Abstract 5339
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.
Clinical trial identification
Legal entity responsible for the study
Mackay Memorial Hospital, Taipei, Taiwan.
Funding
Mackay Memorial Hospital, Taipei, Taiwan.
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.