Genetic Determinants of Myocarditis Induced by Immune-checkpoint Inhibitors

Condition(s) studied

Study summary

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.

Eligibility

Primary outcome measure(s)

• Identify common and rare variants in HLA regions and elsewhere in the genome associated with ICI Myocarditis. — Baseline before ICI start and one follow-up point between 3 to 6 months after ICI
  -Identify common single nucleotide variants(SNV) associated with ICI-myocarditis, such as variants in HLA regions with a genome-wide association study using 100 ICIM and 400 ICI-controls. Any association that reach the genome wide significance levels of 5.10-8 as well as any association mapping to candidate HLA and immune checkpoint genes with p-value\<10-5 will be tested for replication in an external international validation cohort.
• Identify common and rare variants in HLA regions and elsewhere in the genome associated with ICI — Baseline before ICI start and one follow-up point between 3 to 6 months after ICI
  -Sequence the entire protein-coding regions of the genome of all patients to identify extremely rare SNV associated with a strong risk of ICI-myocarditis. Investigators will focus on the search of rare SNV that are present only in the group of ICI-myocarditis patients and prioritize those with high predicted deleteriousness and mapping to candidate genes (immunity genes,cardiac genes).Candidate variants/genes will be further explored in an international validation cohort and by functional studies using a mice model phenocopying ICI-myocarditis condition.

Trial sites (1)

More Assistance Publique - Hôpitaux de Paris trials in France