Cord-Blood Engraftment with Ex Vivo Mesenchymal-Cell Coculture

Abstract

BACKGROUND Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells. METHODS We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood. RESULTS Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×107 total nucleated cells per kilogram of body weight and 1.81×106 CD34+ cells per kilogram — doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P = 0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001). CONCLUSIONS Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00498316.)

Characterization of the growth modulatory activities of osteoblast conditioned media on cord blood progenitor cells

“…One strategy has been focused on the ex vivo expansion of HSPC prior to transplantation which has now been tested in several clinical trials (Pineault and Abu-Khader 2015;Norkin et al 2013;Delaney et al 2005;Cairo et al 2016;de Lima et al 2012). Indeed, decreased graft failure and accelerated neutrophil recovery have been reported in patients undergoing double CB transplantation with an expanded and unmanipulated units, each unit providing short-and long-term engraftment, respectively (de Lima et al 2012;Delaney et al 2010;Horwitz et al 2014).…”

Evaluating Interaction of Cord Blood Hematopoietic Stem/Progenitor Cells with Functionally Integrated Three-Dimensional Microenvironments

“…Still, expansion of the true hematopoietic stem cell pool has been limited 2, 4, 45, 46. We 4, 5, 6, 7 and others 38 have previously shown that CB‐HSPC can be effectively expanded and driven to differentiate toward both the myeloid and lymphoid lineages in a serum‐free culture system, using a feeder layer of adult human BM‐derived stromal cells. Using this system, we have optimized initial progenitor content and cytokine concentrations 7, 8, 9, and demonstrated that the expanded human CB‐HSPC had the ability to engraft pre‐immune fetal sheep 5.…”

“…The first attempts at ex vivo expansion of CB‐HSPC used growth factors alone, and led to inadequate outcomes. However, when patients were transplanted with HSPC that had been cocultured in the presence of supportive stromal layers, the time to neutrophil and platelet reconstitution was significantly shortened 38. Other approaches to expand the numbers of transplantable HSPC within a unit of CB have included or involved activation of endogenous Notch receptors 39, nicotinamide analogs 40, aryl hydrocarbon receptor antagonists 41, copper chelators 1, histone deacetylase inhibitors 42, and engraftment enhancers such as PEG2 43 and CXCR4 44.…”

A prospective investigation of cell dose in single-unit umbilical cord blood transplantation for adults with high-risk hematologic malignancies

“…Double cord blood transplantation has been extensively investigated but, to date, a survival advantage has not been shown over single UCB units or unrelated donor grafts 7,28-37 and additional efforts are being investigated in clinical trials. 4,38,39 As these attempts are explored and potentially practice-changing data emerges, improvements and expertise in our current transplant procedures are of great importance.…”