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

Cancers

卷:11

Chung-Lieh Hung¹  Hung-I Yeh¹  Chun-Chuan Ko¹  Hui-Ru Shieh²  Yu-Jen Chen²  Shin-Yi Liu²  Tung-Ying Chen³  Wen-Chien Huang⁴ 

[1] Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan;

[2] Department of Medical Research, MacKay Memorial Hospital, New Taipei City 25160, Taiwan;

[3] Department of Pathology, MacKay Memorial Hospital, Taipei 10449, Taiwan;

[4] Department of Thoracic Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan;

关键词: check point inhibitors;    programmed cell death protein 1;    programmed cell death 1 ligand 1;    cardiotoxicity;    lung metastasis;   

DOI  :  10.3390/cancers11040580

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown