? Delayed myeloid engraftment after umbilical cord blood transplantation (UCBT), often associated with increased early transplant related morbidity and mortality, remains the primary obstacle for the successful use of cord blood as an alternative source of stem cells for allogeneic transplantation and novel strategies are required to overcome this problem. Although the delayed engraftment following UCBT has been thought to result from inadequate stem cell numbers in a cord blood graft, attempts to increase the stem cell numbers available by ex vivo cytokine-mediated expansion has not improved time to engraftment. Similarly, infusion of multiple cord blood units, while possibly effective in increasing the overall incidence of engraftment, has not overcome the problem of the slow pace of hematopoietic recovery. Our laboratory has developed novel methods for enhancing the repopulating capacity of cord blood progenitors, using the Notch ligand, Delta1. With support from this R24 grant, we have developed the required clinical grade reagents and methodology for the ex vivo expansion of cord blood progenitors, thereby establishing a potential resource to provide these reagents and methods to improve the outcome following cord blood transplantation. Preclinical data has demonstrated not only the ability to expand ex vivo progenitor cells with enhanced repopulating ability, but also indicates that the expanded cells may lead to more rapid engraftment, the major disadvantage after undergoing UCBT. Thus, based on the encouraging data generated during the preclinical development phase, we are now ready to establish the safety and toxicity of our approach in a phase I clinical trial, and then to provide this technology as a resource for multi-institutional phase II and III trials to test efficacy. Specifically, we propose to determine the safety and toxicity associated with infusion of ex vivo expanded cord blood cells to augment conventional umbilical cord blood transplantation in a phase I clinical trial. These studies will also address ancillary aims of estimating the kinetics and durability of hematopoietic reconstitution of the ex vivo expanded cord blood cells (Aim IA) and estimating the kinetics of immune cell reconstitution (Aim IB). ? ? ?
