Placenta-Derived Decidua Stromal Cells for Treatment of Severe Acute Graft-Versus-Host Disease

Olle Ringden, Arjang Baygan, Mats Remberger, Britt Gustafsson, Jacek Winiarski, Bita Khoein, Guido Moll, Lena Klingspor, Magnus Westgren, Behnam Sadeghi, Olle Ringden, Arjang Baygan, Mats Remberger, Britt Gustafsson, Jacek Winiarski, Bita Khoein, Guido Moll, Lena Klingspor, Magnus Westgren, Behnam Sadeghi

Abstract

Severe acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). The placenta protects the fetus from the mother's immune system. We evaluated placenta-derived decidua stromal cells (DSCs), which differ from bone marrow mesenchymal stromal cells (BM-MSCs), as a treatment for severe acute GVHD. DSCs were obtained from term placentas. The DSCs were given to 38 patients with severe acute GVHD; 25 were steroid refractory (SR). DSCs were thawed and infused in buffer supplemented with either 10% AB plasma (group 1, n = 17), or 5% albumin (group 2, n = 21). The viability of cells was higher when thawed in albumin rather than AB plasma (p < .001). Group 1 received a higher cell dose (p < .001), cells of lower passage number (p < .001), and fewer infusions (p = .002) than group 2. The GVHD response (no/partial/complete) was 7/5/5 in group 1 and 0/10/11 in group 2 (p = .01). One-year survival in the two groups was 47% (95% confidence interval [CI] 23-68) and 76% (95% CI 51-89), respectively (p = .016). For the SR patients, 1-year survival was 73% (95% CI 37-90) in SR group 2 (n = 11), which was better than 31% (95% CI 11-54) in SR group 1 (n = 13; p = .02), 20% (95% CI 5-42) in BM-MSC treated (n = 15; p = .0015), and 3% (95% CI 0-14) in historic controls (n = 32; p < .001). DSCs are a promising new treatment for severe acute GVHD. Prospective randomized trials are needed for evaluation of efficacy. (Clinical trial NCT-02172937.) Stem Cells Translational Medicine 2018;7:325-332.

Keywords: Acute graft-versus-host disease; Allogeneic hematopoietic stem cell transplantation; Decidua stromal cells; Mesenchymal stromal cells.

© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
(A): Kaplan‐Meier estimate of the overall survival of patients with severe acute GVHD who were treated with DSCs. The patients were divided into two groups based on differences in the cell handling procedure (Table 1). Group 2 had a significantly higher chance of survival than group 1 (p = .016). There were no significant differences in the relapse incidence (B) or incidence of chronic GVHD (C) between the two groups. (D): The relative risk of having GVHD symptoms at the time of death was significantly higher for the patients in group 1 (p = .016). Abbreviations: DSC, decidua stromal cell; GVHD, graft‐versus‐host disease; HSCT, allogeneic hematopoietic stem cell transplantation; MSC, mesenchymal stromal cell.
Figure 2
Figure 2
(A): Kaplan‐Meier estimate of the overall survival of patients with acute SR GVHD treated with decidua stromal cells and SR controls. SR group 2 had a significantly higher chance of survival than SR group 1 (p = .02), MSC‐treated patients (p = .0015), and the SR controls (p < .001). (B): The relative risk of having GVHD symptoms at the time of death was significantly higher for SR group 1, MSC group, and the SR controls than for SR group 2, (p < .01; p < .01, and p < .001, respectively). Abbreviations: GVHD, graft‐versus‐host disease; SR, steroid refractory; MSC, mesenchymal stromal cell.
Figure 3
Figure 3
Kaplan‐Meier estimate of the overall survival of patients with severe acute graft‐versus‐host disease treated with DSCs (group 2) and historic controls (2000–2010) compared with that in all patients who were transplanted at our center in the period 2010–2015. The chance of survival for group 2 was similar to that for all the patients treated at our center and was significantly better than historical control group (p < .001). Abbreviations: DSC, decidua stromal cell.

References

    1. Thomas ED, Buckner CD, Banaji M et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977;49:511–533.
    1. Hoogerbrugge PM, Brouwer OF, Bordigoni P et al. Allogeneic bone marrow transplantation for lysosomal storage diseases. The European Group for Bone Marrow Transplantation. Lancet 1995;345:1398–1402.
    1. Storb R, Thomas ED. Graft‐versus‐host disease in dog and man: The Seattle experience. Immunol Rev 1985;88:215–238.
    1. Ringdén O, Nilsson B. Death by graft‐versus‐host disease associated with HLA mismatch, high recipient age, low marrow cell dose, and splenectomy. Transplantation 1985;40:39–44.
    1. Ferrara JL, Levine JE, Reddy P et al. Graft‐versus‐host disease. Lancet 2009;373:1550–1561.
    1. Dignan FL, Clark A, Amrolia P et al. Diagnosis and management of acute graft‐versus‐host disease. Br J Haematol 2012;158:30–45.
    1. Martin PJ, Inamoto Y, Flowers ME et al. Secondary treatment of acute graft‐versus‐host disease: A critical review. Biol Blood Marrow Transplant 2012;18:982–988.
    1. Westin JR, Saliba RM, De Lima M et al. Steroid‐refractory acute GVHD: Predictors and outcomes. Adv Hematol 2011;2011:601953.
    1. Le Blanc K, Rasmusson I, Sundberg B et al. Treatment of severe acute graft‐versus‐host disease with third party haploidentical mesenchymal stem cells. Lancet 2004;363:1439–1441.
    1. Ringdén O, Uzunel M, Rasmusson I et al. Mesenchymal stem cells for treatment of therapy‐resistant graft‐versus‐host disease. Transplantation 2006;81:1390–1397.
    1. Le Blanc K, Frassoni F, Ball L et al. Mesenchymal stem cells for treatment of steroid‐resistant, severe, acute graft‐versus‐host disease: A phase II study. Lancet 2008;371:1579–1586.
    1. Remberger M, Ringdén O. Treatment of severe acute graft‐versus‐host disease with mesenchymal stromal cells: A comparison with non‐MSC treated patients. Int J Hematol 2012;96:822–824.
    1. von Bahr L, Sundberg B, Lönnies L et al. Long‐term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol Blood Marrow Transplant 2012;18:557–564.
    1. Hashmi S, Ahmed M, Murad MH et al. Survival after mesenchymal stromal cell therapy in steroid‐refractory acute graft‐versus‐host disease: Systematic review and meta‐analysis. Lancet Haematol 2016;3:e45–e52.
    1. Brooke G, Rossetti T, Pelekanos R et al. Manufacturing of human placenta‐derived mesenchymal stem cells for clinical trials. Br J Haematol 2009;144:571–579.
    1. In 't Anker PS, Scherjon SA, Kleijburg‐van der Keur C et al. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 2004;22:1338–1345.
    1. Karlsson H, Erkers T, Nava S et al. Stromal cells from term fetal membrane are highly suppressive in allogeneic settings in vitro. Clin Exp Immunol 2012;167:543–555.
    1. Ringdén O, Erkers T, Nava S et al. Fetal membrane cells for treatment of steroid‐refractory acute graft‐versus‐host disease. Stem Cells 2013;31:592–601.
    1. Erkers T, Nava S, Yosef J et al. Decidual stromal cells promote regulatory T cells and suppress alloreactivity in a cell contact‐dependent manner. Stem Cells Dev 2013;22:2596–2605.
    1. Moll G, Ignatowicz L, Catar R et al. Different procoagulant activity of therapeutic mesenchymal stromal cells derived from bone marrow and placental decidua. Stem Cells Dev 2015;24:2269–2279.
    1. Erkers T, Kaipe H, Nava S et al. Treatment of severe chronic graft‐versus‐host disease with decidual stromal cells and tracing with (111)indium radiolabeling. Stem Cells Dev 2015;24:253–263.
    1. Törlén J, Ringdén O, Garming‐Legert K et al. A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft‐versus‐host disease prophylaxis after allogeneic hematopoietic stem cell transplantation. Haematologica 2016;101:1417–1425.
    1. Svahn BM, Remberger M, Myrbäck KE et al. Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 2002;100:4317–4324.
    1. Mielcarek M, Storer BE, Boeckh M et al. Initial therapy of acute graft‐versus‐host disease with low‐dose prednisone does not compromise patient outcomes. Blood 2009;113:2888–2894.
    1. Baygan A, Aronsson‐Kurttila W, Moretti G et al. Safety and side effects of using placenta‐derived decidual stromal cells for graft‐versus‐host disease and hemorrhagic cystitis. Front Immunol 2017;8:795.
    1. Ringdén O, Labopin M, Sadeghi B et al. What is the outcome in patients with acute leukaemia who survive severe acute graft‐versus‐host disease? J Intern Med 2018;283:166–177.
    1. Li Y, Lin F. Mesenchymal stem cells are injured by complement after their contact with serum. Blood 2012;120:3436–3443.
    1. Zhao K, Lou R, Huang F et al. Immunomodulation effects of mesenchymal stromal cells on acute graft‐versus‐host disease after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015;21:97–104.
    1. Witherspoon RP, Fisher LD, Schoch G et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989;321:784–789.
    1. Olsson R, Remberger M, Schaffer M et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant 2013;48:537–543.
    1. Parekkadan B, Upadhyay R, Dunham J et al. Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes. Gastroenterology 2011;140:966–975.
    1. Remberger M, Ackefors M, Berglund S et al. Improved survival after allogeneic hematopoietic stem cell transplantation in recent years. A single‐center study. Biol Blood Marrow Transplant 2011;17:1688–1697.
    1. Ringdén O, Solders M, Erkers T et al. Successful reversal of acute lung injury using placenta‐derived decidual stromal cells. J Stem Cell Res Ther 2014;4:244.
    1. Aronsson‐Kurttila W, Baygan A, Moretti G et al. Placenta‐derived decidua stromal cells for hemorrhagic cystitis after stem cell transplantation. Acta Haematol 2018;139:106–114.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel