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Immune Checkpoint Inhibitors

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Christian Houbois, MD

Navpreet Sekhon, MB Bch BAO

Patients undergoing dual treatment with Immune checkpoint inhibitors (ICI) for various cancers, e.g. melanoma, are at increased risk of developing myocarditis and cardiomyopathy. Currently, only limited data on serial myocardial tissue changes during treatment and whether they predict outcomes are available. Cardiac MRI (CMR) is the reference standard for non-invasive myocardial volumes/function analysis and uniquely characterizes myocardial tissue. Therefore, it may help detect myocardial tissue changes during treatment and help early treatment and prevent adverse cardiac outcomes.

As patients going through cancer therapy live longer, they are at a higher risk of developing cardiovascular disease. Hence the evolving field of Cardio-Oncology has garnered much attention and importance. In recent years, immune checkpoint inhibitors (ICI) have become an essential component of cancer therapy, significantly improving patient outcomes that were previously considered palliative, e.g. metastatic melanoma, renal cell or lung cancer, and these therapies have improved survival.

With ICI therapy and especially with combination therapy, patients may develop severe ICI-related adverse events, e.g. myocarditis (1-5%) which is fatal in 30-50% of the patients. Another more significant subgroup of patients will develop non-inflammatory cardiomyopathy or other major cardiac events like cardiovascular death, cardiac arrest etc. There is also evidence that during ICI treatment atherosclerotic disease may progress. Identifying patients at risk for both remains a major challenge and is a knowledge gap in Cardio-Oncology.

Cardiovascular magnetic resonance (CMR) is a unique, highly reproducible, multiparametric method for non-invasive myocardial tissue characterization for diagnosing myocardial inflammation. Biomarkers like quantitative cardiac relaxometry (T1/T2-Mapping) with extracellular volume fraction (ECV), delayed gadolinium enhancement (LGE) or myocardial strain show insights into myocardial tissue composition. These biomarkers have the potential to identify early myocardial changes before the risk of clinical myocarditis or non-inflammatory cardiomyopathy occurs and may therefore help identify early myocardial tissue changes during ICI treatment and help identify patients at risk early on. Also, CMR can assess the aorta with high temporal and spatial resolution to identify atherosclerotic changes.

Only a few retrospective studies and case reports with small numbers of patients have investigated ICI-related cardiac events during treatment. Evidence shows that many patients present with heart failure (\~80%), but troponin is only elevated in \~45%. This indicates that ICI-associated left ventricular (LV) dysfunction may exist without troponin elevation. Other data suggests that the ICI-associated myocardial tissue inflammation pattern might differ from viral myocarditis. The myocardial T1/T2 relaxation times may be elevated during ICI-associated myocardial inflammation. There is also evidence that strain changes are associated with adverse events within 30 days of treatment. However, all these studies demonstrate CMR findings when patients have already developed LV dysfunction or myocarditis. The proposed project would be the first prospective study to get deeper insights into serial, systematic ICI-associated myocardial tissue changes during treatment and their correlation with serum biomarkers and clinical symptoms.

Immune Checkpoint Inhibitor Therapy for Cancer and Risk of Myocarditis or Cardiomyopathy

Association of Immune Checkpoint Inhibitor Therapy for Cancer With Early Myocardial Tissue and Biomarker Changes During Treatment - Implication for Risk of Myocarditis and Cardiomyopathy

No plan to share individual participant data with other researchers.

The following parameters are investigated to assess for underlying myocardial remodelling and/or inflammation during treatment with ICI.

Left ventricular volumes in ml Left ventricular ejection fraction in percentage T1 Mapping: T1 relaxation time in milliseconds T2 Mapping: T2 relaxation time in milliseconds ECV = (1-hematocrit) × (Δ(1/T1myocardium)/Δ(1/T1blood)) in percentage Strain (GCS, GLS, GRS) reported as a percentage, formula =(Max Length-Initial Length)/Initial Length LGE is qualitatively described as categorical variables e.g. epicardial, mid-myocardial, subendocardial or transmural.

LGE is quantified as mass in gram and as percentage of the LV mass. High sensitivity troponin 1 nanogram/ mL B-type natriuretic peptide (BNP) nanogram/L High sensitivity CRP in mg/L

This analysis is to determine if the biomarkers are associated with LVEF changes over time.

Left ventricular volumes in ml Left ventricular ejection fraction in percentage T1 Mapping: T1 relaxation time in milliseconds T2 Mapping: T2 relaxation time in milliseconds ECV = (1-hematocrit) × (Δ(1/T1myocardium)/Δ(1/T1blood)) in percentage Strain (GCS, GLS, GRS) reported as a percentage, formula =(Max Length-Initial Length)/Initial Length LGE is qualitatively described as categorical variables e.g. epicardial, mid-myocardial, subendocardial or transmural.

LGE is quantified as mass in gram and as percentage of the LV mass.

This analysis is to determine if blood biomarkers are associated with LVEF changes over time.

High sensitivity troponin 1 nanogram/ mL B-type natriuretic peptide (BNP) nanogram/L High sensitivity CRP in mg/L

Spots Global Cancer Trial Database for myocardial tissue changes