The introduction of cord blood (CB) as an alternative graft source for patients without a human leukocyte antigen (HLA) matched donor was a clear breakthrough in the field of stem cell transplantation. Yet, consistently low doses of CB progenitor cells, resulting in delayed engraftment and immune reconstitution, unacceptable rates of infection, and high rates of relapse in CB recipients with cancer, have restricted the use of this procedure, especially in adults. Hence, the long-range goal of this proposal is to improve the outcome of CB transplantation by translating compelling laboratory findings into clinical trials, all within the framework of a multidisciplinary P01grant. The investigators in this program, representing 4 research projects and 4 Core services, have strong records of collaborative investigation in cancer immunology, viral immunology, CB transplantation, adoptive T-cell therapy, and stem cell biology - predicting extensive (and synergistic) interactions in pursuit of the goals outlined here. Project 1 will test the hypothesis that CB progenitors expanded on marrow stromal cells prior to infusion will engraft more rapidly than unmanipulated CB cells, and will further evaluate treatment of CB progenitors with fucosyltransferase as a novel means to improve bone marrow homing and engraftment. Project 2 asks if the infusion of CB-derived cytotoxic T cells (CTLs) targeting multiple viruses will provide broad protection against post-transplant viral infections, while Project 3 will direct the specificity of these virus-specific CTLs, using a chimeric antigen receptor (CAR), to the tumor-associated antigen CD19 in an effort to target malignant B cells as well as viruses. Finally, in Project 4, the ability of CB-derived CTLs to recognize the PR1 antigen aberrantly expressed on myeloid leukemias will be exploited to determine the feasibility and potential efficacy of PRI-specific CTL therapy in patients with myeloid leukemia undergoing CB transplantation. Ultimately, the information generated through this P01mechanism should yield a single, comprehensive plan of CB transplantation that will overcome most current limitations of this procedure, making it a realistic option for larger numbers of adult and childhood cancer patients.
Cord blood transplantation is a potentially useful treatment for leukemias and other hematologic malignancies, but its effectiveness has been limited by delayed engraftment, poor immune reconstitution, viral infections and relapse of the primary disease. The studies proposed in this application are designed to improve the outcome of this procedure so that it can be used more widely in cancer patients without other therapeutic options.
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