolog (KRAS) are most frequently observed. They may represent up to 30% of lung cancer in the Caucasian smoking population [4], with 80% of them are altered in codon12 [5]. Unlike EGFR mutation, there’s no specific targeted therapies have been developed for KRAS mutations yet, partially due to the lack of druggable pockets and cavities on the RAS surface [6], except for the new compounds recently discovered that target mutant KRASG12C [7], the development of alternative therapies or preventive measures has great appeal
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