Myocarditis in Cynomolgus Monkeys Following Treatment with Immune Checkpoint Inhibitors.

Area of Science:

• Immunology
• Toxicology
• Cardiology

Background:

• Immune checkpoint inhibitors (ICIs) like PD1, PDL1, and CTLA4 can cause immune-related adverse events (irAEs), including myocarditis.
• The mechanisms and early diagnostic markers for ICI-induced myocarditis are not well understood.
• A lack of suitable animal models hinders research into ICI-associated myocarditis.

Purpose of the Study:

• To develop a preclinical model of ICI-induced myocarditis using cynomolgus monkeys.
• To investigate the pathogenesis and potential biomarkers of ICI-induced myocarditis.

Main Methods:

• Cynomolgus monkeys received intravenous infusions of nivolumab plus ipilimumab or a vehicle control.
• Monkeys were monitored for toxicities and euthanized on day 29 for comprehensive analysis.
• Histopathological, immunological, and transcriptomic analyses were performed on multiple organs, including the heart.

Main Results:

• Monkeys treated with ICIs developed multi-organ toxicities, including myocarditis characterized by T-cell infiltration in the myocardium.
• Increased proliferation and activation of T cells were observed in blood, spleen, and lymph nodes.
• Cardiac biomarkers (troponin-I, NT-pro-BNP) were elevated, and cardiac lesions resembled human ICI myocarditis.

Conclusions:

• A cynomolgus monkey model successfully replicates ICI-induced myocarditis and other organ toxicities.
• This model offers a valuable platform for understanding ICI-associated immune mechanisms.
• The model can facilitate the identification of diagnostic biomarkers for ICI-induced adverse events.