The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia

Abstract

For patients with hematologic malignancies, allogeneic hematopoietic cell transplantation (alloHCT) offers a potential curative treatment option, primarily due to an allogeneic immune response against recipient tumor cells (ie, graft-versus-leukemia [GVL] activity). However, many recipients of alloHCT develop graft-versus-host disease (GVHD), in which allogeneic immune responses lead to the damage of healthy tissue. GVHD is a leading cause of nonrelapse mortality and a key contributor to morbidity among patients undergoing alloHCT. Therefore, improving alloHCT outcomes will require treatment strategies that prevent or mitigate GVHD without disrupting GVL activity. Janus kinases (JAKs) are intracellular signaling molecules that are well positioned to regulate GVHD. A variety of cytokines that signal through the JAK signaling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for GVHD pathogenesis, including dendritic cells, macrophages, T cells, B cells, and neutrophils. Importantly, despite JAK regulation of GVHD, preclinical evidence suggests that JAK inhibition preserves GVL activity. Here we provide an overview of potential roles for JAK signaling in the pathogenesis of acute and chronic GVHD as well as effects on GVL activity. We also review preclinical and clinical results with JAK inhibitors in acute and chronic GVHD settings, with added focus on those actively being evaluated in patients with acute and chronic GVHD.

Treatment and unmet needs in steroid-refractory acute graft-versus-host disease

“…Ruxolitinib is a Janus kinase (JAK) 1/JAK2 inhibitor that became the first JAK inhibitor approved for the treatment of myelofibrosis [76]. JAKs are intracellular signaling molecules and are important effectors of all three phases of the pathogenesis of aGVHD [77][78][79][80]. Ruxolitinib's inhibition of JAK1/JAK2 influences a wide range of immune system components, both adaptive (dendritic cells and CD4 + T cells) and innate (natural killer cells and neutrophils) [81].…”

“…Ruxolitinib's inhibition of JAK1/JAK2 influences a wide range of immune system components, both adaptive (dendritic cells and CD4 + T cells) and innate (natural killer cells and neutrophils) [81]. In preclinical studies, ruxolitinib reduced the severity of GVHD and prolonged survival in animal models of GVHD while preserving the graft-versus-leukemic effect through inhibition of the production of proinflammatory cytokines, suppression of T-cell expansion, and promotion of Treg proliferation (Table 2) [77,79].…”

Advances in the treatment of chronic graft‐versus‐host disease

“…Preclinical and clinical studies suggest that JAK inhibition may disrupt GVHD without negatively affecting GVL activity. After alloHCT, JAKs are important effectors of all three phases leading to GVHD, (ie tissue inflammation, T cell/ APC interaction and immune cell migration with tissue damage), transducing inflammatory signaling downstream of cytokines and regulating development and function of immune cells including APCs and T cells . The most common side effects related to JAK inhibition include: significant cytopenias; in particular drug‐induced anemia and thrombocytopenia.…”

“…JAK inhibition has shown promise on a variety of organ systems, there are ongoing studies investigating the efficacy of JAK inhibitors in the prevention and treatment of cGVHD . Ruxolitinib is an oral selective Janus‐associated kinase 1(JAK1) and JAK2 inhibitor that was approved by the FDA in 2011 for the treatment of patients with myelofibrosis.…”

Targeting IFNGR/IL6R or downstream JAK1/JAK2 to control GvHD

“…These results provide important insights into optimal JAKs to target for the prevention and treatment of GvHD without abrogating GvL. While comprised of four different non-receptor kinases (JAK1, JAK2, JAK3 and TYK2), the first three members of the JAK families have been reported to be ideal targets for GvHD treatments due to their ability to regulate the immune cells that underlie GvHD [ 6 ]. Our data, however, strongly suggest that balanced inhibition of JAK1/JAK2, while preserving JAK3 that is necessary for regulatory T cells (see below), is critical for complete eradication of GvHD [ 3 - 5 ] (Figure 1 ).…”