Zelltherapie in den Zeiten von SARS-CoV-2

Zusammenfassung

Ein breites Spektrum von Disruptionen, aber auch blitzschnelle Innovationen, hat die SARS-CoV-2 Pandemie gebracht. Dieser Übersichtsartikel betrachtet die Pandemie aus der Warte der Zelltherapie; konkret werden vier Aspekte untersucht: Wie unterscheiden sich die Risiken von Zelltherapie-Patienten mit SARS-CoV-2 Infektion und COVID von denen der Allgemeinbevölkerung? Sind Empfänger von Zelltherapien, hier speziell autologe und allogene Stammzelltransplantationsempfänger sowie Empfänger von CAR-T-Zell-Präparaten, klinisch relevant durch SARS-CoV-2 Vakzine immunisierbar? Welche Auswirkungen hat die Pandemie mit Spenderausfallrisiko und Zusammenbruch von Supply Chains auf die Versorgung mit Zelltherapeutika? Gibt es Zelltherapeutika, die bei schwerem COVID therapeutisch nutzbringend eingesetzt werden können? In aller Kürze, das erwartete massiv erhöhte Risiko von Zelltherapie-Patienten, im Infektionsfall einen schweren Verlauf zu erleiden oder zu sterben, wurde bestätigt. Die Vakzine induziert jedoch bei vielen dieser Patienten humorale und zelluläre Immunität, wenn auch weniger zuverlässig als bei Gesunden. Dank kreativer Lösungen gelang es, die Versorgung mit Zelltherapeutika im Wesentlichen uneingeschränkt aufrecht zu erhalten. SARS-CoV-2-spezifische T-Zell-Präparate für den adoptiven Immuntransfer wurden entwickelt, eine therapeutische Konstellation diese anzuwenden ergab sich jedoch nicht. Therapiestudien mit mesenchymalen Stromazellen beim schweren COVID laufen weltweit; die Frage der Wirksamkeit bleibt zurzeit offen, bei jedoch substanziellem Optimismus in der Szene. Einige der Erkenntnisse und Innovationen aus der SARS-CoV-2-Pandemie können möglicherweise verallgemeinert werden und so auf die Zeit nach ihrem Ende langfristig nachwirken.

Abstract

An entire spectrum of disruptions, but also some lightning fast innovations, were brought on by the SARS-CoV-2 pandemic. This focused review looks at the pandemic from the vantage point of cellular therapy; specifically four aspects are considered: How do risks of cell therapy patients with SARS-CoV-2 infection and COVID differ from the general population? Do recipients of cellular therapies, here specifically recipients of autologous and allogeneic stem cell transplants and CAR-T-cells, meaningfully respond to SARS-CoV-2 vaccines? What effects does the pandemic have on donor availability and cell therapy supply chains and hence, on the accessibility of cellular therapies? What cell therapies, if any, are therapeutically beneficial in severe COVID? Briefly, the excessive risk of an unfavorable, frequently lethal course of cell therapy patients with SARS-CoV-2 infection was confirmed. The vaccine frequently, albeit not with the same regularity as in healthy vaccinees, induces presumably clinically meaningful humoral and/or cellular immunity. Creative solutions have quantitatively maintained access to cellular therapeutics. SARS-CoV-2-specific T-cell products for adoptive immune transfer were developed, although an opportunity for their clinical evaluation did not arise. Clinical trials with mesenchymal stromal cells for severe COVID are being pursued world-wide; the question of efficacy currently remains unanswered, but initial data fuel considerable optimism of the scene. Some of the insights and innovations from the SARS-CoV-2-pandemic can possibly be generalized and may thus prevail.

Schlüsselwörter

Zelltherapie - Zelltherapeutika - zelluläre Immunität - Stammzelltransplantation - Kryokonservierung

Key words

Cell therapy - cellular therapeutics - cellular immunity - stem cell transplantation - cryopreservation

• Literatur

• 1 Schaffrath J, Brummer C, Wolff D. et al. High Mortality of COVID-19 Early after Allogeneic Stem Cell Transplantation: A Retrospective Multicenter Analysis on Behalf of the German Cooperative Transplant Study Group. Transplant Cell Ther 2022;
• 2 Greco R, Alexander T, Burman J. et al. Hematopoietic stem cell transplantation for autoimmune diseases in the time of COVID-19: EBMT guidelines and recommendations. Bone Marrow Transplant 2021; 56: 1493-1508
• 3 Ifversen M, Meisel R, Sedlacek P. et al. Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT). Front Pediatr 2021; 9: 705179
• 4 Bailey AJM, Kirkham AM, Monaghan M. et al. A Portrait of SARS-CoV-2 Infection in Patients Undergoing Hematopoietic Cell Transplantation: A Systematic Review of the Literature. Curr Oncol 2022; 29: 337-349
• 5 Sharma A, Bhatt NS, St Martin A. et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol 2021; 8: e185-e193
• 6 Lupo-Stanghellini MT, Xue E, Mastaglio S. et al. COVID-19 in recipients of allogeneic stem cell transplantation: favorable outcome. Bone Marrow Transplant 2021; 56: 2312-2315
• 7 Camargo JF, Mendoza MA, Lin R. et al. Clinical presentation and outcomes of COVID-19 following hematopoietic cell transplantation and cellular therapy. Transpl Infect Dis 2021; 23: e13625
• 8 Mushtaq MU, Shahzad M, Chaudhary SG. et al. Impact of SARS-CoV-2 in Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Recipients. Transplant Cell Ther 2021; 27: 796
• 9 Spanjaart AM, Ljungman P, de La Camara R. et al. Poor outcome of patients with COVID-19 after CAR T-cell therapy for B-cell malignancies: results of a multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the European Hematology Association (EHA) Lymphoma Group. Leukemia 2021; 35: 3585-3588
• 10 Haas EJ, McLaughlin JM, Khan F. et al. Infections, hospitalisations, and deaths averted via a nationwide vaccination campaign using the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine in Israel: a retrospective surveillance study. Lancet Infect Dis 2022; 22: 357-366
• 11 Worel N, Shaw BE, Aljurf M. et al. Changes in Hematopoietic Cell Transplantation Practices in Response to COVID-19: A Survey from the Worldwide Network for Blood & Marrow Transplantation. Transplant Cell Ther 2021; 27: 270
• 12 Hayden PJ, Roddie C, Bader P. et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol 2022; 33: 259-275
• 13 Jarisch A, Wiercinska E, Daqiq-Mirdad S. et al. SARS-CoV-2 specific T-cells are generated in less than half of allogeneic HSCT recipients failing to seroconvert after COVID-19 vaccination. Eur J Immunol 2022;
• 14 Clemenceau B, Guillaume T, Coste-Burel M. et al. SARS-CoV-2 T-Cell Responses in Allogeneic Hematopoietic Stem Cell Recipients following Two Doses of BNT162b2 mRNA Vaccine. Vaccines (Basel) 2022; 10: 448
• 15 Harrington P, Doores KJ, Saha C. et al. Repeated vaccination against SARS-CoV-2 elicits robust polyfunctional T cell response in allogeneic stem cell transplantation recipients. Cancer Cell 2021; 39: 1654
• 16 Le Bourgeois A, Coste-Burel M, Guillaume T. et al. Safety and Antibody Response After 1 and 2 Doses of BNT162b2 mRNA Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant. JAMA Netw Open 2021; 4: e2126344
• 17 Jarisch A, Wiercinska E, Huenecke S. et al. Immune responses to SARS-CoV-2 vaccination in young patients with anti-CD19 CAR-T-induced B-cell aplasia. Transplant Cell Ther 2022;
• 18 Bergman P, Blennow O, Hansson L. et al. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine 2021; 74: 103705
• 19 Ram R, Hagin D, Kikozashvilli N. et al. Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study. Transplant Cell Ther 2021; 27: 788-794
• 20 Abid MB, Rubin M, Ledeboer N. et al. Efficacy of a third SARS-CoV-2 mRNA vaccine dose among hematopoietic cell transplantation, CAR T cell, and BiTE recipients. Cancer Cell 2022; 40: 340-342
• 21 Chiarucci M, Paolasini S, Isidori A. et al. Immunological Response Against SARS-COV-2 After BNT162b2 Vaccine Administration Is Impaired in Allogeneic but Not in Autologous Stem Cell Transplant Recipients. Front Oncol 2021; 11: 737300
• 22 Wiercinska E, Schlipfenbacher V, Bug G. et al. Allogeneic transplant procurement in the times of COVID-19: Quality report from the central European cryopreservation site. J Transl Med 2021; 19: 145
• 23 Purtill D, Hutchins C, Kennedy G. et al. Good Engraftment but Quality and Donor Concerns for Cryopreserved Hemopoietic Progenitor Cell Products Collected During the COVID-19 Pandemic. Transplant Cell Ther 2021; 27: 1022
• 24 Maurer K, Kim HT, Kuczmarski TM. et al. Impact of cryopreservation and transit times of allogeneic grafts on hematopoietic and immune reconstitution. Blood Adv 2021; 5: 5140-5149
• 25 Hamadani M, Zhang MJ, Tang XY. et al. Graft Cryopreservation Does Not Impact Overall Survival after Allogeneic Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis. Biol Blood Marrow Transplant 2020; 26: 1312-1317
• 26 Bankova AK, Caveney J, Yao B. et al. Real-World Experience of Cryopreserved Allogeneic Hematopoietic Grafts during the COVID-19 Pandemic: A Single-Center Report. Transplant Cell Ther 2022; 28: 215
• 27 Schmidt AH, Buk D, Platz A. et al. Cryopreservation for All Is No Option in Unrelated Stem Cell Transplantation. Comment on Dholaria B, et al. Securing the Graft During Pandemic: Are We Ready for Cryopreservation for All?. Biol Blood Marrow Transplant 2020; 26: e145-e146 Biol Blood Marrow Transplant 2020; 26: e298-e299
• 28 Passweg JR, Baldomero H, Chabannon C. et al. Impact of the SARS-CoV-2 pandemic on hematopoietic cell transplantation and cellular therapies in Europe 2020: a report from the EBMT activity survey. Bone Marrow Transplant 2022; 57: 742-752
• 29 Ghorashian S, Malard F, Yuksel MK. et al. Defining the impact of SARS-COV-2 on delivery of CAR T-cell therapy in Europe: a retrospective survey from the CTIWP of the EBMT. Bone Marrow Transplant 2022; 57: 299-301
• 30 Feucht J, Opherk K, Lang P. et al. Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood 2015; 125: 1986-1994
• 31 Feuchtinger T, Opherk K, Bethge WA. et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 2010; 116: 4360-4367
• 32 Neuenhahn M, Albrecht J, Odendahl M. et al. Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT. Leukemia 2017; 31: 2161-2171
• 33 Stemberger C, Graef P, Odendahl M. et al. Lowest numbers of primary CD8(+) T cells can reconstitute protective immunity upon adoptive immunotherapy. Blood 2014; 124: 628-637
• 34 Hopfner F, Möhn N, Eiz-Vesper B. et al. Allogeneic BK Virus-Specific T-Cell Treatment in 2 Patients With Progressive Multifocal Leukoencephalopathy. Neurol Neuroimmunol Neuroinflamm 2021; 8: e1020
• 35 Kallay K, Kassa C, Reti M. et al. Early Experience With CliniMACS Prodigy CCS (IFN-gamma) System in Selection of Virus-specific T Cells From Third-party Donors for Pediatric Patients With Severe Viral Infections After Hematopoietic Stem Cell Transplantation. J Immunother 2018; 41: 158-163
• 36 Lindemann M, Eiz-Vesper B, Steckel NK. et al. Adoptive transfer of cellular immunity against cytomegalovirus by virus-specific lymphocytes from a third-party family donor. Bone Marrow Transplant 2018; 53: 1351-1355
• 37 Tzannou I, Watanabe A, Naik S. et al. “Mini” bank of only 8 donors supplies CMV-directed T cells to diverse recipients. Blood Adv 2019; 3: 2571-2580
• 38 Tramsen L, Schmidt S, Roeger F. et al. Immunosuppressive compounds exhibit particular effects on functional properties of human anti-Aspergillus Th1 cells. Infect Immun 2014; 82: 2649-2656
• 39 Bunos M, Hummer C, Wingenfeld E. et al. Automated isolation of primary antigen-specific T cells from donor lymphocyte concentrates: results of a feasibility exercise. Vox Sang 2015; 109: 387-393
• 40 Feuchtinger T, Lang P, Hamprecht K. et al. Isolation and expansion of human adenovirus-specific CD4+and CD8+T cells according to IFN-gamma secretion for adjuvant immunotherapy. Exp Hematol 2004; 32: 282-289
• 41 Kim N, Nam YS, Im KI. et al. Robust Production of Cytomegalovirus pp65-Specific T Cells Using a Fully Automated IFN-gamma Cytokine Capture System. Transfus Med Hemother 2018; 45: 13-22
• 42 Tischer S, Priesner C, Heuft HG. et al. Rapid generation of clinical-grade antiviral T cells: selection of suitable T-cell donors and GMP-compliant manufacturing of antiviral T cells. J Transl Med 2014; 12: 336
• 43 Chakupurakal G, Onion D, Bonney S. et al. HLA-peptide multimer selection of adenovirus-specific T cells for adoptive T-cell therapy. J Immunother 2013; 36: 423-431
• 44 Odendahl M, Grigoleit GU, Bonig H. et al. Clinical-scale isolation of ‘minimally manipulated’ cytomegalovirus-specific donor lymphocytes for the treatment of refractory cytomegalovirus disease. Cytotherapy 2014; 16: 1245-1256
• 45 Bacher P, Jochheim-Richter A, Mockel-Tenbrink N. et al. Clinical-scale isolation of the total Aspergillus fumigatus-reactive T-helper cell repertoire for adoptive transfer. Cytotherapy 2015; 17: 1396-1405
• 46 Gary R, Aigner M, Moi S. et al. Clinical-grade generation of peptide-stimulated CMV/EBV-specific T cells from G-CSF mobilized stem cell grafts. J Transl Med 2018; 16: 124
• 47 Greenberg PD, Reusser P, Goodrich JM. et al. Development of a treatment regimen for human cytomegalovirus (CMV) infection in bone marrow transplantation recipients by adoptive transfer of donor-derived CMV-specific T cell clones expanded in vitro. Ann N Y Acad Sci 1991; 636: 184-195
• 48 Walter EA, Greenberg PD, Gilbert MJ. et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995; 333: 1038-1044
• 49 Cooper RS, Fraser AR, Smith L. et al. Rapid GMP-Compliant Expansion of SARS-CoV-2-Specific T Cells From Convalescent Donors for Use as an Allogeneic Cell Therapy for COVID-19. Front Immunol 2020; 11: 598402
• 50 Ferreras C, Pascual-Miguel B, Mestre-Duran C. et al. SARS-CoV-2-Specific Memory T Lymphocytes From COVID-19 Convalescent Donors: Identification, Biobanking, and Large-Scale Production for Adoptive Cell Therapy. Front Cell Dev Biol 2021; 9: 620730
• 51 Leung W, Soh TG, Linn YC. et al. Rapid production of clinical-grade SARS-CoV-2 specific T cells. Adv Cell Gene Ther 2020; e101
• 52 Sivapalan R, Liu J, Chakraborty K. et al. Virus Induced Lymphocytes (VIL) as a novel viral antigen-specific T cell therapy for COVID-19 and potential future pandemics. Sci Rep 2021; 11: 15295
• 53 Bonig H, Kuci Z, Kuci S. et al. Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation “MSC-FFM”-Outcome Report of 92 Patients. Cells 2019; 8: 1577
• 54 Kurtzberg J, Abdel-Azim H, Carpenter P. et al. A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 2020; 26: 845-854
• 55 Macias-Sanchez MDM, Morata-Tarifa C, Cuende N. et al. Mesenchymal Stromal Cells for Treating Steroid-Resistant Acute and Chronic Graft Versus Host Disease: A Multicenter Compassionate Use Experience. Stem Cells Transl Med 2022; 11: 343-355
• 56 Murata M, Teshima T. Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease Using Commercial Mesenchymal Stem Cell Products. Front Immunol 2021; 12: 724380
• 57 Chakraverty R, Teshima T. Graft-versus-host disease: a disorder of tissue regeneration and repair. Blood 2021; 138: 1657-1665
• 58 Elgaz S, Kuci Z, Kuci S. et al. Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease. Transfus Med Hemother 2019; 46: 27-34
• 59 Elgaz S, Bonig H, Bader P. Mesenchymal stromal cells for osteonecrosis. J Transl Med 2020; 18: 399
• 60 Rojweski M, Schafer R, Bieback K. et al. Mesenchymale Stromazellen auf dem Weg zur klinischen Anwendung: Update 2018. Transfusionsmedizin 2018; 8: 148-159
• 61 Borger V, Weiss DJ, Anderson JD. et al. International Society for Extracellular Vesicles and International Society for Cell and Gene Therapy statement on extracellular vesicles from mesenchymal stromal cells and other cells: considerations for potential therapeutic agents to suppress coronavirus disease-19. Cytotherapy 2020; 22: 482-485
• 62 Khoury M, Rocco PRM, Phinney DG. et al. Cell-based therapies for coronavirus disease 2019: proper clinical investigations are essential. Cytotherapy 2020; 22: 602-605
• 63 Rogers CJ, Harman RJ, Bunnell BA. et al. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. J Transl Med 2020; 18: 203
• 64 Song N, Wakimoto H, Rossignoli F. et al. Mesenchymal stem cell immunomodulation: In pursuit of controlling COVID-19 related cytokine storm. Stem Cells 2021; 39: 707-722
• 65 Tovar I, Guerrero R, Lopez-Penalver JJ. et al. Rationale for the Use of Radiation-Activated Mesenchymal Stromal/Stem Cells in Acute Respiratory Distress Syndrome. Cells 2020; 9: 2015
• 66 Wang W, Lei W, Jiang L. et al. Therapeutic mechanisms of mesenchymal stem cells in acute respiratory distress syndrome reveal potentials for Covid-19 treatment. J Transl Med 2021; 19: 198
• 67 Moll G, Drzeniek N, Kamhieh-Milz J. et al. MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy. Front Immunol 2020; 11: 1091
• 68 Atluri S, Manocha V, Boddu N. et al. Safety and Effectiveness of Intravascular Mesenchymal Stem Cells to Treat Organ Failure and Possible Application in COVID-19 Complications. Pain Physician 2020; 23: S391-S420
• 69 Chen J, Hu C, Chen L. et al. Clinical Study of Mesenchymal Stem Cell Treatment for Acute Respiratory Distress Syndrome Induced by Epidemic Influenza A (H7N9) Infection: A Hint for COVID-19 Treatment. Engineering (Beijing) 2020; 6: 1153-1161
• 70 Chen X, Shan Y, Wen Y. et al. Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of short-term treatment efficacy and side effects. J Infect 2020; 81: 647-679
• 71 Deffune E, Prudenciatti A, Moroz A. Mesenchymal stem cell (MSc) secretome: A possible therapeutic strategy for intensive-care COVID-19 patients. Med Hypotheses 2020; 142: 109769
• 72 Eckard AR, Borow KM, Mack EH. et al. Remestemcel-L Therapy for COVID-19-Associated Multisystem Inflammatory Syndrome in Children. Pediatrics 2021; 147: e2020046573
• 73 Gentile P, Sterodimas A. Adipose-derived stromal stem cells (ASCs) as a new regenerative immediate therapy combating coronavirus (COVID-19)-induced pneumonia. Expert Opin Biol Ther 2020; 20: 711-716
• 74 Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal Stem Cell Therapy for COVID-19: Present or Future. Stem Cell Rev Rep 2020; 16: 427-433
• 75 Haberle H, Magunia H, Lang P. et al. Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS. J Intensive Care Med 2021; 36: 681-688
• 76 Hashemian SR, Aliannejad R, Zarrabi M. et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem Cell Res Ther 2021; 12: 91
• 77 Iglesias M, Butron P, Torre-Villalvazo I. et al. Mesenchymal Stem Cells for the Compassionate Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID 19. Aging Dis 2021; 12: 360-370
• 78 Lanzoni G, Linetsky E, Correa D. et al. Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS). CellR4 Repair Replace Regen Reprogram 2020; 8: e2839
• 79 Leng Z, Zhu R, Hou W. et al. Transplantation of ACE2(-) Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging Dis 2020; 11: 216-228
• 80 Liu S, Peng D, Qiu H. et al. Mesenchymal stem cells as a potential therapy for COVID-19. Stem Cell Res Ther 2020; 11: 169
• 81 Primorac D, Stojanovic SS, Strbad M. et al. Compassionate mesenchymal stem cell treatment in a severe COVID-19 patient: a case report. Croat Med J 2021; 62: 288-296
• 82 Sanchez-Guijo F, Garcia-Arranz M, Lopez-Parra M. et al. Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study. EClinicalMedicine 2020; 25: 100454
• 83 Sengupta V, Sengupta S, Lazo A. et al. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev 2020; 29: 747-754
• 84 Tang L, Jiang Y, Zhu M. et al. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19. Front Med 2020; 14: 664-673
• 85 Xu X, Jiang W, Chen L. et al. Evaluation of the safety and efficacy of using human menstrual blood-derived mesenchymal stromal cells in treating severe and critically ill COVID-19 patients: An exploratory clinical trial. Clin Transl Med 2021; 11: e297
• 86 Wang J, Shi P, Chen D. et al. Research Status of the Safety and Efficacy of Mesenchymal Stem Cells in the Treatment of COVID-19-Related Pneumonia: A Systematic Review and Meta-Analysis. Stem Cells Dev 2021; 30: 947-969
• 87 Qu W, Wang Z, Hare JM. et al. Cell-based therapy to reduce mortality from COVID-19: Systematic review and meta-analysis of human studies on acute respiratory distress syndrome. Stem Cells Transl Med 2020; 9: 1007-1022