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.
Resources from the same session
2262 - Real world experience of Nivolumab therapy in Metastatic Renal Cancer patients: a 3 year multi-centre review
Presenter: Joanna Hack
Session: Poster Display session 3
Resources:
Abstract
4441 - “A pilot study of tremelimumab (treme) with or without cryoablation (cryo) in patients (pts) in metastatic renal cell carcinoma (mRCC).”
Presenter: Matthew Campbell
Session: Poster Display session 3
Resources:
Abstract
2613 - Lenvatinib (Len) alone or in combination with Everolimus (Eve) in heavily pretreated patients (pts) with metastatic renal cell carcinoma (mRCC) after immune checkpoint inhibitors (ICI) and VEGFR-targeted therapies: A single-institution experience
Presenter: Andrew Wiele
Session: Poster Display session 3
Resources:
Abstract
3249 - Weight loss is an underestimated adverse event with cabozantinib in patients with metastastic renal cell carcinoma (mRCC).
Presenter: Emeline Colomba
Session: Poster Display session 3
Resources:
Abstract
2405 - Impact of corticosteroids on nivolumab activity in metastatic clear cell renal cell carcinoma.
Presenter: Felix Lefort
Session: Poster Display session 3
Resources:
Abstract
4020 - Skeletal muscle loss as an adverse event during Cabozantinib treatment in patients with metastatic renal cell carcinoma
Presenter: Carolina Alves Costa Silva
Session: Poster Display session 3
Resources:
Abstract
2407 - Long term relative survival (RS) in patients with primary metastatic kidney cancer (primary mRCC): an analysis of 2,167 patients from the Austrian National Cancer Registry (ANCR).
Presenter: Monika Hackl
Session: Poster Display session 3
Resources:
Abstract
2470 - Advanced renal cell carcinoma: first results from the prospective research platform CARAT for patients with mRCC in Germany
Presenter: Peter Goebell
Session: Poster Display session 3
Resources:
Abstract
1533 - Are immune checkpoint inhibitors a valid option for papillary Renal Cell Carcinoma? Transcriptomic characterization of the immune infiltrate
Presenter: Manon De Vries-brilland
Session: Poster Display session 3
Resources:
Abstract
3367 - Treatment-Free Survival, With and Without Toxicity, as a Novel Outcome Applied to Immuno-Oncology Agents in Advanced Renal Cell Carcinoma
Presenter: Meredith Regan
Session: Poster Display session 3
Resources:
Abstract