The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation
Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells...
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Frontiers Media S.A.
2019-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02816/full |
| _version_ | 1828464591649112064 |
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| author | Annekathrin Heinze Annekathrin Heinze Annekathrin Heinze Beatrice Grebe Beatrice Grebe Melanie Bremm Melanie Bremm Sabine Huenecke Sabine Huenecke Tasleem Ah. Munir Tasleem Ah. Munir Lea Graafen Lea Graafen Jochen T. Frueh Jochen T. Frueh Michael Merker Michael Merker Eva Rettinger Eva Rettinger Jan Soerensen Jan Soerensen Thomas Klingebiel Peter Bader Peter Bader Evelyn Ullrich Evelyn Ullrich Evelyn Ullrich Evelyn Ullrich Claudia Cappel Claudia Cappel |
| author_facet | Annekathrin Heinze Annekathrin Heinze Annekathrin Heinze Beatrice Grebe Beatrice Grebe Melanie Bremm Melanie Bremm Sabine Huenecke Sabine Huenecke Tasleem Ah. Munir Tasleem Ah. Munir Lea Graafen Lea Graafen Jochen T. Frueh Jochen T. Frueh Michael Merker Michael Merker Eva Rettinger Eva Rettinger Jan Soerensen Jan Soerensen Thomas Klingebiel Peter Bader Peter Bader Evelyn Ullrich Evelyn Ullrich Evelyn Ullrich Evelyn Ullrich Claudia Cappel Claudia Cappel |
| author_sort | Annekathrin Heinze |
| collection | DOAJ |
| description | Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells compared to cytokine-induced killer (CIK) cells for the treatment of NB. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by indirect CD56-enrichment or CD3/CD19-depletion and expanded with different cytokine combinations, such as IL-2, IL-15, and/or IL-21 under feeder-cell free conditions. CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3, and IL-15. Comparative analysis of expansion rate, purity, phenotype and cytotoxicity was performed. CD56-enriched NK cells showed a median expansion rate of 4.3-fold with up to 99% NK cell content. The cell product after CD3/CD19-depletion consisted of a median 43.5% NK cells that expanded significantly faster reaching also 99% of NK cell purity. After 10–12 days of expansion, both NK cell preparations showed a significantly higher median cytotoxic capacity against NB cells relative to CIK cells. Remarkably, these NK cells were also capable of efficiently killing NB spheroidal 3D culture in long-term cytotoxicity assays. Further optimization using a novel NK cell culture medium and a prolonged culturing procedure after CD3/CD19-depletion for up to 15 days enhanced the expansion rate up to 24.4-fold by maintaining the cytotoxic potential. Addition of an IL-21 boost prior to harvesting significantly increased the cytotoxicity. The final cell product consisted for the major part of CD16−, NCR-expressing, poly-functional NK cells with regard to cytokine production, CD107a degranulation and antitumor capacity. In summary, our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation. Therefore, the use of IL-15+IL-21 expanded NK cells generated from CD3/CD19-depleted apheresis products seems to be highly promising as an immunotherapy in combination with haploidentical stem cell transplantation (SCT) for high-risk NB patients. |
| first_indexed | 2024-12-11T03:17:08Z |
| format | Article |
| id | doaj.art-439d2ee84c6d456f9f5a2cce5888bc1f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T03:17:08Z |
| publishDate | 2019-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-439d2ee84c6d456f9f5a2cce5888bc1f2022-12-22T01:22:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-12-011010.3389/fimmu.2019.02816491554The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell TransplantationAnnekathrin Heinze0Annekathrin Heinze1Annekathrin Heinze2Beatrice Grebe3Beatrice Grebe4Melanie Bremm5Melanie Bremm6Sabine Huenecke7Sabine Huenecke8Tasleem Ah. Munir9Tasleem Ah. Munir10Lea Graafen11Lea Graafen12Jochen T. Frueh13Jochen T. Frueh14Michael Merker15Michael Merker16Eva Rettinger17Eva Rettinger18Jan Soerensen19Jan Soerensen20Thomas Klingebiel21Peter Bader22Peter Bader23Evelyn Ullrich24Evelyn Ullrich25Evelyn Ullrich26Evelyn Ullrich27Claudia Cappel28Claudia Cappel29Experimental Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyExperimental Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyExperimental Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyExperimental Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyExperimental Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyExperimental Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyGerman Cancer Consortium (DKTK), Partner Site Frankfurt am Main, Frankfurt am Main, GermanyDivision for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyDepartment for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, GermanyNeuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells compared to cytokine-induced killer (CIK) cells for the treatment of NB. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by indirect CD56-enrichment or CD3/CD19-depletion and expanded with different cytokine combinations, such as IL-2, IL-15, and/or IL-21 under feeder-cell free conditions. CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3, and IL-15. Comparative analysis of expansion rate, purity, phenotype and cytotoxicity was performed. CD56-enriched NK cells showed a median expansion rate of 4.3-fold with up to 99% NK cell content. The cell product after CD3/CD19-depletion consisted of a median 43.5% NK cells that expanded significantly faster reaching also 99% of NK cell purity. After 10–12 days of expansion, both NK cell preparations showed a significantly higher median cytotoxic capacity against NB cells relative to CIK cells. Remarkably, these NK cells were also capable of efficiently killing NB spheroidal 3D culture in long-term cytotoxicity assays. Further optimization using a novel NK cell culture medium and a prolonged culturing procedure after CD3/CD19-depletion for up to 15 days enhanced the expansion rate up to 24.4-fold by maintaining the cytotoxic potential. Addition of an IL-21 boost prior to harvesting significantly increased the cytotoxicity. The final cell product consisted for the major part of CD16−, NCR-expressing, poly-functional NK cells with regard to cytokine production, CD107a degranulation and antitumor capacity. In summary, our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation. Therefore, the use of IL-15+IL-21 expanded NK cells generated from CD3/CD19-depleted apheresis products seems to be highly promising as an immunotherapy in combination with haploidentical stem cell transplantation (SCT) for high-risk NB patients.https://www.frontiersin.org/article/10.3389/fimmu.2019.02816/fullimmunotherapyNK cellsCD3/CD19 depletionCIK cellsIL-21IL-15 |
| spellingShingle | Annekathrin Heinze Annekathrin Heinze Annekathrin Heinze Beatrice Grebe Beatrice Grebe Melanie Bremm Melanie Bremm Sabine Huenecke Sabine Huenecke Tasleem Ah. Munir Tasleem Ah. Munir Lea Graafen Lea Graafen Jochen T. Frueh Jochen T. Frueh Michael Merker Michael Merker Eva Rettinger Eva Rettinger Jan Soerensen Jan Soerensen Thomas Klingebiel Peter Bader Peter Bader Evelyn Ullrich Evelyn Ullrich Evelyn Ullrich Evelyn Ullrich Claudia Cappel Claudia Cappel The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation Frontiers in Immunology immunotherapy NK cells CD3/CD19 depletion CIK cells IL-21 IL-15 |
| title | The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation |
| title_full | The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation |
| title_fullStr | The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation |
| title_full_unstemmed | The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation |
| title_short | The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation |
| title_sort | synergistic use of il 15 and il 21 for the generation of nk cells from cd3 cd19 depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma perspective for optimized immunotherapy post haploidentical stem cell transplantation |
| topic | immunotherapy NK cells CD3/CD19 depletion CIK cells IL-21 IL-15 |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02816/full |
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