Pharmacologic Blockade of JAK1/JAK2 Reduces GvHD and Preserves the Graft-Versus-Leukemia Effect

Abstract

We have recently reported that interferon gamma receptor deficient (IFNγR−/−) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft-versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNγR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNγR−/− T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo-HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases.

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

“…In this study, we provide further strength to the recent findings by Choi and colleagues (35): that is, pharmacologic inhibition of the JAK1-JAK2 pathway by ruxolitinib was associated with a preserved GVT effect. Building upon this prior study, we now show that the preserved GVT activity by ruxolitinib is associated with maintained in vivo polarization of donor T cells toward the Th1 and Th17 phenotypes that are generally recognized as efficient mediators of antitumor effects (36,37).…”

CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression

“…44,45 However, despite its anti-inflammatory properties, RUX was able to preserve the graft-versus-leukemia effect in graft-versus-host disease mouse models comprising in vivo tumor inoculation. 46,47 Some of these selective effects were explained by differential responses of distinct T-cell subsets to RUX, particularly when used at different concentrations. 45 It is therefore possible to speculate that the modulation of the immune system by RUX is cell context dependent and potentially affected by the intensity of the inflammatory responses.…”

Mechanistic approaches for the prevention and treatment of chronic GVHD

“…Proinflammatory cytokines are characteristically elevated in both acute and chronic GVHD, and inhibition of JAK1/JAK2 signaling with ruxolitinib has been shown to reduce GVHD in murine models. [46][47][48] This novel approach has been tested in patients with steroid-refractory acute and chronic GVHD with encouraging results in both settings. 46 [50][51][52][53][54][55] Treg impairment is associated with loss of tolerance, autoimmunity, and chronic GVHD.…”