Checkpoint Inhibitor-Induced Colitis: From Pathogenesis to Management

Abstract

The advent of immunotherapy, specifically of immune checkpoint inhibitors (ICIs), for the treatment of solid tumors has deeply transformed therapeutic algorithms in medical oncology. Approximately one-third of patients treated with ICIs may de velop immune-related adverse events, and the gastrointestinal tract is often affected by different grades of mucosal inflammation. Checkpoint inhibitors colitis (CIC) presents with watery or bloody diarrhea and, in the case of severe symptoms, requires ICIs discontinuation. The pathogenesis of CIC is multifactorial and still partially unknown: anti-tumor activity that collaterally effects the colonic tissue and the upregulation of specific systemic inflammatory pathways (i.e., CD8+ cytotoxic and CD4+ T lymphocytes) are mainly involved. Many questions remain regarding treatment timing and options, and biological treatment, especially with anti-TNF alpha, can be offered to these patients with the aim of rapidly resuming oncological therapies. CIC shares similar pathogenesis and aspects with inflammatory bowel disease (IBD) and the use of ICI in IBD patients is under evaluation. This review aims to summarize the pathogenetic mechanism underlying CIC and to discuss the current evidenced-based management options, including the role of biological therapy, emphasizing the relevant clinical impact on CIC and the need for prompt recognition and treatment.

Medicine and Psychology: Modern Problems, New Technologies and Ways of Developing Outdated Theories

“…Symptoms of immune toxicities usually appear 6-9 weeks after the start of treatment, that is, after receiving 2-3 doses of the drug. However, there are cases of "delayed" toxicity, where symptoms appear several months after the end of treatment [365].…”

The JAK-STAT Pathway as a Therapeutic Strategy in Cancer Patients with Immune Checkpoint Inhibitor-Induced Colitis: A Narrative Review

“…Certainly, JAK inhibitors are also gaining prominence in gastroenterology for managing IBD. While sharing commonalities with ICI colitis, the pathogenesis of IBD does exhibit differences, including a self-sustained inflammatory process characterized by a relapsing-remitting course independent of any previous patient treatment [47,48]. Despite this, these two pathologies share a wide range of molecular characteristics concerning the inflammatory pathways involved, as well as frequently exhibiting overlapping clinical and endoscopic presentations [49,50].…”

“…Conversely, the interaction between PD-1 and PD-L1 results in the downregulation of transcription factors like the factor forkhead box protein 3 (Foxp3), causing a further reduction in the immunoregulatory activities of regulatory T cells [86]. This interplay, when activated by anti-CTLA4 and anti-PD1/PD-L1, contributes to the genesis of a microenvironment within the intestines that is highly conducive to the onset of ICI colitis [48]. On the other hand, members of the JAK-STAT family have connections with Foxp3.…”

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“…Indeed, approximately, one third of patients treated with ICIs develop adverse events including colitis, and in severe cases, ICI treatment might need to be discontinued. ICI-induced colitis is one of the leading causes of discontinuation and shows similar pathogenesis to inflammatory bowel disease, and therefore anti-TNF-α treatment is often offered to these patients [ 15 ].…”