GSE183883
Inhibition of Bromodomain and Extra Terminal (BET) domain activity modulates the IL-23R/IL17 axis and suppresses acute Graft-Versus-Host Disease [ChIP-seq]
Acute graft-versus-host disease (GVHD) is the major cause of non-relapse mortality post-allogeneic stem cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Treatment options for steroid-refractory acute GVHD are limited. Bromodomain and Extraterminal Domain (BET) inhibitors PLX51107 and PLX2853, deemed safe in human clinical trials in high risk malignancies, significantly downregulate pro-inflammatory Th1 and Th17 responses without impacting T regulatory cells, improving survival in murine models of acute GVHD while retaining beneficial graft-versus-leukemia effects.  Modulation of the IL23/STAT3 axis via BET inhibition resulted in a reduction of pathogenic Th1/Th17 cells in the spleen and acute GVHD target organs such as the gastrointestinal tract.  Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial. Overall design: 6 samples; 3 control (DMSO) vs. 3 treated (PLX2)