Current nonclinical approaches for immune assessments of immuno-oncology biotherapeutics.

Harnessing the immune system to kill tumors has been revolutionary and, as a result, has had an enormous benefit for patients in extending life and resulting in effective cures in some. However, activation of the immune system can come at the cost of undesirable adverse events such as cytokine release syndrome, immune-related adverse events, on-target/off-tumor toxicity, neurotoxicity and tumor lysis syndrome, which are safety risks that can be challenging to assess non-clinically. This article provides a review of the biology and mechanisms that can result in immune-mediated adverse effects and describes industry approaches using in vitro and in vivo models to aid in the nonclinical safety risk assessments for immune-oncology modalities. Challenges and limitations of knowledge and models are also discussed.

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.

Immunization with peptides derived from the idiotypic region of lupus-associated autoantibodies delays the development of lupus nephritis in the (SWR x NZB)F1 murine model.

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease affecting 40-50/100,000 Americans. Although most of the research on pathogenic antibodies focuses on antigenic specificity, there is increasing evidence that specific immunoglobulin idiotypes may mediate lupus nephritis independent of autoantigen specificity. In previous work, our laboratory characterized a set of nephritogenic monoclonal antibodies with substantial idiotypic cross-reactivity, produced by the spontaneous SLE model (SWR x NZB)F(1) (SNF(1)), termed Id(LN)F(1). Peptides derived from one of these antibodies, Id540, was previously shown to stimulate pathogenic T-cells from prenephritic SNF(1) mice, similar to what has been seen for pathogenic A6.1 antibody produced by the (NZB x NZW)F(1) model. In this study, we immunized pre-nephritic SNF(1) mice with p62-73, a peptide derived from the variable region of Id540 and, in separate experiments, with p58-69, a peptide derived from the variable region of A6.1. In both cases, immunization resulted in increased survival and delayed nephritis; however, while both peptides affected levels of anti-DNA antibodies, immunization with p62-73 only affected levels of Id(LN)F(1) antibodies. These findings confirm the roles of pathogenic idiotypes in the pathogenesis of lupus nephritis and suggest that therapies that target specific idiotypes might be a potential tool in the management of SLE.