Cord blood (CB) transplantation has greatly extended availability of a hematopoietic cell transplant (HCT) to patients who would not otherwise have received this curative treatment. CB has several advantages over bone marrow (BM) and mobilized peripheral blood (mPB), including ease and safety of collection, ready availability, and lessened acute and chronic graft vs. host disease (GVHD). However, a disadvantage with CB is low numbers of nucleated cells, hematopoietic progenitors (HPC), and likely stem cells (HSC), compared with BM or mPB, which has translated into increase risk of graft failure, delayed engraftment, and delayed immune reconstitution. Based on our published laboratory and preclinical animal model studies, preliminary clinical data, and mechanistic studies on CD26/Dipeptidylpeptidase (DPP) IV activities reported herein, we believe that inhibition of CD26/DPPIV will significantly enhance engraftment capability of limiting numbers of human CB cells, and accelerate time to engraftment of single CB units. This multi-PI grant proposes the following specific aims:
Aim 1 : Conduct a multicenter phase II clinical trial to assess efficacy and safety of systemic inhibition of CD26/DPPIV using sitagliptin, to enhance engraftment of single CB units in adults with hematological cancers. Hypothesis: Inhibition of CD26/DPPIV by systemic administration of CD26 inhibitor sitagliptin will enhance engraftment, without negatively impacting relatively lower levels of GVHD associated with single CB transplantation. Primary Objective: Evaluate proportion of patients with neutrophil recovery by day +30 after transplant as a measure of speed of engraftment. Using an optimal two-stage design, <50% of patients engrafting by day +30 will be considered unacceptable (null hypothesis;H0: p0<0.5), while 70% or more engrafting will be considered worthy of further study (alternate hypothesis: H1: p1e0.7).
Sub aims are: a) Evaluate time to platelet engraftment, patient survival, graft failure, relapse rate, acute and chronic GVHD levels;b) Use correlative assays to assess recovery of immune cells through phenotypic and functional analysis;and c) Assess blood levels of CD26/DPPIV, and hematopoietically relevant cytokines.
Aim 2 : Evaluate how CD26/DPPIV mechanistically regulates hematopoiesis, using cell culture and biochemical studies on mouse and human cytokines and with cells from mouse BM and human CB. Hypothesis: CD26/DPPIV regulates hematopoiesis through: its specific enzymatic capability to truncate and inactivate different hematopoietically active cytokines. We will compare results to clinical study in Aim 1 to better understand and utilize this new treatment modality.
Sub aims i nclude: a) Evaluate how GM-CSF, G-CSF, IL-3 and EPO truncated by CD26/DPPIV, compared to full length form, signal intracellularly;b) Determine if systemic administration of sitagliptin to mice enhances homing of HSC and influences cytokine production;and c) Study other molecules for CD26/DPPIV truncation and activity.
Cord blood transplantation is a viable treatment, but one disadvantage is the limiting number of cells in single cord blood collections, especially for adult recipients. By understanding how a cell surface enzyme, CD26, regulates blood cell production, and by specifically inhibiting this enzyme systemically in recipients of cord blood transplantation, we believe that donor cell engraftment will be greatly enhanced in adult recipients.
|Capitano, Maegan; Zhao, Liang; Cooper, Scott et al. (2018) Phosphatidylinositol transfer proteins regulate megakaryocyte TGF-?1 secretion and hematopoiesis in mice. Blood 132:1027-1038|
|Huang, Xinxin; Guo, Bin; Liu, Sheng et al. (2018) Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment. Nat Commun 9:2741|
|Guo, Bin; Huang, Xinxin; Broxmeyer, Hal E (2018) Enhancing human cord blood hematopoietic stem cell engraftment by targeting nuclear hormone receptors. Curr Opin Hematol 25:245-252|
|Ha, Tae Won; Kang, Hyun Soo; Kim, Tae-Hee et al. (2018) MiR-9 Controls Chemotactic Activity of Cord Blood CD34? Cells by Repressing CXCR4 Expression. Int J Stem Cells 11:187-195|
|Broxmeyer, Hal E (2018) Enhancement of stem cell engraftment on a WHIM. J Clin Invest 128:3240-3242|
|Guo, Bin; Huang, Xinxin; Lee, Man Ryul et al. (2018) Antagonism of PPAR-? signaling expands human hematopoietic stem and progenitor cells by enhancing glycolysis. Nat Med 24:360-367|
|Capitano, Maegan L; Broxmeyer, Hal E (2017) A role for intracellular and extracellular DEK in regulating hematopoiesis. Curr Opin Hematol 24:300-306|
|Guo, Bin; Huang, Xinxin; Cooper, Scott et al. (2017) Glucocorticoid hormone-induced chromatin remodeling enhances human hematopoietic stem cell homing and engraftment. Nat Med 23:424-428|
|Farag, Sherif S; Nelson, Robert; Cairo, Mitchell S et al. (2017) High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation. Oncotarget 8:110350-110357|
|O'Leary, H A; Capitano, M; Cooper, S et al. (2017) DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms. Leukemia 31:2468-2478|
Showing the most recent 10 out of 48 publications