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Mesenchymal Stem Cells for Prophylaxis of Chronic Graft-vs-Host Disease After Haploidentical Hematopoietic Stem Cell Transplant: An Open-Label Randomized Clinical Trial
Huang, R., Chen, T., Wang, S., Wang, J., Su, Y., Liu, J., Zhang, Y., Ma, X., Wen, Q., Kong, P., et al
JAMA oncology. 2023
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Abstract
IMPORTANCE Chronic graft-vs-host disease (GVHD) limits the long-term benefit of haploidentical hematopoietic stem cell transplant (HSCT). This clinical trial evaluated repeated infusions of umbilical cord mesenchymal stem cells (MSCs) during the early stage (45 days and 100 days) after haplo-HSCT to prevent chronic GVHD. OBJECTIVE To determine whether repeated infusions of MSCs during the early stage after haplo-HSCT decreases the incidence of severe chronic GVHD. DESIGN, SETTING, AND PARTICIPANTS This open-label, multicenter, parallel randomized clinical trial was conducted from April 2016 to January 2022. Eligibility criteria included a diagnosis of acute leukemia and having a haploidentical, suitable related donor for HSCT. The median (range) follow-up time was 39.0 (1.5-67.0) months. INTERVENTIONS The enrolled patients with a haploidentical relative for HSCT received the modified busulfan/cyclophosphamide + antithymocyte globulin modified regimen and standard GVHD prophylaxis. Patients were randomly chosen to receive MSCs (the MSC group) (1 × 106 cells/kg, every 2 weeks, starting from 45 days after transplant, 4 times total) or regular prophylaxis (control group). MAIN OUTCOME AND MEASURE The cumulative incidence of severe chronic GVHD. RESULTS Of 158 patients, 58 (36.7%) were female individuals; the median (range) age for the MSC and control groups was 28 (18-60) years and 28 (18-56) years, respectively. A total of 158 patients were screened, and 148 patients were randomly assigned to the MSC group (n = 74) or control group (n = 74) 1 day before MSCs infusion. The estimated 2-year cumulative incidence of severe chronic GVHD was 5.4% (95% CI, 1.8%-14.0%) in the MSC group and 17.4% (95% CI, 10.1%-28.5%) in the control group (hazard ratio [HR], 0.29; 95% CI, 0.10-0.88; P = .03). There was no difference between the MSC and control groups in the cumulative incidence of leukemia relapse (HR, 1.17; 95% CI, 0.55-2.47; P = .68). The cumulative incidence of stage II to IV acute GVHD in the MSC group was significantly lower than that in the control group (HR, 0.25; 95% CI, 0.09-0.67; P = .01). The MSC group had better GVHD-free and relapse-free survival rates than the control group (HR, 0.62; 95% CI, 0.39-0.98; P = .04). CONCLUSIONS AND RELEVANCE The results of this randomized clinical trial show that early repeated infusions of MSCs decreased the incidence and severity of chronic GVHD, and the incidence and severity of acute GVHD manifested as a better GVHD-free and relapse-free survival rate for patients after haplo-HSCT. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR-IIR-16007806.
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Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review
Li, Y., Hao, J., Hu, Z., Yang, Y. G., Zhou, Q., Sun, L., Wu, J.
Stem cell research & therapy. 2022;13(1):93
Abstract
BACKGROUND Graft-versus-host disease (GVHD) is a common fatal complication of hematopoietic stem cell transplantation (HSCT), where steroids are used as a treatment option. However, there are currently no second-line treatments for patients that develop steroid-resistance (SR). Mesenchymal stem cells (MSCs) have immunomodulatory functions and can exert immunosuppressive effects on the inflammatory microenvironment. A large number of in vitro experiments have confirmed that MSCs can significantly inhibit the proliferation or activation of innate and adaptive immune cells. In a mouse model of GVHD, MSCs improved weight loss and increased survival rate. Therefore, there is great promise for the clinical translation of MSCs for the prevention or treatment of GVHD, and several clinical trials have already been conducted to date. MAIN BODY In this study, we searched multiple databases and found 79 clinical trials involving the use of MSCs to prevent or treat GVHD and summarized the characteristics of these clinical trials, including study design, phase, status, and locations. We analyzed the results of these clinical trials, including the response and survival rates, to enable researchers to obtain a comprehensive understanding of the field's progress, challenges, limitations, and future development trends. Additionally, factors that might result in inconsistencies in clinical trial results were discussed. CONCLUSION In this study, we attempted to analyze the clinical trials for MSCs in GVHD, identify the most suitable group of patients for MSC therapy, and provide a new perspective for the design of such trials in the future.
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T-cell and cytokine dynamics in the blood of patients after hematopoietic stem cell transplantation and multipotent mesenchymal stromal cells administration
Petinati, N., Davydova, Y., Nikiforova, K., Bigildeev, A., Belyavsky, A., Arapidi, G., Drize, N., Kuzmina, L., Parovichnikova, E., Savchenko, V.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSCs) are currently under intense investigation for treatment and prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), owing to their substantial immunomodulatory properties. The responses of recipients to MSC infusion following allo-HSCT are not yet well understood. T-cells are central to the adaptive immune system, protecting organism from infection and malignant cells. Memory T-cells with different phenotypes, gene expression profiles and functional properties are critical for immune processes regulation. OBJECTIVE The aim of this work was to study the dynamics of memory T-cells subpopulations and cytokines in blood of allo-HSCT patients after MSCs administration. STUDY DESIGN In clinical trial NCT01941394 patients after allo-HSCT were randomized into two groups: the one receiving standard GVHD prophylaxis and another one receiving additionally MSCs infusion on the day of recovery of leukocytes to 1000 cells/μl (engraftment, day E0). The blood samples of patients from both groups were analyzed on days E0, E+3 and E+30. Subpopulations of T-cells were studied by flow cytometry and concentration of cytokines was evaluated by the Bio-Plex Pro Human Cytokine Panel. RESULTS Administration of MSCs to patients on day E0 did not affect the overall dynamics of restoration of absolute numbers and the proportion of T and B lymphocytes after 3 and 30 days. Three days after MSCs injection, only the numbers of CD8+ effector cells (CD8+TE, CD8+TM, CD8+EM) were found to increase significantly. Significant increase in a number of CD4+ cells after 30 days compared to day E0 was observed only in patients who received MSCs, which indicates a faster recovery of CD4+ cell population following MSC injection. Increase in CD8+ cell number by day E+30 was significant regardless of MSC administration. To characterize the immune status of patients following allo-HSCT in more detail, changes in the cytokine concentration in the peripheral blood of patients on days E0, E+3 and E+30 after the administration of MSCs were investigated. On day E+30, significant increase in the number of CD4+CM and activated CD4+CD25+ cells was observed. The concentration of pro- and anti-inflammatory cytokines IL-6, IL-8, IL-17, TNF-α and IFN-γ, significantly increased in patients injected with MSCs. Analysis of the growth factor levels showed that in the group of patients who received MSCs, the concentration of G-CSF, CM-CSF, PDGFbb, FGFb and IL-5 increased by day E+30. Among the cytokines involved in the regulation of the immune response, the concentration of IL-9, Eotaxin, IP-10, MCP-1, and MIP-1a increased after 30 days, regardless of the MSCs administration. CONCLUSION The administration of MSCs exerts a positive effect on restoration of T-cell subpopulations and recovery of immune system of patients after allo-HSCT.
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Wnt/ß-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients
Qi, H. Z., Ye, Y. L., Suo, Y., Qu, H., Zhang, H. Y., Yang, K. B., Fan, Z. P., Huang, F., Xuan, L., Chen, Y. Q., et al
Cell death & disease. 2021;12(4):308
Abstract
Chronic graft-versus-host disease (cGVHD) is the main cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stem cells (MSCs) in bone marrow (BM) remain unclear in the pathophysiology of cGVHD. In this study, we analyzed BM-MSCs from 66 patients after allo-HSCT, including 33 with active cGVHD and 33 without cGVHD. BM-MSCs showed similar morphology, frequency, phenotype, and proliferation in patients with or without cGVHD. MSCs from the active cGVHD group showed a decreased apoptosis rate (P?0.01). Osteogenic capacity was increased while adipogenic capacity was decreased in the active cGVHD MSCs compared with no-cGVHD MSCs. The expressions of osteogenic gene RUNX2 and COL1A1 were higher (P?0.001) while adipogenic gene PPAR-? and FABP4 were lower (P?0.001) in the active cGVHD MSCs than no-cGVHD MSCs. These changes were associated with the severity of cGVHD (P?0.0001; r?=?0.534, r?=?0.476, r?=?-0.796, and r?=?-0.747, respectively in RUNX2, COL1A1, PPAR-?, and FABP4). The expression of Wnt/ß-catenin pathway ligand Wnt3a was increased in cGVHD-MSCs. The dysfunction of cGVHD-MSCs could be reversed by Dickkopf related protein 1(DKK1) to inhibit the binding of Wnt3a. In summary, the differentiation of BM-MSCs was abnormal in active cGVHD, and its underlying mechanism is the upregulated of Wnt3a through Wnt/ß-catenin signaling pathway of MSCs.
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Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?-a systematic review and meta-analysis
Li, R., Tu, J., Zhao, J., Pan, H., Fang, L., Shi, J.
Stem cell research & therapy. 2021;12(1):106
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are an emerging prophylaxis option for graft-versus-host disease (GVHD) in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) recipients with severe aplastic anemia (SAA), but studies have reported inconsistent results. This systematic review and meta-analysis evaluates the efficacy of MSCs as prophylaxis for GVHD in SAA patients with haplo-HSCT. METHODS Studies were retrieved from PubMed, EMBASE, Cochrane, Web of Science, and http://clinicaltrials.gov from establishment to February 2020. Twenty-nine single-arm studies (n?=?1456) were included, in which eight (n?=?241) studies combined with MSCs and eleven (n?=?1215) reports without MSCs in haplo-HSCT for SAA patients. The primary outcomes were the incidences of GVHD. Other outcomes included 2-year overall survival (OS) and the incidence of cytomegalovirus (CMV) infection. Odds ratios (ORs) were calculated to compare the results pooled through random or fixed effects models. RESULTS Between MSCs and no MSCs groups, no significant differences were found in the pooled incidences of acute GVHD (56.0%, 95% CI 48.6-63.5% vs. 47.2%, 95% CI 29.0-65.4%; OR 1.43, 95% CI 0.91-2.25; p?=?0.123), grade II-IV acute GVHD (29.8%, 95% CI 24.1-35.5% vs. 30.6%, 95% CI 26.6-34.6%; OR 0.97, 95% CI 0.70-1.32; p?=?0.889), and chronic GVHD (25.4%, 95% CI 19.8-31.0% vs. 30.0%, 95% CI 23.3-36.6%; OR 0.79, 95% CI 0.56-1.11; p?=?0.187). Furtherly, there was no obvious difference in 2-year OS (OR 0.98, 95% CI 0.60-1.61; p?=?1.000) and incidence of CMV infection (OR 0.61, 95% CI 0.40-1.92; p?=?0.018). CONCLUSIONS Our meta-analysis indicates that the prophylactic use of MSC co-transplantation is not an effective option for SAA patients undergoing haplo-HSCT. Hence, the general co-transplantation of MSCs for SAA haplo-HSCT recipients may lack evidence-based practice.
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Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis
Li, T., Luo, C., Zhang, J., Wei, L., Sun, W., Xie, Q., Liu, Y., Zhao, Y., Xu, S., Wang, L.
Stem cell research & therapy. 2021;12(1):246
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is life-saving for severe hematological conditions. However, its outcomes need further improvement, and co-infusion of mesenchymal stem cells (MSCs) may show promise. A growing body of research on this subject exists, while the results of different trials are conflicting. A systematic review and meta-analysis is needed to appraise the real efficacy and safety of MSC co-transplantation in allo-HSCT. METHODS Studies comparing MSC co-transplantation in allo-HSCT with allo-HSCT alone were searched in six medical databases from inception to June 10, 2020. The primary outcomes were engraftment and graft-versus-host disease (aGVHD and cGVHD, respectively). Other outcomes included overall survival (OS), relapse rate (RR), non-relapse mortality (NRM), and immune reconstitution. Information was independently extracted by two investigators. Methodological quality was assessed using the Cochrane Collaboration tool. Meta-analysis was performed using RevMan 5.4. RESULTS Six randomized controlled trials (RCTs) and 13 non-randomized controlled trials (nRCTs) were included. MSC co-infusion resulted in shorter times to neutrophil engraftment (RCTs: standardized mean difference (SMD) -?1.20, p =?0.04; nRCTs: SMD -?0.54, p =?0.04) and platelet engraftment (RCTs: SMD -?0.60, p =?0.04; nRCTs: SMD -?0.70, p =?0.01), a lower risk of cGVHD (RCTs: risk ratio (RR) 0.53, p =?0.01; nRCTs: RR 0.50, p 0.01), and a slightly positive trend towards reducing the risk of aGVHD and NRM, without affecting RR and OS. Subgroup analyses revealed that when MSCs were co-transplanted, children and adolescents, and patients receiving human leukocyte antigen (HLA)-nonidentical HSCT showed improvements in engraftment and incidence of GVHD and NRM; adults and patients who received HLA-identical HSCT had lower cGVHD; patients with malignancies exhibited improvements in GVHD and NRM incidence; and patients with non-malignancies experienced accelerated engraftment. Notably, a reduced OS was observed in patients with hematological malignancies undergoing HLA-identical HSCT. CONCLUSION MSC co-infusion generally improved engraftment and reduced cGVHD, without increasing mortality or relapse. Regarding aGVHD and NRM, the effects of MSCs were not quite significant. Specifically, our data support the utilization of MSC co-transplantation in children and young individuals with HLA-nonidentical HSCT, but not in adult patients with hematological malignancies undergoing HLA-identical HSCT.
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Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation
Goto, T., Murata, M., Nishida, T., Terakura, S., Kamoshita, S., Ishikawa, Y., Ushijima, Y., Adachi, Y., Suzuki, S., Kato, K., et al
Stem cells translational medicine. 2020
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Abstract
Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy not only to prevent graft-vs-host disease (GVHD) but also enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra-BM injection of MSCs (MSC-CBT) was designed. Third-party BM-derived MSCs were injected intra-BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra-BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC-CBT, and no adverse events related to intra-BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38?days, respectively, comparable with controls. Grade II-IV acute GVHD developed in three controls but not in MSC-CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC-CBT patients survived without relapse. This study shows the safety of MSC-CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as number 000024291.
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Pre-infusion single-dose mesenchymal stem cells promote platelet engraftment and decrease severe acute graft versus host disease without relapse in haploidentical peripheral blood stem cell transplantation
Wang, X., Zhang, M., He, P.
The Journal of international medical research. 2020;48(5):300060520920438
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) may be used to treat steroid-refractory graft versus host disease (GVHD). However, the effects of MSCs in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) have not been confirmed in randomized studies. METHODS We conducted a randomized clinical study to investigate the effects of pre-infusion (1 x 10(6) cells/kg) MSCs on hematopoietic recovery, Epstein-Barr and cytomegalovirus infection, GVHD, and relapse in patients undergoing haplo-PBSCT. Fifty patients with acute leukemia or myelodysplastic syndrome were randomly divided into an MSC group administered 1 x 10(6) MSCs/kg 4 to 6 hours before infusion of peripheral stem cells and a control group without MSCs. RESULTS Mean platelet engraftment time was significantly faster in the MSC compared with the control group (12.28 vs 13.29 days). The mean neutrophil engraftment time was comparable in both groups (10.76 +/- 2.40 vs. 10.29 +/- 1.72 days). Grade II or above acute GVHD was significantly decreased in the MSC compared with the control group (12% vs. 36%). There were no significant differences in relapse rate or overall survival between the groups. CONCLUSION These results suggest that pre-infusion single-dose MSCs promote platelet engraftment and decrease severe acute GVHD without increasing relapse rate.
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Co-transplantation of mesenchymal stem cells makes haploidentical HSCT a potential comparable therapy with matched sibling donor HSCT for patients with severe aplastic anemia
Liu, Z., Wu, X., Wang, S., Xia, L., Xiao, H., Li, Y., Li, H., Zhang, Y., Xu, D., Nie, D., et al
Therapeutic advances in hematology. 2020;11:2040620720965411
Abstract
The application of haploidentical hematopoietic stem cell transplantation (HSCT) with mesenchymal stem cell (MSC) infusion as a treatment regimen for severe aplastic anemia (SAA) has been reported to be efficacious in single-arm trials. However, it is difficult to assess without comparing the results with those from a first-line, matched-sibling HSCT. Herein, we retrospectively reviewed 91 patients with acquired SAA. They received HSCT from haploidentical donors combined with MSC transfer (HID group). We compared these patients with 103 others who received first-line matched-sibling HSCT (MSD group) to evaluate relative treatment efficacy. Compared with the patients in the MSD group, those in the HID group presented with higher incidences of grades II-IV and III-IV acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) (p?0.05). However, the incidence of myeloid and platelet engraftment, graft failure, poor graft function, and extensive cGvHD were comparable for both groups. The median follow-up was 36.6?months and the 3-year overall survival rate was similar for both groups (83.5% versus 79.1%). Univariate and multivariate analyses revealed that time intervals greater than 4?months from diagnosis to transplantation, experienced graft failure, poor graft function, or grade III-IV aGvHD were significantly associated with adverse outcomes. All HID patients received MSC co-transplantation with hematopoietic stem cells. However, the infused MSCs were derived from umbilical cord (UC-MSC group; 43 patients) or bone marrow (BM-MSC group; 48 patients) and were administered at different medical centers. We first compared the outcomes between the two groups and detected that the BM-MSC group exhibited lower incidences of grade III-IV aGvHD and cGvHD (p?0.05). This study suggests that co-transplantation of hematopoietic and MSCs significantly reduces the risk and incidence of graft rejection and may effectively improve overall survival in patients with SAA even in the absence of closely related histocompatible donor material.
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Immunophenotypic characteristics of multipotent mesenchymal stromal cells that affect the efficacy of their use in the prevention of acute graft vs host disease
Petinati, N., Kapranov, N., Davydova, Y., Bigildeev, A., Pshenichnikova, O., Karpenko, D., Drize, N., Kuzmina, L., Parovichnikova, E., Savchenko, V.
World journal of stem cells. 2020;12(11):1377-1395
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSCs) are widely used in the clinic due to their unique properties, namely, their ability to differentiate in all mesenchymal directions and their immunomodulatory activity. Healthy donor MSCs were used to prevent the development of acute graft vs host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). The administration of MSCs to patients was not always effective. The MSCs obtained from different donors have individual characteristics. The differences between MSC samples may affect their clinical efficacy. AIM: To study the differences between effective and ineffective MSCs. METHODS MSCs derived from the bone marrow of a hematopoietic stem cells donor were injected intravenously into allo-BMT recipients for GVHD prophylaxis at the moment of blood cell reconstitution. Aliquots of 52 MSC samples that were administered to patients were examined, and the same cells were cultured in the presence of peripheral blood mononuclear cells (PBMCs) from a third-party donor or treated with the pro-inflammatory cytokines IL-1ß, IFN and TNF. Flow cytometry revealed the immunophenotype of the nontreated MSCs, the MSCs cocultured with PBMCs for 4 d and the MSCs exposed to cytokines. The proportions of CD25-, CD146-, CD69-, HLA-DR- and PD-1-positive CD4+ and CD8+ cells and the distribution of various effector and memory cell subpopulations in the PBMCs cocultured with the MSCs were also determined. RESULTS Differences in the immunophenotypes of effective and ineffective MSCs were observed. In the effective samples, the mean fluorescence intensity (MFI) of HLA-ABC, HLA-DR, CD105, and CD146 was significantly higher. After MSCs were treated with IFN or cocultured with PBMCs, the HLA-ABC, HLA-DR, CD90 and CD54 MFI showed a stronger increase in the effective MSCs, which indicated an increase in the immunomodulatory activity of these cells. When PBMCs were cocultured with effective MSCs, the proportions of CD4+ and CD8+central memory cells significantly decreased, and the proportion of CD8+CD146+ lymphocytes increased more than in the subpopulations of lymphocytes cocultured with MSC samples that were ineffective in the prevention of GVHD; in addition, the proportion of CD8+effector memory lymphocytes decreased in the PBMCs cocultured with the effective MSC samples but increased in the PBMCs cocultured with the ineffective MSC samples. The proportion of CD4+CD146+ lymphocytes increased only when cocultured with the inefficient samples. CONCLUSION For the first time, differences were observed between MSC samples that were effective for GVHD prophylaxis and those that were ineffective. Thus, it was shown that the immunomodulatory activity of MSCs depends on the individual characteristics of the MSC population.