Researchers from the Icahn School of Medicine at Mount Sinai have been awarded a $10 million from the National Cancer Institute to explore the cellular and molecular mechanisms of acute graft-versus-host disease (GVHD), a common side effect that occurs after allogeneic bone marrow transplantation (BMT), and to develop novel therapeutic strategies for BMT patients with cancer that begin in the cells of blood-forming tissue or hematologic malignancies. James Ferrara, MD, DSc, Ward-Coleman Professor of Cancer Medicine and Director of the Center for Translational Research in Hematological Malignancies at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, will lead the collaborative project which includes research teams at University of Michigan-Ann Arbor, and Baylor College of Medicine in Texas, as well as a consortium of 20 transplant centers that will conduct trials in GVHD.
GVHD develops when the donor's immune cells attack the patient's normal cells after transplant. Nearly 6,000 patients develop acute GVHD each year and up to 50 percent of these patients will die from the disease. GVHD is the primary cause of transplant-related death.
Recent studies have demonstrated that alterations in intestinal microbiota composition are linked to GVHD, and this grant will fund unique research projects this intestinal environment and the role that it plays in GVHD. The studies seek to understand the ability of microbial metabolites to influence the resistance of intestinal epithelial cells to donor T-cell-mediated damage and the role of the antimicrobial peptide regenerative 3 alpha in protecting intestinal stem cells. Researchers will also design a clinical trial of biomarker-guided therapy to prevent the development of steroid-refractory gastrointestinal GVHD.
"My colleagues and I have developed an exciting prognostic tool to identify those who will get GVHD and those who will not," explained Dr. Ferrara. "In doing so, we will design treatment to respond to each patient's disease progression and possibly stop its escalation. The studies are highly significant and translational, and have the potential to impact patients' care."
The study will also look at how the microbiome affects immune responses, and the proposed studies will likely have implications not only in gastrointestinal GVHD but in cancer immunotherapy in general. The projects all interact, and the study is highly integrated around a strong central theme of exploring the cellular and molecular mechanisms of GVHD to improve the care for the BMT patients.
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