1215P - Sequential blockade of PD-1 and PD-L1 causes fulminant cardiotoxicity: From case report to mice model validation

Abstract

Background: In clinical practice, the sequential use of shifting from a programmed cell death 1 (PD-1) inhibitor to its ligand 1 (PD-L1) inhibitors in consideration of ineffectiveness or toxicity is becoming more common due to prolonged survival. We report a patient in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. To validate this finding, a syngeneic tumor-bearing mice model was used. Methods: A 61-year-old woman with metastatic lung adenocarcinoma, who had received 5 doses of nivolumab (3 mg/kg) and then 1 dose of atezolimumab (1200 mg), complained of chest tightness and dyspnea 4 weeks later. The workup revealed sinus tachycardia, a normal Troponin I level (< 0.01 ng/mL), an elevated creatine kinase-myocardial band (CK-MB) level (10 ng/mL), and an elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) level (2960 ng/mL). Serial echocardiograms revealed left ventricular ejection fractions declining from 66.3 to 59.2 %. Under a diagnosis of myocarditis, she was treated with intravenous methylprednisolone at 5 mg/kg/day and oral mycophenolate mofetil at 1000 mg/day. The progressive clinical deterioration was noted with serial elevation of Troponin I, CK-MB and NT-proBNP levels up to 1.3, 24 and 15738 ng/mL, respectively. Cardiac arrest was noted later. The Balb/c mice bearing lung metastasis of CT26 colon cancer cells were treated with PD-1 and PD-L1 inhibitors for pathological and immuohistochemical studies. Results: The pathology shows that the combination of anti-PD-1 and anti-PD-L1, either sequentially or simultaneously administered, caused myocarditis lesions with myocyte injury and patchy mononuclear infiltrates in the myocardium in all combination group mice (n = 3 for each). The myocarditis lesions were not seen in mice treated with anti-PD-1 or anti-PD-L1 alone. Marked expression of PD-L1 in infiltrating lymphocytes and expression of PD-1 in myocytes was noted only in mice with combination blockade, implying a possible role for pathogenesis of myocarditis. Conclusions: The combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, and such usage should be cautious. Legal entity responsible for the study: Mackay Memorial Hospital, Taipei, Taiwan. Funding: Mackay Memorial Hospital, Taipei, Taiwan. Disclosure: All authors have declared no conflicts of interest.