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Manufacturing and validation of Good Manufacturing Practice–compliant regulatory dendritic cells for infusion into organ transplant recipients

  • Alan F. Zahorchak
    Affiliations
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Misty L. DeRiggi
    Affiliations
    Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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  • Jennifer L. Muzzio
    Affiliations
    Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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  • Veronica Sutherland
    Affiliations
    Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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  • Abhinav Humar
    Affiliations
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Fadi G. Lakkis
    Affiliations
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • Author Footnotes
    # Co-senior authors.
    Yen-Michael S. Hsu
    Correspondence
    Correspondence: Yen-Michael S Hsu, MD, PhD, University of Pittsburgh Hillman Cancer Center, 5117 Centre Ave, Pittsburgh, PA 15213, USA.
    Footnotes
    # Co-senior authors.
    Affiliations
    Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA

    Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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  • Author Footnotes
    # Co-senior authors.
    Angus W. Thomson
    Correspondence
    Correspondence: Angus W. Thomson PhD, DSc, FAST, W1544 Starzl Biomedical Science Tower, University of Pittsburgh School of Medicine, 200 Lothrop St, Pittsburgh, PA 15213, USA.
    Footnotes
    # Co-senior authors.
    Affiliations
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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  • Author Footnotes
    # Co-senior authors.
Published:January 12, 2023DOI:https://doi.org/10.1016/j.jcyt.2022.11.005

      Abstract

      Background aims

      Regulatory (or “tolerogenic”) dendritic cells (DCregs) are a highly promising, innovative cell therapy for the induction or restoration of antigen-specific tolerance in immune-mediated inflammatory disorders. These conditions include organ allograft rejection, graft-versus-host disease following bone marrow transplantation and various autoimmune disorders. DCregs generated for adoptive transfer have potential to reduce patients’ dependence on non-specific immunosuppressive drugs that can induce serious side effects and enhance the risk of infection and certain types of cancer. Here, our aim was to provide a detailed account of our experience manufacturing and validating comparatively large numbers of Good Manufacturing Practice–grade DCregs for systemic (intravenous) infusion into 28 organ (liver) transplant recipients and to discuss factors that influence the satisfaction of release criteria and attainment of target cell numbers.

      Results

      DCregs were generated in granulocyte-macrophage colony stimulating factor and interleukin (IL)-4 from elutriated monocyte fractions isolated from non-mobilized leukapheresis products of consenting healthy adult prospective liver transplant donors. Vitamin D3 was added on day 0 and 4 and IL-10 on day 4 during the 7-day culture period. Release and post-release criteria included cell viability, purity, phenotype, sterility and functional assessment. The overall conversion rate of monocytes to DCregs was 28 ± 8.2%, with 94 ± 5.1% product viability. The mean cell surface T-cell co-inhibitory to co-stimulatory molecule (programmed death ligand-1:CD86) mean fluorescence intensity ratio was 3.9 ± 2.2, and the mean ratio of anti-inflammatory:pro-inflammatory cytokine product (IL-10:IL-12p70) secreted upon CD40 ligation was 60 ± 63 (median = 40). The mean total number of DCregs generated from a single leukapheresis product (n = 25 donors) and from two leukapheresis products (n = 3 donors) was 489 ± 223 × 106 (n = 28). The mean total number of DCregs infused was 5.9 ± 2.8 × 106 per kg body weight. DCreg numbers within a target cell range of 2.5–10 × 106/kg were achieved for 25 of 27 (92.6%) of products generated.

      Conclusions

      High-purity DCregs meeting a range of quality criteria were readily generated from circulating blood monocytes under Good Manufacturing Practice conditions to meet target cell numbers for infusion into prospective organ transplant recipients.

      Key Words

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