Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents

Abstract

Immune checkpoint inhibitors (ICIs) block CTLA-4, PD-1 and PD-L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune-related toxicities affecting a variety of organs, including the liver. ICI-associated immune-mediated hepatitis (IMH) ranges in severity between mild and life-threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of ICIs that are powered for efficacy. Risk levels for ICI-induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the ICI dose levels, and the presence of a pre-existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during ICI treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after ICI treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued ICI treatment with close patient monitoring, ICI treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non-steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour-specific ICI treatment responses, as well as an increased susceptibility for clinically serious immune-related adverse events, would help optimize treatment decisions for individual patients.

A review of cancer immunotherapy toxicity

“…Transaminase elevation is observed between 6 and 14 weeks after the initiation of treatment . Although most cases resolve with treatment discontinuation, multiple reports of acute liver failure secondary to nivolumab, pembrolizumab, and ipilimumab have been published . A series of 16 patients who developed grade ≥3 hepatitis during ICI therapy identified different histologic patterns of liver injury in patients treated who received anti–CTLA‐4 compared with anti–PD‐1/anti–PD‐L1 therapies …”

“…11 Although most cases resolve with treatment discontinuation, multiple reports of acute liver failure secondary to nivolumab, pembrolizumab, and ipilimumab have been published. 50 A series of 16 patients who developed grade ≥3 hepatitis during ICI therapy identified different histologic patterns of liver injury in patients treated who received anti-CTLA-4 compared with anti-PD-1/anti-PD-L1 therapies. 55 The differential diagnosis for transaminase elevation during ICI therapy includes drugs (ICI or other), alcohol, and infection, especially viral hepatitis.…”

Immune Response Checkpoint Inhibitors: New Risks of a New Class of Antitumor Agents

“…У пациентов с аутоиммунным гепатитом чаще всего наблюдалось бессимптомное повышение уровня печеночных трансаминаз. Однако в научной литературе появляется все больше данных о тяжелых случаях, связанных с дисфункцией печени (гипербилирубинемия и коагулопатия), а также о редких угрожающих жизни иоНР, сопровождающихся острой печеночной недостаточностью [6,92,98,109].…”

The DILI‐sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation

“…Modeling of adaptive immune responses to the liver has begun and is an area of emphasis going forward. This modeling should provide novel insights into mechanisms underlying idiosyncrasy as well as hepatotoxicity observed with immune modulators, such as the check‐point inhibitors …”

“…This modeling should provide novel insights into mechanisms underlying idiosyncrasy as well as hepatotoxicity observed with immune modulators, such as the check-point inhibitors. 40 Another area of focus will be creation of additional simulated patient populations in DILIsym, including pediatric and elderly patients and patients with liver or kidney dysfunction. At some point in the future, liver safety of a new drug candidate may not have to be tested in these populations if the modeling result is accepted by regulators.…”