Vascular Toxicities of Immune ChecKpoint Inhibitors : From Bed to Benchside (VICKI)

Immune checkpoint inhibitors (ICIs) are largely prescribed in a growing number of cancer diseases and at earlier stages (non metastatic cancer). Among immune-related adverse events, (iRAEs), the incidence of major cardiovascular events due to atherosclerosis reaches 13% at one year in patients at high risk. To the best of our knowledge, the mechanisms of this acceleration of atherosclerosis have not been studied to this date. The VICKI study aims at furthering our knowledge on the mechanisms of atherosclerotic plaque instability by means of a prospective single-centre pilot study, by comparing: surrogate markers of clinical vasculo-toxicity with arterial Doppler (flow mediated reserve) as defined by the International Cardio-Oncology Society; circulating biomarkers Before and after receiving ICIs for solid cancer treatment.

Context. Immune checkpoint inhibitors (ICIs) are largely prescribed in a growing number of cancer diseases and at earlier stages (non metastatic cancer). Among immune-related adverse events, (iRAEs), the incidence of major cardiovascular events due to atherosclerosis reaches 13% at one year in patients at high risk. To the best of our knowledge, the mechanisms of this acceleration of atherosclerosis have not been studied to this date. Endothelial dysfunction is a predictor of the development of atherosclerotic plaque and events related to erosion or rupture. Endothelial dysfunction correlates well with the increase of circulating microparticles in various populations. The increase of circulating microparticles is also associated with major cardiovascular events. The International society of Cardio-Oncology (IC-OS) recently published a definition for subclinical vascular toxicities due to ICIs. It includes non-invasive imaging methods readily available at the bedside (Herrmann et al. European Heart Journal 2022), largely replicated in the recent European Society of Cardiology (ESC) guidelines 2022. It includes the decrease of flow mediated reserve <7% or hyperhemia index <2; or the decrease of any of these biomarkers > 50% from baseline. Aims and Methods. The VICKI study aims at furthering our knowledge on the mechanisms of atherosclerotic plaque instability by means of a prospective single-centre pilot study, by comparing: surrogate markers of clinical vasculo-toxicity with arterial Doppler (flow mediated reserve, hyperhemia index, plaque volume) as defined by IC-OS; circulating microparticles; Before and after receiving ICIs for solid cancer treatment. The number of participants: 40 patients receiving ICIs for solid cancer (alone or in combination of other cancer drugs); 40 controls (matched by age, gender, cancer type) not treated by ICIs. Duration of participation: up to 6 weeks. Inclusion period: 12 months. Perspectives. The VICKI study may improve our understanding of the mechanisms of atherosclerosis mediated major cardiovascular events. If circulating biomarkers correlate well with Doppler surrogate markers of vascular toxicity, larger studies to refine prediction models could be undertaken. This would be a step forward personalized care for the prediction of major cardiovascular events on ICIs.

All participants will undergo the same cardiovascular assessment; only cancer therapies differ according to standard of care.

Arterial Doppler (ultrasound, no radiation, no contrast agent) and blood sampling twice for participants on ICIs

Surrogate marker of endothelial dysfunction : Signifiant FMD variation on ICIs as defined by the International Cardio-Oncology Society

Correlation of blood biomarkers to endothelial dysfunction (surrogate marker: Flow Mediated Dilatation variation)

Increase in microparticles (CD144+, CD31+/41-, CD62e+, CD235a+, CD41+, CD11+, CD3+); cytokines (e.g., IL-1b, IFNg, TNFa, VEGF-A, C, D, HGF); single-cell profiling and deep immunophenotyping.

Collection of clinically relevant MACE at clinical follow-up: acute coronary syndrome; coronary angioplasty; stroke; cardiac suddent death, myocarditis, myositis.

Inclusion Criteria: All patients scheduled for first ICI therapy at our institution; Matched controls with cancer and no ICI therapy; Exclusion Criteria: Major cardiovascular event in the past 6 months; Unable to provide informed consent; History of ICI therapy