Cotransplantation of Mesenchymal Stem Cells Might Prevent Death from Graft-versus-Host Disease (GVHD) without Abrogating Graft-versus-Tumor Effects after HLA-Mismatched Allogeneic Transplantation following Nonmyeloablative Conditioning

Abstract

Recent studies have suggested that coinfusion of mesenchymal stem cells (MSCs) the day of hematopoietic cell transplantation (HCT) might promote engraftment and prevent graft-versus-host disease (GVHD) after myeloablative allogeneic HCT. This prompted us to investigate in a pilot study whether MSC infusion before HCT could allow nonmyeloablative (NMA) HCT (a transplant strategy based nearly exclusively on graft-versus-tumor effects for tumor eradication) from HLA-mismatched donors to be performed safely. Twenty patients with hematologic malignancies were given MSCs from third party unrelated donors 30-120 minutes before peripheral blood stem cells (PBSCs) from HLA-mismatched unrelated donors, after conditioning with 2 Gy total body irradiation (TBI) and fludarabine. The primary endpoint was safety, defined as a 100-day incidence of nonrelapse mortality (NRM) <35%. One patient had primary graft rejection, whereas the remaining 19 patients had sustained engraftment. The 100-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was 35%, whereas 65% of the patients experienced moderate/severe chronic GVHD (cGVHD). One-year NRM (10%), relapse (30%), overall survival (OS) (80%) and progression-free survival (PFS) (60%), and 1-year incidence of death from GVHD or infection with GVHD (10%) were encouraging. These figures compare favorably with those observed in a historic group of 16 patients given HLA-mismatched PBSCs (but no MSCs) after NMA conditioning, which had a 1-year incidence of NRM of 37% (P = .02), a 1-year incidence of relapse of 25% (NS), a 1-year OS and PFS of 44% (P = .02), and 38% (P = .1), respectively, and a 1-year rate of death from GVHD or infection with GVHD of 31% (P = .04). In conclusion, our data suggest that HLA-mismatched NMA HCT with MSC coinfusion appeared to be safe.

Good outcome of haploidentical hematopoietic SCT as a salvage therapy in children and adolescents with acquired severe aplastic anemia

“…24 In a mismatched unrelated transplantation setting, Baron reported that the proportion of patients with severe aGVHD was lower in MSC co-transplantation and the 1-year probability of dying from GVHD or infection while on treatment for GVHD was significantly lower than control (10% versus 31%). 25 Basliximab and MSCs were used in all our patients to further reduce GVHD incidence besides CsA, MTX and MMF. Although the overall incidence of aGVHD was high, most were well controlled and the severity is mild-moderate because only 1 case died of grade III-IV aGVHD.…”

Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+T-Cell Activation by Inducing IL-10-Producing Th1 Cells

“…Gene expression profiling of CD4 + T-cells, stimulated with allogeneic mDCs (with a CD4 + T-cell-to-mDC ratio of 40:1) for 6 days in the presence and absence of MSCs (with a CD4 + T-cell-to-MSC ratio of 10:1), was investigated using a Human Th1-Th2-Th3 RT 2 Profiler polymerase chain reaction (PCR) Array (Qiagen, Inc., Toronto, ON). Cells obtained from 3 healthy donors were tested.…”

“…Gene expression profiles were generated by PCR array (Human Th1-Th2-Th3 RT 2 Profiler PCR Array from Qiagen). The class comparison analysis shows that stimulated cells upregulated several genes indicative of a Th1 signature induced by the presence of allogeneic mDCs.…”

“…Although the mechanism of action of MSCs is not well understood, they have already entered into clinical trials and, given their low immunogenicity, few if any adverse events have emerged to date [2][3][4][5][6].…”

Allogeneic hematopoietic stem cell transplantation (HSCT) after reduced intensity conditioning

“…Several groups have evaluated the potential of MSC infusions to prevent or to treat acute GVHD after allogeneic HSCT [43]. Recently, Baron et al have investigated the impact on GVHD occurence of MSC co-infusion in 20 patients receiving HLA-mismatched allogeneic grafts after nonmyeloablative conditioning [44]. Compared with 16 similar historical controls, MSC co-transplantation was associated with a lower incidence of severe acute GVHD, lower NRM and improved survival.…”