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Adult human mesenchymal stromal cells and the treatment of graft versus host disease.

ABSTRACT: Graft versus host disease is a difficult and potentially lethal complication of hematopoietic stem cell transplantation. It occurs with minor human leucocyte antigen (HLA) mismatch and is normally treated with corticosteroid and other immunosuppressive therapy. When it is refractory to steroid therapy, mortality approaches 80%. Mesenchymal stromal cells are rare cells found in bone marrow and other tissues. They can be expanded in culture and possess complex and diverse immunomodulatory activity. Moreover, human mesenchymal stromal cells carry low levels of class 1 and no class 2 HLA antigens, making them immunoprivileged and able to be used without HLA matching. Their use in steroid-refractory graft versus host disease was first described in 2004. Subsequently, they have been used in a number of Phase I and II trials in acute and chronic graft versus host disease trials with success. We discuss their mode of action, the results, their production, and potential dangers with a view to future application.

SUBMITTER: Herrmann RP

PROVIDER: S-EPMC3945047 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Adult human mesenchymal stromal cells and the treatment of graft versus host disease.

Herrmann Richard P RP Sturm Marian J MJ

Stem cells and cloning : advances and applications 20140228

Graft versus host disease is a difficult and potentially lethal complication of hematopoietic stem cell transplantation. It occurs with minor human leucocyte antigen (HLA) mismatch and is normally treated with corticosteroid and other immunosuppressive therapy. When it is refractory to steroid therapy, mortality approaches 80%. Mesenchymal stromal cells are rare cells found in bone marrow and other tissues. They can be expanded in culture and possess complex and diverse immunomodulatory activity ...[more]

PMID: 24627644

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Project description:BackgroundGraft-versus-host disease (GvHD) is the main life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty to 80% of GvHD patients do not respond to first-line treatment and a second-line treatment is not universally established. Based on their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed for the prevention and the treatment of GvHD in patients undergoing HSCT. Unfortunately, previous studies reported conflicting results regarding the prophylactic and therapeutic effects of MSC for GvHD. Consequently, we carried out a meta-analysis to clarify whether MSC administration can improve the dismal outcome of these patients.MethodsWe carried out a systematic review and selected studies (2004-2019) reporting data about the administration of allogeneic MSC for the prevention (n = 654 patients) or treatment of acute (n = 943 patients) or chronic (n = 76 patients) GvHD after HSCT. Our primary outcome was overall survival at the last follow-up. The secondary outcomes were the response and development of GvHD. Subgroup analyses included age, MSC dose, first infusion day after HSCT, number of organs and organ-specific involvement, acute GvHD grade (I-IV), and chronic GvHD grade (limited or extensive).ResultsPatients infused with MSC for GvHD prophylaxis showed a 17% increased overall survival (95% CI, 1.02-1.33) and a reduced incidence of acute GvHD grade IV (RR = 0.22; 95% CI, 0.06-0.81) and chronic GvHD (RR = 0.64; 95% CI, 0.47-0.88) compared with controls. Overall survival of acute GvHD patients (0.50; 95% CI, 0.41-0.59) was positively correlated with MSC dose (P = 0.0214). The overall response was achieved in 67% (95% CI, 0.61-0.74) and was complete in 39% (95% CI, 0.31-0.48) of acute patients. Organ-specific response was higher for the skin. Twenty-two percent (95% CI, 0.16-0.29) of acute patients infused with MSC developed chronic GvHD. Sixty-four percent (95% CI, 0.47-0.80) of chronic patients infused with MSC survived; the overall response was 66% (95% CI, 0.55-0.76) and was complete in 23% (95% CI 0.12-0.34) of patients.ConclusionsOur meta-analysis indicates that allogeneic MSC could be instrumental for the prophylaxis and treatment of GvHD. Future trials should investigate the effect of the administration of MSC as an adjuvant therapy for the treatment of patients with GvHD from the onset of the disease.

Project description:Despite the curative potential of hematopoietic cell transplantation (HCT) for hematologic malignancies, graft-versus-host disease (GVHD) remains a substantial cause of morbidity and mortality, particularly if treatment is refractory. Treatment with additional immunosuppression including steroids often leads to opportunistic infections and organ dysfunction. Novel therapies are greatly needed, specifically ones that lead to responses in treatment-refractory patients and are better tolerated. Mesenchymal stromal cells (MSCs) are non-hematopoietic tolerogenic cells present in normal bone marrow (BM), which can be expanded ex vivo to therapeutic doses. Their safety and efficacy have been assessed in inflammatory disorders including GVHD, but heterogeneity in clinical responses has led some to examine MSC manufacturing and administration procedures, which may impact in vivo efficacy. We hypothesized that autologous, early-passage, and culture-recovered (after freeze and thaw) MSCs would be safe and may have superior efficacy. In this phase I single-center trial, we assessed MSC safety and early efficacy of an escalating number of doses (2 × 106/kg doses; dose level 1, single dose; dose level 2, two weekly doses; dose level 3, four weekly doses) in patients aged ≥12 years with treatment-refractory acute or chronic GVHD. Eleven enrolled patients received some or all planned MSC infusions, with a median age at enrollment of 37 years. The most common primary HCT indication was leukemia, and the median time from HCT to first MSC infusion was 2.6 years. MSC infusion was well tolerated, with all severe adverse events expected and determined to be unlikely or definitely not related to the study. Thus, no dose-limiting toxicities occurred in the three dose levels. Three of four patients with acute GVHD (or overlap with acute features) had responses seen at any timepoint, ranging from partial to complete. In those with a chronic GVHD indication (n = 7), an overall response at 3 months was partial in five, stable in one, and progressive in one. No appreciable differences were seen between dose levels in peripheral blood lymphocyte subsets. In conclusion, autologous and culture-recovered MSCs were safe in the setting of refractory GVHD following HCT for hematologic malignancy, and clinical responses were most notable in patients with acute GVHD.

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Adult human mesenchymal stromal cells and the treatment of graft versus host disease.

Publications

Adult human mesenchymal stromal cells and the treatment of graft versus host disease.

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