TY - JOUR
T1 - A genetic mouse model recapitulates immune checkpoint inhibitor–associated myocarditis and supports a mechanism-based therapeutic intervention
AU - Wei, Spencer C.
AU - Meijers, Wouter C.
AU - Axelrod, Margaret L.
AU - Anang, Nana Ama A.S.
AU - Screever, Elles M.
AU - Wescott, Elizabeth C.
AU - Johnson, Douglas B.
AU - Whitley, Elizabeth
AU - Lehmann, Lorenz
AU - Courand, Pierre Yves
AU - Mancuso, James J.
AU - Himmel, Lauren E.
AU - Lebrun-Vignes, Benedicte
AU - Wleklinski, Matthew J.
AU - Knollmann, Bjorn C.
AU - Srinivasan, Jayashree
AU - Li, Yu
AU - Atolagbe, Oluwatomisin T.
AU - Rao, Xiayu
AU - Zhao, Yang
AU - Wang, Jing
AU - Ehrlich, Lauren I.R.
AU - Sharma, Padmanee
AU - Salem, Joe Elie
AU - Balko, Justin M.
AU - Moslehi, Javid J.
AU - Allison, James P.
N1 - Funding Information:
This work was supported by a grant from Cancer Prevention and Research in Texas to J.P. Allison (R1203) and NCI Cancer Center Support Grant (CCSG) P30CA16672 which supports core facilities at MD Anderson Cancer Center including the Reverse Phase Proteomic array, Veterinary Pathology, Laboratory Animal Genetics, and Statistical Support cores that were utilized in the described work, as well as NCI/NIH Cancer Center Support Grant 5P30 CA68485?19 (to Vanderbilt) and the Vanderbilt Mouse Metabolic Phenotyping Center Grant 2 U24 DK059637?16. J.J. Moslehi was supported by NIH grants R56 HL141466 and R01 HL141466. D.B. Johnson and J.M. Balko were supported by NCI/NIH R01CA227481. Additional funding was provided by NIH T32GM007347 (M.L. Axelrod) and F30CA236157 (M.L. Axelrod). S.C. Wei was an MD Anderson Cancer Center Odyssey postdoctoral fellow and is currently an employee of Spotlight Therapeutics. J.P. Allison is a CPRIT Scholar in Cancer Research and a Director of the Parker Institute for Cancer Immuno-therapy. The supplied data from VigiBase come from various sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of the WHO. We also thank Lin Zhong from the Vanderbilt University Cardiology Physiology Core for assistance with echocardiogram.
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/3
Y1 - 2021/3
N2 - 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 Ctla4 in the context of complete genetic absence of Pdcd1 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 Ctla4 and Pdcd1 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.
AB - 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 Ctla4 in the context of complete genetic absence of Pdcd1 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 Ctla4 and Pdcd1 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85102125354&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-20-0856
DO - 10.1158/2159-8290.CD-20-0856
M3 - Article
C2 - 33257470
AN - SCOPUS:85102125354
SN - 2159-8274
VL - 11
SP - 614
EP - 625
JO - Cancer discovery
JF - Cancer discovery
IS - 3
ER -