Treatment of clonal hematopoiesis associated atherosclerosis via vaccine-based clearance of the mutant cells

INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP), driven by somatic mutations (e.g., TET2), is an independent risk factor for atherosclerosis (AS). CHIP-mutant macrophages promote plaque inflammation, but targeted therapies are lacking. Crucially, whether these clones acquire immunogenic neoantigens-enabling immune clearance-remains unexplored. OBJECTIVE: To investigate if Tet2-mutant cells in CHIP-associated AS develop immunogenic neoantigens and evaluate a neoantigen-targeting vaccine strategy. METHODS: mice fed a high-fat diet to model CHIP-accelerated AS. DNA and RNA sequencing of Tet2-mutant macrophages identified nonsynonymous mutations. Neoantigen immunogenicity was predicted in NetMHCpan. A therapeutic vaccine (GelVax) encapsulating mutant cell lysates (neoantigen source), GM-CSF (DC recruitment), and R848 (TLR agonist) within a biocompatible hydrogel was developed. Efficacy was assessed in the AS model. RESULTS: T-cell dependent. CONCLUSION: T cell responses, clears pathogenic macrophages, and ameliorates atherosclerosis. This validates mutant neoantigens as actionable targets for CHIP-driven cardiovascular disease.