Umbilical cord blood (CB) is a valuable source of hematopoietic progenitor cells (HPCs) for the treatment of a broad range of malignant and nonmalignant disorders in individuals who otherwise would lack a suitable HLA-matched donor. Ultimately, the future of CB transplant will rest on how well certain limitations of this procedure are addressed, including the relatively low numbers of HPCs in CB collections; the slower times to engraftment and immune recovery; and the apparent reduced ability of CB cells to home to bone marrow. Hence, the initial long-term goal of this P01 grant-supported research was to enhance the efficacy of CB transplant for hematologic malignancies. Although still focused on several of the program's original objectives, this competitive renewal application now encompasses CB-based therapies with the potential to extend the benefits of our research to nontransplant settings. This emerging emphasis has led to a change in the title of the proposal, from ?Improving Cord Blood Transplantation? to ?Novel Cord Blood Cellular Therapies,? and to a new overall central hypothesis: that CB-derived HPCs can be modified in diverse ways ex vivo to improve the outcomes not only of CB transplant but also of cellular therapies in general. The investigators chosen for this renewal effort represent four research projects and three Core services, all with stellar records of collaborative investigation in transplant medicine, cell therapy, immunology, and adult and pediatric hematology ? predicting synergistic interactions in pursuit of the specific aims outlined here. Project 1 (E. Shpall, R. Sackstein) seeks to further enhance CB engraftment by combining, in MSC-mediated expansion with exofucosylation of CB cells to boost HPC numbers and homing capacity, and to lessen or abrogate GvHD using CB tissue-derived MSCs. In Project 2 (C. Bollard, D. Nixon), the safety, feasibility and efficacy of infusing ex vivo-expanded CB-derived T cells targeting four viruses will be tested in patients undergoing CB transplant for resistant hematologic malignancies, The investigators will also determine whether the highly effective virus-specific T-cell (VST) strategy can be extended to the prevention of HIV post-transplant. Project 3 (K. Rezvani, J. Orange) plans to prospectively assess an intriguing hypothesis that the persistence and activity of CB-natural killer cells against lymphoid malignancies can be enhanced, without undue toxicity, by genetically modifying these cells to express a CD19-specific CAR and IL-15. Finally, Project 4 (J. Molldrem, G. Al-Atrash, Q. Ma) will continue to develop a novel strategy to lower relapse rates in the myeloid leukemias by redirecting T- cell specificity to the HLA-A2-restricted PR1 epitope, using both animal models and human trials.
Cord blood contains primitive cells with the ability to engraft in bone marrow and regenerate the immune system, and is therefore an attractive source of cells for transplantation and other therapeutic applications. The research outlined in this proposal seeks to boost the effectiveness of cord blood for both of these purposes, to a level that would make it the treatment of choice for greater numbers of individuals with leukemia, lymphoma and other hematologic disorders.
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