Immunotherapy and Gene Therapy: New Challenges in the Diagnosis and Management of Drug-Induced Liver Injury

Abstract

In the last 5 years, the landscape of oncologic treatment has been deeply modified with the development and use of immune checkpoint inhibitors (ICIs) that exert their antitumoral effect by reverting the exhausted phenotype of tumor-infiltrating lymphocytes. This innovative therapeutic strategy has widely changed the prognosis of some advanced neoplastic diseases such as melanoma and lung cancer, providing durable remission for a significant number of patients. Unfortunately, immune-related adverse events (irAEs), especially ICI-induced hepatitis, may be very severe in some cases, impairing the prognosis of the patient. Guidelines available today on the diagnosis and management of ICI-induced hepatitis are mainly based on expert opinions and case series. This lack of large data is explained not only by the low incidence of hepatic adverse events but also by their clinical heterogeneity and variable severity. In this article, we will review the clinical, biological, and histological characteristics of ICI-induced liver injury. We will discuss the current knowledge on their pathological mechanisms and their therapeutic strategy based on immunosuppressive treatment for more severe cases. Regarding severity assessment, we will discuss the gap between the oncologist and the hepatologist’s point of view, highlighting the need for multidisciplinary management. While initially developed for notably less frequent diseases than neoplastic ones, gene therapy is going to be a revolution for the treatment of diseases not responding to pharmacological therapy. Limited but growing data describe liver injury after the administration of such therapy whose exact physiopathology remains unknown. In this article, we will discuss the available data supporting the role of gene therapies in the onset of drug-induced liver injury and related mechanisms. We will describe the clinical context, the biological and histological features, and the management currently proposed.

Effectiveness of immunosuppressant use for the treatment of immune checkpoint inhibitor-induced liver injury: A systematic review and meta-analysis

“…9 Infliximab was used for the treatment of checkpoint inhibitor-induced pneumonitis. 10 2 patients had initial lab data unavailable to be graded. progressive worsening of ALT despite corticosteroid use, which led to the introduction of MMF.…”

“…Several meta-analyses have shown that the incidence of ILICI ranges from 2% to 30% (7)(8)(9). According to previous studies, a few factors have been illustrated to influence the risk of ILICI development or patterns of ILICI, such as the type, dose, or duration of immunotherapy (10,11). ILICI clinical presentation is extremely heterogeneous, from asymptomatic elevations of liver enzymes to, more rarely, severe fulminant hepatitis and liver failure (9,12).…”

The changes of gut microbiota and metabolites in different drug-induced liver injuries

“…Metabolic idiosyncrasy implies that a subject metabolizes drugs in a different way from the majority of people due to the diversity of drug-metabolizing enzymes in each individual. Immunological idiosyncrasy refers to the production of immune responses in the body that are triggered by drugs [22].…”

Postpandemic rebound of adeno‐associated virus type 2 (AAV2) infections temporally associated with an outbreak of unexplained severe acute hepatitis in children in the United Kingdom

“…7 Infections are generally believed to be apathogenic, evoking only a minor inflammatory response, although they have been associated with mild hepatitis when used in gene therapy. [8][9][10] However, AAV2 has recently been implicated in the etiology of the 2022 outbreak of unexplained severe acute hepatitis in children (UHC). [11][12][13][14] Infections with human AdV, specifically AdV type F-41, were initially suspected as it was detected in the majority of cases and at rates statistically significantly higher than control groups, 15 although generally with low virus loads.…”

“…Infections are generally believed to be apathogenic, evoking only a minor inflammatory response, although they have been associated with mild hepatitis when used in gene therapy 8–10 . However, AAV2 has recently been implicated in the etiology of the 2022 outbreak of unexplained severe acute hepatitis in children (UHC) 11–14 .…”