The Blood and Marrow Transplant Program at the University of Michigan (Ann Arbor, MI) has made major scientific contributions to the BMT CTN over the past 15 years. The University of Michigan is now partnering with Indiana University (Indianapolis, IN) and the Karmanos Cancer Institute (Detroit, MI) to participate as a Core Clinical Consortia for the BMT CTN Network. Collectively, our 3-member consortia currently perform over 750 transplants/year, including 300+ allogeneic and 85 pediatric transplants annually. Our consortia has a strong emphasis in non-malignant disorders, with over 1500 patients with sickle cell disease currently followed at consortium sites, and 46 transplants for sickle cell disorders collectively performed to date. Our consortia is likewise strong in pediatric disorders, with each site affiliated with a Children's Hospital on their respective campus. We have a track record for translating early phase, clinical trials to multicenter studies, have comprehensive biorepositories as foundations for our programs, and have physician scientists (Dr. Pavan Reddy, Dr. Hal Broxmeyer, Dr. Sophie Paczesny) with a history of academic success. Our research strategy will propose a new paradigm, one that focuses on the inhibition of damage response pathways as a potential mechanism to prevent the organ toxicity associated with conditioning and GVHD. The release of damage associated molecular patterns (DAMPs) from non-specific host tissue injury is a consequence of pre-HCT conditioning. DAMPs provide crucial initiating signals that lead to activation of antigen presenting cells (APC), triggering potentially lethal inflammatory responses. Based upon pre-clinical work from the laboratory of Pavan Reddy (PI: Scientific Lead), and a pilot study currently being run at consortia sites, we are now proposing a randomized, placebo controlled trial of a damage response modifier, CD24Fc, in unrelated donor transplant recipients. Due to its long half-life, the agent is only required to be given only once during transplant, on day -1 pre-transplant. The primary endpoint will be day 100 acute GVHD. Secondary endpoints will examine the effect of CD24Fc administration on DAMP's dependent inflammatory signaling post-HCT. We anticipate that this trial will not only mitigate the onset and severity of GVHD in recipients, but will advance our understanding of the biology and clinical importance of regulating key damage response pathways after HCT. Our consortia is committed to advancing the scientific agenda of the BMT CTN, and feel this research strategy will provide new insights into reducing both GVHD and regimen related toxicities associated with HCT. Our three centers are not just close in geographic proximity, but are closely aligned to address key transplant issues within the CTN.
(Lay-person narrative): The University of Michigan has been a strong supporter of BMT CTN Network activities over the past 15 years. We have now formed a consortia with Indiana University (Indianapolis, IN) and the Karmanos Cancer Institute (Detroit, MI). In the current RFA, the BMT CTN Network requests that centers focus on clinical trials for patients with non-malignant diseases (including sickle cell anemia), children, and novel trials that use the immune system to target cancer cells. Our consortia is well positioned to support BMT CTN trials that focus on non-malignant diseases, with a large population of patients (1500+) with sickle cell disease currently being cared for at member sites. Our consortia will be strong in BMT CTN trials that focus on children, with each consortia site affiliated with a large pediatric hospital and pediatric transplant program, including Mott Children's Hospital (University of Michigan), Riley Children's Hospital (Indiana University), and the Children's Hospital of Michigan (Karmanos Cancer Institute). The strength of our consortia is our physician scientists, with Dr. Pavan Reddy (Transplant Immunology/ GVHD), Hal Broxmeyer (Hematopoiesis, Cord Blood Biology), Sophie Paczesny (Biomarkers) all internationally recognized for their bench research. We have an incredibly strong group of clinical / translational scientists with a history of running multicenter and national trials, including Dr. Greg Yanik (Transplant Lung Injury), Sherif Farag (Cord Blood Transplantation) and Joseph Uberti (GVHD). In our Research Proposal, we propose looking at a relatively new concept in bone marrow transplantation, specifically looking at the importance of the ?damage pathway.? The laboratory of Dr. Pavan Reddy has found that chemotherapy can damage tissues, leading to the release of ?damage proteins?. These damage proteins are able to activate the immune system, subsequently leading to graft versus host disease (GVHD) and ultimately more inflammation in the body. Working with an industry partner, Dr. Reddy found a protein called CD24Fc that was able to block the damage proteins and thus decrease the amount of inflammation in subjects. Just as important, he was able to show that the use of CD24Fc did NOT lead to more infections or relapse. We are now proposing a clinical trial that uses CD24Fc in patients undergoing bone marrow transplant. The drug will only be given once, by intravenous infusion one day prior to the transplant. We will examine the ability of CD24Fc to decrease the toxicity of transplant, and specifically the amount of GVHD that patients can develop. If successful, this study would be a novel step forward in understanding the biology of transplant, and limiting its complications.
|Kitko, Carrie L; Braun, Thomas; Couriel, Daniel R et al. (2016) Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial. Biol Blood Marrow Transplant 22:862-8|