Effects of IL-1 beta inhibition on vascular inflammation in TET2 clonal hematopoiesis

Massachusetts General Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging atherosclerotic cardiovascular disease (ASCVD) risk factor. Myeloid driver mutations in the epigenetic regulator TET2 represent the second-most common CHIP subtype, and TET2 CHIP confers particularly high risk for incident and recurrent ASCVD events. Multiple lines of evidence implicate inflammation as a key mechanism of TET2 CHIP-associated ASCVD risk. Our central hypotheses are that, among individuals with ASCVD (prior myocardial infarction [MI]), those with TET2 CHIP will have greater vascular inflammation compared to those without CHIP and that IL-1 inhibition will decrease vascular inflammation in this high-risk group. To test these hypotheses, we will enroll participants from the Mass General Brigham Biobank (with prior whole exome sequencing) and prospectively investigate vascular inflammation in individuals with (n=60) and without (n=60) TET2 CHIP using multiple complementary modalities (Aim 1). Specifically, vascular inflammation will be quantified through the perivascular fat attenuation index (FAI) on CCTA imaging and macrophage-specific arterial infiltration on 99mTc-tilmanocept SPECT/CT imaging. Participants will then be randomized 1:1 to receive canakinumab (n=60) versus placebo (n=60), with reassessment of vascular inflammation after 12 months of therapy (Aim 2) paired with serial whole exome sequencing (Aim 3). Our multidisciplinary team brings extensive experience with cardiac CT imaging, molecular imaging, somatic variant curation to ascertain CHIP status, clinical trial conduct and genotype-based research recruitment, positioning us uniquely well to study vascular inflammation in the context of TET2 CHIP. Further, this study will provide critically needed information on mechanisms by which TET2 CHIP confers heightened ASCVD risk, reveal biomarkers of CHIP extractable from routine clinical imaging, and inform the development of targeted secondary ASCVD prevention strategies among individuals with CHIP, with potential for rapid clinical translation. Thus, the proposed trial would advance our ultimate goal of reducing ASCVD morbidity and mortality in the aging population through novel precision medicine approaches.