Genetic Determinants of Myocarditis Induced by Immune-checkpoint Inhibitors

Genetic Determinants of Myocarditis Induced by Immune-checkpoint Inhibitors

Immune checkpoint inhibitors (ICI) are active in multiple cancers. Their main drawback is the incidence of immune related adverse events; among which ICI-myocarditis (ICIM) is rare but can be the most life-threatening (up to 50% lethal). ICIM is due to ICI unleashing cytotoxic auto-reactive T-cells recognizing a culprit target antigen located on muscles and destroying them. Most often, ICIM occurs within a systemic ICI-myotoxicity, with peripheral muscular involvement (ICI-myositis), mimicking eventually myasthenia-gravis syndrome. Human Leukocyte Antigen (HLA) are cell surface proteins key for the regulation of the immune system acting via presentation of culprit antigens by antigen presenting cells (macrophages) to T-cells, subsequently triggering the destruction/tolerance of cells carrying this antigen. The HLA system (chromosome 6) is the most polymorphic region in the human genome and is associated with auto-immunity including myocarditis. HLA class I alleles have been strongly associated with some T-cell-mediated drug hypersensitivity reactions with handful patients needed to be tested to prevent a single case, leading to globally required cost-effective HLA typing pre-prescription for some drugs.

Immune checkpoint inhibitors (ICI) are revolutionary anticancer therapeutics indicated and active in multiple different cancer types. Approved ICI include antibodies targeting and blocking four main molecules, normally toning down immune system activation: CTLA4 (cytotoxic T-lymphocyte antigen 4), LAG3 (Lymphocyte Activation Gene-3), PD1 (Programmed cell Death protein 1) and its ligand (PDL1). Notably, a set of ~30-40 other molecules are considered as key in immune-checkpoint system and currently investigated as potential drug targets. A main drawback of ICI is the incidence of immune related adverse events (irAE), occurring after unleashing the immune system and which can potentially affect any organ and eventually be fatal. Among IrAE, myocarditis is rare (0.25-1% of ICI treated patients) but is the most life-threatening irAE (up to 50% mortality). ICI-myocarditis occur fast after ICI start (1-3 doses) and is mainly driven by T-cells and macrophages infiltrating muscles including the heart and leading to its necrosis, which manifest clinically with fatal arrhythmias and cardiogenic shock. Another key clinical feature of this myotoxic syndrome induced by ICI is the co-occurrence of ICI-myocarditis with ICI-myositis affecting virtually any other muscle (potentially mimicking ICI-myasthenia gravis), including the respiratory muscles which can lead to severe hypercapnia and death. This mechanism is triggered by ICI boosting a subset of cytotoxic T-cells recognizing a culprit muscular target antigen located on muscles. Co-occurrence of ICI-myocarditis with ICI-myositis has been reported to be almost universal (>90%) in a prospective consecutive cohort of 40 ICI-myocarditis with cardiac and muscular biopsies performed.

Human Leukocyte Antigen (HLA) are key cell-surface proteins responsible for the regulation of the immune system, notably by acting thru the presentation of culprit antigens by antigen presenting cells (e.g macrophages) to T-lymphocytes triggering the destruction/tolerance of cells carrying the culprit antigen in the organism. The HLA system (a complex of genes on chromosome 6) is the most polymorphic region/locus in the human genome and has been associated with protection and predisposition to a broad array of infectious, malignant, and autoimmune diseases including myocarditis. In the past two decades, HLA class I alleles have been strongly associated with T-cell-mediated drug hypersensitivity reactions. For example, in the case of abacavir hypersensitivity and HLA-B*57:01, the negative predictive value is 100% and there is low number of patients (dozens) needed to be tested to prevent a single case, which has led to a durable and effective global pre-prescription cost-effective screening strategy, required by regulatory such as FDA. Indeed, only 18 patients with abacavir associated hypersensitivity versus ~160 drug-tolerant were needed to identify the association with the HLA-B*57:01 allele that demonstrated a frequency of 78% in cases versus 2% in drug-tolerant controls. Similar examples with comparable magnitude of effects, i.e. high frequency (~30%-70%) of risk alleles in cases and low frequency (~2%) in controls, have been observed with various HLA (e.g., -B,-C,-A,-DRB1) alleles and auto-immune conditions (e.g., carbamazepine-Toxidermia, allopurinol-Toxidermia, flucloxacillin-hepatitis and statins-necrotizing myopathies).

Altogether, these observations have led us to hypothesize that the susceptibility to ICI-myocarditis could be under the influence of genetic factors within HLA genes but also elsewhere in the genome. Therefore, the investigators propose to perform a genetic study to identify common and rare variants associated with the risk of myocarditis induced by ICI in cancer patients.

The main hypothesis of this proposed work is that common and/or rare polymorphism with large effect size might predispose to the incidence of myocarditis/myotoxicities induced by immune-checkpoint inhibitors.

Inclusion Criteria:

1. Cancer patients on ICI since at least 3 months with a minimum of 2 ICI doses received having no appearance (as compared to baseline known pre-ICI) of a new cardio-muscular symptoms or ECG abnormality or WMA or troponin-T increase (above ULN if normal prior to ICI start, or over twice its troponin-T baseline value if abnormal before ICI start).
2. Signature of informed consent before any trial procedure from the patient
3. Patients covered by social security regimen (excepting AME).

Exclusion Criteria:

1. Age <18 years of age.
2. Pregnant or breast-feeding women
3. People under legal protection measure (safeguard measures)

Specific exclusion criteria for the magnetic resonance imaging sub-study (MRI)

• Patients with a contraindication to MRI (claustrophobia, some wearing equipment with magnetic properties: pacemaker, ferromagnetic equipment, etc.)
• Intolerance to gadolinium, or severe renal insufficiency (GFR<30 ml/min/1.73 m2).

Of note, the other groups of patients needed to complete this study; i.e the patients with refuted suspicion of ICI-myocarditis who will serve as controls, and the patients with ICI-myocarditis (cases) are included in another protocol (NCT05454527)