Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.

Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs). Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens. In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1-49) weeks and median number of immunotherapy injections was two (range, 1-36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5-1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction. Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration. Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.

De Martin E ，Michot JM ，Papouin B ，Champiat S ，Mateus C ，Lambotte O ，Roche B ，Antonini TM ，Coilly A ，Laghouati S ，Robert C ，Marabelle A ，Guettier C ，Samuel D ... -  《-》

New insight in endocrine-related adverse events associated to immune checkpoint blockade.

Anticancer immunotherapy, in the form of immune checkpoint inhibition, is a paradigm shift that has transformed the care of patients with different types of solid and hematologic cancers. The most notable improvements have been seen in patients with melanoma, non-small-cell lung, bladder, renal, cervical, urotherial, and colorectal cancers, Merkel cell carcinoma, and Hodgkin lymphoma. Monoclonal antibodies (mAbs) targeting immune checkpoints (i.e., anti-CTLA: ipilimumab; anti-PD-1: nivolumab, pembrolizumab; anti-PD-L1: durvalumab, atezolizumab, avelumab) unleash the immune system against tumor cells targeting mainly T cells. Treatment with immune checkpoint inhibitors (ICIs) is associated with a variety of diverse and distinct immune-related adverse events (irAEs), reflecting the mechanistic underpinning of each target (i.e., CTLA-4, and PD-1/PD-L1 network). The most frequent endocrine irAEs associated with anti-PD-1 mAb treatment are thyroid dysfunctions, whereas hypophysitis is mostly linked to anti-CTLA-4 treatment. Type 1 diabetes mellitus and adrenalitis are rare irAEs. Combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) can be associated with an increased risk and prevalence of endocrine irAEs. In this paper we discuss the pathophysiological and clinical aspects of irAEs with specific emphasis on endocrine irAEs associated with ICIs. With a growing number of patients treated with ICIs, a tight collaboration among oncologists, endocrinologists and immunologists appears necessary when the circumstances are more challenging and for better management of severe endocrine irAEs. Further investigations are urgently needed to better understand the mechanisms by which different ICIs can induce a variety of endocrine irAEs.

Elia G ，Ferrari SM ，Galdiero MR ，Ragusa F ，Paparo SR ，Ruffilli I ，Varricchi G ，Fallahi P ，Antonelli A ... -  《-》

Immunopathogenesis of Immune Checkpoint Inhibitor-Related Adverse Events: Roles of the Intestinal Microbiome and Th17 Cells.

The advent of novel, innovative, and effective anti-cancer immunotherapies has engendered an era of renewed optimism among cancer specialists and their patients. Foremost among these successful immunotherapies are monoclonal antibodies (MAbs) which target immune checkpoint inhibitor (ICI) molecules, most prominently cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed cell death protein-1 (PD-1) and its major ligand, PD-L1. These immunotherapeutic agents are, however, often associated with the occurrence of immune-mediated toxicities known as immune-related adverse events (IRAEs). The incidence of severe toxicities increases substantially when these agents are used together, particularly with CTLA-4 in combination with PD-1 or PD-L1 antagonists. Accordingly, dissociating the beneficial anti-tumor therapeutic activity of these agents from the emergence of IRAEs represents a significant challenge to attaining the optimum efficacy of ICI-targeted immunotherapy of cancer. This situation is compounded by an increasing awareness, possibly unsurprising, that both the beneficial and harmful effects of ICI-targeted therapies appear to result from an over-reactive immune system. Nevertheless, this challenge may not be insurmountable. This contention is based on acquisition of recent insights into the role of the gut microbiome and its products as determinants of the efficacy of ICI-targeted immunotherapy, as well as an increasing realization of the enigmatic involvement of Th17 cells in both anti-tumor activity and the pathogenesis of some types of IRAEs. Evidence linking the beneficial and harmful activities of ICI-targeted immunotherapy, recent mechanistic insights focusing on the gut microbiome and Th17 cells, as well as strategies to attenuate IRAEs in the setting of retention of therapeutic activity, therefore represent the major thrusts of this review.

Anderson R ，Theron AJ ，Rapoport BL 《Frontiers in Immunology》

Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study.

Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1. In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry. We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51-75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients. Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted. Gustave Roussy and Gustave Roussy Immunotherapy Program.

Delanoy N ，Michot JM ，Comont T ，Kramkimel N ，Lazarovici J ，Dupont R ，Champiat S ，Chahine C ，Robert C ，Herbaux C ，Besse B ，Guillemin A ，Mateus C ，Pautier P ，Saïag P ，Madonna E ，Maerevoet M ，Bout JC ，Leduc C ，Biscay P ，Quere G ，Nardin C ，Ebbo M ，Albigès L ，Marret G ，Levrat V ，Dujon C ，Vargaftig J ，Laghouati S ，Croisille L ，Voisin AL ，Godeau B ，Massard C ，Ribrag V ，Marabelle A ，Michel M ，Lambotte O ... -  《Lancet Haematology》

[Toxicity of immune checkpoints inhibitors].

Anti-tumoral immunotherapy is currently the basis of a profound modification of therapeutic concepts in oncology, in particular since the arrival of immune checkpoint inhibitors (ICI). In addition to their efficacy profile, these immune-targeted agents also generate adverse events. With the increasing use of ICI for a growing number of tumor types, awareness of immunotherapy-related adverse events is essential to ensure prompt diagnosis and effective management of these potentially serious adverse events. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (irAEs), which resemble autoimmune disease. Though severe irAEs remain rare, they can be fatal if not diagnosed and treated in an appropriate manner. Additional studies are needed to better understand the clinical characteristics and chronology of these adverse effects and to clarify their pathophysiological mechanisms.

Delaunay M ，Caron P ，Sibaud V ，Godillot C ，Collot S ，Milia J ，Prévot G ，Mazières J ... -  《-》