Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Display session 3

2089 - Pathogenesis of Myocarditis Following Treatment with Immune Checkpoint Inhibitors in a Cynomolgus Monkey Model

Date

30 Sep 2019

Session

Poster Display session 3

Topics

Translational Research

Tumour Site

Presenters

Changhua Ji

Citation

Annals of Oncology (2019) 30 (suppl_5): v760-v796. 10.1093/annonc/mdz268

Authors

C. Ji

Author affiliations

  • Drug Safety Research & Development, Pfizer La Jolla Laboratories, 92121-1150 - San Diego/US

Resources

Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 2089

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Disclosure

C. Ji: Full / Part-time employment: Pfizer.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.