Project 3 Prevention and Treatment of Graft-versus-host Disease: The goal of this project is to improvesurvival after allogeneic hematopoietic cell transplantation (HCT) by more effective prevention and treatmentof acute graft-versus-host disease (GVHD).
Aim 1 is directed toward prevention of GVHD throughprophylactic oral administration of a topically active glucocorticoid that has little systemic effect. Separatephase II clinical trials will be carried out among patients who have myeloablative and non-myeloablativeconditioning regimens before HCT. These studies will test the hypothesis that prophylactic administration ofbeclomethasone diproprionate can greatly decrease the incidence of GVHD involving the gastro-intestinaltract and possibly other target organs as well.
Aim 2 is directed toward decreasing the amount of steroidtreatment needed to control GVHD among patients who develop this complication after HCT. Patients whodevelop acute GVHD after HCT with a myeloablative conditioning regimen will be treated with low-dosealemtuzumab to test the hypothesis that depletion of T cells after administration of the antibody willaccelerate resolution of the disease and permit more rapid withdrawal of steroid treatment, withoutincreasing the risk of opportunistic infections. Patients who develop GVHD after HCT with a non-myeloablative conditioning regimen will be treated with low-dose methotrexate to test the hypothesis that theeffects of this drug on donor T cells will accelerate resolution of the disease and permit more rapidwithdrawal of steroid treatment, without increasing the risk of recurrent malignancy.
In Aim 3, phase I andphase II clinical trials will be carried out to test the hypothesis that administration of a CD28-specific antibodyis effective for treatment or prevention of acute GVHD, as suggested by previous laboratory studies. Patientswith GVHD that cannot be controlled by currently available treatments will be enrolled in a phase I clinicaltrial. If results of the phase I study are encouraging, then a phase II study will be carried out to test whetheradministration of the antibody can prevent GVHD in humans.Relevance to Public Health: The studies in this project could lead to the development of more effectivemethods for preventing or treating harmful immune reactions that can occur when blood or marrowtransplantation is used to treat leukemia, lymphoma, myeloma and other related disorders. Successfuldevelopment of such methods would improve the safety and applicability of blood or marrow transplantationfor treatment of these diseases. '
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