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Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity—From Case Report to Mouse Model Validation

1
Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan
2
Department of Thoracic Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan
3
Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
4
Department of Pathology, MacKay Memorial Hospital, Taipei 10449, Taiwan
5
Department of Radiation Oncology, MacKay Memorial Hospital, Taipei 10449, Taiwan
6
Department of Chinese Medicine, China Medical University Hospital, Taichung 40402, Taiwan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(4), 580; https://doi.org/10.3390/cancers11040580
Received: 25 March 2019 / Revised: 17 April 2019 / Accepted: 22 April 2019 / Published: 24 April 2019
(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)
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Abstract

The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. This finding was validated in syngeneic tumor-bearing mice. The mice bearing lung metastases of CT26 colon cancer cells treated with PD-1 and/or PD-L1 inhibitors showed 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. A significant increase of infiltrating neutrophils in myocytes was noted only in mice with sequential blockade, implying a role for the pathogenesis of myocarditis. Among circulating leukocytes, concurrent and subsequent treatment of PD-1 and PD-L1 inhibitors led to sustained suppression of neutrophils. Among tumor-infiltrating leukocytes, combinatorial blockade increased CD8+ T cells and NKG2D+ T cells, and reduced tumor-associated macrophages, neutrophils, and natural killer (NK) cells in the lung metastatic microenvironment. The combinatorial treatments exhibited better control and anti-PD-L1 followed by anti-PD-1 was the most effective. In conclusion, the combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, although it gives better tumor control, and such usage should be cautionary. View Full-Text
Keywords: check point inhibitors; programmed cell death protein 1; programmed cell death 1 ligand 1; cardiotoxicity; lung metastasis check point inhibitors; programmed cell death protein 1; programmed cell death 1 ligand 1; cardiotoxicity; lung metastasis
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Liu, S.-Y.; Huang, W.-C.; Yeh, H.-I.; Ko, C.-C.; Shieh, H.-R.; Hung, C.-L.; Chen, T.-Y.; Chen, Y.-J. Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity—From Case Report to Mouse Model Validation. Cancers 2019, 11, 580.

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