Regulatory T Cells for Treating Patients With COVID-19 and Acute Respiratory Distress Syndrome: Two Case Reports
Authors: Douglas E. Gladstone, Bo Soo Kim, Kathy Mooney, Andrew H. Karaba, Franco R. D'Alessio
Journal: Annals of Internal Medicine (2020)

Letters6 July 2020Regulatory T Cells for Treating Patients With COVID-19 and Acute Respiratory Distress Syndrome: Two Case ReportsFREEDouglas E. Gladstone, MD, Bo Soo Kim, MD, Kathy Mooney, RN, Andrew H. Karaba, MD, and Franco R. D'Alessio, MDDouglas E. Gladstone, MDSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (D.E.G., K.M.)Search for more papers by this author, Bo Soo Kim, MDJohns Hopkins University School of Medicine, Baltimore, Maryland (B.S.K., A.H.K., F.R.D.)Search for more papers by this author, Kathy Mooney, RNSidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (D.E.G., K.M.)Search for more papers by this author, Andrew H. Karaba, MDJohns Hopkins University School of Medicine, Baltimore, Maryland (B.S.K., A.H.K., F.R.D.)Search for more papers by this author, and Franco R. D'Alessio, MDJohns Hopkins University School of Medicine, Baltimore, Maryland (B.S.K., A.H.K., F.R.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-0681 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Normally, regulatory T cells (also known as T regulatory cells or Tregs) migrate into inflamed tissues, dampening inflammatory responses and hastening tissue repair (1). Patients with coronavirus disease 2019 (COVID-19) and acute respiratory distress syndrome (ARDS) have protracted hospitalizations characterized by excessive systemic inflammation (cytokine storm) and delayed lung repair, which is partly due to reduced or defective Tregs (2).Objective: To describe outcomes in 2 patients with COVID-19 and ARDS who were treated with Tregs.Case Reports: The first patient was a 69-year-old man with autism who was hospitalized from his nursing home with COVID-19–induced fever and dyspnea 1 week after initial symptom onset. Despite 5 days of receiving hydroxychloroquine and broad-spectrum antimicrobial agents, he progressed to ARDS and received tocilizumab on day 7 and mechanical ventilation beginning on day 8. Renal failure and shock developed, requiring continuous, venovenous hemofiltration and vasopressors. Refractory hypoxemia required prone positioning, neuromuscular paralysis, inhaled nitric oxide, and FIO2 greater than 70%. We administered compassionate use, cryopreserved, allogeneic Tregs derived from cord blood (CB) and expanded ex vivo (Cellenkos) at 1 × 108 cells per dose intravenously on days 13 and 17. By day 17, he had returned to supine positioning, paralytics were withdrawn, inhaled nitric oxide was weaned to zero, FIO2 was decreased to 50%, vasopressors were withdrawn, and inflammatory markers were reduced (Table 1). He was extubated on day 22. On day 25, he required a tracheostomy. He is currently receiving care in a weaning facility.Table 1. Laboratory Values: Patient 1The second patient was a 47-year-old man who was hospitalized for COVID-19–induced fever and dyspnea 1 week after initial symptom onset. On day 2 of his hospitalization, he received tocilizumab, and hours later, he had increasing lactate levels and required mechanical ventilation and high-dose vasopressors. Despite prone positioning, neuromuscular paralysis, inhaled nitric oxide, and 100% FIO2, he required venovenous, extracorporeal membrane oxygenation on day 7. We administered compassionate use of the same Treg treatment on days 8, 11, and 15. By day 9, vasopressors were withdrawn and inflammatory markers were reduced (Table 2). By day 13, tidal volumes improved despite no change in the pressure mode of ventilation or in the driving pressure of 10-cm H2O. He had a tracheostomy on day 19 and a pulmonary embolus on day 33. He was taken off extracorporeal membrane oxygenation support on day 34 and was weaned to room air by day 51. His tracheostomy was decannulated on day 53, and he was discharged home on day 54.Table 2. Laboratory Values: Patient 2Discussion: There are several reasons to believe that Tregs may be effective in patients with COVID-19 and ARDS. Adoptive Treg therapy has been effective in multiple preclinical models of ARDS (1). In addition, phenotypic CD4+25+127loFOXP3hi, ex vivo–expanded CB Tregs express the lung homing markers CD49d, CCR4, and P-selectin glycoprotein ligand-1 (3). Moreover, compared with adult Tregs, CB Tregs are readily available, maintain suppressive function in inflammatory milieu, and have a low risk for converting into pathogenic RORγt-expressing T helper type 17 cells (4). In a xenogeneic model, CB Tregs can accumulate in lung tissue up to 14 days after intravenous infusion, with a reciprocal decrease in systemic and parenchymal effector T cells, which correlates with the resolution of inflammation (Lyu M, Parmar S. Adoptive therapy with cord blood regulatory T cells treats the inflammatory syndromes of lupus. In preparation.). In a phase 1 trial of CB Tregs manufactured by Cellenkos (CK0801) to treat inflammatory bone marrow failure, at 1 month there was a decrease in Janus kinase 2 mutant allele burden, significant improvement in myelofibrosis symptoms, and improvement in blood and platelet transfusion requirement even though circulating CB Tregs were undetectable (4).To our knowledge, this is the first report of human therapy with Tregs for ARDS mediated by COVID-19. We emphasize that the Tregs used were allogeneic, off-the-shelf, and CB Tregs and that both patients became critically ill despite receiving tocilizumab. We planned 3 infusions for each patient, with the first infusion on day 1, the second on day 3, and the third on day 7. Neither patient had an infusion reaction, inflammatory rebound, or other adverse reaction.We recognize that both patients received multiple interventions that could have contributed to their recovery, but we believe that the temporal relationship between Treg infusions and recovery cannot be ignored. Tables 1 and 2 show that the infusions were rapidly followed by decreases in interleukin (IL)-6, tumor necrosis factor-α, and interferon-γ. Decreases also occurred in IL-8, which is a potent neutrophil attractant or activator and modulator of acute lung injury, and in IL-12, which is important for defining T helper type 1 or type 2 cell commitment in lung inflammatory responses induced by respiratory syncytial virus infection. Monocyte chemoattractant protein-1 and monocyte chemoattractant protein-4 levels, which are associated with mononuclear pulmonary cellular infiltration, decreased in the first patient, but only the monocyte chemoattractant protein-4 level decreased in the second patient.We expect that future treatment of patients with COVID-19 and ARDS will be multifaceted (5), and we are planning a multicenter, randomized, double-blind, placebo-controlled trial of CB Tregs for ARDS associated with COVID-19.References1. D'Alessio FR, Tsushima K, Aggarwal NR, et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119:2898-913. [PMID: 19770521] doi:10.1172/JCI36498 CrossrefMedlineGoogle Scholar2. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181:1036-1045. [PMID: 32416070] doi:10.1016/j.cell.2020.04.026 CrossrefMedlineGoogle Scholar3. Lyu M, Khoury JD, Nishimoto M, et al. Single injection of cord blood regulatory T cells can delay the manifestations of systemic lupus erythematosus. Blood. 2019;134:1938. doi:10.1182/blood-2019-131436 CrossrefGoogle Scholar4. Kadia TM, Ma H, Zeng K, et al. Phase I clinical trial of CK0801 (cord blood regulatory T cells) in patients with bone marrow failure syndrome (BMF) including aplastic anemia, myelodysplasia and myelofibrosis. Blood. 2019;134:1221. doi:10.1182/blood-2019-127702 CrossrefGoogle Scholar5. Valk SJ, Piechotta V, Chai KL, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. Cochrane Database Syst Rev. 2020;5:CD013600. [PMID: 32406927] doi:10.1002/14651858.CD013600 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment J.R. Seco Vasco, R. Curado CastanoSCCU Sevilla Sur. Hospital Universitario de Valme. Servicio Andaluz de Salud. Spain16 July 2020 AN INCREASING ROLE OF CELL-MEDIATED IMMUNITY IN MULTIDIMENSIONAL TREATMENT FOR COVID-19 In their interesting and innovative report, D.E. Gladstone et al. describe an evident improvement, and probable determining changing outcomes, of two critically ill COVID-19 patients after giving them compassionate treatment with allogenic T regulatory cells (Treg) derived from cord blood through intermittent intravenous infusions. Indeed, this is the first time that a treatment with Treg is used for severe acute respiratory syndrome associated with COVID-19 and, even though authors don’t make reference to other treatments currently used (e.g. corticoids, heparins), and we find lacking of further notes on evolution, particularly about lung repair, the fact is that clinical and analytical changes reported may be attributed to the use of Treg. These clinical results, now first described, are not entirely surprising, since with current knowledge it is recognized the important role that cell-mediated immunity seems to play in response to infection by SARS-CoV-21, and not only in severe forms of the disease. A recent work by T. Sekine et al. have suggested that in many individuals, exposition to SARS-CoV-2 or a mild pattern of infection could lead to high functional durable memory T cell responses, even in the absence of detectable antibodies2. Cell-mediated response to limit early virus replication could be considered as a factor for explaining a high rate of asymptomatic infected individuals not detected by serological testing3. It is quite possible that those responses may be mediated through S protein in SARS-CoV-2, which develops robust T cell-mediated immunity4. Be as it may, unquestionable results reported by D.E. Gladstone et al. support their planned multicenter trial. Furthermore, it seems very likely that treatment with Treg may be appropriate in previous stages of the disease, not only in critically ill patients. This type of treatment could find its place alongside others, since future therapeutics for advanced COVID-19 will be multidimensional: directly acting on virus, immunity and immunization, coagulation, ventilation and hemodynamics, among others. 1 N. Vabret, G.J. Britton, C. Gruber, S. Hegde, J. Kim, M. Kuksin, et al.Immunology of COVID-19: Current State of the Science Immunity vol. 52, pg 910-941. June 16, 2020. 2 T. Sekine, A. Perez-Potti, O. Rivera-Ballesteros, K. Strålin, JB. Gorin, A. Olsson, et al. Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. BioRxiv 2020.06.29.174888. 3 J.R. Seco Vasco, C. García Garrote. Inadequate detection of asymptomatic patients infected by SARS-CoV-2. British Medical Journal 2020;370:m2516/rr-1. 4 A.C. Walls, Y.J. Park. M.A Tortorici, A. Wall, A.T. McGuire, D.Veesle.Structure, Function, and Antigenicity of the SARS-CoV-2 Spike GlycoproteinCell vol 180, pg 281–292, April 16, 2020. Disclosures: - Author, Article, and Disclosure InformationAuthors: Douglas E. Gladstone, MD; Bo Soo Kim, MD; Kathy Mooney, RN; Andrew H. Karaba, MD; Franco R. D'Alessio, MDAffiliations: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (D.E.G., K.M.)Johns Hopkins University School of Medicine, Baltimore, Maryland (B.S.K., A.H.K., F.R.D.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-0681.Corresponding Author: Douglas E. Gladstone, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-288, Baltimore, MD 21287; e-mail, dgladst1@jhmi.edu.This article was published at Annals.org on 6 July 2020. 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