Immune Checkpoint Inhibitor Associated Hepatotoxicity in Primary Liver Cancer Versus Other Cancers: A Systematic Review and Meta‐Analysis

Fu, Jianyang; Li, Wang‐Zhong; McGrath, Nicole A; Lai, Chih‐Ming; Brar, Gagandeep; Xiang, Yan‐Qun; Xie, Changqing

doi:10.3389/fonc.2021.650292

Cited by 28 publications

(25 citation statements)

References 144 publications

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“…Liver related toxicities are increasingly recognized and with the approval of ICIs for HCC 79 and in patients with underlying liver disease understanding this form of immune mediated hepatotoxicity is of paramount importance. A recent meta-analysis of checkpoint inhibitor studies in HCC demonstrated that the risk of liver injury as measured by liver enzyme elevations (AST and ALT) in patients with HCC is three times higher than other solid tumors 127 . Certain characteristics such as dual ICI therapy, male sex, younger age have been associated with increased risk of hepatotoxicity, however, the reason why certain individuals develop ILICI while others do not, is not clear.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of immune checkpoint inhibitor-mediated liver injury

Shojaie

Ali

Iorga

et al. 2021

Acta Pharmaceutica Sinica B

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The immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1/ligand-1 (PD-1/PD-L1) are vital contributors to immune regulation and tolerance. Recently immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, they come with the cost of immune related adverse events involving multiple organs such as the liver. Due to its constant exposure to foreign antigens, the liver has evolved a high capacity for immune tolerance, therefore, blockade of the immune checkpoints can result in aberrant immune activation affecting the liver in up to 20% of patients depending on the agent(s) used and underlying factors. This type of hepatotoxicity is termed immune mediated liver injury from checkpoint inhibitors (ILICI) and is more common when CTLA4 and PD-1/PD-L1 are used in combination. The underlying mechanisms of this unique type of hepatotoxicity are not fully understood; however, the contribution of CD8 + cytotoxic T lymphocytes, various CD4 + T cells populations, cytokines, and the secondary activation of the innate immune system leading to liver injury have all been suggested. This review summarizes our current understanding of the underlying mechanisms of liver injury in immunotherapy using animal models of ILICI and available patient data from clinical studies.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of immune checkpoint inhibitor-mediated liver injury

Shojaie

Ali

Iorga

et al. 2021

Acta Pharmaceutica Sinica B

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“…Most patients experiencing high-grade hepatitis received anti-PD-1 antibodies, but the small sample size does not allow drawing any firm conclusion about safety aspects related to the specific type of antibody. Importantly, it has been reported that anti-PD-1 therapy is associated with a higher risk of hepatotoxicity in comparison with anti-PD-L1 [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

Personeni

Pressiani

D’Alessio

et al. 2021

Cancers

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Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included—20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4–2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.

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“…While the incidence of ≥ grade 3 ALT elevation in patients treated with Nivolumab for HCC was 8% in an initial trial (Checkmate 040) ( 28 ), the reported incidence of a similar increase in major trials for lung cancer was 0% ( 29 – 31 ) and ranged from 0-4% in trials for melanoma ( 32 – 35 ). In a meta-analysis of 117 trials, the incidence of elevated liver enzymes was increased twofold in patients with liver cancer when compared to other solid tumors overall ( 36 ), higher than in patients treated for melanoma or non-small cell lung cancer ( 6 ). However, this did not lead to an interruption of therapy for HCC patients ( 6 ).…”

Section: Cancer Immunotherapymentioning

confidence: 99%

“…In a meta-analysis of 17 clinical trials, CTLA-4 inhibitors had a higher propensity to cause hepatotoxicity than PD-1 inhibitors (Odds ratio for high-grade hepatoxicity 1.52 vs 0.48) ( 41 ). In a meta-analysis of 117 trials, any-grade ALT and AST elevation was noted in less than 6% of cases and was slightly higher in anti-PD-1 when compared to anti-PD-L1 therapy with ≥ grade 3 increase in 1.3% of cases ( 36 ). In combination therapy, up to a third of patients developed elevated liver enzymes, with ≥ grade 3 hepatitis occurring in 6.4-31% of cases, of which 80% required treatment, representing the most common ≥ grade 3 irAE ( 2 , 3 , 42 ).…”

Section: Cancer Immunotherapymentioning

confidence: 99%

Immune-Mediated Hepatitis During Immune Checkpoint Inhibitor cancer Immunotherapy: Lessons From Autoimmune Hepatitis and Liver Immunology

et al. 2022

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Immune checkpoint inhibitors (ICI) are being increasingly used to successfully treat several types of cancer. However, due to their mode of action, these treatments are associated with several immune-related adverse events (irAEs), including immune-mediated autoimmune-like hepatitis in 5 to 10% of cases. The specific immune mechanism responsible for the development of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI) is currently unknown. This review summarizes the current knowledge on hepatic irAEs during cancer immunotherapy. It also addresses the clinical management of ILICI and how it is becoming an increasingly important clinical issue. Clinical, histological, and laboratory features of autoimmune hepatitis (AIH) and ILICI are compared, and their shared and distinctive traits are discussed in an effort to better understand the development of hepatic irAEs. Finally, based on the current knowledge of liver immunology and AIH pathogenesis, we propose a series of events that could trigger the observed liver injury in ICI-treated patients. This model could be useful in the design of future studies aiming to identify the specific immune mechanism(s) at play in ILICI and improve immune checkpoint inhibitor cancer immunotherapy.

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Immune Checkpoint Inhibitor Associated Hepatotoxicity in Primary Liver Cancer Versus Other Cancers: A Systematic Review and Meta‐Analysis

Cited by 28 publications

References 144 publications

Mechanisms of immune checkpoint inhibitor-mediated liver injury

Mechanisms of immune checkpoint inhibitor-mediated liver injury

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

Immune-Mediated Hepatitis During Immune Checkpoint Inhibitor cancer Immunotherapy: Lessons From Autoimmune Hepatitis and Liver Immunology

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