WHAT NEW TREATMENTS ARE UNDER CLINICAL DEVELOPMENT?
There are multiple novel therapies currently being investigated for the treatment of chronic graft-versus-host disease with the hopes of improving patient outcomes.
Selective rho-associated coiled-coil kinase (ROCK) 2 inhibitors have been studied as a potential treatment option for cGVHD, given that this molecular pathway mediates both the inflammatory and fibrotic components of the disease.1,2
Selective ROCK2 inhibition has been shown to help resolve immune dysregulation by downregulating pro-inflammatory T helper (Th) 17 cells and increasing regulatory T (Treg) cells. Furthermore, selective ROCK2 inhibition has been shown to downregulate key fibrotic processes, such as TGF-β and LPA, leading to a decrease in fibrosis and collagen deposition.1-4
Clinical studies are currently ongoing to evaluate the potential benefits of selective ROCK2 inhibition in cGVHD.
The involvement of JAKs in the signaling of pro-inflammatory cytokines involved in cGVHD pathogenesis has been a large area of interest. The potential use of JAK1 selective inhibitors in the treatment of cGVHD is currently being explored.
The important role that IL-2 plays in Treg cell development, expansion, activity and survival has led to interest in its use for the treatment of cGVHD. Clinical studies in patients with cGVHD have shown that low-dose subcutaneous IL-2 has increased Treg cells, with minimal effect on CD4+ T cells.
Clinical studies are currently ongoing to explore the potential benefits of IL-2 therapy.
Combination therapy that is intended to disrupt each phase of the GVHD cascade is another area in which research is underway. This approach to therapy would ideally use synergistic agents with different mechanisms of action and nonoverlapping toxicities.
As research continues, promising targets in cGVHD are being uncovered, with the possibility of offering patients more comprehensive and optimized treatments in the near future.
cGVHD, chronic graft-versus-host disease; IL-2, interleukin 2; JAK, Janus-associated kinase; LPA, lysophosphatidic acid; ROCK, rho-associated coiled-coil kinase; TGF-β, transforming growth factor-beta.
References: 1. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci USA. 2014;111(47):16814-16819. doi:10.1073/pnas.1414189111 2. Riches DWH, Backos DS, Redente EF. ROCK and rho: promising therapeutic targets to ameliorate pulmonary fibrosis. Am J Pathol. 2015;185(4):909-912. doi:10.1016/j.ajpath.2015.01.005 3. Flynn R, Paz K, Du J, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144-2154. doi:10.1182/blood-2015-10-678706 4. Takeda Y, Matoba K, Kawanami D, et al. ROCK2 regulates monocyte migration and cell to cell adhesion in vascular endothelial cells. Int J Mol Sci. 2019;20(6):1331. doi:10.3390/ijms20061331 5. Im A, Morariu-Zamfir R, Bleam M, Yan Y, Pavletic SZ. Trial in progress: a phase 3 study of itacitinib or placebo in combination with corticosteroids as initial treatment for chronic graft-versus-host disease (GRAVITAS-309). Blood. 2019;134(suppl 1):3277. doi:10.1182/blood-2019-128586 6. Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood. 2016;128(1):130-137. doi:10.1182/blood-2016-02-702852 7. Jacobsohn DA. Emerging therapies for graft-versus-host disease. Expert Opin Emerg Drugs. 2003;8(2):323-338. doi:10.1517/14728188.8.131.523