Abstract
Apart from peripheral blood stem cell (PBSC), umbilical cord blood (UCB) is now a recognized source of stem cells for transplantation. UCB is an especially important source of stem cells for minority populations, which would otherwise be unable to find appropriately matched adult donors. UCB has fewer mature T lymphocytes compared with peripheral blood, thus making a UCB transplantation (UCBT) with a greater degree of HLA mismatch possible. The limited cell dose per UCB sample is however associated with delayed engraftment and a higher risk of graft failure, especially in adult recipients. This lower cell dose can be optimized by performing double unit UCBT, ex vivo UCB expansion prior to transplant and enhancement of the capabilities of the stem cells to home to the bone marrow. UCB contains naïve and immature T cells, thus posing significant challenges with increased risk of infections, graft versus host diseases (GVHD) and relapse following UCBT. Cell engineering techniques have been developed to circumnavigate the immaturity of the T cells, and include virus-specific cytotoxic T cells (VSTs), T cells transduced with disease-specific chimeric antigen receptor (CAR T cells) and regulatory T cell (Tregs) engineering. In this article, we review the advances in UCB ex vivo expansion and engineering to improve engraftment and reduce complications. As further research continues to find ways to overcome the current challenges, outcomes from UCBT will likely improve.
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References
Baron, F, Ruggeri, A, Nagler, A. Methods of ex vivo expansion of human cord blood cells: challenges, successes and clinical implications. Expert Rev Hematol 2016;9;297–314.
Gluckman, E, et al. Hematopoietic reconstitution in a patient with Fanconi’s Anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989;321;1174–8.
Wagner, JE, et al. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood 1992; 79;1874–81.
Laporte, J-P, et al. Cord-blood transplantation from an unrelated donor in an adult with chronic myelogenous leukemia. N Engl J Med 1996;335;167–70.
Stanevsky, A, Goldstein, G, Nagler, A. Umbilical cord blood transplantation: pros, cons and beyond. Blood Rev 2009;23;199–204.
Gammaitoni, L. Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication. Blood 2004;103;4440–8.
Terakura, S, et al. Comparison of outcomes of 8/8 and 7/8 Allele– matched unrelated bone marrow transplantation and single-unit cord blood transplantation in adults with acute leukemia. Biol Blood Marrow Transplant 2016;22;330–8.
Eapen, M, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 2010;11; 653–60.
Baron, F, et al. Unrelated cord blood transplantation for adult patients with acute myeloid leukemia: higher incidence of acute graft-versus-host disease and lower survival in male patients transplanted with female unrelated cord blood—a report from Eurocord, the Acute L. J Hematol Oncol 2015;8;107.
Dehn, J, et al. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR. Blood 2019;134;924–34.
Horwitz, ME, Frassoni, F. Improving the outcome of umbilical cord blood transplantation through ex vivo expansion or graft manipulation. Cytotherapy 2015;17;730–8.
Lund, TC, Boitano, AE, Delaney, CS, Shpall, EJ, Wagner, JE. Advances in umbilical cord blood manipulation-from niche to bedside. Nat Rev Clin Oncol 2015;12;163–74.
Pineault, N, Abu-Khader, A. Advances in umbilical cord blood stem cell expansion and clinical translation. Exp Hematol 2015;43;498–513.
Breems, DA, et al. Stroma-contact prevents loss of hematopoietic stem cell quality during ex vivo expansion of CD34+ mobilized peripheral blood stem cells. Blood 1998;91;111–17.
Dexter, TM, Allen, TD, Lajtha, LG. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J Cell Physiol 1977;91;335–44.
Shpall, EJ, et al. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 2002;8;368–76.
de Lima, M, et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant 2008;41;771–8.
Ohishi, K, Varnum-Finney, B, Bernstein, ID. Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest 2002;110; 1165–74.
de Lima, M, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med 2012;367; 2305–15.
Horwitz, ME, et al. Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. J Clin Oncol 2019;37;367–74.
Wagner, JE, Brunstein, C, McKenna, D, Sumstad, D, Maahs, S, Laughlin, M, Perry, MS, Boitano, AE, Cooke, MP, Bleul, CC. StemRegenin-1 (SR1) expansion culture abrogates the engraftment barrier associated with umbilical cord blood transplantation (UCBT). Blood 2014;124;728.
Subramaniam, S, Talkhoncheh, MS, Zemaitis, K, Debnath, S, Chen, J, Jain, M, Galeev, R, Larsson, J. Inhibition of lysine-specific demethylase 1A (LSD1) supports human HSCs in culture by preserving their immature state. Blood 2018;132;194.
Peled, T, et al. Linear polyamine copper chelator tetraethylenepentamine augments long-term ex vivo expansion of cord blood-derived CD34+ cells and increases their engraftment potential in NOD/SCID mice. Exp Hematol 2004;32;547–55.
Kiernan, J, et al. Clinical studies of ex vivo expansion to accelerate engraftment after umbilical cord blood transplantation: a systematic review. Transfus Med Rev 2017;31;173–82.
Sorrentino, BP. Clinical strategies for expansion of haematopoietic stem cells. Nat Rev Immunol 2004;4;878–88.
Stier, S, Cheng, T, Dombkowski, D, Carlesso, N, Scadden, DT. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 2002;99;2369–78.
Karanu, FN, et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med 2000;192;1365–72.
Delaney, C, et al. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 2010;16;232.
Dallas, MH, Varnum-Finney, B, Delaney, C, Kato, K, Bernstein, ID. Density of the notch ligand delta1 determines generation of B and T cell precursors from hematopoietic stem cells. J Exp Med 2005;201;1361–6.
Friedenstein, AJ, Petrakova, KV, Kurolesova, AI, Frolova, GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968;6; 230–47.
Briquet, A, et al. Prolonged ex vivo culture of human bone marrow mesenchymal stem cells influences their supportive activity toward NOD/SCID-repopulating cells and committed progenitor cells of B lymphoid and myeloid lineages. Haematologica 2010;95;47–56.
Robinson, SN, et al. Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells. Bone Marrow Transplant 2006;37;359–66.
Cooney, J. Expansion of cord blood stem cells and enhancing their mobilization and homing potential using mesenchymal stromal cells. Blood 2018;132;3344.
Peled, T, et al. Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Exp Hematol 2012;40;342–55.el.
Horwitz, ME, et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest 2014;124;3121–8.
Anand, S, et al. Transplantation of ex vivo expanded umbilical cord blood (NiCord) decreases early infection and hospitalization. Biol Blood Marrow Transplant 2017;23;1151–7.
Boitano, AE, et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 2010;329;1345–8.
Wagner, JE, et al. Phase I/II trial of stemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 2016;18;144–55.
Fares, I, et al. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 2014;345;1509–12.
Peled, A, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999;283;845–8.
Heazlewood, SY, Oteiza, A, Cao, H, Nilsson, SK. Analyzing hematopoietic stem cell homing, lodgment, and engraftment to better understand the bone marrow niche. Ann N Y Acad Sci 2014;1310;119–28.
Frassoni, F, et al. Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol 2008;9;831–9.
Rocha, V, et al. Unrelated cord blood transplantation: outcomes after single-unit intrabone injection compared with double-unit intravenous injection in patients with hematological malignancies. Transplantation 2013;95;1284–91.
Christopherson, KW, Hangoc, G, Broxmeyer, HE. Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 2002;169;7000–8.
Christopherson, KW, Paganessi, LA, Napier, S, Porecha, NK. CD26 inhibition on CD34+ or lineage- human umbilical cord blood donor hematopoietic stem cells/hematopoietic progenitor cells improves long-term engraftment into NOD/SCID/Beta2null immunodeficient mice. Stem Cells Dev 2007;16;355–60.
Farag, SS, et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev 2013;22;1007–15.
Brunstein, CG, et al. Complement fragment 3a priming of umbilical cord blood progenitors: safety profile. Biol Blood Marrow Transplant 2013;19;1474–9.
Hoggatt, J, Singh, P, Sampath, J, Pelus, LM. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 2009;113;5444–55.
Goessling, W, et al. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models. Cell Stem Cell 2011;8;445–58.
Cutler, C, et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood 2013;122; 3074–81.
Hidalgo, A, Weiss, LA, Frenette, PS. Functional selectin ligands mediating human CD34(+) cell interactions with bone marrow endothelium are enhanced postnatally. J Clin Invest 2002;110; 559–69.
Xia, L, McDaniel, JM, Yago, T, Doeden, A, McEver, RP. Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow. Blood 2004;104;3091–6.
Popat, U, et al. Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood 2015;125;2885–92.
Zhang, X, et al. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus. Sci Transl Med 2014;6;238ra72.
June, CH, Sadelain,M. Chimeric antigen receptor therapy. N Engl J Med 2018;379;64–73.
Singh, H, et al. Manufacture of clinical-grade CD19-specific T cells stably expressing chimeric antigen receptor using Sleeping Beauty system and artificial antigen presenting cells. PLOS ONE 2013;8;e64138.
Pegram, HJ, et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 2015;29;415–22.
Liston, A, Gray, DHD. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol 2014;14;154–65.
Sakaguchi, S, Sakaguchi, N, Asano, M, Itoh, M, Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155;1151–64.
Koreth, J, et al.Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011;365;2055–66.
Koreth, J, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood 2016;128;130–7.
Matsuoka, K, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 2013;5;179ra43.
Hippen, KL, et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med 2011;3;83ra41.
Brunstein, CG, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 2011;117;1061–70.
Brunstein, CG, et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood 2016;127;1044–51.
Do, J-S, et al. Human bone marrow derived mesenchymal stromal cells enhance the number and function of umbilical cord blood peripheral tregs during IL-2 driven ex vivo Expansion. Blood 2018;132; 1116.
Su, J, et al. Human mesenchymal stromal cells enhance the stability of umbilical cord blood inducible tregs during ex vivo expansion via mitochondria transfer. Biol Blood Marrow Transplant 2019;25;S330.
Kellner, JN, Yvon, E, Parmar, S. Ex vivo generation of umbilical cord blood T regulatory cells expressing the homing markers CD62L and cutaneous lymphocyte antigen. Oncotarget 2018;9; 33694–701.
Vivier, E, Tomasello, E, Baratin, M, Walzer, T, Ugolini, S. Functions of natural killer cells. Nat Immunol 2008;9;503–10.
Ruggeri, L, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002;295;2097–100.
Giebel, S,et al.Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003;102;814–19.
Willemze, R, et al. KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia 2009;23;492–500.
Condiotti, R, Zakai, YB, Barak, V, Nagler, A. Ex vivo expansion of CD56+ cytotoxic cells from human umbilical cord blood. Exp Hematol 2001;29;104–13.
Vasu, S, et al. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. Cytotherapy 2015;17;1582–93.
Hu, W, Wang, G, Huang, D, Sui, M, Xu, Y. Cancer immunotherapy based on natural killer cells: current progress and new opportunities. Front Immunol 2019;10;1205.
Hu, Y, Tian, Z-G, Zhang, C. Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy. Acta Pharmacol Sin 2018;39;167–76.
Saliba, RM, et al. General and virus-specific immune cell reconstitution after double cord blood transplantation. Biol Blood Marrow Transplant 2015;21;1284–90.
Bosch, M, et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 2012;14;1258–75.
Hannon, M, et al. Immune recovery after allogeneic hematopoietic stem cell transplantation following flu-TBI versus TLI-ATG conditioning. Clin Cancer Res 2015;21;3131–9.
Pascal, L, et al. Impact of rabbit ATG-containing myeloablative conditioning regimens on the outcome of patients undergoing unrelated single-unit cord blood transplantation for hematological malignancies. Bone Marrow Transplant 2015;50;45–50.
Leen, AM, et al. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med 2006;12;1160–6.
Hanley, PJ, et al. Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood 2009;114;1958–67.
Papadopoulou, A, et al. Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Sci Transl Med 2014;6;242ra83.
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Emiloju, O.E., Potdar, R., Jorge, V. et al. Clinical Advancement and Challenges of ex vivo Expansion of Human Cord Blood Cells. Clin Hematol Int 2, 18–26 (2020). https://doi.org/10.2991/chi.d.191121.001
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DOI: https://doi.org/10.2991/chi.d.191121.001