This Program Project Grant application seeks support for translational clinical research studies to address some of the major obstacles to successful autologous and allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies. Thus, the overall goals of this grant are to: 1. To improve the long-term, disease-free survival of patients with hematological malignancy, 2. To extend the potential benefits of HCT to older patients with leukemia and lymphoma by the development of more effective and safer transplant regimens, 3. To translate previous laboratory observations in virology and tumor immunology made during the previous funding period into effective treatment strategies for patients undergoing HCT, and 4. To systematically delineate the short-term and long-term neurocognitive problems that afflict HCT recipients. This grant consists of four translational clinical projects and three cores. Project I entitled """"""""Radioimmunotherapy-based Transplant Regimens for Treatment of B-cell Lymphoma and Acute Myelogenous Leukemia"""""""" is focused on developing novel RIT-based preparative regimens in both the autologous and allogeneic with improved anti-tumor potency and tolerability and which can be tested in older patients with these diseases. Project II entitled """"""""Targeting Post-Transplant Minimal Residual CD19+ ALL with Genetically Modified CD19-specific T-cells,"""""""" will pilot adoptive therapy utilizing CD19-specific genetically-modified T cells as a strategy to target post-HCT minimal residual disease. In this project we also answer important questions about the immunobiology (in vivo expansion, homing and targeting to sites of disease) of donor-derived T-cell adoptive transfer in recipients of allogeneic T-cell depleted HCT for CD19+ ALL. Project III entitled """"""""Vaccine Induced Immunity to CMV"""""""", will test the first CMV vaccine intended for PBSC donors for augmenting transfer of CMV immunity to the patient with the goal of limiting post-HCT viremia. The investigators in this grant will be supported by three cores. The Administrative/Regulatory Affairs Core will oversee all administrative, financial, scientific review and data sharing for investigators in the grant and because seven of the trials will be conducted under institutionally-sponsored FDA INDs, Core A will also oversee the timely completion and submission of documents related to these INDs. Core B will continue to do data collection and management, and statistical analysis, and provide input into the design and publication of studies resulting from work in this grant. Core C will continue to provide long term follow-up and analysis of the recovery and health problems encountered by HCT-recipients treated on studies in this grant. In summary, the Program Project Grant renewal represents the ongoing, highly translational evolution of research by an integrated group of investigators focused on improving the outcome of HCT for patients with hematologic malignancies, and in particular, the first clinical applications of novel therapeutic interventions derived from laboratories in our program.
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