Preclinical development of a mutant KRAS targeting therapeutic cancer vaccine.

KRAS mutations are frequent oncogenic drivers in several indications, yet limited targeted therapy options are available. Here we engineered our clinically validated artARENA platform to develop an "off-the-shelf" shared neoantigen vaccine, capable of triggering potent CD8+ T-cell responses against the five most prevalent KRAS mutations (G12D, G12V, G12C, G12R, and G13D). Alternating two-vector therapy (sequential administration of artPICV-based vector followed by artLCMV-based vector, encoding the same optimized antigen construct) induced KRAS neoepitope-specific polyfunctional T-cell responses in HLA transgenic mouse strains, showing direct cytotoxicity against KRAS-mutant cell targets in an in vivo assay. Importantly, no cross-reactivity to wt KRAS was observed, highlighting the safety of the approach. Immunogenicity data in mice was corroborated in vitro using T cell stimulation assays, confirming the antigenicity of the construct. Taken together, these results and the clinically validated favorable safety and immunogenicity profiles of our platform warrant clinical translation of this program with the aim to provide more durable and comprehensive tumor control in patients harboring KRAS mutated tumors.