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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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Infusion of haploidentical HSCs combined with allogenic MSCs for the treatment of ALL patients
Ding, L., Han, D. M., Yan, H. M., Zhou, J. X., Zheng, X. L., Zhu, L., Xue, M., Liu, J., Mao, N., Guo, Z. K., et al
Bone marrow transplantation. 2022
Abstract
Although haploidentical stem cell transplantation (haplo-HSCT) offers almost all acute lymphoblastic leukaemia (ALL) patients an opportunity for immediate transplantation, it exhibits a higher incidence of graft failure and graft versus host disease (GVHD). Mesenchymal stem cells (MSCs) are characterised by their haematopoiesis-promoting and immunomodulatory capacity. Thus, we designed a combination of haplo-HSCT and MSCs for ALL patients. ALL patients (n = 110) were given haploidentical HSCs combined with allogenic MSCs, and ALL patients without MSC infusion (n = 56) were included as controls. The 100-day cumulative incidences of grade ≥2 acute GVHD (aGVHD) and grade ≥3 aGVHD were 40.00% and 9.09% compared to 42.32% (P = 0.79) and 22.79% (P = 0.03) in patients without MSC infusion, respectively. The 3-year cumulative incidences of chronic GVHD (cGVHD) and extensive cGVHD were 22.27% and 10.27% compared to 32.14% (P = 0.19) and 22.21% (P = 0.04) in patients without MSC infusion, respectively. No significant differences in the 3-year relapse incidence, nonrelapse mortality, leukaemia-free survival or overall survival in groups with and without MSC cotransplantation were observed. Multivariate analysis showed that MSC infusion contributed to a lower risk of developing extensive cGVHD. Our data suggested that haplo-HSCT combined with MSCs may provide an effective and safe treatment for ALL patients.
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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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Differences in Protein Secretion by Multipotent Mesenchymal Stromal Cells Effective and Ineffective in the Prevention of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
Petinati, N. A., Drize, N. I., Arapidi, G. P., Shender, V. O., Lagar'kova, M. A., Kuz'mina, L. A., Parovichnikova, E. N., Savchenko, V. G.
Bulletin of experimental biology and medicine. 2022
Abstract
Multipotent mesenchymal stromal cells (MSC) were administered to patients after allogeneic hematopoietic stem cell transplantation to prevent the development of acute graft-versus- host disease (GVHD). The injection of MSC did not always prevent the development of GVHD. The aim of the work was to compare the secretome of MSC effective and ineffective in the prevention of GVHD. MSC were obtained from the bone marrow of hematopoietic stem cells donors. The secretome was studied using a TripleTOF 5600+ mass spectrometer with a NanoSpray III ion source coupled to a NanoLC Ultra 2D Plus nano-HPLC System. A total of 1,965 proteins were analyzed. Analysis of the secretome of effective and ineffective MSC samples revealed significant differences in the secretion of 1,119 proteins associated with ribosomes, exosomes, focal contacts, and others. Analysis of proteins secreted by MSC can be used to identify prognostically effective samples.
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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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Co-transplantation of bone marrow-derived mesenchymal stem cells with hematopoietic stem cells does not improve transplantation outcome in class III beta-thalassemia major: A prospective cohort study with long-term follow-up
Rostami, T., Maleki, N., Kasaeian, A., Nikbakht, M., Kiumarsi, A., Asadollah Mousavi, S., Ghavamzadeh, A.
Pediatric transplantation. 2020;:e13905
Abstract
Bone marrow transplantation is the only curative treatment for beta-thalassemia major. Data on the co-transplantation of MSCs with HSCs in beta-thalassemia major patients are scarce. We aimed to investigate the outcomes of thalassemia major patients who underwent bone marrow-derived MSC co-transplantation with HSCs compared with those who only received HSCs. This prospective randomized study included patients with class III thalassemia major undergoing HSCT divided randomly into two groups: Thirty-three patients underwent co-transplantation of bone marrow-derived MSCs with HSCs, and 26 patients only received HSCs. Five-year OS, TFS, TRM, graft rejection rate, and GVHD were estimated. The 5-year OS was 66.54% (95% CI, 47.8% to 79.9%) in patients who underwent co-transplantation of MSCs with HSCs vs 76.92% (95% CI, 55.7% to 88.9%) in patients who only received HSCs (P = .54). No significant difference was observed in the 5-year TFS between the two groups (59.1% vs 69.2%; P = .49). The 5-year cumulative incidence of TRM was not statistically significant among patients who underwent co-transplantation of MSCs with HSCs (27.27%) vs those who only received HSCs (19.23%; P = .61). There was no statistically significant difference in graft rejection, acute GvHD, and chronic GvHD between the two groups. Based on our findings, the co-transplantation of MSCs and HSCs to class III thalassemia major patients does not alter their transplantation outcomes including OS, TFS, rejection rate, transplant-related mortality, and GvHD.
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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.