Gastrointestinal mucosal toxicities from immune checkpoint inhibitors: Current understanding and future directions

Abstract

SummaryImmune checkpoint inhibitor (ICI) therapy has revolutionized the field of oncology over the past decade, leading to durable remissions in some patients but also producing a wide spectrum of treatment‐limiting inflammatory toxicities that are referred to as immune‐related adverse events (irAEs). Although irAEs can involve any organ system in the body, they most commonly affect the barrier tissues, including the gastrointestinal tract with colitis and enterocolitis affecting a significant fraction of patients on ICIs. We are beginning to understand the mechanisms that drive ICI colitis, with early experiments indicating a role for CD8+ resident memory T cells (TRMs) in the gut, which become activated and differentiate into cytotoxic cells in response to ICI therapy. The risk factors that define who will develop ICI colitis are not understood and substantial efforts are underway to identify potential biomarkers for risk of this and other toxicities. Optimal management of ICI colitis is also an area of active investigation. Current standard treatments are based largely on small, retrospective analyses, and while drugs like systemic glucocorticoids or the TNFα inhibitor infliximab do appear to be highly active in ICI colitis, the impact of these therapies on antitumor responses is poorly understood. As discussed in this review, future work will have to define the immune mechanisms driving ICI colitis in more detail and in comparison to antitumor responses in order to identify candidate pathways that can be targeted to improve ICI colitis without interfering in antitumor immunity. Studying these interventions will require randomized, controlled trials with both tumor and colitis endpoints, a goal that will necessitate collaboration across institutions and funding agencies. We are at a point where such collaborative trials are feasible, and have the potential to greatly improve the care of patients with ICI colitis as well as other irAEs.

The evolving landscape of immune‐related adverse events that follow immune checkpoint immunotherapy in cancer patients

“…The review by Michael Dougan provides a comprehensive review on the gastrointestinal (GI) toxicities caused by ICIs 32 . Although most of the GI irAEs are mild in nature, their high occurrence rate makes them the leading cause of severe toxicities associated with ICIs.…”

“…The review by Michael Dougan provides a comprehensive review on the gastrointestinal (GI) toxicities caused by ICIs. 32 Although most of the GI irAEs are mild in nature, their high occurrence rate makes them the leading cause of severe toxicities associated with ICIs. In his review, he provides an in-depth description of the clinical manifestations along with a thorough discussion of the immune mechanisms known to-date (e.g., gut CD8 + TRMs) associated with ICI-colitis, which is the most common GI toxicity associated with the use of ICIs.…”