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

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

Tuesday, February 18, 2014

The New York Academy of Sciences

Presented By


Graft-versus-host disease (GvHD) is the major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplant (HSCT). Allogeneic HCST is most commonly performed as a treatment for hematological malignancies, thus a crucial consideration when treating GvHD is to inhibit the pathological mechanisms that cause GvHD while at the same time ensuring the graft-versus-tumor (GvT) response is preserved. It is therefore critical for transplant physicians and drug discovery scientists alike to understand the immunologic pathways that underlie both the beneficial GvT and the harmful GvH responses. This symposium will bring together clinical, basic, and industry scientists to discuss the current and emerging treatment options for GvHD, highlight recent advances in our understanding of disease and anti-tumor immune pathways, and will suggest new approaches to develop immunomodulatory therapies to separate GvHD from GvT effects.

*Reception to follow.

Registration Pricing

Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

The Biochemical Pharmacology Discussion Group is proudly supported by

  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer


* Presentation titles and times are subject to change.

Tuesday, February 18, 2014

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Kelli Ryan, PhD, Boehringer Ingelheim Pharmaceuticals

9:15 AM

Allogeneic Hematopoietic Stem Cell Transplantation: The Original Immunotherapy of Cancer
Marcel R. M. van den Brink, MD, PhD, Memorial Sloan Kettering Cancer Center

10:15 AM

Coffee Break

10:45 AM

Epigenetic Modulation of GvHD
John DiPersio, MD, PhD, Washington University School of Medicine

11:30 AM

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

12:15 PM

Lunch Break

1:00 PM

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

1:45 PM

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

2:30 PM

Coffee Break

3:00 PM

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

3:45 PM

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

4:30 PM

Closing remarks
Joshua Apgar, PhD, Applied BioMath

Networking Reception

5:30 PM




Joshua Apgar, PhD

Applied BioMath, LLC

Joshua Apgar, PhD, is a cofounder of Applied BioMath, LLC. Their goal is to substantially reduce the overall cost of drug discovery by providing modeling services that enable smarter decision making earlier in the discovery pipeline. Applied BioMath leverages physics based models to: translate in vitro and in vivo data, assess target feasibility, understand drug mechanism of action, and predict human doses and responses. The ultimate goal of this work is to reduce late stage attrition in drug development through a deep and quantitative interrogation of drug pharmacology and disease pathophysiology. Josh received his PhD from MIT in Biological Engineering where he worked on experimental design for Systems Biology, focusing on the identification of tractable experiments that could allow for the estimation of unknown parameters and reveal complex mechanisms in signal transduction networks. Previously he was a Principal Scientist in the Systems Biology Group of the Department of Immunology and Inflammation at Boehringer Ingelheim Pharmaceuticals.

Kelli Ryan, PhD

Boehringer Ingelheim Pharmaceuticals

Dr. Kelli Ryan holds a B.S. degree in Biology from Marquette University in Milwaukee, WI, and obtained a PhD in Immunology and Molecular Pathogenesis from Emory University in Atlanta, GA. She then completed postdoctoral training at Edinburgh University in the lab of Professor Steve Anderton and at Newcastle University in the lab of Dr. Desa Lilic. While in the Anderton lab Kelli’s work focused on T cell tolerance in a mouse model of multiple sclerosis. At Newcastle University, she investigated dendritic cell and T cell function in CMC and APECED patient samples to understand the basis for their susceptibility to candida infections. Kelli is currently a senior scientist at Boehringer Ingelheim Pharmaceuticals in the department of Immunology and Inflammation. Her research is focused on in vivo models of inflammation and the identification of novel therapies for the treatment of autoimmune and inflammatory diseases.

Anthony Slavin, PhD

Boehringer Ingelheim Pharmaceuticals

Anthony Slavin received his PhD from the University of Melbourne studying the then novel encephalitogenic properties of MOG. He subsequently completed post-doctoral studies at the Center for Neurologic Diseases in Boston before taking a position at Stanford University Division of Rheumatology. He left Stanford to join a start-up company, Tularik, which was eventually acquired by Amgen before moving to Novartis. Anthony is currently Director of Immunology and Inflammation at Boehringer Ingelheim.

Jennifer Henry, PhD

The New York Academy of Sciences


John DiPersio, MD, PhD

Washington University School of Medicine

Dr. John DiPersio, Deputy Director, Alvin J. Siteman Cancer Center and Chief of the Division of Oncology at Washington University School of Medicine in St. Louis and the Virginia E. and Samuel J. Golman Professor of Medicine.

Dr. DiPersio’s clinical research focuses on fundamental and translational aspects of leukemia and stem cell biology. These studies include identification of genetic abnormalities in human leukemias, understanding processes involving stem cell and leukemia cell trafficking, and clinical and translational programs in both leukemia/myelodysplastic syndrome and stem cell transplantation.

Dr. DiPersio is Chair of ASH Scientific Committee on Hematopoiesis, a member of the Board of Scientific Counselors (Clinical Science and Epidemiology) for the National Cancer Institute, and the 2013 recipient of the Daniel P. Schuster Distinguished Translational Investigator Award from Washington University. He has authored or co-authored more than 230 publications.

Dr. DiPersio received his M.D. and Ph.D. from the University of Rochester and his B.A. in Biology (Magna Cum Laude) from Williams College.

William R. Drobyski, MD

Medical College of Wisconsin

William R. Drobyski, MD is a Professor of Medicine, Pediatrics and Microbiology at the Medical College of Wisconsin, and leader of the Hematologic Malignancy and Transplantation Program of the MCW Cancer Center. He received his undergraduate training at Brown University and his medical degree from the University of Rochester. He completed residency training at the University of Rochester and subsequently received fellowship training in Hematology and Bone Marrow Transplantation at the University of Rochester and the Medical College of Wisconsin (MCW), respectively. He participates in the care of adult patients undergoing stem cell transplantation for the treatment of hematological malignancies. His major research focus is on the immunobiology of allogeneic stem cell transplantation with specific emphasis on the pathophysiology of graft versus host disease. He also serves on the editorial board of the journal Biology of Blood and Marrow Transplantation.

James Ferrara, MD, DSc

University of Michigan

James L.M. Ferrara, MD, DSc, is Professor of Pediatrics and Communicable Diseases, Professor of Internal Medicine, and the Ruth Heyn Professor of Pediatric Oncology in the University of Michigan Medical School. Dr. Ferrara completed his residency in Pediatrics at Boston Children’s Hospital and his fellowship in Pediatric Hematology/Oncology at Boston Children’s/Dana-Farber Cancer Institute. He then joined the faculty of Harvard Medical School where he developed his experimental research program and where he remained until he came to direct the BMT program at the University of Michigan. His research focuses on graft versus host disease (GVHD), a common, and lethal complication of BMT. His laboratory has discovered and validated a number of important biomarkers of acute GVHD, and he has devised a new scoring system using biomarkers alone that successfully stratifies GVHD for risk of non relapse mortality. Dr. Ferrara’s research program has been continuously funded by the NIH for more than 25 years, and he has received several major awards, including an American Cancer Society Clinical Research Professorship, and a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation. His national leadership includes program committee chair for the Annual Meeting of the American Society for Blood and Marrow Transplantation, chairmanship of the steering committee for the BMT Clinical Trials Network.

David L. Porter, MD

University of Pennsylvania Medical Center

Dr. Porter is the Jodi Fisher-Horowitz Professor of Leukemia Care Excellence at the Perelman School of Medicine and Abramson Cancer Center, and Director of the Blood and Marrow Transplantation and Cellular Therapeutics program at the Hospital of the University of Pennsylvania. He is a graduate of the University of Rochester and earned a medical degree at Brown University. He completed internship and residency at Boston University Hospital, and fellowship training at Brigham and Women’s Hospital and Harvard Medical School in Boston. He chairs or serves on multiple local, national and international committees focused on hematologic malignancies and hematopoietic stem cell transplantation and is a member of the Board of Directors of the National Marrow Donor Program.

Dr. Porter is a member of the American Society of Hematology, the American Society of Clinical Oncology, and the American Society of Blood and Marrow Transplantation. He has authored more than 120 research articles and book chapters, is an Associate Editor for the American Journal of Hematology and has served as a manuscript reviewer for numerous medical journals, including Blood, Annals of Internal Medicine and The New England Journal of Medicine.

Dr. Porter has expertise in the care of patients with hematologic malignancies including acute and chronic leukemia, and in all aspects of autologous and allogeneic SCT and leads numerous local and national research activities. He is an accomplished clinical investigator and has published extensively in the field of stem cell transplantation and hematologic malignancies. His principal research interests are in development of novel methods of cellular therapy, stem cell transplantation and allogeneic adoptive immunotherapy. Recent research highlights include the successful use of genetically modified T cells to treat CLL and ALL, novel trials designed to prevent GVHD after allogeneic SCT by blocking lymphocyte trafficking, and studies to enhance graft-vs-tumor activity at the time of transplant, after non-myeloablative therapy, and for relapse after SCT.

Robert J. Soiffer, MD

Dana-Farber Cancer Institute

Dr. Robert J. Soiffer received his MD from the New York University School of Medicine. He completed his residency in internal medicine at Brigham and Women’s Hospital where he also served as Chief Medical Resident. He completed fellowship in medical oncology at Dana-Farber. He is currently Professor of Medicine at Harvard Medical School and Chief of the Division of Hematologic Malignancies. He is also Co-Director of Bone Marrow Transplant Service at DFCI. Dr. Soiffer’s research focuses on modulation of immune responses in the setting of hematopoietic stem cell transplantation. The ultimate goal for his clinical trials and research grants is to optimize graft versus leukemia activity without inducing graft-versus-host disease.

Dr. Soiffer is a former President of the American Society for Blood and Marrow Transplantation. He serves on the advisory board for the Center for International Blood and Marrow Transplant Research and the Executive Steering Committees for Blood and Marrow Transplant Clinical Trials Network. Dr. Soiffer has co-authored over 200 peer-reviewed manuscripts and numerous book chapters, review articles, editorials, and monographs. He is editor of a textbook on BMT. He is also on the editorial boards of Clinical Cancer Research, Biology of Blood and Marrow Transplantation, and Blood and is associate editor of Biology of Blood and Marrow Transplant.  Dr. Soiffer has received several honors and awards including the Brian O’Dell Memorial Research Award and the Compassionate Caregiver Award from the Leukemia and Lymphoma Society.

Megan Sykes, MD

Columbia University

Dr. Sykes is the Michael J. Friedlander Professor of Medicine and Professor of Microbiology & Immunology and Surgical Sciences (in Surgery), Columbia University. She is Director of the Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons. She also serves as Director of Research for the Transplant Initiative and as Director of Bone Marrow Transplantation Research at Columbia University Medical Center. Dr. Sykes joined Columbia University in April, 2010 after spending 19 years at Massachusetts General Hospital/Harvard Medical School, where she was the Harold and Ellen Danser Professor of Surgery and Professor of Medicine (Immunology) and Associate Director of the Transplantation Biology Research Center. Dr. Sykes’ research career, during which she has published 397 papers and book chapters, has focused on hematopoietic cell transplantation, organ allograft tolerance induction, xenotransplantation tolerance and Type 1 diabetes. Dr. Sykes has developed novel strategies for achieving graft-versus-tumor effects without graft-versus-host disease following hematopoietic cell transplantation (HCT). She developed an approach that has been evaluated in clinical trials of non-myeloablative haploidentical HCT whose safety and efficacy allowed trials of HCT for the induction of organ allograft tolerance, allowing intentional achievement of tolerance in humans for the first time. Dr. Sykes has dissected the tolerance mechanisms and pioneered minimal conditioning approaches for using HCT to achieve allograft and xenograft tolerance. Her work on xenogeneic thymic transplantation for tolerance induction has led, for the first time, to long-term kidney xenograft survival in non-human primates. More recently, she has extended the HCT approach to the problem of reversing autoimmunity while replacing destroyed islets of Langerhans in Type 1 diabetes. She has developed novel “humanized mouse” models that allow personalized analysis of human immune disorders and therapies. Dr. Sykes is Past President of the International Xenotransplantation Association and was Vice President of The Transplantation Society. She has received numerous honors and awards, and is a member of the Institute of Medicine.

Marcel RM van den Brink, MD, PhD

Memorial Sloan Kettering Cancer Center

Dr. van den Brink is the Head of the Division of Hematologic Oncology at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. He studies the mechanisms of graft-versus-host disease, graft-versus-tumor activity and immune reconstitution in his laboratory and has developed novel therapeutic approaches to enhance post-transplant T cell reconstitution, which are currently in clinical trials at the MSKCC. Dr. van den Brink earned his MD and PhD from the University of Leiden (The Netherlands). He trained in Internal Medicine at Duke University Medical Center (Durham, NC), followed by fellowship training in Hematology and Oncology at the Beth Israel Deaconess Medical Center (Boston, MA). He is Member and holds the Alan N. Houghton Chair in Immunology at Memorial Sloan-Kettering Cancer, and Associate Professor at Weill Medical College of Cornell University.


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The Biochemical Pharmacology Discussion Group is proudly supported by

  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer


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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