Umbilical cord blood (CB) has become a valuable source of hematopoietic progenitor cells (HPCs) for the treatment of cancer, but its utility continues to be restricted by the limited cell numbers and relative immaturity of CB allografts. Although numerous strategies have been proposed to increase the engraftment potential of CB cells, there is still no agreement over the best and most efficient way to achieve this critical log-term goal. The applicant's research group has shown that ex vivo culture of the entire CB unit with mesenchymal stromal cells (MSCs) will significantly expand lineage-committed hematopoietic progenitors, leading to faster times to neutrophil and platelet engraftment. This progress, together with emerging evidence that fucosylation of CB can improve both progenitor homing and engraftment times, has led to the current renewal application. Through a series of iterative clinical and mechanistic studies, the applicant now proposes three specific aims to bring the results of CB transplantation in line with those of bone marrow and peripheral blood transplantation.
Aim 1 : To further enhance the engraftment of CB by using a combination of ex vivo MSC-mediated expansion and fucosylation strategies. The underlying rationale of this clinical trial is that expansion and surface fucosylation of CB cells appear to shorten engraftment times by non-overlapping mechanisms, raising the possibility of potent synergistic activity leading to meaningful advances in outcome.
Aim 2 : To generate an expanded megakaryocyte (MK)-rich CB product that yields more rapid engratment, the applicant proposes to identify the progenitor subpopulation(s) among expanded CB cells that produces optimally rapid platelet recovery in an NSG mouse model, with a clinical trial planned if warranted by the experimental animal studies and other laboratory findings.
Aim 3 : To comprehensively characterize immune reconstitution in our CBT patients and determine whether it can be improved with systemic administration of IL- 7. By conducting a phase I/II clinical trial, the applicants will propose to est the safety and feasibility, as well as efficacy of systemic administration of IL-7, which has a pivotal role in T cell development and survival. Success in this project will provide means to manipulate CB-derived cells towards greater clinical advantage, thus broadening the impact of CB transplantation on the treatment of human cancers.
The expansion of cord blood or adding a sugar molecule to the cell surface shortens engraftment. Interleukin-7 posttransplant improves immune recovery. All three strategies will be explored thereby reducing infectious and bleeding complications and will thus improve survival.
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