Notch-Mediated Expansion of Cord Blood Progenitors for Stem Cell Transplant

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DESCRIPTION (provided by applicant): With the goal of overcoming the significant delay in neutrophil recovery that occurs following cord blood transplantation (CBT), we have successfully developed a novel and clinically feasible methodology utilizing an engineered Notch ligand for the ex vivo generation of increased numbers of CD34+ progenitor cells. We have previously demonstrated that, in patients undergoing a myeloablative partially HLA-matched CBT, infusion of the expanded cells along with a conventional unmanipulated unit can significantly reduce the time to neutrophil recovery. Now, in an effort to develop a more economically and clinically feasible source of expanded hematopoietic progenitor cells, we are focused on evaluating our expanded progenitor cell product as an "off-the-shelf therapy without the need for HLA-matching. We have established a small "bank" of CB progenitors that have been ex vivo expanded and cryopreserved for future use, and a pilot clinical trial is underway to evaluate the safety of this approach. Four patients have been enrolled and undergone a standard CBT with infusion of a non HLA-matched expanded product from our bank. Infusion of this product has been well-tolerated in all patients, without observed toxicities or evidence for increased GVHD. Furthermore, analysis of donor chimerism post CBT has confirmed the ability of the expanded cells to provide a rapid low level burst of myeloid engraftment, with possible facilitation activit that can enhance reconstitution from the unmanipulated cells. We are now poised to conduct a Phase II randomized, multi-center prospective study of CBT with or without ex vivo expanded off-the-shelf CB progenitor cells in patients with hematologic malignancies. The primary objective will be to compare the time to engraftment in the two groups. Secondary objectives are aimed at further assessment of clinical and economic (e.g. time to platelet recovery, duration of initial hospitalization, day 200 TRM and incidence of severe infection) will also be collected. Studies conducted in the lab will be aimed at better understanding the factors that predict engraftment kinetics, in vivo persistence and facilitation activity from our off-the-shelf product, with a focus on the role of HLA and the cellular composition of the product infused. RELEVANCE: Cord blood transplantation is associated with increased risk of early transplant related mortality due to a prolonged period of severe neutropenia post transplant. We have developed novel methods for the ex vivo expansion of cord blood progenitors capable of providing a rapid burst of early neutrophil engraftment after infusion. Our goal is to now determine the clinical efficacy of this approach in a phase II clinical trial.