Blood Protein Markers of Biologic Treatment Response in Crohn's Disease

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Project Summary Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract often complicated by intestinal fistulas and strictures that can result in irreversible bowel damage. Anti-tumor necrosis factor alpha (anti-TNF) biologics are efficacious in treating CD but many patients do not respond to anti-TNF therapy. The armamentarium for CD is rapidly increasing with new therapies that target novel pathways, such as anti- interleukin 12/23 (anti-IL12/23) agents. There is an urgent need to develop precision medicine approaches for selecting the right treatment for the individual CD patient. Our group has identified a novel cellular module in ileal surgical resection tissue from severe CD patients called the IgG plasma cells, Inflammatory Mononuclear phagocytes, Activated T cells, and Stromal cells (GIMATS) module. We have demonstrated that treatment naïve patients with high GIMATS enrichment in ileal biopsies are significantly more likely to fail anti-TNF therapy. However, tissue-based biomarkers are less scalable for clinical application, while blood-based markers will be more easily implemented and validated. More recently, in work as part of my K23, we demonstrated that a panel of peripheral blood proteins assayed at time of diagnosis in CD patients can predict anti-TNF treatment response. This blood protein panel performed similarly in two independent cohorts and could distinguish anti-TNF responders better than clinical features alone. We aim to build upon this prior work by expanding the number of proteins assayed as potential biomarkers of anti-TNF response. We hypothesize that the performance of our anti-TNF blood protein panel will improve through the addition of markers selected from a discovery panel enriched for proteins highly expressed in cell types associated with anti-TNF resistance (GIMATS module). In Aim 1, we propose to evaluate the association of an expanded panel of blood proteomic markers with anti-TNF response in anti-TNF treated CD patients from the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease (RISK) and the Ocean State Crohn’s Colitis Area Registry (OSCCAR) cohorts. In Aim 2, we will then explore the association of blood proteomic markers with anti-IL12/23 response, including understanding the drug specificity of anti-TNF response protein panels, in two prospective cohorts of CD patients treated with anti-IL12/23 therapy. In both aims, we will utilize a highly sensitive, robust, replicable proteomics assay that is sample sparing with high potential for scalability. Data generated through this R03 award will serve as a foundation for future R01 applications by expanding our proteomic discovery efforts, improving the performance of blood protein panels of anti-TNF response, and exploring blood markers of response to a new class of biologic (anti-IL12/23 therapy).