A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention

• Published in: Cancer discovery Vol. 11; no. 3; pp. 614 - 625
• Main Authors: Wei, Spencer C, Meijers, Wouter C, Axelrod, Margaret L, Anang, Nana-Ama A S, Screever, Elles M, Wescott, Elizabeth C, Johnson, Douglas B, Whitley, Elizabeth, Lehmann, Lorenz, Courand, Pierre-Yves, Mancuso, James J, Himmel, Lauren E, Lebrun-Vignes, Benedicte, Wleklinski, Matthew J, Knollmann, Bjorn C, Srinivasan, Jayashree, Li, Yu, Atolagbe, Oluwatomisin T, Rao, Xiayu, Zhao, Yang, Wang, Jing, Ehrlich, Lauren I R, Sharma, Padmanee, Salem, Joe-Elie, Balko, Justin M, Moslehi, Javid J, Allison, James P
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.03.2021
• Subjects: Animals; Biomarkers, Tumor - antagonists & inhibitors; Cardiotoxicity; Disease Management; Disease Models, Animal; Disease Susceptibility; Electrocardiography; Humans; Immune Checkpoint Inhibitors - adverse effects; Immune Checkpoint Inhibitors - therapeutic use; Immunology; Life Sciences; Mice; Molecular Targeted Therapy - adverse effects; Myocarditis - diagnosis; Myocarditis - etiology; Myocarditis - metabolism; Neoplasms - complications; Neoplasms - drug therapy; Neoplasms - etiology; Pharmaceutical sciences; Pharmacology; negative costimulation; haploinsufficiency; autoimmunity; PD -1; T cell; myocarditis; Ctla4; CTLA-4; Pdcd1; cardio-oncology; immune- related adverse events
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-20-0856

Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of in the context of complete genetic absence of leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that and functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies. . .