Project 1 will serve to translate concepts developed in other Projects to the clinic and build upon our prior work on developing novel strategies to improve outcomes in patients undergoing allogeneic hematopoietic cell transplantation (HCT). The concepts developed will likely benefit patients with serious hematological malignancies but could also provide novel treatment strategies for patients with severe autoimmune disorders and those undergoing solid organ transplantation. Therefore, the concepts developed are broad and have significant implications for a number of fields. We will build upon our successful translation of the studies developed in Project 4 where the novel non-myeloablative regimen of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) has been explored with marked reduction in acute graft vs host disease (GVHD) risk with retained graft vs tumor (GVT) responses, The TLI/ATG regimen will be tested as compared to standard chemotherapy in older (ages 50-75) patients with AML in first CR in a multi-institutional phase III trial with those patients with HLA matched sibling donors receiving allogeneic HCT and those without treated with standard chemotherapy (Specific Aim #1). We will attempt to augment the TLI/ATG regimen in two important ways by utilizing prophylactic administration of cytokine induced killer (CIK) cells developed in Project 3 in an effort to reduce relapse risk in patients with high risk myeloid malignancies (Specific Aim #2). A second approach will be to utilize the anti-CD20 monoclonal antibody rituximab in combination with TLI/ATG in patients with mantle cell lymphoma and chronic lymphocytic leukemia to explore whether this combined approach will reduce chronic GVHD and disease relapse (Specific Aim #3). Finally we will translate basic observations in regulatory T cell biology where we have observed that cyclosporine A has a major impact on Treg function whereas rapamycin and MMF do not. We will test the combination of RAPA/MMF following myeloablative HCT in patients with high risk malignancies in an effort to reduce GVHD risk. This Project interacts with all of the other Projects and utilizes all four of the Cores.
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