Ex vivo expansion of cord blood

Abstract

A marked increase in the utilization of umbilical cord blood (UCB) transplantation has been observed in recent years; however, the use of UCB as a hematopoietic stem cell (HSC) source is limited primarily by the number of progenitor cells contained in the graft. Graft failure, delayed engraftment and profound delay in immune reconstitution lead to significant morbidity and mortality in adults. The lack of cells available for post transplant therapies, such as donor lymphocyte infusions, has also been considered to be a disadvantage of UCB. To improve outcomes and extend applicability of UCB transplantation, one potential solution is ex vivo expansion of UCB. Investigators have used several methods, including liquid suspension culture with various cytokines and expansion factors, co-culture with stromal elements and continuous perfusion systems. Techniques combining ex vivo expanded and unmanipulated UCB are being explored to optimize the initial engraftment kinetics as well as the long-term durability. The optimal expansion conditions are still not known; however, recent studies suggest that expanded UCB is safe. It is hoped that by ex vivo expansion of UCB, a resulting decrease in the morbidity and mortality of UCB transplantation will be observed, and that the availability of additional cells may allow adoptive immunotherapy or gene transfer therapies in the UCB setting.

Exploring the Human Term Placenta as a Novel Source for Stem Cells and their Application in the Clinic

“…As with clinical trials using cytokine-expanded HSC, the study transfused one unmanipulated UCB unit together with one 14-day expanded unit. Expansion using this method enhanced neutrophil recovery by 14 days and the grafts were shown to elicit less GVHD compared to that of published reports using unmanipulated UCB transplants (Mesoblast ASX announcement, 06 Nov 2009, www.mesoblast.com) (Kelly et al, 2009). While long-term follow up results are yet to be reported, it will be interesting to determine whether the therapeutic value of the expanded unit is purely short-term myeloid support, as is the case in the Delaney's cytokine-mediated expansion trial (Delaney et al, 2010), or whether the expanded unit also provides durable long-term engraftment.…”

Hematopoetic stem cell transplantation in children

“…When compatibility of human leukocyte antigens is also considered, the recommended cell dose is >3.0x10 7 /kg for 6/6 HLA compatible cord blood, >4.0x10 7 /kg for 5/6 HLA compatible cord blood and >5.0x10 7 /kg for 4/6 HLA compatible cord blood (16). In recent years, applications directed to increase the low cell number which is the major problem in cord blood transplantation have been tried including ex-vivo expansion, transplantation with double cord blood and peripheral blood stem cell infusion from the same donor simultaneously with cord blood transplantation (17)(18)(19)(20)(21)(22). In cord blood, compatibility for HLA-A and HLA-B at the antigen level (low or moderate resolution) and compatibility for HLA-DRB1 at the allele level are considered standard compatibility.…”

Cord Blood Transplantation in Adults with Acute Leukemia

“…Initial CB expansion attempts have used a variety of cytokines, such as stem cell factor (SCF), fms-like tyrosine kinase 3 (flt-3) ligand, thrombopoietin (TPO) and G-CSF (granulocyte colony-stimulating factor), reagents, such as polyamine copper chelator, tetraethylenepentamine (TEPA), and mesenchymal stem cells (MSCs), to cell culture. Several clinical studies were investigated, but have not achieved clinically relevant effects (Shpall et al, 2002;de Lima et al, 2008de Lima et al, , 2010Jaroscak et al, 2003;Kelly et al, 2009) (Table 3). Delancy et al report the development of a clinically relevant Notchmediated ex vivo expansion system for CB CD34+ cells and the phase I study involving transplantation of a non-manipulated unit along with CB progenitors from a second CB unit that have undergone Notch-mediated ex vivo expansion in 10 patients with acute leukemia CBT indicates cord blood transplantation; CB, cord blood; SCF, stem cell factor; G-CSF, granulocyte colony-stimulating factor; TPO, thrombopoietin; Flt3L, fms-like tyrosine kinase 3 ligand; IL, interleukin; TEPA, tetraethylenepentamine; MSCs, mesenchymal stem cells; PIXY321, granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein; EPO, erythropoietin; TNC, total nucleated cell; ANC, absolute neutrophil count; PLT, platelet; NA, information not available; GVHD, graft-versus-host disease.…”