Treatment of immune checkpoint inhibitor-induced myocarditis: a retrospective analysis and cell culture model

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, providing improved outcomes for numerous patients. However, treatment with ICIs can result in ICI-myocarditis, a rare yet severe complication. While current guidelines recommend high-dose glucocorticoids as the first-line approach, steroid-refractory cases require alternative immunosuppressive treatment, such as mycophenolate mofetil (MMF). Given the role of the inflammasome activation in ICI-myocarditis, the NLRP3 inhibitor MCC950 is of potential interest. Purpose We aimed to identify early predictors of steroid resistance in patients with ICI-myocarditis. Additionally, a cell culture model was used to explore NLRP3 inhibition as a potential treatment option. Methods In a retrospective study, 73 patients from March 2019 to November 2024 were included. All patients were either hospitalized or assessed at the outpatient clinic due to suspected ICI-myocarditis, indicated by elevation of cardiac biomarkers, typical symptoms, or abnormalities in electrocardiography or echocardiography. 25 patients received glucocorticoids and did not require further immunosuppressive treatment (GC), 20 needed MMF after initial first-line treatment (GC+MMF). In 28 patients, no immunomodulatory treatment was given. In vitro, neonatal rat ventricular myocytes (NRVMs) were treated with Pembrolizumab (ICI), interferon-gamma (INF-γ), human peripheral blood mononuclear cells (hPBMCs) and MCC950. Results Baseline characteristics of the GC and GC+MMF groups from the day of presentation or the subsequent three days were analyzed. Initial levels of troponin T (hs-cTnT) and troponin I (cTnI) compared with upper reference limits did not differ significantly. Baseline echocardiographic parameters were comparable except for lower TAPSE (tricuspid annular plane systolic excursion) in the GC group. Anti-PD1 treatment was slightly overrepresented in the GC+MMF group (p=0.062). Based on age, sex, BMI, cardiovascular risk factors (arterial hypertension, hypercholesterolemia, tabacco use), presence of symptoms, time between first dose of ICI and suspicion of cardiotoxicity and cardiac biomarkers (hs-cTnT, cTnI, NT-proBNP and CRP) no parameter identified steroid resistance within the first three days following presentation. In vitro, NRVMs exposed to hPBMCs and INF-γ showed increased troponin release, while INF-γ alone was sufficient to induce NLRP3 expression. Conclusion So far, no early clinical parameter predicts higher risk of steroid resistance and the need for additional treatment in our cohort. At the cellular level, INF-γ drives inflammation and cardiomyocyte injury. Further investigation is needed to assess NLRP3 inhibitors like MCC950 as a therapeutic option or co-therapy for ICI-Myocarditis.