Hepatotoxicity of Immune Checkpoint Inhibitors: An Evolving Picture of Risk Associated With a Vital Class of Immunotherapy Agents

Daniel L. Suzman; Lorraine Pelosof; Amy Rosenberg; Mark I. Avigan

Disclosures

Liver International. 2018;38(6):976-987. 

In This Article

Abstract and Introduction

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.

Introduction

The pharmacological targeting of checkpoint molecules in T–cells or their complementary ligands in antigen–presenting cells (APCs), tumour cells and other cell types, has emerged as a leading strategy for the treatment of a variety of neoplastic diseases.[1–4] Normally, these cell surface molecules play a central role in tightly regulating T–cell responses to antigen–MHC complexes on APCs, together with accessory molecule signalling. A growing number of monoclonal antibodies (mAb) have been designed to disrupt this balance in T–cell regulation for the treatment of human neoplastic diseases, either by blocking one of a set of checkpoint molecules that normally blunt T–cell activity directed against tumour cells or by acting in an agonist fashion in stimulating one of the molecules that normally accelerates T–cell mediated tumour cell surveillance and destruction.[5–8] The 6 mAb targeting checkpoint molecules that have been approved to date by FDA block the normal braking activities of cytotoxic T–lymphocyte associated protein 4 (CTLA–4; ipilimumab), the programmed cell death 1 receptor (PD–1; pembrolizumab and nivolumab) or the programmed death ligand 1 (PD–L1; atezolizumab, avelumab and durvalumab) to increase T–cell responses directed against a variety of neoplasms.[3,9,10]

The importance of immune checkpoint inhibitors (ICIs) as a new broad class of anticancer drugs is evident by the significant response rates to these agents across varying tumour types, the durability of these responses, and their associated improved overall survival rates. This includes 20–30% rates of response to therapeutic antibodies against PD–1 or PD–L1, (eg atezolizumab, nivolumab and pembrolizumab) across multiple tumour types, a 25.2–month median duration of response of squamous non–small cell lung cancer to nivolumab, and a 20–26% 3–year survival rate of patients with unresectable and/or metastatic melanoma after treatment with ipilimumab.[11–14] Crucially, although responses are not seen in all patients, the duration of responses and the survival benefits achieved by these agents in some patients have altered the treatment landscape and ICIs are increasingly part of the standard of care for certain oncological diseases.

Because checkpoint molecules are also expressed in T–cell populations that have specificity for self–antigens, the monoclonal antibodies which target these molecules may also cause autoimmune responses, either by direct effects on autoreactive T–killer cells or on T–regulatory cells (T–regs) that normally suppress the autoimmune reacting cells. Thus, it is not a surprise that a broad range of unintended immune–related adverse events (irAEs) affecting different organs have been associated with exposure to these products.[15–21] Although clinically significant hepatotoxicity owing to ICI monotherapy occurs less commonly than some other irAEs associated with these products,[16] fatal immune–related liver injury has been observed both in some clinical trials and the posT–market setting, indicating the critical importance of early recognition and appropriate management of these events.

This review addresses findings of clinical studies of FDA–approved checkpoint inhibitors that have been developed to block CTLA–4, the PD–1 receptor or its ligands for the treatment of different tumours, and their unintended immunologically mediated clinical profiles of hepatotoxicity.

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