Immune checkpoint inhibitor colitis: the flip side of the wonder drugs

Abstract

Immune checkpoint inhibitors block the co-inhibitory receptors on T cells to activate their cytotoxic immune function and are rapidly being explored for the treatment of various advanced-stage malignancies. These novel drugs have already significantly increased survival rates. The first available immune checkpoint inhibitors were cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors (such as ipilimumab), followed by programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors (such as pembrolizumab and nivolumab). Anti-PD-1 and anti-PD-L1 therapies have demonstrated better efficacy and tolerability and less severe adverse effects compared to anti-CTLA-4 agents. Idelalisib, a PI3Kδ isoform inhibitor, is another immunotherapeutic agent that is often classified separately and is currently used in treatment of chronic lymphocytic leukemia and non-Hodgkin lymphomas. Despite successful therapeutic responses, immune-related adverse events have been reported with the use of these agents. The gastrointestinal side effects, particularly diarrhea, are among the most commonly reported symptoms. The histologic features of immune checkpoint inhibitor-associated colitis show a spectrum of patterns of injury among various drug classes. There is significant overlap between immune checkpoint inhibitor-associated colitis and other colitides, making the differential diagnosis difficult-especially in the absence of clinical history. The histopathology data on immune checkpoint inhibitor-associated colitis are limited. Here we review clinical features as well as various histologic patterns of colitis associated with these groups of medications.

Management of Gastrointestinal Toxicity from Immune Checkpoint Inhibitor

“…One study found that diarrhoea of any grade occurs in approximately 45% of patients on combination therapy, 34% of patients on ipilimumab monotherapy, and 21% of patients on nivolumab monotherapy; with grade 3–4 colitis occurring in 8% of patients on combination therapy, 8% of patients on ipilimumab monotherapy, and 1% of patients on nivolumab monotherapy [11]. PD-1 and PDL-1 inhibitors, either nivolumab or pembrolizumab, seem to be less toxic to the gastrointestinal tract than anti-CTLA-4 agents, with grade 3 to 4 irAEs occurring only in 1–2% of cases [1-3, 5]. Recent studies have suggested that patients exposed to nivolumab followed by ipilimumab, or the reverse sequence, who developed previous gastrointestinal toxicity with one of the drugs do not necessarily do so when subsequently treated with the other agent [1, 5].…”

“…CTLA-4 is constitutively expressed by regulatory T cells (Treg cells), an immunomodulatory subset of CD4+ effector T cells, which have an instrumental role in immunological tolerance. In addition to producing immunosuppressive cytokines, Treg cells might also affect activation of conventional CD4+ T cells and CD8+ T cells [3-5]. …”

“…Binding of PD-L1 to PD-1 triggers the inhibition of the TCR signaling pathway and reduces the expression and production of cytokines and transcription factors that are associated with effector T-cell function. The PD-1 pathway might also promote Treg cell suppression and has been implicated as an important checkpoint in the activation and development of innate lymphoid cells, involved as significant effector cells at mucosal surfaces and especially the gut [3-5]. …”

“…In recent years, targeted immunotherapy against these immune checkpoints has been widely explored and is now approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of advanced melanoma, non-small cell lung carcinoma, renal cell carcinoma, colorectal carcinoma, Hodgkin’s lymphoma, and urothelial carcinoma [1, 3, 5]. Approved immune checkpoint inhibitors (ICPIs) include five anti-PD-1 antibodies (nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab) and one CTLA-4 inhibitor (ipilimumab) [3, 5].…”

“…Approved immune checkpoint inhibitors (ICPIs) include five anti-PD-1 antibodies (nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab) and one CTLA-4 inhibitor (ipilimumab) [3, 5]. …”