Preclinical development of a mutant KRAS targeting therapeutic cancer vaccine

Area of Science:

• Oncology
• Immunotherapy
• Vaccine Development

Background:

• KRAS mutations are prevalent oncogenic drivers across multiple cancers.
• Limited targeted therapy options exist for KRAS-mutant tumors.
• There is a need for effective treatments to improve tumor control.

Purpose of the Study:

• To engineer an "off-the-shelf" neoantigen vaccine targeting common KRAS mutations.
• To evaluate the vaccine's ability to elicit robust CD8+ T-cell responses.
• To assess the safety and efficacy of the vaccine in preclinical models.

Main Methods:

• Development of a shared neoantigen vaccine using the artARENA platform.
• Utilized an alternating two-vector therapy (artPICV and artLCMV) encoding KRAS neoantigens.
• Tested immunogenicity and anti-tumor activity in HLA transgenic mouse models.
• Validated findings through in vitro T cell stimulation assays.

Main Results:

• The vaccine induced KRAS neoepitope-specific polyfunctional T-cell responses.
• Demonstrated direct cytotoxicity against KRAS-mutant cancer cells in vivo.
• Confirmed no cross-reactivity with wild-type KRAS, indicating a favorable safety profile.
• In vitro assays corroborated the construct's antigenicity.

Conclusions:

• The engineered KRAS neoantigen vaccine elicits potent and specific anti-tumor T-cell responses.
• The platform's validated safety and immunogenicity support clinical translation.
• This approach holds potential for durable tumor control in KRAS-mutated cancers.