Cotransplantation of HLA-Identical Sibling Culture-Expanded Mesenchymal Stem Cells and Hematopoietic Stem Cells in Hematologic Malignancy Patients

Abstract

Mesenchymal stem cells (MSCs) are found in a variety of tissues, including human bone marrow; secrete hematopoietic cytokines; support hematopoietic progenitors in vitro; and possess potent immunosuppressive properties. We hypothesized that cotransplantation of culture-expanded MSCs and hematopoietic stem cells (HSCs) from HLA-identical sibling donors after myeloablative therapy could facilitate engraftment and lessen graft-versus-host disease (GVHD); however, the safety and feasibility of this approach needed to be established. In an open-label, multicenter trial, we coadministered culture-expanded MSCs with HLA-identical sibling-matched HSCs in hematologic malignancy patients. Patients received either bone marrow or peripheral blood stem cells as the HSC source. Patients received 1 of 4 study-specified transplant conditioning regimens and methotrexate (days 1, 3, and 6) and cyclosporine as GVHD prophylaxis. On day 0, patients were given culture-expanded MSCs intravenously (1.0-5.0 x 10(6)/kg) 4 hours before infusion of either bone marrow or peripheral blood stem cells. Forty-six patients (median age, 44.5 years; range, 19-61 years) received MSCs and HLA-matched sibling allografts. MSC infusions were well tolerated, without any infusion-related adverse events. The median times to neutrophil (absolute neutrophil count > or = 0.500 x 10(9)/L) and platelet (platelet count > or = 20 x 10(9)/L) engraftment were 14.0 days (range, 11.0-26.0 days) and 20 days (range, 15.0-36.0 days), respectively. Grade II to IV acute GVHD was observed in 13 (28%) of 46 patients. Chronic GVHD was observed in 22 (61%) of 36 patients who survived at least 90 days; it was extensive in 8 patients. Eleven patients (24%) experienced relapse at a median time to progression of 213.5 days (range, 14-688 days). The probability of patients attaining disease- or progression-free survival at 2 years after MSC infusion was 53%. Cotransplantation of HLA-identical sibling culture-expanded MSCs with an HLA-identical sibling HSC transplant is feasible and seems to be safe, without immediate infusional or late MSC-associated toxicities. The optimal MSC dose and frequency of administration to prevent or treat GVHD during allogeneic HSC transplantation should be evaluated further in phase II clinical trials.

IFN‐γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease

“…Using cells isolated in this manner, we observed that MSC significantly reduced the mortality of GVHD as evidenced by survival data and supportive histological analyses. These data correlate to findings reported in clinical studies [22,24,47]. MSC had no significant efficacy when given at the time of transplant, on day 0, but significantly improved GVHD mortality when given during ongoing GVHD, on day 20.…”

“…In contrast, when given at the time of BM transplant, for the prevention of GVHD, the incidence of grade III/ IV GVHD was not significantly improved [24], suggesting the absence of necessary initiating factors for MSC activation and subsequent efficient suppression of donor-derived T cells. MSC may require activating signals from robustly proliferating T cells to induce their suppressive effects.…”

“…In contrast, when given at the time of BM transplant, for the prevention of GVHD, the incidence of grade III/ IV GVHD was not significantly improved [24], suggesting the [26,27,29,30]. In addition, MSC do not suppress the modest T cell proliferative response to recall antigens [31].…”

Derivation and immunological characterization of mesenchymal stromal cells from human embryonic stem cells

“…Nevertheless, interest in MSCs has already moved from in vitro and animal studies into actual clinical trials in patients [36]. Several phase I-II clinical trials have already shown the safety and efficacy of BM-derived MSCs for enhancing the engraftment of co-transplanted HSCs in patients with hematologic and non-hematologic malignancies [37,38]. BM-derived MSCs have also shown promising results for the treatment of mesenchymal diseases such as osteogenesis imperfecta [39] and congenital disorders such as metachromatic leukodystrophy [40].…”

Immunoregulatory function of mesenchymal stem cells

“…Notably, the i.v. infusion of allogeneic MSC in humans has led to encouraging results in different human diseases including GVHD [15], breast cancer [71], osteogenesis imperfecta [72], metachromatic leukodystrophy and Hurler syndrome [73], hematological malignancies [74] and stroke [75]. However, recent in vivo experiments raised some doubts about the reported immunoprivilege of MSC, indicating that at least in some cases, administration of allogeneic MSC into an MHC-mismatched host may result in their rejection [19].…”