Insights into the role of the JAK/STAT signaling pathway in graft-versus-host disease

Abstract

Allogeneic hematopoietic transplantation (allo-HCT) is a curative therapy for a variety of hematologic malignancies, primarily through immune-mediated clearance of malignant cells. This graft- versus-leukemia (GvL) effect is mediated by alloreactive donor T-cells against recipient malignant cells. Unfortunately, graft versus host disease is a potentially lethal complication of this procedure, also mediated by alloreactive donor T-cells against recipient normal tissues. Graft- versus-host disease (GVHD) remains a key contributor to nonrelapse mortality and long-term morbidity in patients undergoing allo-HCT. Reducing GVHD without interfering with – or ideally while enhancing – GvL, would improve outcomes and increase patient eligibility for allo-HCT. The JAK/STAT signaling pathway acts downstream of over 50 cytokines and is central to a wide variety of inflammatory pathways. These pathways play a role in the development and maintenance of GVHD throughout the disease process and within T-cells, B-cells, macrophages, neutrophils, and natural killer cells. Agents targeting JAK/STAT signaling pathways have shown clinical efficacy and gained US Food and Drug Administration approval for numerous diseases. Here, we review the preclinical and clinical evidence for the role of JAK/STAT signaling in the development and maintenance of GVHD and the utility of blocking agents at preventing and treating GVHD.

Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

“…A recent phase 3 study of JAK1 inhibitor Itacitinib on aGVHD showed the overall response rates in Itacitinib and placebo groups were 74% and 66% ( P = 0.0782), respectively, and 6-month NRM also did not favor Itacitinib (NCT03139604), which suggested that balanced inhibition of JAK1/JAK2 is vital in treatment of GVHD 10 , 41 . The JAK1/2 inhibitor Ruxolitinib, the most common used JAK inhibitor in clinical practice, has been proven to be effective in the treatment of patients with aGVHD and has been approved by FDA 14 , 15 . We found that the novel JAK inhibitor SHR0302 has a lower half maximal inhibitory concentration (IC50) for JAK1 and JAK2 than Ruxolitinib, which suggested that SHR0302 might have stronger effects than Ruxolitinib on GVHD.…”

“…Several reports indicated the therapeutic effects of JAK1/2 inhibitor Ruxolitinib for patients with acute and chronic GVHD 12 – 14 . The clinical trials of another JAK1/2 inhibitor Baricitinib for acute or chronic GVHD is ongoing (NCT04131738, NCT02759731) 15 . Recently, a JAK1 inhibitor Itacitinib was demonstrated to have a good response rate for acute GVHD in clinical trials 16 , 17 and its effects on chronic GVHD remain to be elucidated.…”

The clinical landscape of chronic graft‐versus‐host disease management in 2021

“…Ruxolitinib is an inhibitor of Janus kinase 1 (JAK1) and JAK2, currently FDA‐approved for treatment of myeloproliferative neoplasms and steroid‐refractory acute GVHD 39 . Through inhibition of the JAK/STAT (signal transducers and activators of transcription) pathway, ruxolitinib induces numerous downstream immunomodulatory effects on immune cell development and also promotes an anti‐inflammatory environment through changes in the cytokine milieu 40 …”

“…39 Through inhibition of the JAK/STAT (signal transducers and activators of transcription) pathway, ruxolitinib induces numerous downstream immunomodulatory effects on immune cell development and also promotes an antiinflammatory environment through changes in the cytokine milieu. 40 Three multicentre retrospective studies reported on ruxolitinib use for cGVHD. ORR across these studies ranged between 57Á1% and 100%, with CR rates of 3-7Á3%.…”

Transitioning tacrolimus to sirolimus in allogeneic hematopoietic cell transplantation

“…They inhibit the activation and proliferation of T‐lymphocytes which blocks growth factor‐induced transduction signals that mediate cellular division in response to alloantigens 8 . Sirolimus has been used in the prevention and treatment of GVHD after allo‐HCT 9 . Its safety and efficacy have been compared in several trials to tacrolimus and were found to provide similar GVHD‐free survival 10,11 …”