Immune checkpoint inhibitors (ICI) targeting PD1, PDL1, or CTLA4 are associated with Multi-organ immune-related adverse events (irAEs) including myocarditis. The pathogenesis and early diagnostic markers for ICI-induced myocarditis are poorly understood. We aimed to develop a preclinical model to further understand ICI associated myocarditis.
Chinese-origin cynomolgus monkeys were dosed intravenously with vehicle or nivolumab 20 mg/kg plus ipilimumab 15 mg/kg once weekly for a total of four doses. Immunophenotyping of lymphocyte subsets was performed on blood and tissue samples. Microscopic examination of formalin-fixed, paraffin-embedded, hematoxylin and eosin-stained sections was performed on all major organs. Immunohistochemistry and RNA sequencing were performed using heart sections.
ICI combination resulted in loose faeces, lymphadenopathy, and mononuclear cell infiltrations of varying severity in heart, colon, kidneys, liver, salivary glands and endocrine organs. Three of 5 monkeys developed myocarditis characterized by mononuclear cell infiltration in myocardium, cardiomyocyte degeneration, and or increases in cardiac troponin-I and NT-pro-BNP. Mononuclear cell infiltration primarily comprised of T cells, with lower numbers of macrophages and occasional B cells. Morphologically, cardiac lesions in our monkey model are similar to the reported ICI myocarditis in humans. Increased proliferation of CD4+ and CD8+ T lymphocytes as well as an increase in activated T cells and central memory T cells in the blood, spleen, and lymph nodes, were observed. Transcriptomic analysis suggested increased migration and activation of T cells and increased phagocytosis and antigen presentation in the heart.
We have developed a monkey model characterized by multiple organ toxicities including myocarditis. This model may provide insight into the immune mechanisms and facilitate biomarker identification for ICI-associated irAEs.
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Legal entity responsible for the study
C. Ji: Full / Part-time employment: Pfizer.