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

Abstract

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.

Stromal cells–are they really useful for GVHD?

“…48 The results are more promising when used at an early stage of GVHD. 86 Bernardo et al 96 treated grade-II acute GVHD with MSCs and reported no deaths that were attributable to acute GVHD as compared with 26% in retrospective control patients. According to animal data, not only early treatment, but also repeated doses may be needed.…”

“…No acute side effects were seen after infusion of MSC doses at a range of 1-5 Â 10 6 cells/kg in 46 HLA-identical sibling transplant recipients. Bernardo et al 96 used MSCs at the time of HSCT transplantation in children who were recipients of cord blood grafts. Ball et al 97 performed co-transplantation of MSCs in children undergoing haploidentical HSCT.…”

Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation?

“…50 In another pediatric, phase I/II clinical study, the safety and efficacy of co-transplantation of parental MSCs was tested in 13 pediatric patients given UCB-derived HCs; the results were compared with those obtained in historical controls receiving UCBT alone. 16 The feasibility and safety of the approach was confirmed; however, in contrast with pre-clinical results 36 and the experience reported in the haploidentical transplants, 15 no difference was found in terms of both engraftment rate and speed of hematological recovery between the two groups, although much less study patients were given G-CSF as compared with controls. Interestingly, MSC co-infusion significantly reduced the incidence of life-threatening acute GvHD and GvHD-associated TRM, as compared with controls.…”

“…Interestingly, MSC co-infusion significantly reduced the incidence of life-threatening acute GvHD and GvHD-associated TRM, as compared with controls. 16 In adult patients receiving UCBT with coinfusion of third-party donor-mobilized HCs, MSC administration at the time of transplantation had no effect on the kinetics of UCB cell engraftment, as well as on GvHD prevention. 51 Altogether, these data indicate that co-transplantation of HCs and MSCs is safe, while there is still uncertainty about a real efficacy of MSCs on promoting engraftment of donor cells and accelerating the speed of hematological recovery.…”

“…[15][16][17] Standard conditions for ex vivo expansion of MSCs are based on the presence of 10% FCS and serum batches are routinely prescreened to guarantee both the optimal growth of MSCs and the bio-safety of the cellular product. [15][16][17] However, the use of FCS raises concerns when utilized in clinical grade preparations, because it might theoretically be responsible for the transmission of zoonoses or cause immune reactions in the host, especially if repeated infusions are needed, leading to the risk of consequent rejection of the transplanted cells. 18,19 In this regard, Horwitz et al 19 reported sensitization in a child with Osteogenesis Imperfecta treated with repeated infusions of MSCs.…”