Umbilical cord blood (CB) can serve as an alternative graft for patients lacking a matched related donor, yet intrinsically low cell doses leading to delayed engraftment and graft failure severely restrict wider use of this valuable resource. Hence, the central hypothesis of Project 1 is that CB progenitors expanded ex vivo on mesenchymal stem cells (MSCs) will provide more rapid hematopoietic reconstitution, as well as less engraftment failure, than unmanipulated CB cells. Indeed, the CB mononuclear cell/MSC co-culture system we have developed should avoid the significant CD34+ cell losses we experienced in earlier liquid suspension culture studies and, because it provides a surrogate niche for the propagation of CB progenitors, should yield improved CB cell expansion overall. This prediction will be tested in a phase 1 clinical trial in patients undergoing CB transplantation for hematologic malignancies (Aim 1.1), coupled with mechanistic studies to determine if optimal expansion is inhibited by specific CB """"""""accessory"""""""" cells in the coculture system (Aim 1.2). Although a low cell dose is clearly the chief limitation of CB transplantation, a number of investigators have reported a defect in the homing of CB cells to the bone marrow. Thus, even with improved CB expansion. Inadequate homing may limit the rapidity of engraftment ~ the focus of this research project. The homing defect has been attributed to low levels of fucosylation of cell surface molecules responsible for binding to P- and/or E-selections, a key component of the mechanism by which circulating blood progenitors are recruited to the marrow microvasculature. We hypothesize that increasing the level of CB cell surface fucosylation will improve interactions with selectins, thereby improving homing and then engraftment. Thus, to assess the modification of unmanipulated and expanded CB progenitors with fucosyltransferase, as means to facilitate their recruitment to the marrow, we have planned both a clinical trial (Aim 2) and mechanistic studies in mice (Aim 3) that will model the CB transplant setting. Success in this project will help to circumvent two of the remaining barriers to effective CB transplantation, thereby broadening the use of this procedure in patients who otherwise lack practical therapeutic options.

Public Health Relevance

Slow recovery of white blood cells to fight infection, platelets to prevent bleeding and red cells to carry oxygen represent major obstacles to wider use of cord blood transplantation. Project 1 seeks to overcome these barriers by improving the expansion of cord blood cells, and by directing their migration to the bone marrow, before their transplantation into patients. If successful, this strategy will improve the survival of cord blood transplant patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-J)
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University of Texas MD Anderson Cancer Center
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Cruz, Conrad R Y; Bollard, Catherine M (2017) Adoptive Immunotherapy For Leukemia With Ex vivo Expanded T Cells. Curr Drug Targets 18:271-280
Kerros, Celine; Tripathi, Satyendra C; Zha, Dongxing et al. (2017) Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells. J Biol Chem 292:10295-10305
Kolonin, Mikhail G; Sergeeva, Anna; Staquicini, Daniela I et al. (2017) Interaction between Tumor Cell Surface Receptor RAGE and Proteinase 3 Mediates Prostate Cancer Metastasis to Bone. Cancer Res 77:3144-3150
Alsuliman, Abdullah; Muftuoglu, Muharrem; Khoder, Ahmad et al. (2017) A subset of virus-specific CD161+ T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML. Blood 129:740-758
Peters, Haley L; Tripathi, Satyendra C; Kerros, Celine et al. (2017) Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells. Cancer Immunol Res 5:319-329
Houghtelin, Amy; Bollard, Catherine M (2017) Virus-Specific T Cells for the Immunocompromised Patient. Front Immunol 8:1272
Robinson, Simon N; Thomas, Michael W; Simmons, Paul J et al. (2017) Non-fucosylated CB CD34+ cells represent a good target for enforced fucosylation to improve engraftment following cord blood transplantation. Cytotherapy 19:285-292
Dave, Hema; Luo, Min; Blaney, J W et al. (2017) Toward a Rapid Production of Multivirus-Specific T Cells Targeting BKV, Adenovirus, CMV, and EBV from Umbilical Cord Blood. Mol Ther Methods Clin Dev 5:13-21
Naik, Swati; Nicholas, Sarah K; Martinez, Caridad A et al. (2016) Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol 137:1498-1505.e1
Nesher, Lior; Shah, Dimpy P; Ariza-Heredia, Ella J et al. (2016) Utility of the Enzyme-Linked Immunospot Interferon-?-Release Assay to Predict the Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients. J Infect Dis 213:1701-7

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