Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with various malignancies, however, they are associated with a wide range of immune-related toxicities affecting many organs, including the liver. Immune-mediated liver injury caused by checkpoint inhibitors (ILICI) is a distinctive form of drug induced liver injury (DILI), that differs from most DILI types in presumed underlying mechanism, incidence, and response to therapeutic interventions. Despite increased awareness of ILICI and other immune-related adverse effects of ICIs reflected by recent guidelines for their management in post marketing clinical practice, there is lack of uniform best practices to address ILICI risk during drug development. As efforts to develop safer and more effective ICIs for additional indications grow, and as combination therapies including ICIs are increasingly investigated, there is a growing need for consistent practices for ILICI in drug development. This publication summarizes current best practices to optimize the monitoring, diagnosis, assessment, and management of suspected ILICI in clinical trials using ICI as a single agent and in combination with other ICIs or other oncological agents. It is one of several publications developed by the IQ DILI Initiative in collaboration with DILI experts from academia and regulatory agencies. Recommended best practices are outlined pertaining to hepatic inclusion and exclusion criteria, monitoring of liver tests, ILICI detection, approach to a suspected ILICI signal, causality assessment, hepatic discontinuation rules and additional medical treatment.

Lymphocytes with aberrant expression of Fas or Fas ligand attenuate immune bone marrow failure in a mouse model.

Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression, respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL, serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when coincubated with C.B10-H2(b)/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sublethally irradiated CB10 mice. All donor LN cells showed significant T cell expansion and activation, but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of proapoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction.

Enrichment of hematopoietic stem cells with SLAM and LSK markers for the detection of hematopoietic stem cell function in normal and Trp53 null mice.

OBJECTIVE: To test function of hematopoietic stem cells (HSCs) in vivo in C57BL/6 (B6) and Trp53-deficient (Trp53 null) mice by using two HSC enrichment schemes. MATERIALS AND METHODS: Bone marrow (BM) Lin-CD41-CD48-CD150+ (signaling lymphocyte activation molecules [SLAM]), Lin-CD41-CD48-CD150- (SLAM-) and Lin-Sca1+CD117+ (LSK) cells were defined by fluorescence-activated cell staining (FACS). Cellular reactive oxygen species (ROS) level was also analyzed by FACS. Sorted SLAM, SLAM-, and LSK cells were tested in vivo in the competitive repopulation (CR) and serial transplantation assays. RESULTS: SLAM cell fraction was 0.0078%+/-0.0010% and 0.0135%+/-0.0010% of total BM cells in B6 and Trp53 null mice, and was highly correlated (R2=0.7116) with LSK cells. CD150+ BM cells also contained more ROSlow cells than did CD150- cells. B6 SLAM cells repopulated recipients much better than B6 SLAM- cells, showing high HSC enrichment. B6 SLAM cells also engrafted recipients better than Trp53 null SLAM cells in the CR and the follow-up serial transplantation assays. Similarly, LSK cells from B6 donors also had higher repopulating ability than those from Trp53 null donors. However, whole BM cells from the same B6 and Trp53 null donors showed the opposite functional trend in recipient engraftment. CONCLUSION: Both SLAM and LSK marker sets can enrich HSCs from B6 and Trp53 mice. Deficiency of Trp53 upregulates HSC self-renewal but causes no gain of HSC function.

Epstein-Barr virus-associated central nervous system lymphoproliferative disease in a patient with acquired immunodeficiency syndrome responsive to highly active antiretroviral therapy.

A 20-year-old man with acquired immunodeficiency syndrome (AIDS) and central nervous system (CNS) lymphoproliferative disease experienced improvement with highly active antiretroviral therapy (HAART) without radiation therapy. Our experience highlights the importance of biopsy in evaluating multifocal radiographic CNS lesions and the central role of HAART in treating AIDS-related CNS disease.