Serum cytokines and autoantibodies to GM-CSF and immune-related colitis in ipilimumab-treated patients with cancer.
Authors: Gonzalez-Kozlova Edgar , Del Valle Diane , Tuballes Kevin , Barcessat Vanessa , King Stephanie , Huang Hsin hui , Patel Manishkumar , Cabal Rafael , Ioannou Giorgio , Merand Raphael , Postow Michael A. , Faith Jeremiah , Kim-Schulze Seunghee , Faleck David M. , Colombel Jean-Frederic , Gnjatic Sacha 
Published: June 2023

12080

Background: Despite the demonstrated efficacy of immune checkpoint inhibitors (ICI) including CTLA-4 and PD-(L)1 blockade, serious immune related adverse events including immune-related colitis (irColitis) often limit their use. Understanding the mechanisms that drive irColitis as well as predictive biomarkers is critical to informing the benefit:toxicity ratio of these medications. Methods: We tested serial blood specimens from 63 patients enrolled in six ipilimumab-containing clinical trials to evaluate changes in circulating cytokines and autoantibodies (auAb) to GM-CSF with irColitis occurrence. Retrospective blood specimens were analyzed from 31 patients who developed irColitis and 32 age and sex matched controls. irColitis was defined as either: 1) histologically confirmed colitis or 2) clinically significant diarrhea prompting initiation of corticosteroid therapy. Over a 24-week period, serum samples were collected at baseline, week 6, symptom onset, and post-symptom resolution. Serum proteins were assessed using the Immuno-Oncology and Inflammatory Olink panels. Anti-GM-CSF auAb were measured by enzyme-linked immunosorbent assay. Unsupervised clustering and mixed linear models were used to evaluate the changes associated with irColitis. Demographics, treatments, and technical variables were modeled for controlling artifacts. Significance was defined as Log2FC > 0.5, P < 0.05 and FDR < 0.05 (false discovery rate adjusted p-values) denoted with * and **, respectively. Results: While 69 proteins were significantly dysregulated with ICI treatment, patients who developed irColitis compared to those who did not showed higher levels of CD8A*, CXCL10* at baseline and prior to colitis onset at week 6, and then higher MMP10**, IL17A*-C*, CCL20**, OSM**, among others, at time of colitis and resolution. Further, patients who experienced irColitis showed an increase in anti-GM-CSF IgA** and IgG** Ab titers at Week 6 and at colitis onset compared with baseline, with higher IgA* after irColitis resolution compared to no colitis, while no significant differences were identified at baseline. Conclusions: Indicators of clinical outcomes can be obtained easily and minimally invasively by measuring circulating soluble proteins. Here, we identified differentially expressed cytokines associated with irColitis from retrospective cohorts. These potential biomarkers point to transient dysregulation of gut homeostasis that could help to stratify patients developing irColitis and to consider targeted mitigation strategies. These observations are currently being prospectively investigated. NCI support: Scientific and financial support for the IOTN Network is provided through the National Cancer Institute (NCI) U01DK124165. Institutional Review Board (IRB) STUDY #19-0246. This research was funded in part through the NIH/NCI P30 CA008748.