Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity—From Case Report to Mouse Model Validation
AbstractThe 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
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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.
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(4):580.Chicago/Turabian Style
Liu, Shin-Yi; Huang, Wen-Chien; Yeh, Hung-I; Ko, Chun-Chuan; Shieh, Hui-Ru; Hung, Chung-Lieh; Chen, Tung-Ying; Chen, Yu-Jen. 2019. "Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity—From Case Report to Mouse Model Validation." Cancers 11, no. 4: 580.
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