Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora?

Abstract

Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident T in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases.

What did we learn from CTLA‐4 insufficiency on the human immune system?

“…Furthermore, the anti‐CTLA‐4 drugs revealed diverse adverse effects . Colitis is most frequently observed during and after the treatment with ipilimumab, whereas anti‐PD‐1 drugs induce less frequent enterocolitis . The ipilimumab‐associated colitis is mostly characterized by high rate of colonic ulcerations and acute colitis observed in histological examinations, and half of the patients with the ipilimumab‐associated colitis showed chronic, mild, patchy inflammation in the stomach; therefore, the colitis seems to be similar to a severe form of IBD, indicating that the CTLA‐4 blockade provokes diffuse gastrointestinal inflammation, as seen in CTLA‐4‐insufficient patients who develop gastrointestinal symptoms including enteropathy or IBD …”

“…The influence of the individual gut microbiota on the susceptibility to develop colitis under the treatment with checkpoint‐inhibitors has been studied . Dubin et al investigated the relation between the gut microbiota and colitis . The intestinal microbiome composition by using the stool samples from patients with metastatic melanoma undergoing ipilimumab treatment showed that an increase in bacteria belonging to the Bacteroidetes phylum .…”

“…130 Colitis is most frequently observed during and after the treatment with ipilimumab, whereas anti-PD-1 drugs induce less frequent enterocolitis. 146 The ipilimumab-associated colitis is mostly characterized by high rate of colonic ulcerations and acute colitis observed in histological examinations, and half of the patients with the ipilimumab-associated colitis showed chronic, mild, patchy inflammation in the stomach 146 ; therefore, the colitis seems to be similar to a severe form of IBD,…”

“…indicating that the CTLA-4 blockade provokes diffuse gastrointestinal inflammation, 146 as seen in CTLA-4-insufficient patients who develop gastrointestinal symptoms including enteropathy or IBD. 5 The influence of the individual gut microbiota on the susceptibility to develop colitis under the treatment with checkpoint-inhibitors has been studied.…”

“…147 Dubin et al 148 investigated the relation between the gut microbiota and colitis. 146 The intestinal microbiome composition by using the stool samples from patients with metastatic melanoma undergoing ipilimumab treatment showed that an increase in bacteria belonging to the Bacteroidetes phylum. 148 This was correlated with the resistance to the development of the ipilimumab-induced colitis.…”