Javid Moslehi, MD and Justin M. Balko, Pharm.D., Ph.D. from Vanderbilt-Ingram Cancer Center discuss A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention.
Cancer therapy has been transformed by immune control point inhibitors (ICI) targeting CTLA-4 or PD-1/PD-L1 but is associated with immune-related adverse effects (irAEs), including myocarditis. A robust preclinical mouse model of ICI-associated myocarditis is reported here, in which mono-allelic loss of Ctla4 in the sense of complete genetic absence of Pdcd1 leads to premature death in about half of the mice. Premature death results from T cell and macrophage myocardial invasion and significant electrocardiographic defects, closely recapitulating the clinical and pathological characteristics of ICI-associated myocarditis found in patients. Using this model, we demonstrate that in a gene dosage-dependent way, Ctla4 and Pdcd1 interact functionally, providing a mechanism by which myocarditis occurs in the setting of combination ICI therapy with increased frequency. We show that CTLA-4-Ig (abatacept) intervention is appropriate to boost the progression of the disease and also include a case series of patients in whom abatacept mitigates the fulminant course of ICI-myocarditis.