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Madhuri V, Ramesh S, Goos A, Paul TV, Nidugala Kesava S, Mathews V, Walther-Jallow L, Götherström C. Evaluation of safety and efficacy of multiple intravenous and intraosseous doses of foetal liver-derived mesenchymal stem cells in children with severe osteogenesis imperfecta : the BOOST2B clinical trial protocol. Bone Jt Open 2025; 6:361-372. [PMID: 40122106 PMCID: PMC11930377 DOI: 10.1302/2633-1462.63.bjo-2024-0115.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2025] Open
Abstract
Aims Current off-label bisphosphonate treatment for osteogenesis imperfecta (OI) does not induce healthy bone formation. Therefore, novel strategies to stimulate osteogenesis and reduce fractures are needed to meet the medical needs of these patients. Preclinical data and case studies show that multiple intravenous (IV) administrations of mesenchymal stem cells (MSCs) provide promising outcomes in the treatment of OI. In the Boost to Brittle Bones (BOOST2B) trial, we aim to assess the safety and tolerability of multiple IV and intraosseous (IO) administrations of foetal liver-derived MSCs in children aged one to five years diagnosed with severe OI. Methods A total of 15 children will receive four doses of foetal MSCs IV (3 × 106 cells per kg of body weight) and IO (0.1 × 106 cells per kg of body weight per long bone) at four-month intervals. As a secondary endpoint, the therapeutic effect of the four MSC doses will be assessed based on the annual fracture rate, time to first fracture, bone mineral density, growth, clinical status of OI, and biochemical bone turnover in peripheral blood. Exploratory parameters include quality of life and donor cell engraftment. Conclusion The BOOST2B trial has been approved by the regulatory agencies in India and is ongoing. It is the first clinical trial designed to evaluate IO administration of MSCs as a potential therapy for OI. Here, we describe the BOOST2B clinical trial protocol. The long-term data on safety and efficacy will be reported once completed.
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Affiliation(s)
- Vrisha Madhuri
- Department of Paediatric Orthopaedics, Christian Medical College, Vellore, India
- Center for Stem Cell Research, (a unit of inStem, Bengaluru, Christian Medical College), Vellore, India
- Department of Orthopaedics, Amara Hospital, Tirupati, India
| | - Sowmya Ramesh
- Department of Paediatric Orthopaedics, Christian Medical College, Vellore, India
- Center for Stem Cell Research, (a unit of inStem, Bengaluru, Christian Medical College), Vellore, India
| | - Annika Goos
- Department of Clinical Science, Intervention & Technology, Karolinska Institutet, Stockholm, Sweden
| | - Thomas V. Paul
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, India
| | | | - Vikram Mathews
- Department of Haematology, Christian Medical College, Vellore, India
| | - Lilian Walther-Jallow
- Department of Clinical Science, Intervention & Technology, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Götherström
- Department of Clinical Science, Intervention & Technology, Karolinska Institutet, Stockholm, Sweden
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Bulliard Y, Freeborn R, Uyeda MJ, Humes D, Bjordahl R, de Vries D, Roncarolo MG. From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases. Front Immunol 2024; 15:1509956. [PMID: 39697333 PMCID: PMC11653210 DOI: 10.3389/fimmu.2024.1509956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024] Open
Abstract
Autoimmune diseases, characterized by the immune system's attack on the body's own tissues, affect millions of people worldwide. Current treatments, which primarily rely on broad immunosuppression and symptom management, are often associated with significant adverse effects and necessitate lifelong therapy. This review explores the next generation of therapies for immune-mediated diseases, including chimeric antigen receptor (CAR) T cell and regulatory T cell (Treg)-based approaches, which offer the prospect of targeted, durable disease remission. Notably, we highlight the emergence of CD19-targeted CAR T cell therapies, and their ability to drive sustained remission in B cell-mediated autoimmune diseases, suggesting a possible paradigm shift. Further, we discuss the therapeutic potential of Type 1 and FOXP3+ Treg and CAR-Treg cells, which aim to achieve localized immune modulation by targeting their activity to specific tissues or cell types, thereby minimizing the risk of generalized immunosuppression. By examining the latest advances in this rapidly evolving field, we underscore the potential of these innovative cell therapies to address the unmet need for long-term remission and potential tolerance induction in individuals with autoimmune and immune-mediated diseases.
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Affiliation(s)
- Yannick Bulliard
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Robert Freeborn
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Molly Javier Uyeda
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Daryl Humes
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Ryan Bjordahl
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - David de Vries
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Maria Grazia Roncarolo
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
- Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
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Mamo T, Cox CA, Demorest C, Fontaine MJ, Hubel A, Kelley L, Khan A, Marks DC, Pati S, Reems JA, Spohn G, Schäfer R, Shi R, Shao L, Stroncek D, McKenna DH. Cryopreservation of mesenchymal stem/stromal cells using a DMSO-free solution is comparable to DMSO-containing cryoprotectants: results of an international multicenter PACT/BEST collaborative study. Cytotherapy 2024; 26:1522-1531. [PMID: 39066775 PMCID: PMC11841823 DOI: 10.1016/j.jcyt.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/02/2024] [Accepted: 07/02/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND AND AIM An essential aspect of ensuring availability and stability of mesenchymal stem/stromal cells (MSCs) products for clinical use is that these cells are cryopreserved before individual infusion into patients. Currently, cryopreservation of MSCs involves use of a cryoprotectant solution containing dimethyl sulfoxide (DMSO). However, it is recognized that DMSO may be toxic for both the patient and the MSC product. In this Production Assistance for Cellular Therapies (PACT) and Biomedical Excellence for Safer Transfusion (BEST) Collaborative study, we compared a novel DMSO-free solution with DMSO containing cryoprotectant solutions for freezing MSCs. METHODS A DMSO-free cryoprotectant solution containing sucrose, glycerol, and isoleucine (SGI) in a base of Plasmalyte A was prepared at the University of Minnesota. Cryoprotectant solutions containing 5-10% DMSO (in-house) were prepared at seven participating centers (five from USA, one each from Australia and Germany). The MSCs were isolated from bone marrow or adipose tissue and cultured ex vivo per local protocols at each center. The cells in suspension were frozen by aliquoting into vials/bags. For six out of the seven centers, the vials/bags were placed in a controlled rate freezer (one center placed them at -80°C freezer overnight) before transferring to liquid nitrogen. The cells were kept frozen for at least one week before thawing and testing. Pre- and post-thaw assessment included cell viability and recovery, immunophenotype as well as transcriptional and gene expression profiles. Linear regression, mixed effects models and two-sided t-tests were applied for statistical analysis. RESULTS MSCs had an average viability of 94.3% (95% CI: 87.2-100%) before cryopreservation, decreasing by 4.5% (95% CI: 0.03-9.0%; P: 0.049) and 11.4% (95% CI: 6.9-15.8%; P< 0.001), for MSCs cryopreserved in the in-house and SGI solutions, respectively. The average recovery of viable MSCs cryopreserved in the SGI was 92.9% (95% CI: 85.7-100.0%), and it was lower by 5.6% (95% CI: 1.3-9.8%, P < 0.013) for the in-house solution. Additionally, MSCs cryopreserved in the two solutions had expected level of expressions for CD45, CD73, CD90, and CD105 with no significant difference in global gene expression profiles. CONCLUSION MSCs cryopreserved in a DMSO-free solution containing sucrose, glycerol, and isoleucine in a base of Plasmalyte A had slightly lower cell viability, better recovery, and comparable immunophenotype and global gene expression profiles compared to MSCs cryopreserved in DMSO containing solutions. The average viability of MSCs in the novel solution was above 80% and, thus, likely clinically acceptable. Future studies are suggested to test the post-thaw functions of MSCs cryopreserved in the novel DMSO-free solution.
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Affiliation(s)
- Theodros Mamo
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
| | | | - Connor Demorest
- Masonic Cancer Center Biostatistics Core, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Allison Hubel
- Department of Mechanical Engineering, University of Minnesota, Minneapolis, Minnesota, USA; Evia Bio, Minneapolis, Minnesota, USA
| | | | - Aisha Khan
- University of Miami, Coral Gables, Florida, USA
| | - Denese C Marks
- Research and Development, Australian Red Cross Lifeblood, Sydney, Australia
| | - Shibani Pati
- University of California San Francisco, San Francisco, California, USA
| | | | - Gabriele Spohn
- German Red Cross Blood Donor Service and Goethe University Hospital, Frankfurt am Main, Germany
| | - Richard Schäfer
- German Red Cross Blood Donor Service and Goethe University Hospital, Frankfurt am Main, Germany; Medical Center, Center for Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany
| | - Rongye Shi
- Center for Cellular Engineering, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Lipei Shao
- Center for Cellular Engineering, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - David Stroncek
- Center for Cellular Engineering, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - David H McKenna
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA; Molecular and Cellular Therapeutics, University of Minnesota, Saint Paul, Minnesota, USA
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Alsultan A, Farge D, Kili S, Forte M, Weiss DJ, Grignon F, Boelens JJ. International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges. Cytotherapy 2024; 26:1132-1140. [PMID: 38804990 DOI: 10.1016/j.jcyt.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.
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Affiliation(s)
- Abdulrahman Alsultan
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Transplantation and Cellular Therapy, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dominique Farge
- Internal Medicine Unit (UF 04): CRMR MATHEC, Autoimmune diseases and Cellular Therapy, St-Louis Hospital, Center of reference for rare systemic autoimmune diseases of Ile-de-France (FAI2R), AP-HP, Hôpital St-Louis, Paris University, IRSL, Paris, France; Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Sven Kili
- Sven Kili Consulting Ltd., Shrewsbury, UK; Saisei Ventures, Boston, Massachusetts, USA; CCRM, Toronto, Canada
| | | | - Daniel J Weiss
- University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Felix Grignon
- International Society for Cell & Gene Therapy, Vancouver, Canada
| | - Jaap Jan Boelens
- Transplantation and Cellular Therapy, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
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Kelly K, Bloor AJC, Griffin JE, Radia R, Yeung DT, Rasko JEJ. Two-year safety outcomes of iPS cell-derived mesenchymal stromal cells in acute steroid-resistant graft-versus-host disease. Nat Med 2024; 30:1556-1558. [PMID: 38778211 PMCID: PMC11186752 DOI: 10.1038/s41591-024-02990-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 04/10/2024] [Indexed: 05/25/2024]
Abstract
The first completed clinical trial of induced pluripotent stem cell (iPS cell)-derived cells was conducted in 15 participants with steroid-resistant acute graft-versus-host disease. After intravenous infusion of mesenchymal stromal cells (CYP-001 derived from a clone of human iPS cells), we reported the safety, tolerability and efficacy within the primary evaluation period at day 100. We now report results at the 2-year follow-up: 9 of 15 (60%) participants survived, which compares favorably with previously reported outcomes in studies of steroid-resistant acute graft-versus-host disease. Causes of death were complications commonly observed in recipients of allogeneic hematopoietic stem cell transplantation, and not considered by the investigators to be related to CYP-001 treatment. There were no serious adverse events, tumors or other safety concerns related to CYP-001. In conclusion, systemic delivery of iPS cell-derived cells was safe and well tolerated over 2 years of follow-up, with sustained outcomes up to 2 years after the first infusion. ClinicalTrials.gov registration: NCT02923375 .
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Affiliation(s)
- Kilian Kelly
- Cynata Therapeutics Limited, Cremorne, Victoria, Australia
| | - Adrian J C Bloor
- Haematology & Transplant Unit, The Christie NHS Foundation Trust, Manchester, UK
| | - James E Griffin
- Department of Bone Marrow Transplantation, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Rohini Radia
- Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - David T Yeung
- School of Medicine, University of Adelaide, Adelaide, South Australia, Australia
- Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - John E J Rasko
- Central Clinical School, Faculty of Medicine & Health, University of Sydney, Sydney, New South Wales, Australia.
- Gene and Stem Cell Therapy Program Centenary Institute, University of Sydney, Sydney, New South Wales, Australia.
- Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
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Bicer M. Revolutionizing dermatology: harnessing mesenchymal stem/stromal cells and exosomes in 3D platform for skin regeneration. Arch Dermatol Res 2024; 316:242. [PMID: 38795200 PMCID: PMC11127839 DOI: 10.1007/s00403-024-03055-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/09/2024] [Accepted: 04/26/2024] [Indexed: 05/27/2024]
Abstract
Contemporary trends reveal an escalating interest in regenerative medicine-based interventions for addressing refractory skin defects. Conventional wound healing treatments, characterized by high costs and limited efficacy, necessitate a more efficient therapeutic paradigm to alleviate the economic and psychological burdens associated with chronic wounds. Mesenchymal stem/stromal cells (MSCs) constitute cell-based therapies, whereas cell-free approaches predominantly involve the utilization of MSC-derived extracellular vesicles or exosomes, both purportedly safe and effective. Exploiting the impact of MSCs by paracrine signaling, exosomes have emerged as a novel avenue capable of positively impacting wound healing and skin regeneration. MSC-exosomes confer several advantages, including the facilitation of angiogenesis, augmentation of cell proliferation, elevation of collagen production, and enhancement of tissue regenerative capacity. Despite these merits, challenges persist in clinical applications due to issues such as poor targeting and facile removal of MSC-derived exosomes from skin wounds. Addressing these concerns, a three-dimensional (3D) platform has been implemented to emend exosomes, allowing for elevated levels, and constructing more stable granules possessing distinct therapeutic capabilities. Incorporating biomaterials to encapsulate MSC-exosomes emerges as a favorable approach, concentrating doses, achieving intended therapeutic effectiveness, and ensuring continual release. While the therapeutic potential of MSC-exosomes in skin repair is broadly recognized, their application with 3D biomaterial scenarios remains underexplored. This review synthesizes the therapeutic purposes of MSCs and exosomes in 3D for the skin restoration, underscoring their promising role in diverse dermatological conditions. Further research may establish MSCs and their exosomes in 3D as a viable therapeutic option for various skin conditions.
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Affiliation(s)
- Mesude Bicer
- Department of Bioengineering, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, 38080, Turkey.
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Pérez-Torres Lobato M, Benitez-Carabante MI, Alonso L, Torrents S, Castillo Flores N, Uria Oficialdegui ML, Panesso M, Alonso-Martínez C, Oliveras M, Renedo-Miró B, Vives J, Diaz-de-Heredia C. Mesenchymal stromal cells in the treatment of pediatric hematopoietic cell transplantation-related complications (graft vs. host disease, hemorrhagic cystitis, graft failure and poor graft function): a single center experience. Front Pediatr 2024; 12:1375493. [PMID: 38783918 PMCID: PMC11112085 DOI: 10.3389/fped.2024.1375493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 03/28/2024] [Indexed: 05/25/2024] Open
Abstract
Objectives To describe mesenchymal stromal cells (MSCs) in the treatment of hematopoietic stem cell transplantation (HSCT) complications and to assess its safety and efficacy. Methods Single-center retrospective study (2016-2023). Patients under 20 years who received MSCs for the treatment of HSCT-related complications were included. Results Thirty patients (53.7% boys), median age at transplant 11 years (range 2-19) were included. MSCs indications were: graft-vs.-host disease (GVHD) in 18 patients (60%), of them 13 had acute GVHD (43.3%) and 5 chronic GVHD (16.7%); Grade 3-4 hemorrhagic cystitis (HC) in 4 (13.3%); poor graft function (PGF) in 6 (20%), 5 of them receiving MSCs with a CD34 stem cell-boost coinfusion; graft failure (GF) in 2 (6.7%), to enhance engraftment after a subsequent HSCT. Infusion-related-adverse-events were not reported. Overall response (OR) was 83% (25/30); 44% of responders (11/25) showed complete response (CR). OR for GVHD, HC, PGF and GF was 83.3%, 100%, 66.7% and 100% respectively. Response rate was 40% (95% CI: 20-55) and 79% (95% CI: 57-89) at 15 and 30 days. With a median follow-up of 21 months (IQR11-52.5), overall survival (OS) was 86% (95% CI: 74-100) and 79% (95% CI: 65-95) at 6 and 12 months post-MSCs infusion. Conclusion In our study, the most frequent indication of MSCs was refractory aGVHD (43.3%). Response rates were high (OR 83%) and safety profile was good.
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Affiliation(s)
- Maria Pérez-Torres Lobato
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Maria Isabel Benitez-Carabante
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Laura Alonso
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | | | | | - Maria Luz Uria Oficialdegui
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Melissa Panesso
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
| | | | - Maria Oliveras
- Department of Pharmacy, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Berta Renedo-Miró
- Department of Pharmacy, Vall D'Hebron University Hospital, Barcelona, Spain
| | - Joaquim Vives
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
- Banc de Sang I Teixits, Barcelona, Spain
- Department of Medicine, Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain
| | - Cristina Diaz-de-Heredia
- Department of Paediatric Oncology and Haematology, Vall D'Hebron University Hospital, Barcelona, Spain
- Vall D'Hebron Research Institute (VHIR), Barcelona, Spain
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Curley GF, O’Kane CM, McAuley DF, Matthay MA, Laffey JG. Cell-based Therapies for Acute Respiratory Distress Syndrome: Where Are We Now? Am J Respir Crit Care Med 2024; 209:789-797. [PMID: 38324017 PMCID: PMC10995569 DOI: 10.1164/rccm.202311-2046cp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/07/2024] [Indexed: 02/08/2024] Open
Abstract
There is considerable interest in the potential for cell-based therapies, particularly mesenchymal stromal cells (MSCs) and their products, as a therapy for acute respiratory distress syndrome (ARDS). MSCs exert effects via diverse mechanisms including reducing excessive inflammation by modulating neutrophil, macrophage and T-cell function, decreasing pulmonary permeability and lung edema, and promoting tissue repair. Clinical studies indicate that MSCs are safe and well tolerated, with promising therapeutic benefits in specific clinical settings, leading to regulatory approvals of MSCs for specific indications in some countries.This perspective reassesses the therapeutic potential of MSC-based therapies for ARDS given insights from recent cell therapy trials in both COVID-19 and in 'classic' ARDS, and discusses studies in graft-vs.-host disease, one of the few licensed indications for MSC therapies. We identify important unknowns in the current literature, address challenges to clinical translation, and propose an approach to facilitate assessment of the therapeutic promise of MSC-based therapies for ARDS.
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Affiliation(s)
- Gerard F. Curley
- Department of Anaesthesia, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Cecilia M. O’Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom
| | - Daniel F. McAuley
- Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, United Kingdom
- Department of Critical Care, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - Michael A. Matthay
- Department of Medicine and Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California
| | - John G. Laffey
- Department of Anaesthesia and Intensive Care Medicine, Galway University Hospitals, Saolta University Healthcare System, Galway, Ireland; and
- Anaesthesia, School of Medicine, College of Medicine, Nursing and Health Sciences, and CÚRAM Centre for Research in Medical Devices, University of Galway, Galway, Ireland
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9
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Hong J, Fraebel J, Yang Y, Tkacyk E, Kitko C, Kim TK. Understanding and treatment of cutaneous graft-versus-host-disease. Bone Marrow Transplant 2023; 58:1298-1313. [PMID: 37730800 PMCID: PMC11759061 DOI: 10.1038/s41409-023-02109-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/28/2023] [Accepted: 09/08/2023] [Indexed: 09/22/2023]
Abstract
The skin is the outermost mechanical barrier where dynamic immune reactions take place and is the most commonly affected site in both acute and chronic graft-versus-host disease (GVHD). If not properly treated, pain and pruritis resulting from cutaneous GVHD can increase the risk of secondary infection due to erosions, ulcerations, and damage of underlying tissues. Furthermore, resulting disfiguration can cause distress and significantly impact patients' quality of life. Thus, a deeper understanding of skin-specific findings of GVHD is needed. This review will highlight some promising results of recent pre-clinical studies on the pathophysiology of skin GVHD and summarize the diagnostic and staging/grading procedures according to the clinical manifestations of skin GVHD. In addition, we will summarize outcomes of various GVHD treatments, including skin-specific response rates.
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Affiliation(s)
- Junshik Hong
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Johnathan Fraebel
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yenny Yang
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric Tkacyk
- Veterans Affairs Tennessee Valley Health Care, Nashville, TN, USA
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Carrie Kitko
- Monroe Carell Jr Children's Hospital, Vanderbilt Division of Pediatric Hematology-Oncology, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Tae Kon Kim
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Veterans Affairs Tennessee Valley Health Care, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
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10
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Ding Y, Liu C, Cai Y, Hou C, Chen G, Xu Y, Hu S, Wu D. The efficiency of human umbilical cord mesenchymal stem cells as a salvage treatment for steroid-refractory acute graft-versus-host disease. Clin Exp Med 2023; 23:2561-2570. [PMID: 36598673 DOI: 10.1007/s10238-022-00983-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 01/05/2023]
Abstract
Acute graft-versus-host disease (aGVHD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) and is primarily treated with steroids. However, there is no standard treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). Although mesenchymal stem cells (MSCs) have proven effective for SR-aGVHD, few reports have focused on human umbilical cord blood-derived MSCs (hUCB-MSCs). Here, we report on the efficiency of hUCB-MSCs as the salvage therapy for SR-aGVHD in 54 patients. The overall response rate (ORR) reached 59.3% (32/54) 28 days later. Twenty-four patients achieved complete remission (CR), and 8 achieved partial remission (PR). The median follow-up time after the initiation of hUCB-MSC treatment was 19.3 (0.6-59.0) months. The probability of overall survival (OS) and progression-free survival (PFS) was 60.9% (47.4-74.4%, 95% CI) and 58.8% (45.3-72.3%, 95% CI), respectively, while that of GVHD/relapse-free survival (GRFS) was only 30.8% (17.86-43.74%, 95% CI). Multivariate analysis revealed that response on Day 28 was an independent favorable prognostic factor (OS, P < 0.001; PFS, P < 0.001; GRFS, P = 0.001), but an age of ≥ 18 years suggested an unfavorable long-term prognosis (OS, P < 0.001; PFS, P < 0.001; GRFS, P = 0.003). In addition, liver involvement was adversely associated with PFS (P = 0.021) and GRFS (P = 0.009). An infused MNC ≥ 8.66 × 108/kg was also detrimental to GRFS (P = 0.031). Collectively, our results support hUCB-MSCs as an effective treatment for SR-aGVHD.
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Affiliation(s)
- Yihan Ding
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Department of Hematology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Chang Liu
- Department of Hematology, Jiangsu Children's Hematology and Oncology Center, Children's Hospital of Soochow University, Suzhou, China
| | - Yiming Cai
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Chang Hou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Guanghua Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Shaoyan Hu
- Department of Hematology, Jiangsu Children's Hematology and Oncology Center, Children's Hospital of Soochow University, Suzhou, China.
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
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11
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Mendiratta M, Mendiratta M, Mohanty S, Sahoo RK, Prakash H. Breaking the graft-versus-host-disease barrier: Mesenchymal stromal/stem cells as precision healers. Int Rev Immunol 2023; 43:95-112. [PMID: 37639700 DOI: 10.1080/08830185.2023.2252007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Mesenchymal Stromal/Stem Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune modulation and regenerative potential which qualify them as a potential component of cell-based therapy for various autoimmune/chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. Considering this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host-Disease (GvHD), one of the autoimmune manifestations in human. In pre-clinical models, MSCs have been shown to reduce the severity of GvHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in GvHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. Owing to these inevitable issues, here we discuss various mechanisms, and how MSCs can be employed in managing GvHD, as a cellular therapeutic approach for this disease.
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Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Ranjit Kumar Sahoo
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Hridayesh Prakash
- Amity Centre for Translational Research, Amity University, Noida, India
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12
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Zanier ER, Pischiutta F, Rulli E, Vargiolu A, Elli F, Gritti P, Gaipa G, Belotti D, Basso G, Zoerle T, Stocchetti N, Citerio G. MesenchymAl stromal cells for Traumatic bRain Injury (MATRIx): a study protocol for a multicenter, double-blind, randomised, placebo-controlled phase II trial. Intensive Care Med Exp 2023; 11:56. [PMID: 37620640 PMCID: PMC10449745 DOI: 10.1186/s40635-023-00535-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/07/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) is a significant cause of death and disability, with no effective neuroprotective drugs currently available for its treatment. Mesenchymal stromal cell (MSC)-based therapy shows promise as MSCs release various soluble factors that can enhance the injury microenvironment through processes, such as immunomodulation, neuroprotection, and brain repair. Preclinical studies across different TBI models and severities have demonstrated that MSCs can improve functional and structural outcomes. Moreover, clinical evidence supports the safety of third-party donor bank-stored MSCs in adult subjects. Building on this preclinical and clinical data, we present the protocol for an academic, investigator-initiated, multicenter, double-blind, randomised, placebo-controlled, adaptive phase II dose-finding study aiming to evaluate the safety and efficacy of intravenous administration of allogeneic bone marrow-derived MSCs to severe TBI patients within 48 h of injury. METHODS/DESIGN The study will be conducted in two steps. Step 1 will enrol 42 patients, randomised in a 1:1:1 ratio to receive 80 million MSCs, 160 million MSCs or a placebo to establish safety and identify the most promising dose. Step 2 will enrol an additional 36 patients, randomised in a 1:1 ratio to receive the selected dose of MSCs or placebo. The activity of MSCs will be assessed by quantifying the plasmatic levels of neurofilament light (NfL) at 14 days as a biomarker of neuronal damage. It could be a significant breakthrough if the study demonstrates the safety and efficacy of MSC-based therapy for severe TBI patients. The results of this trial could inform the design of a phase III clinical trial aimed at establishing the efficacy of the first neurorestorative therapy for TBI. DISCUSSION Overall, the MATRIx trial is a critical step towards developing an effective treatment for TBI, which could significantly improve the lives of millions worldwide affected by this debilitating condition. Trial Registration EudraCT: 2022-000680-49.
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Affiliation(s)
- Elisa R Zanier
- Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Francesca Pischiutta
- Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Eliana Rulli
- Department of Clinical Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Alessia Vargiolu
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Francesca Elli
- Neurological Intensive Care Unit, Department of Neurosciences, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Paolo Gritti
- Department of Anesthesia, Emergency and Critical Care Medicine, ASST Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Giuseppe Gaipa
- M. Tettamanti Research Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Daniela Belotti
- M. Tettamanti Research Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Gianpaolo Basso
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Neurosciences, Neuroradiology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Tommaso Zoerle
- Neuroscience Intensive Care Unit, Department of Anaesthesia and Critical Care, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplants, University of Milan, Milan, Italy
| | - Nino Stocchetti
- Neuroscience Intensive Care Unit, Department of Anaesthesia and Critical Care, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplants, University of Milan, Milan, Italy
| | - Giuseppe Citerio
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
- Neurological Intensive Care Unit, Department of Neurosciences, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
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13
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Lin T, Yang Y, Chen X. A review of the application of mesenchymal stem cells in the field of hematopoietic stem cell transplantation. Eur J Med Res 2023; 28:268. [PMID: 37550742 PMCID: PMC10405442 DOI: 10.1186/s40001-023-01244-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/25/2023] [Indexed: 08/09/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is an effective treatment for many malignant hematological diseases. Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells with strong self-renewal ability and multidirectional differentiation potential. They have the characteristics of hematopoietic support, immune regulation, tissue repair and regeneration, and homing. Recent studies have shown that HSCT combined with MSC infusion can promote the implantation of hematopoietic stem cells and enhance the reconstruction of hematopoietic function. Researchers have also found that MSCs have good preventive and therapeutic effects on acute and chronic graft-versus-host disease (GVHD), but there is still a lack of validation in large-sample randomized controlled trials. When using MSCs clinically, it is necessary to consider their dose, source, application time, application frequency and other relevant factors, but the specific impact of the above factors on the efficacy of MSCs still needs further clinical trial research. This review introduces the clinical roles of MSCs and summarizes the most recent progress concerning the use of MSCs in the field of HSCT, providing references for the later application of the combination of MSCs and HSCT in hematological diseases.
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Affiliation(s)
- Ting Lin
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yunfan Yang
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xinchuan Chen
- Department of Hematology, Institute of Hematology, West China Hospital, Sichuan University, 37# Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
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14
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Kadri N, Amu S, Iacobaeus E, Boberg E, Le Blanc K. Current perspectives on mesenchymal stromal cell therapy for graft versus host disease. Cell Mol Immunol 2023; 20:613-625. [PMID: 37165014 DOI: 10.1038/s41423-023-01022-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/07/2023] [Indexed: 05/12/2023] Open
Abstract
Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. In this review, we summarize the experience from clinical trials that have paved the way to translation. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. As GvHD diagnosis and staging are based solely on clinical criteria, individual patients recruited in the same clinical trial may have vastly different underlying biology, obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients. An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients. We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.
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Affiliation(s)
- Nadir Kadri
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sylvie Amu
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ellen Iacobaeus
- Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Erik Boberg
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
| | - Katarina Le Blanc
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Cell Therapies and Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
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15
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Jaing TH, Chang TY, Chiu CC. Harnessing and honing mesenchymal stem/stromal cells for the amelioration of graft-versus-host disease. World J Stem Cells 2023; 15:221-234. [PMID: 37180998 PMCID: PMC10173808 DOI: 10.4252/wjsc.v15.i4.221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/19/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency. Despite its increased use, the mortality rate for patients undergoing this procedure remains high, mainly due to the perceived risk of exacerbating graft-versus-host disease (GVHD). However, even with immunosuppressive agents, some patients still develop GVHD. Advanced mesenchymal stem/stromal cell (MSC) strategies have been proposed to achieve better therapeutic outcomes, given their immunosuppressive potential. However, the efficacy and trial designs have varied among the studies, and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs. This review aims to provide real insights into this clinical entity, emphasizing diagnostic, and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues. The indications and timing for the clinical application of MSCs are still subject to debate.
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Affiliation(s)
- Tang-Her Jaing
- Division of Hematology, Oncology, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, Taoyuan 333, Taiwan
| | - Tsung-Yen Chang
- Department of Pediatrics, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Chia-Chi Chiu
- Department of Nursing, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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16
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Keklik M, Deveci B, Celik S, Deniz K, Gonen ZB, Zararsiz G, Saba R, Akyol G, Ozkul Y, Kaynar L, Keklik E, Unal A, Cetin M, Jones OY. Safety and efficacy of mesenchymal stromal cell therapy for multi-drug-resistant acute and late-acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Ann Hematol 2023; 102:1537-1547. [PMID: 37067556 DOI: 10.1007/s00277-023-05216-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 04/08/2023] [Indexed: 04/18/2023]
Abstract
Graft versus host disease (GvHD) remains a significant risk for mortality and morbidity following allogeneic hematopoietic stem cell transplantation (HSCT). A growing literature supports successful applications of mesenchymal stromal cells (MSCs) for the treatment of steroid-refractory acute GvHD (aGvHD). However, there is limited knowledge about the effects of MSC treatment on late-acute GvHD (late aGvHD). In this article, we present our multicenter study on the safety and efficacy of MSC therapy for patients with steroid-refractory late aGvHD in comparison to those with aGvHD. The outcome measures include non-relapse mortality (NRM) and survival probability over a 2-year follow-up. The study includes a total of 76 patients with grades III-IV aGvHD (n = 46) or late aGvHD (n = 30), who had been treated with at least two lines of steroid-containing immunosuppressive therapy. Patients received weekly adipose or umbilical cord-derived MSC infusions at a dose of median 1.55 (ranging from 0.84 to 2.56) × 106/kg in the aGvHD group, and 1.64 (ranging from 0.85 to 2.58) × 106/kg in the late aGvHD group. This was an add-on treatment to ongoing conventional pharmaceutical management. In the aGvHD group, 23 patients received one or two infusions, 20 patients had 3-4, and three had ≥ 5. Likewise, in the late aGvHD group, 20 patients received one or two infusions, nine patients had 3-4, and one had ≥ 5. MSC was safe without acute or late adverse effects in 76 patients receiving over 190 infusions. In aGvHD group, 10.9% of the patients had a complete response (CR), 23.9% had a partial response (PR), and 65.2% had no response (NR). On the other hand, in the late aGvHD group, 23.3% of the patients had CR, 36.7% had PR, and the remaining 40% had NR. These findings were statistically significant (p = 0.031). Also, at the 2-year follow-up, the cumulative incidence of NRM was significantly lower in patients with late aGvHD than in patients with aGvHD at 40% (95% CI, 25-62%) versus 71% (95% CI, 59-86%), respectively (p = 0.032). In addition, the probability of survival at 2 years was significantly higher in patients with late aGvHD than in the aGvHD group at 59% (95% CI, 37-74%) versus 28% (95% CI, 13-40%), respectively (p = 0.002). To our knowledge, our study is the first to compare the safety and efficacy of MSC infusion(s) for the treatment of steroid-resistant late aGVHD and aGVHD. There were no infusion-related adverse effects in either group. The response rate to MSC therapy was significantly higher in the late aGvHD group than in the aGvHD group. In addition, at the 2-year follow-up, the survival and NRM rates were more favorable in patients with late aGVHD than in those with aGVHD. Thus, the results are encouraging and warrant further studies to optimize MSC-based treatment for late aGVHD.
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Affiliation(s)
- Muzaffer Keklik
- Department of Hematology, Erciyes University, Kayseri, Turkey.
| | - Burak Deveci
- Hematology and Stem Cell Transplantation Unit, Medstar Antalya Hospital, Antalya, Turkey
| | - Serhat Celik
- Department of Hematology, Kirikkale University, Kirikkale, Turkey
| | - Kemal Deniz
- Department of Pathology, Erciyes University, Kayseri, Turkey
| | - Zeynep Burcin Gonen
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry and Genome - Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Gokmen Zararsiz
- Department of Biostatistics, Faculty of Medicine, Erciyes University and Turcosa Analytics Solutions Ltd. Co, Erciyes Teknopark, Kayseri, Turkey
| | - Rabin Saba
- Infectious Disease Unit, Medstar Antalya Hospital, Antalya, Turkey
| | - Gulsah Akyol
- Department of Hematology, Erciyes University, Kayseri, Turkey
| | - Yusuf Ozkul
- Department of Medical Genetics, Medical School, Erciyes University, Kayseri, Turkey
| | - Leylagul Kaynar
- Department of Hematology, Erciyes University, Kayseri, Turkey
- Department of Internal Medicine, Division of Hematology, Medipol University, Istanbul, Turkey
| | - Ertugrul Keklik
- Department of Physiology, Kayseri City Hospital, Kayseri, Turkey
| | - Ali Unal
- Department of Hematology, Erciyes University, Kayseri, Turkey
| | - Mustafa Cetin
- Hematology and Stem Cell Transplantation Unit, Medstar Antalya Hospital, Antalya, Turkey
| | - Olcay Y Jones
- Division of Rheumatology, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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Paeoniflorin drives the immunomodulatory effects of mesenchymal stem cells by regulating Th1/Th2 cytokines in oral lichen planus. Sci Rep 2022; 12:18678. [PMID: 36333421 PMCID: PMC9636377 DOI: 10.1038/s41598-022-23158-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022] Open
Abstract
Lichen planus (LP) is a chronic inflammatory disease. Oral lichen planus (OLP) mainly appears as oral mucosal reticular or ulcerative lesions with an unknown etiology. We aimed to explore the immunomodulatory effect of paeoniflorin (PF) in mesenchymal stem cells (MSCs) and the potential involvement of Th1/Th2 cytokines in OLP. The effects of paeoniflorin on the proliferation and migration of MSCs were detected by Cell Counting Kit-8 (CCK8) and Transwell assays. MSCs were subjected to osteogenic, adipogenic and neurogenic induction followed by Alizarin red, oil red O, real-time PCR and immunofluorescence assays. We found that paeoniflorin promoted the proliferation, migration and multilineage differentiation of MSCs from OLP lesions (OLP-MSCs) in vitro. Paeoniflorin pretreatment increased the inhibitory effect of OLP-MSCs on peripheral blood mononuclear cells. Furthermore, paeoniflorin-pretreated OLP-MSCs simultaneously decreased Th1 cytokine levels and increased Th2 cytokine levels in T lymphocyte cocultures. Finally, paeoniflorin-pretreated OLP-MSCs also promoted the Th1/Th2 balance both in vitro and in the serum of mice that received skin allografts. In conclusion, paeoniflorin enhanced MSC immunomodulation and changed the inflammatory microenvironment via T lymphocytes, suggesting that the improvement of OLP-MSCs is a promising therapeutic approach for OLP.
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18
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Xue E, Minniti A, Alexander T, Del Papa N, Greco R. Cellular-Based Therapies in Systemic Sclerosis: From Hematopoietic Stem Cell Transplant to Innovative Approaches. Cells 2022; 11:3346. [PMID: 36359742 PMCID: PMC9658618 DOI: 10.3390/cells11213346] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 08/28/2023] Open
Abstract
Systemic sclerosis (SSc) is a systemic disease characterized by autoimmune responses, vasculopathy and tissue fibrosis. The pathogenic mechanisms involve a wide range of cells and soluble factors. The complexity of interactions leads to heterogeneous clinical features in terms of the extent, severity, and rate of progression of skin fibrosis and internal organ involvement. Available disease-modifying drugs have only modest effects on halting disease progression and may be associated with significant side effects. Therefore, cellular therapies have been developed aiming at the restoration of immunologic self-tolerance in order to provide durable remissions or to foster tissue regeneration. Currently, SSc is recommended as the 'standard indication' for autologous hematopoietic stem cell transplantation by the European Society for Blood and Marrow Transplantation. This review provides an overview on cellular therapies in SSc, from pre-clinical models to clinical applications, opening towards more advanced cellular therapies, such as mesenchymal stem cells, regulatory T cells and potentially CAR-T-cell therapies.
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Affiliation(s)
- Elisabetta Xue
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
| | - Antonina Minniti
- Department of Rheumatology, ASST G. Pini-CTO, 20122 Milan, Italy
| | - Tobias Alexander
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, 10117 Berlin, Germany
| | | | - Raffaella Greco
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
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19
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Meftahpour V, Ghorbani F, Ahmadi M, Aghebati-Maleki A, Abbaspour-Aghdam S, Fotouhi A, Zamani M, Maleki A, Khakpour M, Aghebati-Maleki L. Evaluating the effects of autologous platelet lysate on gene expression of bone growth factors and related cytokines secretion in rabbits with bone fracture. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Insights into mechanisms of graft-versus-host disease through humanised mouse models. Biosci Rep 2022; 42:231673. [PMID: 35993192 PMCID: PMC9446388 DOI: 10.1042/bsr20211986] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 11/17/2022] Open
Abstract
Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic haematopoietic stem cell transplantation (HSCT) for the treatment of haematological cancers and other blood-related disorders. GVHD is an inflammatory disorder, where the transplanted donor immune cells can mediate an immune response against the recipient and attack host tissues. Despite over 60 years of research, broad-range immune suppression is still used to prevent or treat GVHD, leading to an increased risk of cancer relapse and infection. Therefore, further insights into the disease mechanisms and development of predictive and prognostic biomarkers are key to improving outcomes and reducing GVHD development following allogeneic HSCT. An important preclinical tool to examine the pathophysiology of GVHD and to understand the key mechanisms that lead to GVHD development are preclinical humanised mouse models. Such models of GVHD are now well-established and can provide valuable insights into disease development. This review will focus on models where human peripheral blood mononuclear cells are injected into immune-deficient non-obese diabetic (NOD)-scid-interleukin-2(IL-2)Rγ mutant (NOD-scid-IL2Rγnull) mice. Humanised mouse models of GVHD can mimic the clinical setting for GVHD development, with disease progression and tissues impacted like that observed in humans. This review will highlight key findings from preclinical humanised mouse models regarding the role of donor human immune cells, the function of cytokines and cell signalling molecules and their impact on specific target tissues and GVHD development. Further, specific therapeutic strategies tested in these preclinical models reveal key molecular pathways important in reducing the burden of GVHD following allogeneic HSCT.
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21
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Dave C, Mei SHJ, McRae A, Hum C, Sullivan KJ, Champagne J, Ramsay T, McIntyre L. Comparison of freshly cultured versus cryopreserved mesenchymal stem cells in animal models of inflammation: A pre-clinical systematic review. eLife 2022; 11:75053. [PMID: 35838024 PMCID: PMC9286731 DOI: 10.7554/elife.75053] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 06/05/2022] [Indexed: 12/09/2022] Open
Abstract
Background: Mesenchymal stem cells (MSCs) are multipotent cells that demonstrate therapeutic potential for the treatment of acute and chronic inflammatory-mediated conditions. Although controversial, some studies suggest that MSCs may lose their functionality with cryopreservation which could render them non-efficacious. Hence, we conducted a systematic review of comparative pre-clinical models of inflammation to determine if there are differences in in vivo measures of pre-clinical efficacy (primary outcomes) and in vitro potency (secondary outcomes) between freshly cultured and cryopreserved MSCs. Methods: A systematic search on OvidMEDLINE, EMBASE, BIOSIS, and Web of Science (until January 13, 2022) was conducted. The primary outcome included measures of in vivo pre-clinical efficacy; secondary outcomes included measures of in vitro MSC potency. Risk of bias was assessed by the SYRCLE ‘Risk of Bias’ assessment tool for pre-clinical studies. Results: Eighteen studies were included. A total of 257 in vivo pre-clinical efficacy experiments represented 101 distinct outcome measures. Of these outcomes, 2.3% (6/257) were significantly different at the 0.05 level or less; 2 favoured freshly cultured and 4 favoured cryopreserved MSCs. A total of 68 in vitro experiments represented 32 different potency measures; 13% (9/68) of the experiments were significantly different at the 0.05 level or less, with seven experiments favouring freshly cultured MSC and two favouring cryopreserved MSCs. Conclusions: The majority of preclinical primary in vivo efficacy and secondary in vitro potency outcomes were not significantly different (p<0.05) between freshly cultured and cryopreserved MSCs. Our systematic summary of the current evidence base may provide MSC basic and clinical research scientists additional rationale for considering a cryopreserved MSC product in their pre-clinical studies and clinical trials as well as help identify research gaps and guide future related research. Funding: Ontario Institute for Regenerative Medicine
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Affiliation(s)
- Chintan Dave
- Division of Critical Care Medicine, Department of Medicine, Western University, London, Canada
| | - Shirley H J Mei
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Andrea McRae
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Christine Hum
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada.,University of Ottawa, Ottawa, Canada
| | - Katrina J Sullivan
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Josee Champagne
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Tim Ramsay
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Lauralyn McIntyre
- Knowledge Synthesis Group, Ottawa Hospital Research Institute, Ottawa, Canada.,Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, Canada
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22
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Lederer CW, Koniali L, Buerki-Thurnherr T, Papasavva PL, La Grutta S, Licari A, Staud F, Bonifazi D, Kleanthous M. Catching Them Early: Framework Parameters and Progress for Prenatal and Childhood Application of Advanced Therapies. Pharmaceutics 2022; 14:pharmaceutics14040793. [PMID: 35456627 PMCID: PMC9031205 DOI: 10.3390/pharmaceutics14040793] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 01/19/2023] Open
Abstract
Advanced therapy medicinal products (ATMPs) are medicines for human use based on genes, cells or tissue engineering. After clear successes in adults, the nascent technology now sees increasing pediatric application. For many still untreatable disorders with pre- or perinatal onset, timely intervention is simply indispensable; thus, prenatal and pediatric applications of ATMPs hold great promise for curative treatments. Moreover, for most inherited disorders, early ATMP application may substantially improve efficiency, economy and accessibility compared with application in adults. Vindicating this notion, initial data for cell-based ATMPs show better cell yields, success rates and corrections of disease parameters for younger patients, in addition to reduced overall cell and vector requirements, illustrating that early application may resolve key obstacles to the widespread application of ATMPs for inherited disorders. Here, we provide a selective review of the latest ATMP developments for prenatal, perinatal and pediatric use, with special emphasis on its comparison with ATMPs for adults. Taken together, we provide a perspective on the enormous potential and key framework parameters of clinical prenatal and pediatric ATMP application.
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Affiliation(s)
- Carsten W. Lederer
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
- Correspondence: ; Tel.: +357-22-392764
| | - Lola Koniali
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
| | - Tina Buerki-Thurnherr
- Empa, Swiss Federal Laboratories for Materials Science and Technology, 9014 St. Gallen, Switzerland;
| | - Panayiota L. Papasavva
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
| | - Stefania La Grutta
- Institute of Translational Pharmacology, IFT National Research Council, 90146 Palermo, Italy;
| | - Amelia Licari
- Pediatric Clinic, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, Fondazione IRCCS Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy;
| | - Frantisek Staud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, 50005 Hradec Králové, Czech Republic;
| | - Donato Bonifazi
- Consorzio per Valutazioni Biologiche e Farmacologiche (CVBF) and European Paediatric Translational Research Infrastructure (EPTRI), 70122 Bari, Italy;
| | - Marina Kleanthous
- The Molecular Genetics Thalassemia Department, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (L.K.); (P.L.P.); (M.K.)
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23
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Zhao K, Lin R, Fan Z, Chen X, Wang Y, Huang F, Xu N, Zhang X, Zhang X, Xuan L, Wang S, Lin D, Deng L, Nie D, Weng J, Li Y, Zhang X, Li Y, Xiang AP, Liu Q. Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial. J Hematol Oncol 2022; 15:22. [PMID: 35255929 PMCID: PMC8900437 DOI: 10.1186/s13045-022-01240-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/19/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Steroid-resistant (SR) acute graft-versus-host disease (aGVHD) lacks standard second-line treatment. Mesenchymal stromal cells (MSCs) have potential efficacy in SR aGVHD. We aimed to assess the efficacy and safety of MSCs combined with basiliximab and calcineurin inhibitor as second-line therapy for SR aGVHD. METHODS A randomized phase 3 trial involved 203 SR aGVHD patients at nine centers in China (September 2014-March 2019). Participants were randomized at a 1:1 ratio to receive second-line therapy with (n = 101) or without (n = 102) MSCs. The primary endpoint was the overall response (OR) at day 28. Secondary and safety endpoints included durable OR at day 56, failure-free survival, overall survival (OS), chronic GVHD (cGVHD), infection, hematological toxicity and relapse. RESULTS Of 203 patients, 198 (97.5%; mean age, 30.1 years; 40.4% women) completed the study. The OR at day 28 was higher in the MSC group than the control group (82.8% [82 patients] vs. 70.7% [70]; odds ratio, 2.00; 95% confidence interval [CI], 1.01-3.94; P = 0.043). The durable OR at day 56 was also higher in the MSC group (78.8% [78 patients] vs. 64.6% [64]; odds ratio, 2.02; 95% CI, 1.08-3.83; P = 0.027). The median failure-free survival was longer in the MSC group compared with control (11.3 months vs. 6.0 months; hazard ratio (HR) 0.68; 95% CI, 0.48-0.95, P = 0.024). The 2-year cumulative incidence of cGVHD was 39.5% (95% CI, 29.3-49.4%) and 62.7% (51.4-72.1%) in the MSC and control groups (HR 0.55, 95% CI, 0.36-0.84; P = 0.005). Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections (65 [65.7%] in the MSC group vs. 78 [78.8%] in the control group) and hematological toxicity (37 [37.4%] vs. 53 [53.5%]). The 3-year cumulative incidence of tumor relapse was 10.1% (95% CI, 5.2-17.1) and 13.5% (7.5-21.2%) in the MSC and control groups, respectively (HR 0.75, 95% CI, 0.34-1.67, P = 0.610). CONCLUSIONS MSCs plus second-line treatments increase the efficacy of SR aGVHD, decrease drug toxicity of second-line drugs and cGVHD without increasing relapse, and are well-tolerated. MSCs could be recommended as a second-line treatment option for aGVHD patients. Trial registration clinicaltrials.gov identifier: NCT02241018. Registration date: September 16, 2014, https://clinicaltrials.gov/ct2/show/NCT02241018 .
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Affiliation(s)
- Ke Zhao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhiping Fan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoyong Chen
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yu Wang
- Department of Hematology, Peking University People's Hospital, Beijing, 100044, China
| | - Fen Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Na Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Xin Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Xuan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Shunqing Wang
- Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, 510180, China
| | - Dongjun Lin
- Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China
- Department of Hematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Lan Deng
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
- Department of Hematology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Danian Nie
- Department of Hematology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jianyu Weng
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Yonghua Li
- Department of Hematology, General Hospital of Southern Theatre Command, Guangzhou, 440104, China
| | - Xiaohui Zhang
- Department of Hematology, Peking University People's Hospital, Beijing, 100044, China
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - A P Xiang
- Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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24
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Li Y, Hao J, Hu Z, Yang YG, Zhou Q, Sun L, Wu J. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review. Stem Cell Res Ther 2022; 13:93. [PMID: 35246235 PMCID: PMC8895864 DOI: 10.1186/s13287-022-02751-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
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. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02751-0.
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Affiliation(s)
- Ying Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,Department of Gastroenterology, The First Hospital, Jilin University, Changchun, 130021, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.,International Center of Future Science, Jilin University, Changchun, 130021, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Liguang Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China. .,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, 130061, China.
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100101, China.
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25
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Capelli C, Frigerio S, Lisini D, Nava S, Gaipa G, Belotti D, Cabiati B, Budelli S, Lazzari L, Bagnarino J, Tanzi M, Comoli P, Perico N, Introna M, Golay J. A comprehensive report of long-term stability data for a range ATMPs: A need to develop guidelines for safe and harmonized stability studies. Cytotherapy 2022; 24:544-556. [PMID: 35177338 DOI: 10.1016/j.jcyt.2021.12.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND AIMS Advanced therapy medicinal products (ATMPs) are novel drugs based on genes, cells or tissues developed to treat many different diseases. Stability studies of each new ATMP need to be performed to define its shelf life and guarantee efficacy and safety upon infusion, and these are presently based on guidelines originally drafted for standard pharmaceutical drugs, which have properties and are stored in conditions quite different from cell products. The aim of this report is to provide evidence-based information for stability studies on ATMPs that will facilitate the interlaboratory harmonization of practices in this area. METHODS We have collected and analyzed the results of stability studies on 19 different cell-based experimental ATMPs, produced by five authorized cell factories forming the Lombardy "Plagencell network" for use in 36 approved phase I/II clinical trials; most were cryopreserved and stored in liquid nitrogen vapors for 1 to 13 years. RESULTS The cell attributes collected in stability studies included cell viability, immunophenotype and potency assays, in particular immunosuppression, cytotoxicity, cytokine release and proliferation/differentiation capacity. Microbiological attributes including sterility, endotoxin levels and mycoplasma contamination were also analyzed. All drug products (DPs), cryopreserved in various excipients containing 10% DMSO and in different primary containers, were very stable long term at <-150°C and did not show any tendency for diminished viability or efficacy for up to 13.5 years. CONCLUSIONS Our data indicate that new guidelines for stability studies, specific for ATMPs and based on risk analyses, should be drafted to harmonize practices, significantly reduce the costs of stability studies without diminishing safety. Some specific suggestions are presented in the discussion.
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Affiliation(s)
- Chiara Capelli
- Center of Cellular Therapy "G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy; Fondazione per la Ricerca Ospedale di Bergamo, Bergamo, Italy
| | - Simona Frigerio
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Daniela Lisini
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Sara Nava
- Cell Therapy Production Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Giuseppe Gaipa
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Daniela Belotti
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Benedetta Cabiati
- Laboratory of Cell and Gene Therapy Stefano Verri, ASST Monza Ospedale San Gerardo, Monza, Italy
| | - Silvia Budelli
- Laboratory of Regenerative Medicine - Cell Factory, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Lorenza Lazzari
- Laboratory of Regenerative Medicine - Cell Factory, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Jessica Bagnarino
- UOSD Cell Factory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Matteo Tanzi
- UOSD Cell Factory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Patrizia Comoli
- UOSD Cell Factory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Norberto Perico
- Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Istituto Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Martino Introna
- Center of Cellular Therapy "G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy.
| | - Josée Golay
- Center of Cellular Therapy "G. Lanzani", ASST Papa Giovanni XXIII, Bergamo, Italy; Fondazione per la Ricerca Ospedale di Bergamo, Bergamo, Italy
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26
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Najar M, Melki R, Khalife F, Lagneaux L, Bouhtit F, Moussa Agha D, Fahmi H, Lewalle P, Fayyad-Kazan M, Merimi M. Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization. Front Cell Dev Biol 2022; 9:716853. [PMID: 35096805 PMCID: PMC8795900 DOI: 10.3389/fcell.2021.716853] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022] Open
Abstract
Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro, MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.,Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Rahma Melki
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Ferial Khalife
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Fatima Bouhtit
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco.,Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Douaa Moussa Agha
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco.,Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Hadath, Lebanon.,Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Lebanon
| | - Makram Merimi
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco.,Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
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27
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Abstract
Mesenchymal stem cells (MSCs) exhibit regenerative and reparative properties. However, most MSC-related studies remain to be translated for regular clinical usage, partly due to challenges in pre-transplantation cell labelling and post-transplantation cell tracking. Amidst this, there are growing concerns over the toxicity of commonly used gadolinium-based contrast agents that mediate in-vivo cell detection via MRI. This urges to search for equally effective but less toxic alternatives that would facilitate and enhance MSC detection post-administration and provide therapeutic benefits in-vivo. MSCs labelled with iron oxide nanoparticles (IONPs) have shown promising results in-vitro and in-vivo. Thus, it would be useful to revisit these studies before inventing new labelling approaches. Aiming to inform regenerative medicine and augment clinical applications of IONP-labelled MSCs, this review collates and critically evaluates the utility of IONPs in enhancing MSC detection and therapeutics. It explains the rationale, principle, and advantages of labelling MSCs with IONPs, and describes IONP-induced intracellular alterations and consequent cellular manifestations. By exemplifying clinical pathologies, it examines contextual in-vitro, animal, and clinical studies that used IONP-labelled bone marrow-, umbilical cord-, adipose tissue- and dental pulp-derived MSCs. It compiles and discusses studies involving MSC-labelling of IONPs in combinations with carbohydrates (Venofer, ferumoxytol, dextran, glucosamine), non-carbohydrate polymers [poly(L-lysine), poly(lactide-co-glycolide), poly(L-lactide), polydopamine], elements (ruthenium, selenium, gold, zinc), compounds/stains (silica, polyethylene glycol, fluorophore, rhodamine B, DAPI, Prussian blue), DNA, Fibroblast growth Factor-2 and the drug doxorubicin. Furthermore, IONP-labelling of MSC exosomes is reviewed. Also, limitations of IONP-labelling are addressed and methods of tackling those challenges are suggested.
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28
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Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, Mazzucato M, Agostini F. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J Stem Cells 2022; 14:54-75. [PMID: 35126828 PMCID: PMC8788179 DOI: 10.4252/wjsc.v14.i1.54] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.
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Affiliation(s)
- Carla Vicinanza
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Elisabetta Lombardi
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Da Ros
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Miriam Marangon
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Cristina Durante
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Mario Mazzucato
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Agostini
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
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29
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Shen MZ, Liu XX, Qiu ZY, Xu LP, Zhang XH, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu SN, Liu KY, Huang XJ, Mo XD. Efficacy and safety of mesenchymal stem cells treatment for multidrug-resistant graft- versus-host disease after haploidentical allogeneic hematopoietic stem cell transplantation. Ther Adv Hematol 2022; 13:20406207211072838. [PMID: 35096361 PMCID: PMC8796067 DOI: 10.1177/20406207211072838] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/17/2021] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Graft-versus-host disease (GVHD) is an important complication after human leukocyte antigen (HLA) haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT), which may lead to poor prognosis. Our study intends to identify the efficacy and safety of mesenchymal stem cells (MSCs) for multidrug-resistant (MDR)-GVHD after HID HSCT. METHODS MDR-GVHD was referring to GVHD remaining no response to at least two types of therapy, and hUCB-MSCs were given at the dose of (1.0-2.0) × 106/kg once a week. RESULTS A total of 21 patients were enrolled in this retrospective study (acute GVHD (aGVHD): n = 14, chronic GVHD (cGVHD): n = 7). The median dose of MSCs was 1.2 × 106 cells/kg (range, 0.8-1.8 × 106) cells/kg, and the median numbers of infusion were 2 (range, 1-7) and 3 (range, 2-12) for MDR-aGVHD and MDR-cGVHD patients, respectively. In MDR-aGVHD patients, the overall response rate (ORR) was 57.1%, including 50.0% complete response (CR) and 7.1% partial response (PR), and the median time to response was 49.5 days (range, 16-118) days. The 2-year probability of overall survival after MSCs was 64.3%. Five patients (35.7%) developed infections after MSCs, and no obvious hematologic toxicities were observed. Five MDR-aGVHD patients died after MSCs treatments because of GVHD progression (n = 1), severe infection (bacterial central nervous system infection: n = 1; fungal pneumonia: n = 2), and poor graft function (n = 1). In MDR-cGVHD patients, three patients (42.9%) achieved PR after MSCs and the median time to response was 56 days (22-84) days. The ORRs for moderate and severe cGVHD were 50.0% and 33.3%, respectively. Four MDR-cGVHD patients died after MSCs treatments because of GVHD progression (n = 2), severe fungal pneumonia (n = 1), and relapse (n = 1). CONCLUSION MSCs treatment may be safe and effective for MDR-GVHD after HID HSCT.
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Affiliation(s)
- Meng-Zhu Shen
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xin-Xin Liu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
- Department of Hematology, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Zhi-Yuan Qiu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
- Department of Hematology, Weifang People’s Hospital, Weifang, China
| | - Lan-Ping Xu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiao-Hui Zhang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Yu Wang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Chen-Hua Yan
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Huan Chen
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Yu-Hong Chen
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Wei Han
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Feng-Rong Wang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Jing-Zhi Wang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Si-Ning Liu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Kai-Yan Liu
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiao-Jun Huang
- Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Dong Mo
- Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing 2019RU029, China
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Macías-Sánchez MDM, Morata-Tarifa C, Cuende N, Cardesa-Gil A, Cuesta-Casas MÁ, Pascual-Cascon MJ, Pascual A, Martín-Calvo C, Jurado M, Perez-Simón JA, Espigado I, Garzón López S, Carmona Sánchez G, Mata-Alcázar-Caballero R, Sánchez-Pernaute R. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:343-355. [PMID: 35348788 PMCID: PMC9052408 DOI: 10.1093/stcltm/szac003] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 12/12/2021] [Indexed: 11/30/2022] Open
Abstract
Graft versus host disease (GVHD) is a severe complication after allogenic hematopoietic cell transplantation (HSCT). Several clinical trials have reported the use of mesenchymal stromal cells (MSCs) for the treatment of GVHD. In March 2008, the Andalusian Health Care System launched a compassionate use program to treat steroid-resistant GVHD with MSC. Clinical-grade MSC were obtained under GMP conditions. MSC therapy was administered intravenously in four separate doses of 1 × 106 cells/kg. Sixty-two patients, 45 males (7 children) and 17 females (2 children), received the treatment. Patients had a median age of 39 years (range: 7–66) at the time of the allogenic HSCT. The overall response was achieved in 58.7% of patients with acute (a)GVHD. Two years’ survival for aGVHD responders was 51.85%. The overall response for patients with chronic (c)GVHD was 65.50% and the 2-year survival rate for responders was 70%. Age at the time of HSCT was the only predictor found to be inversely correlated with survival in aGVHD. Regarding safety, four adverse events were reported, all recovered without sequelae. Thus, analysis of this compassionate use experience shows MSC to be an effective and safe therapeutic option for treating refractory GVHD, resulting in a significant proportion of patients responding to the therapy.
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Affiliation(s)
- María del Mar Macías-Sánchez
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
- Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Cynthia Morata-Tarifa
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
| | - Natividad Cuende
- Coordinación Autonómica de Trasplantes de Andalucía. Servicio Andaluz de Salud, Sevilla, Spain
| | - Ana Cardesa-Gil
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
| | | | | | - Antonia Pascual
- Departamento de Hematología y Hemoterapia, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Carmen Martín-Calvo
- Departamento de Hematología, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Manuel Jurado
- Departamento de Hematología, Hospital Virgen de las Nieves, Granada, Spain
| | - José Antonio Perez-Simón
- Departamento de Hematología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
- Instituto de Investigación Biomédica de Sevilla (IBIS)/CSIC, Sevilla, Spain
| | - Ildefonso Espigado
- Departamento de Hematología, Hospital Universitario Virgen del Rocío, Sevilla, Spain
- Instituto de Investigación Biomédica de Sevilla (IBIS)/CSIC, Sevilla, Spain
- Universidad de Sevilla, Sevilla, Spain
- Hospital Universitario Virgen Macarena, Sevilla, Spain
| | | | - Gloria Carmona Sánchez
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
| | - Rosario Mata-Alcázar-Caballero
- Corresponding author: Rosario Mata Alcázar-Caballero, c/ Américo Vespucio 15 Edif. S2, 41092 Seville, Spain. Tel: +34 955 89 01 24; Fax: +34 955 267 002;
| | - Rosario Sánchez-Pernaute
- Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía, Spain
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Özdemir AT, Nalbantsoy A, Özgül Özdemir RB, Berdeli A. Effects of 15-Lipoxygenase Overexpressing Adipose Tissue Mesenchymal Stem Cells on The Th17 / Treg Plasticity. Prostaglandins Other Lipid Mediat 2021; 159:106610. [PMID: 34963632 DOI: 10.1016/j.prostaglandins.2021.106610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/15/2021] [Accepted: 12/23/2021] [Indexed: 11/30/2022]
Abstract
15-lipoxygenase (15-LOX) is a critical enzyme that allows the direction of arachidonic acid metabolism to change from inflammation into the resolution. This study aims to reveal how the immunomodulation properties of mesenchymal stem cells (MSC) alter by the 15-LOX overexpression. For this purpose, peripheral blood mononuclear cells (PBMCs) isolated from seven healthy volunteers, and both MSCs and 15-LOX overexpressing MSCs (15-LOXMSCs) were co-cultured at different cell ratios (1/1, 1/5 and 1/10). Alterations of CD4+Tbet+, CD4+Gata3+, CD4+RoRC2+, and CD4+FoxP3+ lymphocyte frequencies were detected by flow cytometry, and IFN-γ, IL-4, IL-6, IL-10, IL-17a, TGF-β and LXA4 levels of medium supernatants were measured by ELISA method. According to our findings, MSC and 15-LOXMSCs have a suppressive effect on PHA activated PBMCs. However, as the ratio of PBMCs increased, the effects of 15-LOXMSCs increased significantly, while the effects of MSCs decreased. The most notable effect of the 15-LOX modification was the significant reduction in IL-6, IL-10 and IL-17a expression and the accompanying increase in TGF-β and LXA4 levels. We also observed a similar situation between CD4+RoRC2+ and CD4+FoxP3+ cell frequencies. These data suggested that the effects of MSCs on the balance of Th17 / Treg could change by the 15-LOX overexpression, and this might be in favor of the Treg cells.
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Affiliation(s)
- Alper Tunga Özdemir
- Ege University, Institute of Health Sciences, Department of Stem Cell, Izmir, Turkey.
| | - Ayşe Nalbantsoy
- Manisa City Hospital, Allergy and Clinical Immunology Clinic, Manisa, Turkey
| | | | - Afig Berdeli
- Ege University, Institute of Health Sciences, Department of Stem Cell, Izmir, Turkey
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Kelly K, Rasko JEJ. Mesenchymal Stromal Cells for the Treatment of Graft Versus Host Disease. Front Immunol 2021; 12:761616. [PMID: 34764962 PMCID: PMC8577186 DOI: 10.3389/fimmu.2021.761616] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/07/2021] [Indexed: 12/28/2022] Open
Abstract
Graft versus host disease (GvHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation, which is initially treated with high dose corticosteroids. Approximately 50% of acute GvHD cases are resistant to steroid treatment, and two-year mortality rates in those steroid-resistant patients exceed 80%. Chronic GvHD necessitates prolonged corticosteroid use, which is typically associated with limited efficacy and troublesome adverse effects. No agent has yet been established as an optimal second line therapy for either acute or chronic GvHD, but mesenchymal stromal cells (MSCs) have shown substantial promise. MSCs promote an immunosuppressive and immunoregulatory environment via multifactorial mechanisms, including: secretion of proteins/peptides/hormones; transfer of mitochondria; and transfer of exosomes or microvesicles containing RNA and other molecules. A large number of clinical studies have investigated MSCs from various sources as a treatment for acute and/or chronic GvHD. MSCs are generally safe and well tolerated, and most clinical studies have generated encouraging efficacy results, but response rates have varied. Confounding factors include variability in MSC donor types, production methodology and dose regimens, as well as variations in study design. It is well-established that extensive culture expansion of primary donor-derived MSCs leads to marked changes in functionality, and that there is a high level of inter-donor variability in MSC properties. However, recent manufacturing innovations may be capable of overcoming these problems. Further adequately powered prospective studies are required to confirm efficacy and establish the place of MSC therapy in the treatment of this condition.
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Affiliation(s)
- Kilian Kelly
- Cynata Therapeutics Limited, Cremorne, VIC, Australia
| | - John E J Rasko
- Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Gene and Stem Cell Therapy Program Centenary Institute, University of Sydney, Sydney, NSW, Australia.,Central Clinical School, Faculty of Medicine & Health, University of Sydney, Sydney, NSW, Australia
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33
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Riedl J, Popp C, Eide C, Ebens C, Tolar J. Mesenchymal stromal cells in wound healing applications: role of the secretome, targeted delivery and impact on recessive dystrophic epidermolysis bullosa treatment. Cytotherapy 2021; 23:961-973. [PMID: 34376336 PMCID: PMC8569889 DOI: 10.1016/j.jcyt.2021.06.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multi-potent stromal-derived cells capable of self-renewal that possess several advantageous properties for wound healing, making them of interest to the field of dermatology. Research has focused on characterizing the unique properties of MSCs, which broadly revolve around their regenerative and more recently discovered immunomodulatory capacities. Because of ease of harvesting and expansion, differentiation potential and low immunogenicity, MSCs have been leading candidates for tissue engineering and regenerative medicine applications for wound healing, yet results from clinical studies have been variable, and promising pre-clinical work has been difficult to reproduce. Therefore, the specific mechanisms of how MSCs influence the local microenvironment in distinct wound etiologies warrant further research. Of specific interest in MSC-mediated healing is harnessing the secretome, which is composed of components known to positively influence wound healing. Molecules released by the MSC secretome can promote re-epithelialization and angiogenesis while inhibiting fibrosis and microbial invasion. This review focuses on the therapeutic interest in MSCs with regard to wound healing applications, including burns and diabetic ulcers, with specific attention to the genetic skin disease recessive dystrophic epidermolysis bullosa. This review also compares various delivery methods to support skin regeneration in the hopes of combating the poor engraftment of MSCs after delivery, which is one of the major pitfalls in clinical studies utilizing MSCs.
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Affiliation(s)
- Julia Riedl
- Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA
| | - Courtney Popp
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Cindy Eide
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christen Ebens
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
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Murata M, Terakura S, Wake A, Miyao K, Ikegame K, Uchida N, Kataoka K, Miyamoto T, Onizuka M, Eto T, Doki N, Ota S, Sato M, Hashii Y, Ichinohe T, Fukuda T, Atsuta Y, Okamoto S, Teshima T. Off-the-shelf bone marrow-derived mesenchymal stem cell treatment for acute graft-versus-host disease: real-world evidence. Bone Marrow Transplant 2021; 56:2355-2366. [PMID: 33976381 DOI: 10.1038/s41409-021-01304-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/29/2021] [Accepted: 04/09/2021] [Indexed: 11/08/2022]
Abstract
Temcell is a cryopreserved, human bone marrow-derived mesenchymal stem cell (MSC) product approved for the treatment of patients of all ages with acute graft-versus-host disease (GVHD). Initial experience with Temcell in a real-world setting from a cellular therapy registry in Japan is presented. A total of 381 consecutive patients were enrolled since its approval in 2016. The median cell number infused was 2.00 × 106/kg. The most common number of infusions was 8 in 100 patients. Of the 306 evaluable patients, the overall response rate (ORR) on day 28 after the start of MSC therapy was 56%. Of the 151 evaluable patients who received it as second-line therapy following first-line steroid therapy for classic acute GVHD, the ORR was 61%. Liver involvement of GVHD and ≥14 days from first-line steroid therapy to second-line MSC therapy was associated with a lower ORR. Day 28 ORR, patient age, GVHD grade, GVHD organ involvement, and a number of GVHD therapies before MSC therapy were associated with nonrelapse mortality. Overall survival at 6 months in 381 patients was 40%. This study suggests that Temcell is one of the treatment options for steroid-refractory acute GVHD until a new treatment with survival benefit is developed.
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Affiliation(s)
- Makoto Murata
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Seitaro Terakura
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Wake
- Department of Hematology, Toranomon Hospital Kajigaya, Kanagawa, Japan
| | - Kotaro Miyao
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Kazuhiro Ikegame
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Naoyuki Uchida
- Department of Hematology, Toranomon Hospital, Tokyo, Japan
| | - Keisuke Kataoka
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Toshihiro Miyamoto
- Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Makoto Onizuka
- Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
| | - Tetsuya Eto
- Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Shuichi Ota
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Maho Sato
- Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Izumi, Japan
| | - Yoshiko Hashii
- Department of Cancer Immunotherapy/Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takahiro Fukuda
- Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinichiro Okamoto
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Graduate School of Medical Science, Sapporo, Japan
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Murata M, Teshima T. Treatment of Steroid-Refractory Acute Graft- Versus-Host Disease Using Commercial Mesenchymal Stem Cell Products. Front Immunol 2021; 12:724380. [PMID: 34489977 PMCID: PMC8417106 DOI: 10.3389/fimmu.2021.724380] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 07/29/2021] [Indexed: 01/09/2023] Open
Abstract
Acute graft-versus-host disease (GVHD) is a life-threatening complication that can develop after allogeneic hematopoietic stem cell transplantation. In particular, the prognosis of patients with steroid-refractory acute GVHD is extremely poor. Ryoncil™ (remestemcel-L), a human bone marrow-derived mesenchymal stem cell (MSC) product, failed to show superiority over placebo in patients with steroid-refractory acute GVHD, but it was approved for use in pediatric patients in Canada and New Zealand based on the results of a subgroup analysis. Temcell®, an equivalent manufactured MSC product to remestemcel-L, was approved in Japan based on small single-arm studies by using a regulation for regenerative medicine in 2016. The efficacy of Temcell was evaluated in 381 consecutive patients treated with Temcell during the initial 3 years after its approval. Interestingly, its real-world efficacy was found to be equivalent to that observed in a prospective study of remestemcel-L with strict eligibility criteria. In this article, the potential of MSC therapy in the treatment of acute GVHD is discussed. A meticulous comparison of studies of remestemcel-L and Temcell, remestemcel-L/Temcell and ruxolitinib, and remestemcel-L/Temcell and thymoglobulin showed that the precise position of remestemcel-L/Temcell therapy in the treatment of acute GVHD remains to be determined.
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Affiliation(s)
- Makoto Murata
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
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Johnson J, Shojaee M, Mitchell Crow J, Khanabdali R. From Mesenchymal Stromal Cells to Engineered Extracellular Vesicles: A New Therapeutic Paradigm. Front Cell Dev Biol 2021; 9:705676. [PMID: 34409037 PMCID: PMC8366519 DOI: 10.3389/fcell.2021.705676] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 06/29/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells obtained from many tissues including bone marrow, adipose tissue, umbilical cord, amniotic fluid, and placenta. MSCs are the leading cell source for stem cell therapy due to their regenerative and immunomodulatory properties, their low risk of tumorigenesis and lack of ethical constraints. However, clinical applications of MSCs remain limited. MSC therapeutic development continues to pose challenges in terms of preparation, purity, consistency, efficiency, reproducibility, processing time and scalability. Additionally, there are issues with their poor engraftment and survival in sites of disease or damage that limit their capacity to directly replace damaged cells. A key recent development in MSC research, however, is the now widely accepted view that MSCs primarily exert therapeutic effects via paracrine factor secretion. One of the major paracrine effectors are extracellular vesicles (EVs). EVs represent a potential cell-free alternative to stem cell therapy but are also rapidly emerging as a novel therapeutic platform in their own right, particularly in the form of engineered EVs (EEVs) tailored to target a broad range of clinical indications. However, the development of EVs and EEVs for therapeutic application still faces a number of hurdles, including the establishment of a consistent, scalable cell source, and the development of robust GMP-compliant upstream and downstream manufacturing processes. In this review we will highlight the clinical challenges of MSC therapeutic development and discuss how EVs and EEVs can overcome the challenges faced in the clinical application of MSCs.
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Affiliation(s)
- Jancy Johnson
- Exopharm Ltd., Melbourne, VIC, Australia.,Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, Australia
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Zha S, Tay JCK, Zhu S, Li Z, Du Z, Wang S. Generation of Mesenchymal Stromal Cells with Low Immunogenicity from Human PBMC-Derived β2 Microglobulin Knockout Induced Pluripotent Stem Cells. Cell Transplant 2021; 29:963689720965529. [PMID: 33172291 PMCID: PMC7784598 DOI: 10.1177/0963689720965529] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are viewed as immune-privileged cells and have been broadly applied in allogeneic adoptive cell transfer for regenerative medicine or immune-suppressing purpose. However, the surface expression of human leukocyte antigen (HLA) class I molecules on MSCs could still possibly induce the rejection of allogeneic MSCs from the recipients. Here, we disrupted the β2 microglobulin (B2M) gene in human peripheral blood mononuclear cell-derived induced pluripotent stem cells (iPSCs) with two clustered regulatory interspaced short palindromic repeat (CRISPR)-associated Cas9 endonuclease-based methods. The B2M knockout iPSCs did not express HLA class I molecules but maintained their pluripotency and genome stability. Subsequently, MSCs were derived from the HLA-negative iPSCs (iMSCs). We demonstrated that B2M knockout did not affect iMSC phenotype, multipotency, and immune suppressive characteristics and, most importantly, reduced iMSC immunogenicity to allogeneic peripheral blood mononuclear cells. Thus, B2M knockout iPSCs could serve as unlimited off-the-shelf cell resources in adoptive cell transfer, while the derived iMSCs hold great potential as universal grafts in allogeneic MSC transplantation.
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Affiliation(s)
- Shijun Zha
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Johan Chin-Kang Tay
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Sumin Zhu
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Zhendong Li
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Zhicheng Du
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Shu Wang
- Department of Biological Sciences, National University of Singapore, Singapore
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Bucar S, Branco ADDM, Mata MF, Milhano JC, Caramalho Í, Cabral JMS, Fernandes-Platzgummer A, da Silva CL. Influence of the mesenchymal stromal cell source on the hematopoietic supportive capacity of umbilical cord blood-derived CD34 +-enriched cells. Stem Cell Res Ther 2021; 12:399. [PMID: 34256848 PMCID: PMC8278708 DOI: 10.1186/s13287-021-02474-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/24/2021] [Indexed: 12/18/2022] Open
Abstract
Background Umbilical cord blood (UCB) is a clinically relevant alternative source of hematopoietic stem/progenitor cells (HSPC). To overcome the low cell number per UCB unit, ex vivo expansion of UCB HSPC in co-culture with mesenchymal stromal cells (MSC) has been established. Bone marrow (BM)-derived MSC have been the standard choice, but the use of MSC from alternative sources, less invasive and discardable, could ease clinical translation of an expanded CD34+ cell product. Here, we compare the capacity of BM-, umbilical cord matrix (UCM)-, and adipose tissue (AT)-derived MSC, expanded with/without xenogeneic components, to expand/maintain UCB CD34+-enriched cells ex vivo. Methods UCB CD34+-enriched cells were isolated from cryopreserved mononuclear cells and cultured for 7 days over an established feeder layer (FL) of BM-, UCM-, or AT-derived MSC, previously expanded using fetal bovine serum (FBS) or fibrinogen-depleted human platelet lysate (HPL) supplemented medium. UCB cells were cultured in serum-free medium supplemented with SCF/TPO/FLT3-L/bFGF. Fold increase in total nucleated cells (TNC) as well as immunophenotype and clonogenic potential (cobblestone area-forming cells and colony-forming unit assays) of the expanded hematopoietic cells were assessed. Results MSC from all sources effectively supported UCB HSPC expansion/maintenance ex vivo, with expansion factors (in TNC) superior to 50x, 70x, and 80x in UCM-, BM-, and AT-derived MSC co-cultures, respectively. Specifically, AT-derived MSC co-culture resulted in expanded cells with similar phenotypic profile compared to BM-derived MSC, but resulting in higher total cell numbers. Importantly, a subpopulation of more primitive cells (CD34+CD90+) was maintained in all co-cultures. In addition, the presence of a MSC FL was essential to maintain and expand a subpopulation of progenitor T cells (CD34+CD7+). The use of HPL to expand MSC prior to co-culture establishment did not influence the expansion potential of UCB cells. Conclusions AT represents a promising alternative to BM as a source of MSC for co-culture protocols to expand/maintain HSPC ex vivo. On the other hand, UCM-derived MSC demonstrated inferior hematopoietic supportive capacity compared to MSC from adult tissues. Despite HPL being considered an alternative to FBS for clinical-scale manufacturing of MSC, further studies are needed to determine its impact on the hematopoietic supportive capacity of these cells.
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Affiliation(s)
- Sara Bucar
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - André Dargen de Matos Branco
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Márcia F Mata
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - João Coutinho Milhano
- Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal
| | | | - Joaquim M S Cabral
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Ana Fernandes-Platzgummer
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal. .,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.
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Infusion of Mesenchymal Stem Cells to Treat Graft Versus Host Disease: the Role of HLA-G and the Impact of its Polymorphisms. Stem Cell Rev Rep 2021; 16:459-471. [PMID: 32088839 DOI: 10.1007/s12015-020-09960-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hematopoietic stem-cell transplantation is widely performed for the treatment of hematologic diseases and is increasingly being used for the experimental treatment of various autoimmune diseases. Despite the rapid evolution of this therapy, the mortality rate of patients undergoing this procedure is still high, mainly due to the development of graft versus host disease (GvHD). Even with the administration of immunosuppressive therapy, some patients manifest the chronic form of the disease. For these cases, infusion of mesenchymal stem cells (MSCs) was proposed as a therapeutic strategy, considering the immunosuppressive potential of these cells. This review describes the main results obtained in cell therapy with MSCs for the treatment of GvHD. Despite the encouraging results found, some points differed among the studies. Although the factors that influence the different results are uncertain, some investigators have suggested that variations in immunosuppressive molecules are responsible for these divergences. We highlight the key role of the HLA-G gene in modulating the immune response, and the importance of the polymorphisms and alleles of this gene associated with the outcome of the transplants. We suggest that the HLA-G gene and its polymorphisms be analyzed as a factor in selecting the MSCs to be used in treating GvHD, given its strong immunosuppressive role.
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40
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Satti HS, Ahmed P, Akram Z, Satti TM, Chaudhry QUN, Sial N, Mahmood SK, Ghafoor T, Shahbaz N, Khan MA, Malik SA. Allogeneic Bone Marrow Mesenchymal Stromal Cell Therapy in Patients with Steroid-Refractory Graft Versus Host Disease—a Pilot Study from Pakistan. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-020-00160-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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41
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Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl Med 2021; 10:1288-1303. [PMID: 34008922 PMCID: PMC8380447 DOI: 10.1002/sctm.21-0021] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan, Republic of China.,Department & Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, NHRI, Zhunan, Taiwan, Republic of China
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42
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Mansourabadi AH, Mohamed Khosroshahi L, Noorbakhsh F, Amirzargar A. Cell therapy in transplantation: A comprehensive review of the current applications of cell therapy in transplant patients with the focus on Tregs, CAR Tregs, and Mesenchymal stem cells. Int Immunopharmacol 2021; 97:107669. [PMID: 33965760 DOI: 10.1016/j.intimp.2021.107669] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
Organ transplantation is a practical treatment for patients with end-stage organ failure. Despite the advances in short-term graft survival, long-term graft survival remains the main challenge considering the increased mortality and morbidity associated with chronic rejection and the toxicity of immunosuppressive drugs. Since a novel therapeutic strategy to induce allograft tolerance seems urgent, focusing on developing novel and safe approaches to prolong graft survival is one of the main goals of transplant investigators. Researchers in the field of organ transplantation are interested in suppressing or optimizing the immune responses by focusing on immune cells including mesenchymal stem cells (MSCs), polyclonal regulatory Tcells (Tregs), and antigen-specific Tregs engineered with chimeric antigen receptors (CAR Tregs). We review the mechanistic pathways, phenotypic and functional characteristics of these cells, and their promising application in organ transplantation.
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Affiliation(s)
- Amir Hossein Mansourabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran; Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran
| | - Leila Mohamed Khosroshahi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
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43
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Crippa S, Santi L, Berti M, De Ponti G, Bernardo ME. Role of ex vivo Expanded Mesenchymal Stromal Cells in Determining Hematopoietic Stem Cell Transplantation Outcome. Front Cell Dev Biol 2021; 9:663316. [PMID: 34017834 PMCID: PMC8129582 DOI: 10.3389/fcell.2021.663316] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Overall, the human organism requires the production of ∼1 trillion new blood cells per day. Such goal is achieved via hematopoiesis occurring within the bone marrow (BM) under the tight regulation of hematopoietic stem and progenitor cell (HSPC) homeostasis made by the BM microenvironment. The BM niche is defined by the close interactions of HSPCs and non-hematopoietic cells of different origin, which control the maintenance of HSPCs and orchestrate hematopoiesis in response to the body’s requirements. The activity of the BM niche is regulated by specific signaling pathways in physiological conditions and in case of stress, including the one induced by the HSPC transplantation (HSCT) procedures. HSCT is the curative option for several hematological and non-hematological diseases, despite being associated with early and late complications, mainly due to a low level of HSPC engraftment, impaired hematopoietic recovery, immune-mediated graft rejection, and graft-versus-host disease (GvHD) in case of allogenic transplant. Mesenchymal stromal cells (MSCs) are key elements of the BM niche, regulating HSPC homeostasis by direct contact and secreting several paracrine factors. In this review, we will explore the several mechanisms through which MSCs impact on the supportive activity of the BM niche and regulate HSPC homeostasis. We will further discuss how the growing understanding of such mechanisms have impacted, under a clinical point of view, on the transplantation field. In more recent years, these results have instructed the design of clinical trials to ameliorate the outcome of HSCT, especially in the allogenic setting, and when low doses of HSPCs were available for transplantation.
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Affiliation(s)
- Stefania Crippa
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ludovica Santi
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Margherita Berti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giada De Ponti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy
| | - Maria Ester Bernardo
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.,University Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
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44
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Bolli R, Solankhi M, Tang XL, Kahlon A. Cell Therapy in Patients with Heart Failure: A Comprehensive Review and Emerging Concepts. Cardiovasc Res 2021; 118:951-976. [PMID: 33871588 PMCID: PMC8930075 DOI: 10.1093/cvr/cvab135] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 04/15/2021] [Indexed: 12/16/2022] Open
Abstract
This review summarizes the results of clinical trials of cell therapy in patients with heart failure (HF). In contrast to acute myocardial infarction (where results have been consistently negative for more than a decade), in the setting of HF the results of Phase I–II trials are encouraging, both in ischaemic and non-ischaemic cardiomyopathy. Several well-designed Phase II studies have met their primary endpoint and demonstrated an efficacy signal, which is remarkable considering that only one dose of cells was used. That an efficacy signal was seen 6–12 months after a single treatment provides a rationale for larger, rigorous trials. Importantly, no safety concerns have emerged. Amongst the various cell types tested, mesenchymal stromal cells derived from bone marrow (BM), umbilical cord, or adipose tissue show the greatest promise. In contrast, embryonic stem cells are not likely to become a clinical therapy. Unfractionated BM cells and cardiosphere-derived cells have been abandoned. The cell products used for HF will most likely be allogeneic. New approaches, such as repeated cell treatment and intravenous delivery, may revolutionize the field. As is the case for most new therapies, the development of cell therapies for HF has been slow, plagued by multifarious problems, and punctuated by many setbacks; at present, the utility of cell therapy in HF remains to be determined. What the field needs is rigorous, well-designed Phase III trials. The most important things to move forward are to keep an open mind, avoid preconceived notions, and let ourselves be guided by the evidence.
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Affiliation(s)
- Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Mitesh Solankhi
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Xiang-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Arunpreet Kahlon
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
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45
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Gruhn B, Brodt G, Ernst J. Extended Treatment With Mesenchymal Stromal Cells-Frankfurt am Main in a Pediatric Patient With Steroid-refractory Acute Gastrointestinal Graft-Versus-Host Disease: Case Report and Review of the Literature. J Pediatr Hematol Oncol 2021; 43:e419-e425. [PMID: 32118816 DOI: 10.1097/mph.0000000000001758] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/30/2020] [Indexed: 12/14/2022]
Abstract
In acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation, there are various options available after the failure of initial steroid therapy. Since the publication of the first study in 2008, mesenchymal stromal cells (MSCs) have also been used with increasing frequency, including in pediatric patients with steroid-refractory aGVHD, and the manufacturing process has undergone further development. MSC-Frankfurt am Main (MSC-FFM, Obnitix), which is manufactured from pooled mononuclear bone marrow cells from 8 donors using a standardized process, resulted in a response rate of 84% in children with steroid-refractory aGVHD. We report on a 13-year-old female patient with acute myeloid leukemia who received Obnitix as a third-line treatment for gastrointestinal (GI) aGVHD in a life-threatening situation. The patient was initially given a total of 4 Obnitix infusions as per the regulatory approval, with her symptoms improving from day 9 after the first infusion. The second cycle of 4 Obnitix infusions followed due to persistent severe protein-losing enteropathy and resulted in complete remission. A systematic review of the literature on MSC in pediatric patients with steroid-refractory aGVHD confirms that MSC treatment beyond 4 weeks is employed in accordance with treatment protocols or on a case-by-case basis. To summarize, aGVHD activity can be checked endoscopically in patients with persistent GI symptoms and a second Obnitix cycle can then be administered if appropriate, with the goal of achieving complete remission. Future studies should also investigate the potential influence of tissue repair properties as an element in MSCs' efficacy in GI aGVHD.
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Affiliation(s)
- Bernd Gruhn
- Department of Pediatrics, Jena University Hospital, Jena, Germany
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46
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Johnstone BH, Messner F, Brandacher G, Woods EJ. A Large-Scale Bank of Organ Donor Bone Marrow and Matched Mesenchymal Stem Cells for Promoting Immunomodulation and Transplant Tolerance. Front Immunol 2021; 12:622604. [PMID: 33732244 PMCID: PMC7959805 DOI: 10.3389/fimmu.2021.622604] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed "hematopoietic progenitor cell (HPC), Marrow," recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is >1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to "delayed tolerance." Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT.
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Affiliation(s)
- Brian H. Johnstone
- Ossium Health, Indianapolis, IN, United States
- Department of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, United States
| | - Franka Messner
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Erik J. Woods
- Ossium Health, Indianapolis, IN, United States
- Department of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, United States
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
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Döring M, Cabanillas Stanchi KM, Lenglinger K, Treuner C, Gieseke F, Erbacher A, Mezger M, Vaegler M, Schlegel PG, Greil J, Bettoni da Cunha Riehm C, Faul C, Schumm M, Lang P, Handgretinger R, Müller I. Long-Term Follow-Up After the Application of Mesenchymal Stromal Cells in Children and Adolescents with Steroid-Refractory Graft-Versus-Host Disease. Stem Cells Dev 2021; 30:234-246. [PMID: 33446053 DOI: 10.1089/scd.2020.0191] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Steroid-refractory graft-versus-host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Alternative treatment options are often insufficient. Several studies have proven the efficacy of mesenchymal stromal cells (MSCs) in the treatment of therapy-refractory acute GvHD in adult and pediatric patients. Long-term data in pediatric patients are scarce. In this retrospective analysis, a total of 25 patients with a median age of 10.6 years (range 0.6-22.1 years) who received bone marrow-derived MSCs after alloHSCT for the treatment of steroid-refractory III and IV GvHD were analyzed. The median observation period of the surviving patients was 9.3 years (1.3-12.7 years) after HSCT. Among the 25 patients, 10 (40.0%) died [relapse (n = 3), multiorgan failure (n = 6), cardiorespiratory failure (n = 1)] at median 0.5 years (0.2-2.3 years) after HSCT. Partial response and complete remission (PR, CR) of the GvHD were achieved in 76.0% and 24.0% of the patients, respectively. Transplant-related mortality was 0% in the patients who achieved CR after MSC treatment and 26.3% for those with PR. A median improvement by one intestinal or liver GvHD stage (range 1-4) could be achieved after MSC application. No potentially MSC-related long-term adverse effects, for example, secondary malignancy, were identified. In conclusion, the intravenous application of allogeneic MSCs was safe and proved effective for the treatment of steroid-refractory GvHD. However, larger, prospective, and randomized trials are needed to evaluate these findings.
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Affiliation(s)
- Michaela Döring
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | | | - Katrin Lenglinger
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Claudia Treuner
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Friederike Gieseke
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Annika Erbacher
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Markus Mezger
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Martin Vaegler
- Experimental and Clinical Research Center, GMP-Facility for Cellular Therapies, Charité Universitätsmedizin Berlin, Campus Berlin Buch, Berlin, Germany
| | - Paul-Gerhardt Schlegel
- Department of Pediatric Hematology and Oncology, University of Würzburg, Würzburg, Germany
| | - Johann Greil
- Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Christoph Faul
- University Hospital and Comprehensive Cancer Center Tübingen, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Michael Schumm
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Peter Lang
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Rupert Handgretinger
- Department I-General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Ingo Müller
- Division for Pediatric Stem Cell Transplantation and Immunology, Clinic for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties. Biomedicines 2021; 9:biomedicines9020209. [PMID: 33670708 PMCID: PMC7922639 DOI: 10.3390/biomedicines9020209] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/15/2021] [Accepted: 02/15/2021] [Indexed: 02/08/2023] Open
Abstract
Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton's jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-β1 (TGFβ), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.
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49
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Zorina T, Black L. Mesenchymal–Hematopoietic Stem Cell Axis: Applications for Induction of Hematopoietic Chimerism and Therapies for Malignancies. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Zorina TD. New Insights on the Role of the Mesenchymal-Hematopoietic Stem Cell Axis in Autologous and Allogeneic Hematopoiesis. Stem Cells Dev 2020; 30:2-16. [PMID: 33231142 DOI: 10.1089/scd.2020.0148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cytoreductive protocols are integral both as conditioning regimens for bone marrow (BM) transplantation and as part of therapies for malignancies, but their associated comorbidities represent a long-standing clinical problem. In particular, they cause myeloablation that debilitates the physiological role of mesenchymal stem and precursor cells (MSPCs) in sustaining hematopoiesis. This review addresses the damaging impact of cytoreductive regimens on MSPCs. In addition, it discusses prospects for alleviating the resulting iatrogenic comorbidities. New insights into the structural and functional dynamics of hematopoietic stem cell (HSC) niches reveal the existence of "empty" niches and the ability of the donor-derived healthy HSCs to outcompete the defective HSCs in occupying these niches. These findings support the notion that conditioning regimens, conventionally used to ablate the recipient hematopoiesis to create space for engraftment of the donor-derived HSCs, may not be a necessity for allogeneic BM transplantation. In addition, the capacity of the MSPCs to cross-talk with HSCs, despite major histocompatibility complex disparity, and suppress graft versus host disease indicates the possibility for development of a conditioning-free, MSPCs-enhanced protocol for BM transplantation. The clinical advantage of supplementing cytoreductive protocols with MSPCs to improve autologous hematopoiesis reconstitution and alleviate cytopenia associated with chemo and radiation therapies for cancer is also discussed.
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Affiliation(s)
- Tatiana D Zorina
- Department of Medical Laboratory Science and Biotechnology, Jefferson College of Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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