Abstract
Aim Immune checkpoint inhibitors (ICIs) have improved the survival rate of patients carrying various malignant neoplasms. Despite their efficacy, ICIs occasionally induce liver injury as an immune-related adverse event (irAE). This study aimed to reveal the clinical features of the hepatic irAE in Japanese patients. Methods Among 387 patients treated with ICIs, those who developed drug-induced liver injury were investigated. We also describe the histological findings and clinical courses of four patients with hepatic irAE who underwent liver biopsy. Results Among the 56 patients with all-grade liver injury, only 11 (19.6%) showed hepatocellular-type liver injury, which resembled autoimmune hepatitis. Thirty-four patients (60.7%) developed cholestatic or mixed-type liver injury, although only one patient showed abnormal image findings in the bile duct. Most patients with grade ≤2 liver injury improved spontaneously, while two patients with biliary dysfunction required ursodeoxycholic acid or prednisolone. Among eight patients with grade ≥3 liver injury, three required no immunosuppressants and five were treated with prednisolone (three of five patients required other types of immunosuppressants). Four patients in the case series showed diverse clinical features in terms of hepatotoxic pattern, symptoms, and the interval time between the initiation of immunotherapy and the onset of the hepatic irAE. Conclusions Our findings suggest that ICIs could cause microscopic biliary disorder without any abnormal image finding. Because the hepatic irAE presents diverse clinical features, liver biopsy is recommended to provide appropriate treatments.
Highlights
Some kinds of cancers escape the host immune system by “immune checkpoint” pathways, which potentiate cancer cell survival [1]
Nivolumab and pembrolizumab recognize programmed cell death 1 (PD-1), which is expressed on the cell surface of T lymphocytes, and block the interaction between PD-1 and programmed death ligand (PDL)-1 and -2, which are expressed on cancer cells
Atezolizumab and durvalumab block PD-L [6, 7] and ipilimumab targets cytotoxic T lymphocyte antigen 4 (CTLA4) on the cell surface of T lymphocytes [8]. e blockage of this ligand-receptor interaction inhibits the inactivation of T lymphocytes and regains the anticancer effects. e clinical benefits of Immune checkpoint inhibitors (ICIs) can be disturbed by the immune-related adverse events caused by the imbalance of the immune system induced by ICIs [9]. e incidence of the allgrade hepatic irAE with anti-PD-1 monoclonal antibodies, anti-CTLA-4 mAb, and their combination therapy is in the range of 1% –3% [10, 11], 3%–9% [12], and 18% [13], respectively. e mechanism of the hepatic irAE is presumed
Summary
Some kinds of cancers escape the host immune system by “immune checkpoint” pathways, which potentiate cancer cell survival [1]. Immune checkpoint inhibitors (ICIs) block the immune checkpoint pathways and re-activate the T-cell responses towards cancer cells. ICIs have improved the survival rate of patients carrying various tumor [2, 3]. Nivolumab and pembrolizumab recognize programmed cell death 1 (PD-1), which is expressed on the cell surface of T lymphocytes, and block the interaction between PD-1 and programmed death ligand (PDL)-1 and -2, which are expressed on cancer cells [4, 5]. Atezolizumab and durvalumab block PD-L [6, 7] and ipilimumab targets cytotoxic T lymphocyte antigen 4 (CTLA4) on the cell surface of T lymphocytes [8]. We describe the histology and clinical course of four patients with hepatic irAE
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