Strategies to Inhibit Graft-Versus-Host Disease While Sparing the Graft-Versus-Tumor Response: Finding the Sweet Spot

Agenda

* Presentation titles and times are subject to change.

Abstracts

Allogeneic Hematopoietic Stem Cell Transplantation: The Original Immunotherapy of Cancer
Marcel RM van den Brink, Memorial Sloan Kettering Cancer Center

Intestinal GVHD is the most important form of acute GVHD and results in significant morbidity and mortality. Its complex pathophysiology involves donor alloreactive immunity (especially T cells), mucosal immunity, microbial flora and epithelial regeneration. In this presentation we will discuss our recent findings in mouse models and patients receiving an allogeneic BMT with special emphasis on the role of the microbial flora and innate lymphoid cells.

Epigenetic Modulation of GvHD
John F. DiPersio, MD, PhD, Siteman Cancer Center, Washington University School of Medicine

Regulatory T cells (Tregs) contribute to the maintenance of self-tolerance and mitigate graft-versus-host disease (GvHD), a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), while preserving the beneficial graft-versus-leukemia (GvL) effect.  It has been shown that the expression of Foxp3, the master gene of Tregs, is regulated by DNA methylation.  We will present evidence that the hypomethylating agent azacitidine (AzaC) induces FOXP3 expression in vitro and increases Tregs in vivo, thereby mitigating GvHD without abrogating GvL in a murine allo-HSCT model.  Of note, the suppressor function of AzaC-induced Tregs turned out to be Foxp3-independent in that AzaC-induced Tregs generated from Foxp3 knockout (KO) mice were equally suppressive as those generated from wild-type (WT) mice7. In subsequent RNA profiling studies comparing non-Treg T cells, natural Tregs, and AzaC-induced Tregs, we show that interferon gamma (INFγ)/INFγR family genes that are upregulated to natural Treg levels following treatment of non-Treg T cells with AzaC.
 
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 we will show that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells.  While we will show that pharmacologic blockade of IFNγR signaling using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), result in a similar effect 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 preserves the beneficial GvL effect after allo-HSCT.  In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/2 inhibitors, such as TG101348 or AZD1480. Pharmacologic inhibition of IFNγR signaling with oral JAK1/2 inhibitors might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases.

Inhibition of Interleukin 23 Signaling as a Strategy to Separate Graft versus Host from Graft Leukemia Responses
William R. Drobyski, Medical College of Wisconsin

Graft versus host disease (GVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (HSCT) and is the major cause of morbidity and mortality associated with this therapy. A prominent characteristic of GVHD is the presence of a proinflammatory milieu that is attributable to conditioning regimen-induced host tissue damage as well as secretion of inflammatory cytokines by alloactivated donor T cells and other effector cell populations. GVHD has been classified into two phases termed acute and chronic, which are distinguishable based on temporal characteristics as well as unique clinical and pathological manifestations. During the acute phase, GVHD generally targets a restricted set of organs which include the skin, liver and gastrointestinal tract.  Of these tissues sites, the gastrointestinal (GI) tract is of particular relevance in the pathophysiology of this disorder. Compelling data in experimental models has demonstrated that, besides being a major target organ of alloactivated donor T cells, the GI tract plays a crucial role in the amplification of systemic GVHD severity.  Clinically, involvement of the GI tract during GVHD is a major cause of morbidity and can result in significant complications which include protracted diarrhea, malnutrition necessitating parental nutrition, prolonged hospitalization, and infections arising from the translocation of bacteria across damaged mucosal surfaces. We have identified that interleukin 23 plays a major role in the pathophysiology of GVHD within the GI tract in murine models of bone marrow transplantation.  Specifically, we have observed that secretion of IL-23 by donor antigen-presenting cells (APCs) is a critical event in the induction of GVHD of the colon linking conditioning regimen-induced mucosal injury and lipopolysaccharide (LPS) translocation to subsequent proinflammatory cytokine production and GVHD-associated pathological damage. Moreover, inhibition of the IL-23 signaling pathway does not result in abrogation of the graft versus leukemia effect, suggesting that IL-23 may be a relevant target for strategies designed to reduce morbidity from GVHD without loss of antileukemia responses mediated by donor immune cells contained within the stem cell graft.

Emergence of Biomarkers for Clinical Application in GVHD
James Ferrara, University of Michigan

Clinical staging systems of acute GVHD (eg, Glucksberg) do not reliably stratify the risk of non relapse mortality at the onset of symptoms. We wished to determine whether plasma biomarkers at the onset of acute GVHD could be used to create such a grading system. We obtained blood samples at onset of acute GVHD from almost 500 patients at two BMT centers (University of Michigan and Regensburg) and measured the plasma concentrations of 5 biomarkers (TNFR1, ST2, REG3α, Elafin and IL2Rα) by ELISA. We created a training set of 330 patients and used logistic regression to develop an algorithm that defines three risk groups. The desired features of the algorithm were clarity of risk stratification, simplicity, and reproducibility. We applied the algorithm in a first validation set from the two centers and then in a second validation set of more than 330 samples obtained from pts enrolled in two multicenter trials of primary treatment for acute GVHD conducted by the BMT Clinical Trials Network. An algorithm using TNFR1, ST2, and REG3α performed as well as that incorporating all 5 biomarkers. This algorithm successfully divided pts in the training set into three Ann Arbor (AA) grades with 6m NRM of 9%, 28%, and 47%, respectively. In the validation set, the algorithm defined three grades with almost identical 6m NRM. In the second validation set of BMT CTN pts, the algorithm again clearly identified the same three groups, while Glucksberg grades of I, II and III/IV did not. In all cohorts, AA3 pts were more likely to have steroid refractory GVHD than AA2 pts. Importantly, AA grading reclassifies pts across all presenting clinical grades. This new grading system may significantly improve the design of future GVHD clinical trials.

Inhibition of Lymphocyte Trafficking to Prevent Graft-versus-Host Disease
David L. Porter, University of Pennsylvania Medical Center

Graft versus host disease (GVHD) is a major limitation to successful allogeneic stem cell transplantation (SCT). Early after transplant, donor lymphocytes migrate into lymphoid organs and peripheral tissues and are in large part responsible for later development of GVHD. Several observations have shown that Chemokine (C-C motif) receptor 5 (CCR5) plays an important role in alloreactivity. CCR5 and its natural ligands CCL3, CCL4, and CCL59 have been implicated in the pathogenesis of GVHD and solid-organ rejection. For instance, CCR 5 is critical for lymphocyte recruitment to tissues involved in GVHD. We therefore hypothesized that inhibition of lymphocyte trafficking early after transplant could decrease the incidence of GVHD without limiting the potential for graft versus leukemia (GVL) activity or increasing the risk for infections.
Maraviroc is a CCR 5 antagonist approved as part of combination anti-retroviral therapy for patients with CCR 5-tropic HIV. We have therefore tested the ability of maraviroc to prevent GVHD after allogeneic transplant when added for 30 days to conventional GVHD prophylactic therapy. Our initial studies showed a low incidence of grade II-IV acute GVHD at day 100 and 180. No liver or gut GVHD were noted before day 100 and the incidence was low even out to day 180. The cumulative incidence of grade III-IV acute GVHD by day 180 was only 6%. The risk of GVHD is significantly lower compared to our historical controls. Furthermore, compared to this historical control population, maraviroc did not resulted in either a higher risk of relapse or infection suggesting it does not impair GVL activity or further limit immune reconstitution. The effects of maraviroc were most prominent in recipients of unrelated donor (URD) stem cell grafts and we did observe several cases of late onset acute GVHD even beyond day 180. Our current clinical trial is testing the activity of prolonged exposure to maraviroc for 90 days after transplant in recipients of URD stem cell grafts and is actively enrolling patients.
We believe inhibition of lymphocyte trafficking is a specific and potentially effective new strategy to prevent visceral acute GVHD after allogeneic transplant without further limiting GVL activity.

Regulatory T cells, Interleukin-2, and Chronic GVHD
Robert J. Soiffer, Dana-Farber Cancer Institute

Regulatory T cells (Treg) are an essential element of immune tolerance and are required for long-term maintenance of normal immune function without severe auto-immunity. Studies from our group have demonstrated that patients with chronic graft versus host disease (cGVHD) after hematopoietic cell transplantation (HCT) have significantly reduced frequency of Treg compared to patients with absent or quiescent cGVHD. Further studies suggested that failure to reconstitute normal numbers of peripheral Treg is linked to specific abnormalities of Treg homeostasis including decreased thymic generation and increased susceptibility to apoptosis. These studies support the hypothesis that impaired reconstitution of Treg contributes to the development of cGVHD. We previously showed that expansion of CD4 Treg in vivo could be achieved by administration of low dose interleukin-2 (IL-2) after hematopoietic cell transplantation (HCT). These observations led to a unique clinical trial of daily low-dose IL-2 in patients with active steroid resistant cGVHD. This trial demonstrated that low-dose IL-2 is well-tolerated, did not exacerbate cGVHD, induced selective proliferation and expansion of highly functional CD4 Treg in vivo, and resulted in improvement of clinical manifestations of cGVHD in approximately 50% of patients. Notably, low dose interleukin-2 could restore previously dysfunctional Treg homeostasis observed in patients with cGVHD. Current efforts are focusing on early intervention with IL-2 to expand Treg in patients at high risk for developing cGVHD as well as combining IL-2 with administration of freshly isolated donor derived Treg. The ability of low dose IL-2 to expand Treg and regulate immune mediated disease manifestations has now been demonstrated in Hepatitis C associated vasculitis and in Type 1 diabetes. Future trials to test this strategy of Treg expansion in inflammatory bowel disease, SLE, and organ allograft rejection are currently being designed.

Control of Inflammatory Mechanisms Governing Donor T cell Trafficking: A Strategy for Separating GVHD and GVL
Megan Sykes, Columbia University

In mice, graft-versus-host reactions (GVHR), associated with powerful graft-versus-tumor effects, can be achieved without graft-versus-host disease (GVHD) by delayed administration of donor lymphocyte infusions (DLI) to established mixed chimeras (MCs). GVH-reactive T cells are activated and expanded in this setting, but do not traffic to the epithelial GVHD target tissues in the absence of inflammatory stimuli, as in quiescent MCs. This approach allows achievement of powerful GVL effects against lymphohematopoietic tumors, where the GVH alloresponse occurs in these MCs, without GVHD in murine mixed chimeras. However, clinical results based on this approach have been less consistent, with GVHD occurring after DLI in some patients whose initial donor grafts were T cell-depleted and who achieved mixed chimerism across HLA barriers. In contrast to mice, in which T cell recovery from the thymus occurs prior to DLI administration, human T cell reconstitution following T cell-depleted HCT is slow, resulting in lymphopenia at the time of DLI. We have found that lymphopenia is an independent risk factor for GVHD following DLI in the absence of known inflammatory stimuli. DLI-induced GVHD was prevented in lymphopenic recipients by prior administration of a small number of non-alloreactive polyclonal T cells, insufficient to prevent lymphopenia-associated expansion of subsequently administered T cells, through a Treg-independent mechanism, but not by T cells with irrelevant specificity. Moreover, administration of antibiotics reduced the severity of GVHD in lymphopenic hosts. Accumulation of DLI-derived effector T cells and host hematopoietic cell elimination were markedly diminished by Treg-depleted, non-alloreactive T cells. Collectively, our data demonstrate that in the absence of known conditioning-induced inflammatory stimuli, lymphopenia is a risk factor for GVHD in MCs receiving delayed DLI and suggest that the predisposition to GVHD can at least in part be explained by the presence of occult inflammatory stimuli due to the absence of lymphocytes to control microbial infections. Thus, improved infectious prophylaxis and TLR antagonists might enhance the clinical application of delayed DLI administration to established, quiescent MCs to achieve GVL without GVHD.

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