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Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process.

Natural killer (NK) cell-based adoptive immunotherapy is a promising treatment approach for many cancers. However, development of protocols that provide large numbers of functional NK cells produced under GMP conditions are required to facilitate clinical studies. In this study, we translated our cy... Full description

Journal Title: PloS one 2011, Vol.6(6), p.e20740
Main Author: Spanholtz, Jan
Other Authors: Preijers, Frank , Tordoir, Marleen , Trilsbeek, Carel , Paardekooper, Jos , de Witte, Theo , Schaap, Nicolaas , Dolstra, Harry
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0020740
Link: http://search.proquest.com/docview/873703125/?pq-origsite=primo
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title: Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process.
format: Article
creator:
  • Spanholtz, Jan
  • Preijers, Frank
  • Tordoir, Marleen
  • Trilsbeek, Carel
  • Paardekooper, Jos
  • de Witte, Theo
  • Schaap, Nicolaas
  • Dolstra, Harry
subjects:
  • Antigens, Cd34–Immunology
  • Bioreactors–Cytology
  • Cell Transplantation–Cytology
  • Cryopreservation–Cytology
  • Fetal Blood–Immunology
  • Hematopoietic Stem Cells–Immunology
  • Humans–Immunology
  • Immunotherapy–Immunology
  • Killer Cells, Natural–Immunology
  • Antigens, Cd34
ispartof: PloS one, 2011, Vol.6(6), p.e20740
description: Natural killer (NK) cell-based adoptive immunotherapy is a promising treatment approach for many cancers. However, development of protocols that provide large numbers of functional NK cells produced under GMP conditions are required to facilitate clinical studies. In this study, we translated our cytokine-based culture protocol for ex vivo expansion of NK cells from umbilical cord blood (UCB) hematopoietic stem cells into a fully closed, large-scale, cell culture bioprocess. We optimized enrichment of CD34.sup.+ cells from cryopreserved UCB units using the CliniMACS system followed by efficient expansion for 14 days in gas-permeable cell culture bags. Thereafter, expanded CD34.sup.+ UCB cells could be reproducibly amplified and differentiated into CD56.sup.+ CD3.sup.- NK cell products using bioreactors with a mean expansion of more than 2,000 fold and a purity of >90%. Moreover, expansion in the bioreactor yielded a clinically relevant dose of NK cells (mean: 2x10.sup.9 NK cells), which display high expression of activating NK receptors and cytolytic activity against K562. Finally, we established a versatile closed washing procedure resulting in optimal reduction of medium, serum and cytokines used in the cell culture process without changes in phenotype and cytotoxic activity. These results demonstrate that large numbers of UCB stem cell-derived NK cell products for adoptive immunotherapy can be produced in closed, large-scale bioreactors for the use in clinical trials.
language: eng
source:
identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0020740
fulltext: fulltext
issn:
  • 19326203
  • 1932-6203
url: Link


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titleClinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process.
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descriptionNatural killer (NK) cell-based adoptive immunotherapy is a promising treatment approach for many cancers. However, development of protocols that provide large numbers of functional NK cells produced under GMP conditions are required to facilitate clinical studies. In this study, we translated our cytokine-based culture protocol for ex vivo expansion of NK cells from umbilical cord blood (UCB) hematopoietic stem cells into a fully closed, large-scale, cell culture bioprocess. We optimized enrichment of CD34.sup.+ cells from cryopreserved UCB units using the CliniMACS system followed by efficient expansion for 14 days in gas-permeable cell culture bags. Thereafter, expanded CD34.sup.+ UCB cells could be reproducibly amplified and differentiated into CD56.sup.+ CD3.sup.- NK cell products using bioreactors with a mean expansion of more than 2,000 fold and a purity of >90%. Moreover, expansion in the bioreactor yielded a clinically relevant dose of NK cells (mean: 2x10.sup.9 NK cells), which display high expression of activating NK receptors and cytolytic activity against K562. Finally, we established a versatile closed washing procedure resulting in optimal reduction of medium, serum and cytokines used in the cell culture process without changes in phenotype and cytotoxic activity. These results demonstrate that large numbers of UCB stem cell-derived NK cell products for adoptive immunotherapy can be produced in closed, large-scale bioreactors for the use in clinical trials.
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