Cotransplantation of third-party mesenchymal stromal cells can alleviate single-donor predominance and increase engraftment from double cord transplantation

157

120

When compared with BMT, umbilical cord blood transplantation (UCBT) is associated with a lower rate of engraftment and delayed hematological/immunological recovery. This leads to increased risk of TRM in the early post transplantation period due to infection. Acute GVHD, although occurring less frequently in UCBT compared with BMT, is also significantly associated with increased rate of early TRM. BM MSCs are known to support normal in vivo hematopoiesis, and co-transplantation of MSCs has been shown to enhance engraftment of human cord blood hematopoietic cells in nonobese diabetic/SCID mice. In 13 children with hematological disorders (median age 2 years) undergoing UCBT, we cotransplanted paternal, HLA-disparate MSCs with the aim of improving hematological recovery and reducing rejection. We observed no differences in hematological recovery or rejection rates compared with 39 matched historical controls, most of whom received G-CSF after UCBT. However, the rate of grade III and IV acute GVHD was significantly decreased in the study cohort when compared with controls (P ¼ 0.05), thus resulting in reduced early TRM. Although these data do not support the use of MSCs in UCBT to support hematopoietic engraftment, they suggest that MSCs, possibly because of their immunosuppressive effect, may abrogate life-threatening acute GVHD and reduce early TRM.

Section: Discussionmentioning

confidence: 99%

Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation

Bernardo

Ball

Cometa

et al. 2010

157

120

“…40 Similar to others, we are investigating alternative strategies to increase the UCB cell dose, such as the double unit UCB transplant, ex vivo expansion 40,41 and co-infusion of mesenchymal stem cells. 37,42,43 …”

Section: Discussionmentioning

confidence: 99%

Outcome following unrelated cord blood transplant in 136 patients with malignant and non-malignant diseases: a report from the Australian and New Zealand children's haematology and oncology group

Petterson

Gabriel

Tiedemann

et al. 2008

Unrelated umbilical cord blood (UCB) is an alternative stem cell source for paediatric patients lacking a matched related or unrelated marrow donor. We report the results of all paediatric unrelated UCB transplants performed in Australia and New Zealand over a 10-year period. A total of 135 patients were transplanted, 100 for malignant disease (74%) and 35 for non-malignant disorders. The majority (88%) of patients received an HLA-mismatched graft. The median infused total nucleated cell dose was 4.7 Â 10 7 /kg and CD34 þ count 1.9 Â 10 5 /kg. Neutrophil engraftment occurred in 83% of patients by day 42 (median 23 days) and platelet engraftment in 55% by day 60 (median 56 days). Grades II-IV and III-IV acute GVHD occurred in 41 and 18% of patients, respectively. TRM and overall survival 1-year post transplant were 32 and 61%, respectively. A higher probability of neutrophil recovery (P ¼ 0.004) and faster time to recovery (median 18 days vs 26 days, P ¼ 0.008) were observed in recipients of a cord unit with a CD34 cell dose X1.7 Â 10 5 /kg. Our results support selection of cord units with CD34 cell doses X1.7 Â 10 5 /kg to promote faster engraftment, improve survival and lower TRM.

“…66 Third-party MSC can be used to alleviate donor deviation in dual-cord transplantation and to facilitate engraftment of multidonor UCBT as shown in NOD/SCID mice. [67][68][69] It is unclear whether the immunomodulatory properties of MSC 70,71 when cocultured with unmanipulated cord cells yielding a 16-37-fold increase in CD34 þ cells 72 will prove useful in the setting of cord blood transplant or adoptive immunotherapy.…”

Section: Stromamentioning

confidence: 99%

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Hofmeister

Zhang

Knight

et al. 2006

198

172

Umbilical cord blood transplantation (UCBT) in adults is limited by the small number of primitive hematopoietic stem cells (HSC) in each graft, resulting in delayed engraftment post transplant, and both short-and longterm infectious complications. Initial efforts to expand UCB progenitors ex vivo have resulted in expansion of mature rather than immature HSC, confounded by the inability to accurately and reliably measure long-term reconstituting cells. Ex vivo expansion of UCB HSC has failed to improve engraftment because of resulting defects that promote apoptosis, disrupt marrow homing and initiate cell cycling. Here we discuss the future of ex vivo expansion, which we suggest will include the isolation of immature hematopoietic progenitors on the basis of function rather than surface phenotype and will employ both cytokines and stroma to maintain and expand the stem cell niche. We suggest that ex vivo expansion could be enhanced by manipulating newly discovered signaling pathways (Notch, Wnt, bone morphogenetic protein 4 and Tie2/angiopoietin-1) and intracellular mediators (phosphatase and tensin homolog and glycogen synthase kinase-3) in a manner that promotes HSC expansion with less differentiation. Improved methods for ex vivo expansion will make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.