The candidate's immediate goal is to acquire critical scientific and clinical training to enable her to pursue independent investigation with the long-term goal of improving the outcome for recipients of hematopoietic cell transplantation (HCT) with umbilical cord blood (UCB). UCB is used as an alternative source of stem cells for HCT only when the patient cannot identify an otherwise suitable related or unrelated donor. This is secondary to poor outcomes following umbilical cord blood transplantation (UCBT), especially in adults and larger children, due to inadequate cell numbers in the graft leading to delayed engraftment that is often associated with lethal infection. The proposed grant will integrate two complimentary approaches: 1. the preclinical development of a novel ex vivo stem cell expansion system using Delta1, a Notch ligand that is a known regulator of cell fate determination, and 2. the clinical evaluation of outcomes of UCBT using ex vivo expanded cells. In preclinical studies, we hypothesize that UCB progenitor cells cultured on Notch ligand will result in self-renewal of repopulating cells, thereby increasing the number of these cells available for transplantation. Our laboratory has developed a novel expansion method for enhancing the repopulating capacity of hematopoietic progenitor cells, and in preliminary studies with cord blood progenitor cells, culture with engineered Notch ligand increased the number of CD34+ precursors and substantially enhanced their repopulating ability in immunodeficient mice. We further hypothesize that the effectiveness of this approach will depend on a number of critical variables, including dose of Notch ligand and signaling, choice of cytokines, starting cell population (CD34+ vs CD34+38-) and cell density. In clinical studies, the candidate will assess the outcome of UCBT using cells expanded by the above optimized methodology. Additionally, a rigorous didactic and mentoring program in clinical trial design will provide the candidate the foundation to implement and supervise clinical trials of conventional UCBT augmented with ex vivo expanded cells.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-J (M1))
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Mondoro, Traci
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Fred Hutchinson Cancer Research Center
United States
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Milano, Filippo; Gooley, Ted; Wood, Brent et al. (2016) Cord-Blood Transplantation in Patients with Minimal Residual Disease. N Engl J Med 375:944-53
Salit, Rachel B; Milano, Filippo; Delaney, Colleen (2016) Outcomes of Cord Blood Transplantation as Salvage Therapy after Graft Failure or Relapse after Prior Allogeneic Transplantation. Biol Blood Marrow Transplant 22:339-343
Ostronoff, F; Milano, F; Gooley, T et al. (2013) Double umbilical cord blood transplantation in patients with hematologic malignancies using a reduced-intensity preparative regimen without antithymocyte globulin. Bone Marrow Transplant 48:782-6
Milano, Filippo; Heimfeld, Shelly; Gooley, Ted et al. (2013) Correlation of infused CD3+CD8+ cells with single-donor dominance after double-unit cord blood transplantation. Biol Blood Marrow Transplant 19:156-60
Newell, L F; Flowers, M E D; Gooley, T A et al. (2013) Characteristics of chronic GVHD after cord blood transplantation. Bone Marrow Transplant 48:1285-90
Newell, Laura F; Milano, Filippo; Nicoud, Ian B et al. (2012) Early CD3 peripheral blood chimerism predicts the long-term engrafting unit following myeloablative double-cord blood transplantation. Biol Blood Marrow Transplant 18:1243-9
Milano, Filippo; Chien, Jason W; Riffkin, Ivy et al. (2012) Stable long-term pulmonary function after myeloablative double cord blood transplant. Biol Blood Marrow Transplant 18:309-13
Milano, Filippo; Pergam, Steven A; Xie, Hu et al. (2011) Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients. Blood 118:5689-96
Gutman, Jonathan A; Turtle, Cameron J; Manley, Thomas J et al. (2010) Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood 115:757-65
Delaney, Colleen; Heimfeld, Shelly; Brashem-Stein, Carolyn et al. (2010) Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 16:232-6

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