mmpc-logo mmpc-logo
twitter-logo    bluesky-logo
| Create Account | login
Publication
A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated
Myocarditis and Supports a Mechanism-Based Therapeutic Intervention.
Authors Wei SC, Meijers WC, Axelrod ML, Anang NAS, Screever EM, Wescott EC, Johnson DB,
Whitley E, Lehmann L, Courand PY, Mancuso JJ, Himmel LE, Lebrun-Vignes B,
Wleklinski MJ, Knollmann BC, Srinivasan J, Li Y, Atolagbe OT, Rao X, Zhao Y,
Wang J, Ehrlich LIR, Sharma P, Salem JE, Balko JM, Moslehi JJ, Allison JP
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Cancer discovery
Year 2021
Date Published 3/1/2021
Volume : Pages 11 : 614 - 625
PubMed Reference 33257470
Abstract 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.See related commentary by Young and Bluestone, p. 537.This article is
highlighted in the In This Issue feature, p. 521.




Menu

Home
Contact
About MMPC
Animal Husbandry
Tests Data
Search Data
Analysis
Clients
MMPC Centers

Newsletter

Interested in receiving MMPC News?
twitter-logo Mouse Phenotyping
@NationalMMPC



2017 National MMPC. All Rights Reserved.