Hepatic Effects, Potential Drug-Induced Liver Injury, and Other Liver Safety Considerations of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in the New Era of Expanding Non-oncology Indications: Literature Review and Expert Consensus

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy is a rapidly expanding key therapeutic category, originally pioneered for haematological malignancies, now being developed into treatments for solid tumours and non-malignant immune-mediated conditions. Chimeric antigen receptor T-cell therapies have some relatively unique toxicities which can affect the liver, in addition to potential drug-induced liver injury and hepatitis B virus reactivation. This manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) Drug-induced Liver Injury (DILI) Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The aim was to produce a comprehensive guide to summarise the hepatic effects of CAR-T, and to propose an approach to the investigation of liver test changes. The clinical characteristics of liver test changes in association with cytokine release syndrome and immune-effector cell haemophagocytic lymphohistiocytosis are described, to enable these anticipated hepatic effects to be distinguished from other causes of abnormal liver tests. The frequency and timing of many primary and secondary liver conditions that may present after CAR-T therapy are described. This review provides the first detailed description of both anticipated and unpredictable hepatic effects of CAR-T cell therapies and is intended to assist in the future characterisation of hepatic effects of CAR-T therapies as programmes move into areas with a different benefit/risk profile, such as autoimmune or other non-oncology indications.