Abstract 2557: Immune modulating agent ibrutinib blocks T-helper 17 activation and release of IL-17A while preserving T-regulatory cell function

Abstract

Abstract T-helper 17 (Th17) cells play a causal role in the pathogenesis of autoimmune and chronic inflammatory diseases. Chronic inflammation has been linked to various malignancies including gastrointestinal cancers, endometrial cancer, and non-Hodgkin lymphoma. Th17 cells secrete effector cytokines that are distinct from other divergent T-cell subsets. The namesake cytokine IL-17A is particularly pro-inflammatory and pro-fibrotic,driving the recruitment, activation, and migration of fibroblasts,endothelial cells, neutrophils, monocytes, and macrophages. Increases in IL-17A have been seen in patients with rheumatoid arthritis, Crohn's disease, multiple sclerosis, systemic lupus erythematosus, psoriasis, and encephalomyelitis. Dysregulated Th17 activity has also been linked to chronic graft versus host disease after allogeneic stem cell transplantation. Studies have shown that Th17 cells and T-regulatory (T-reg) cells are reciprocally regulated in the human body. T-regs produce anti-inflammatory cytokines that play an essential role in the prevention of autoimmune disease. At the molecular level Th17 cells rely upon ITK for T-cell receptor (TCR) induced activation. T-regs, however, utilize both ITK (IL2-inducible kinase) and RLK (resting lymphocyte kinase) establishing compensatory signaling cascades downstream of the TCR. Ibrutinib represents a first-in-class irreversible ITK inhibitor (Dubovsky et al: Blood July 25, 2013) with the established capacity to inhibit the activation of ITK dependent T-cells. Given our understanding of ITK and RLK expression in immune cell subsets we sought to determine whether ibrutinib could block Th17 cellular activation while preserving the functionality of T-regs. Our studies confirm that ibrutinib significantly blocks the TCR-induced activation of Th17 cells by up to 40% (p<0.0001). Moreover, ibrutinib pretreatment significantly limits the production of profibrotic IL-17A after ex-vivo TCR stimulation (p=0.030). Comprehensive and longitudinal murine in-vivo analysis revealed that up to four months of daily ibrutinib at 25mg/kg preserves T-reg numbers. Additional ex-vivo functional analysis demonstrated that the direct immunosuppressive capacity of highly purified(CD4+CD25hiCD127dimFoxP3+) human T-regs to limit activation and proliferation of healthy autologous CD4 or CD8 T-cells was not altered by ibrutinib. Our previously published and currently reported cumulative data along with an impressive clinical safety profile indicate that ibrutinib may therapeutically inhibit Th2 CD4 T-cell function and Th17 driven inflammation and autoimmunity while preserving the anti-inflammatory effects of T-reg cells, thereby justifying its investigation as an immune modulating therapy for cancer and graft versus host disease. Citation Format: Carrie S. Yang, Jason A. Dubovsky, Danielle L. Chappell, Bonnie K. Harrington, Samantha Jaglowski, Jennifer A. Woyach, Amy J. Johnson, Natarajan Muthusamy, John C. Byrd. Immune modulating agent ibrutinib blocks T-helper 17 activation and release of IL-17A while preserving T-regulatory cell function. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2557. doi:10.1158/1538-7445.AM2014-2557