IFNγR Signaling As a Therapeutic Target To Prevent GvHD While Preserving Gvl

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with relapsed/refractory leukemia, and marrow failure states such as myelodysplasia and aplastic anemia. However, allo-HSCT is complicated by allogeneic donor T cell-mediated graft-versus-host disease (GvHD) which can be life-threatening especially in recipients of unrelated or HLA-mismatched hematopoietic stem cell products. These same alloreactive donor T cells also mediate a beneficial graft-versus-leukemia (GvL) effect.

We have recently reported that interferon gamma receptor deficient (IFNγR-/-) allogeneic donor T cells induce significantly less GvHD in both a MHC fully-mismatched (B6 (H-2^b) → Balb/c (H-2^d)) (75% vs 0% overall survival) and a minor-mismatched (B6 (H-2^b) → B6x129 (H-2^b)) allo-HSCT models (100% vs 10% overall survival) compared to WT T cells (Choi et al Blood 2012). In addition, IFNγR-/- donor T cells maintain a beneficial GvL effect, which has been examined in both systemic leukemia and solid tumor models using luciferase-expressing A20 cells derived from Balb/c. We also found that IFNγR-/- T cells migrate primarily to the spleen while WT T cells to GI tract and peripheral lymph nodes (LNs) using bioluminescence imaging (BLI), suggesting that altered T cell trafficking of IFNγR-/- T cells to GvHD target organs might be the major reason for the reduced GvHD. We further demonstrated that the IFNγR-mediated signaling (via JAK1/2 - STAT pathway) in alloreactive donor T cells is required for expression of CXCR3 which has been implicated in trafficking of T cells to areas of inflammation and target organs, commonly known to be the sites of GvHD.

Here, we examine if inhibition of IFNγR signaling using a small molecule inhibitor can recapitulate the reduced GVHD with potent anti-leukemia effects similarly to that seen with IFNγR-/- T cells. We find that INCB018424, an inhibitor of JAK1/JAK2 which mediate IFNγR signaling, blocks CXCR3 expression in vitro. Most importantly, in vivo administration of INCB018424 (100 ug, s.c., twice a day, day 1-31) after allo-HSCT alters T cell trafficking and significantly reduces GvHD (70% vs. 0% overall survival, n=10/group, p=0.0012). We also find that INCB018424 preserves the beneficial GvL effect, which has been examined in both systemic leukemia and solid tumor models using luciferase-expressing A20 cells derived from Balb/c (B6 to Balb/c model) and APL cells from B6x129 (B6 to B6x129 model). Of note is that INCB018424, when given after transplant, had no significant effect on neutrophil or platelet recovery compared to animals receiving placebo. Thus, the IFNγR signaling pathway represents a promising therapeutic target for future efforts to mitigate GvHD while maintaining GvL after allo-HSCT. Moreover, this pathway could be targeted and exploited in other diseases besides GvHD such as those from organ transplantation, chronic inflammatory diseases and autoimmune diseases.