Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Understanding and Overcoming the Inflammatory Toxicities of Immunotherapy


Abstract

Checkpoint blockade immunotherapy has led to impressive therapeutic responses in a wide variety of tumors, but also leads to a spectrum of inflammatory toxicities that can involve any organ system in the body. Although most inflammatory toxicities resolve with systemic immune suppression, fatal toxicities can occur, and interruption and discontinuation of immunotherapy because of toxicity is common. In addition to their clinical impact, these inflammatory toxicities also provide a window into immune regulation in humans. By studying the cellular and molecular mechanisms that drive this inflammation, we have an opportunity to learn how the immune checkpoints, cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1 and its ligand (PD-L1), maintain immune homeostasis throughout the body. Although we have an increasingly detailed understanding of the mechanisms that drive effective antitumor immunity, we have a rudimentary picture of the mechanisms of toxicity. Most toxicities involve barrier organs, suggesting an important role for interactions with the environment, including the microbiome. Early analyses have implicated cytotoxic T cells, though the antigens recognized by these cells, and the pathways activated by and around them are still unknown. By gaining a detailed understanding of the immune mechanisms of toxicity, we have the potential to develop novel interventions for them. These treatments should take advantage of differences between effective antitumor immunity and the principal drivers of organ inflammation. By targeting these mechanistic differences, we can develop therapies that can be used alongside immunotherapy, blocking inflammatory toxicity while preserving or even enhancing the response to cancer.

Keywords: immune-related adverse events, immunotherapy, toxicity, checkpoint blockade


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534604/

Introduction:Immunotherapy toxicities as a model to understand immune regulation

Immunotherapy has transformed the treatment landscape for cancer, producing durable remissions in tumors that were previously almost uniformly fatal. Monoclonal antibodies that block the regulatory immune checkpoints cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1 and its ligand PD-(L)1 have been the most broadly successful cancer immunotherapy to-date, although numerous other strategies are in development (1). Alongside its impressive success, immunotherapy has led to a diverse range of inflammatory side-effects, collectively referred to as immune-related adverse events (irAEs)(2). Yet, irAEs are more than just toxicities from a drug – they are a window into immune regulation in humans. Checkpoint blockade interrupts immune regulatory pathways in an adult who, in most cases, had a relatively normal immune system prior to the start of therapy. From this perspective, the toxicities of checkpoint blockade are the phenotype of receptor loss. Thus, studying irAEs may provide insight into how CTLA-4, PD-1, and PD-L1 maintain immune homeostasis. Building upon these insights, the broad range of immunotherapies in clinical development (e.g. blockade of LAG3, TIGIT, and TIM3) offer a chance at a far deeper understanding of immune regulation (1).

Understanding checkpoint blockade toxicities may also provide key mechanistic information about the onset of autoimmune disease. Unlike for spontaneous autoimmune diseases, the timing and nature of the inciting immune perturbation are known. Organ inflammation can thus be studied from pre-immunotherapy through the initial symptoms of tissue damage, and ultimately into resolution. These toxicities can then serve as a human model of real disease, with the potential for insight into the earliest stages of autoimmunity where novel therapeutic targets may be identified.

The most common inflammatory toxicities of checkpoint blockade occur at barrier organs, including the skin, gastrointestinal mucosa, liver, and to a lesser extent, respiratory epithelium. This distribution of toxicities suggests that both the CTLA-4 and PD-(L)1 pathways have an important function in limiting the responses to non-pathogenic foreign antigens such as commensal microbes (2). Endocrine glands are the other major class of organs affected by checkpoint blockade toxicities, although any organ system in the body, including joints, cardiac muscle, and the central nervous system, can be targeted (2).