Abstract
Blockade of various immune targets such as cytotoxic T-lymphocyte antigen-4 and Programmed cell death leads to immune-mediated tumor regression and immune-related adverse events, predominantly gastrointestinal events including diarrhea and colitis. The current review is done to understand the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of gastrointestinal immune-related adverse events. Histological assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease and colitis secondary to immune mediated antibodies are reviewed. Ipilimumab causes dysregulation of gastrointestinal mucosal immunity, which can be evidenced by altered antibody levels to enteric flora and inflammatory cell infiltration into gastrointestinal mucosa associated with diarrhea and clinical evidence of colitis. The pattern of drug induced antibody titers to microbial flora and the histological features and location of the inflammation were distinct from classic inflammatory bowel disease. Although classic inflammatory bowel disease and immune mediated antibodies related gastrointestinal toxicity are both immune mediated, the pattern of biomarkers and histological features suggests that the later may be a distinct clinicopathologic entity.immunome-research
Highlights
Immunotherapy treatment for cancer was first considered in practice by William Coley who proposed active immunizations of cancer patients in the late 19th century [1]
In Crohn’s disease (CD), approximately half of patients are positive for anti-Saccharomyces cerevisiaeantibody (ASCA), anti-CBir1, and anti-I2, anti-OmpC and less than 25% are positive for perinuclear-staining anti-neutrophil cytoplasmic antibody (pANCA), in ulcerative colitis (UC), approximately half of patients are positive for pANCA, but less than 10% are positive for ASCA, antiCBir1, anti-I2, and anti- OmpC [59]
In GI immune-related adverse events (irAEs), like UC pANCA were positive in approximately 50% of cases, like CD antiOmpC were positive in approximately 50% of cases
Summary
Immunotherapy treatment for cancer was first considered in practice by William Coley who proposed active immunizations (later known as Coley toxins) of cancer patients in the late 19th century [1]. The blockade of CTLA-4 by monoclonal antibodies results in immune-related adverse events (irAEs), including diarrhea and colitis [13]. Defects in intestinal epithelial tight junction barrier function are present in CD patients [25] This barrier dysfunction is associated with NOD2 polymorphisms [26], and experimental models demonstrate that barrier dysfunction can activate innate and adaptive mucosal immunity and sensitize subjects to disease [27]. CTLA-4 is a regulatory molecule expressed by T cells that transmits an inhibitory signal to T cells on binding to CD80 and CD86 on antigen-presenting cells The targeting of this inhibitory receptor in immunotherapy has been used to break immune tolerance of T cells to TAAs, resulting in the expansion of T cells that elicit antitumor effects. In subjects with grade 2 or higher GI irAEs, the highest frequency of patients with positive titers were seen with anti-pANCA (21.4%) and anti-OmpC (40.5%), with
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