Mesenchymal stromal cell therapy for chronic lung allograft dysfunction: Results of a first-in-man study

Daniel C. Chambers, Debra Enever, Sharon Lawrence, Marian Sturm, Richard Herrmann, Stephanie Yerkovich, Michael Musk, Peter M.A. Hopkins

    Research output: Contribution to journalArticle

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    Abstract

    Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long-term survival after lung transplantation. Bone marrow-derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single-arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP-compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade ≥ 2 or grade 1 with risk factors for rapid progression. MSCs (2 x 106 cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow-up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30–59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure-related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p 5.08). Two patients died at 152 and 270 days post-MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow-derived MSCs is feasible and safe even in patients with advanced CLAD.

    Original languageEnglish
    Pages (from-to)1152-1157
    Number of pages6
    JournalStem Cells Translational Medicine
    Volume6
    Issue number4
    DOIs
    Publication statusPublished - 1 Apr 2017

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    Cell- and Tissue-Based Therapy
    Mesenchymal Stromal Cells
    Allografts
    Lung
    Bone Marrow
    Bronchiolitis Obliterans
    Unrelated Donors
    Bronchiolitis
    Lung Transplantation
    Forced Expiratory Volume
    Graft Rejection
    Graft vs Host Disease
    Immunosuppressive Agents
    Kidney Transplantation
    Veins
    Appointments and Schedules
    Safety
    Weights and Measures
    Survival
    Therapeutics

    Cite this

    Chambers, D. C., Enever, D., Lawrence, S., Sturm, M., Herrmann, R., Yerkovich, S., ... Hopkins, P. M. A. (2017). Mesenchymal stromal cell therapy for chronic lung allograft dysfunction: Results of a first-in-man study. Stem Cells Translational Medicine, 6(4), 1152-1157. https://doi.org/10.1002/sctm.16-0372
    Chambers, Daniel C. ; Enever, Debra ; Lawrence, Sharon ; Sturm, Marian ; Herrmann, Richard ; Yerkovich, Stephanie ; Musk, Michael ; Hopkins, Peter M.A. / Mesenchymal stromal cell therapy for chronic lung allograft dysfunction : Results of a first-in-man study. In: Stem Cells Translational Medicine. 2017 ; Vol. 6, No. 4. pp. 1152-1157.
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    abstract = "Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long-term survival after lung transplantation. Bone marrow-derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single-arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP-compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade ≥ 2 or grade 1 with risk factors for rapid progression. MSCs (2 x 106 cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow-up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30–59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure-related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p 5.08). Two patients died at 152 and 270 days post-MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow-derived MSCs is feasible and safe even in patients with advanced CLAD.",
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    Chambers, DC, Enever, D, Lawrence, S, Sturm, M, Herrmann, R, Yerkovich, S, Musk, M & Hopkins, PMA 2017, 'Mesenchymal stromal cell therapy for chronic lung allograft dysfunction: Results of a first-in-man study' Stem Cells Translational Medicine, vol. 6, no. 4, pp. 1152-1157. https://doi.org/10.1002/sctm.16-0372

    Mesenchymal stromal cell therapy for chronic lung allograft dysfunction : Results of a first-in-man study. / Chambers, Daniel C.; Enever, Debra; Lawrence, Sharon; Sturm, Marian; Herrmann, Richard; Yerkovich, Stephanie; Musk, Michael; Hopkins, Peter M.A.

    In: Stem Cells Translational Medicine, Vol. 6, No. 4, 01.04.2017, p. 1152-1157.

    Research output: Contribution to journalArticle

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    T1 - Mesenchymal stromal cell therapy for chronic lung allograft dysfunction

    T2 - Results of a first-in-man study

    AU - Chambers, Daniel C.

    AU - Enever, Debra

    AU - Lawrence, Sharon

    AU - Sturm, Marian

    AU - Herrmann, Richard

    AU - Yerkovich, Stephanie

    AU - Musk, Michael

    AU - Hopkins, Peter M.A.

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    N2 - Chronic lung transplant rejection (termed chronic lung allograft dysfunction [CLAD]) is the main impediment to long-term survival after lung transplantation. Bone marrow-derived mesenchymal stromal cells (MSCs) represent an attractive cell therapy in inflammatory diseases, including organ rejection, given their relative immune privilege and immunosuppressive and tolerogenic properties. Preclinical studies in models of obliterative bronchiolitis and human trials in graft versus host disease and renal transplantation suggest potential efficacy in CLAD. The purpose of this phase 1, single-arm study was to explore the feasibility and safety of intravenous delivery of allogeneic MSCs to patients with advanced CLAD. MSCs from unrelated donors were isolated from bone marrow, expanded and cryopreserved in a GMP-compliant facility. Patients had deteriorating CLAD and were bronchiolitis obliterans (BOS) grade ≥ 2 or grade 1 with risk factors for rapid progression. MSCs (2 x 106 cells per kilogram patient weight) were infused via a peripheral vein twice weekly for 2 weeks, with 52 weeks follow-up. Ten Patients (5 male, 8 bilateral, median [interquartile range] age 40 [30–59] years, 3 BOS2, 7 BOS3) participated. MSC treatment was well tolerated with all patients receiving the full dosing schedule without any procedure-related serious adverse events. The rate of decline in forced expiratory volume in one second slowed after the MSC infusions (120 ml/month preinfusion vs. 30 ml/month postinfusion, p 5.08). Two patients died at 152 and 270 days post-MSC treatment, both from progressive CLAD. In conclusion, infusion of allogeneic bone marrow-derived MSCs is feasible and safe even in patients with advanced CLAD.

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    KW - Graft rejection

    KW - Lung transplantation

    KW - Mesenchymal stromal cells

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