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Cancer Therapy: Clinical

Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML

Andreas T. Björklund, Mattias Carlsten, Ebba Sohlberg, Lisa L. Liu, Trevor Clancy, Mohsen Karimi, Sarah Cooley, Jeffrey S. Miller, Monika Klimkowska, Marie Schaffer, Emma Watz, Kristina Wikström, Pontus Blomberg, Björn Engelbrekt Wahlin, Marzia Palma, Lotta Hansson, Per Ljungman, Eva Hellström-Lindberg, Hans-Gustaf Ljunggren and Karl-Johan Malmberg
Andreas T. Björklund
1Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
2Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
3Department. of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.
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Mattias Carlsten
1Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
4Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Ebba Sohlberg
2Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Lisa L. Liu
2Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Trevor Clancy
5Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
6The KG Jebsen Centre for Cancer Immunotherapy, University of Oslo, Oslo, Norway.
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Mohsen Karimi
4Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Sarah Cooley
7Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
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Jeffrey S. Miller
7Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
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Monika Klimkowska
8Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Marie Schaffer
2Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Emma Watz
9Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
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Kristina Wikström
10Vecura, Karolinska Center for Cell Therapy Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden.
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Pontus Blomberg
10Vecura, Karolinska Center for Cell Therapy Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden.
11Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden.
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Björn Engelbrekt Wahlin
1Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
12Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Marzia Palma
1Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
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Lotta Hansson
1Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
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Per Ljungman
3Department. of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.
12Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Eva Hellström-Lindberg
1Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
4Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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Hans-Gustaf Ljunggren
2Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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  • For correspondence: k.j.malmberg@medisin.uio.no hans-gustaf.ljunggren@ki.se
Karl-Johan Malmberg
2Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
3Department. of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.
5Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
6The KG Jebsen Centre for Cancer Immunotherapy, University of Oslo, Oslo, Norway.
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  • For correspondence: k.j.malmberg@medisin.uio.no hans-gustaf.ljunggren@ki.se
DOI: 10.1158/1078-0432.CCR-17-3196 Published April 2018
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Abstract

Purpose: To evaluate the safety, efficacy, and immunobiological correlates of allogeneic NK-cell–based therapy in primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary AML (MDS/AML), and de novo AML patients.

Experimental Design: Sixteen patients received fludarabine/cyclophosphamide conditioning combined with total lymphoid irradiation followed by adoptive immunotherapy with IL2–activated haploidentical NK cells.

Results: NK-cell infusions were well-tolerated, with only transient adverse events observed in the 16 patients. Six patients achieved objective responses with complete remission (CR), marrow CR, or partial remission (PR). Five patients proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Three patients are still free from disease >3 years after treatment. All evaluable patients with objective responses (5/5 evaluable) had detectable donor NK cells at days 7/14 following infusion and displayed reduction of tumor cell clones, some of which carried poor prognosis mutations. Residual lin−CD34+CD123+CD45RA+ blast cells in responders had increased total HLA class I and HLA-E expression. Responding patients displayed less pronounced activation of CD8+ T cells and lower levels of inflammatory cytokines following NK-cell infusion. Intriguingly, despite omission of systemic IL2, all patients displayed increased frequencies of activated Ki-67+CD127−FoxP3+CD25hiCD4+ Treg cells of recipient origin following NK-cell therapy.

Conclusions: Overall, this study suggests that high-risk MDS is responsive to NK-cell therapy and supports the use of haploidentical NK-cell infusions as a bridge to HSCT in refractory patients. Objective clinical responses and reduction of high-risk clones were associated with detectable donor-derived NK cells, immunoediting of residual blast cells, and less pronounced host immune activation. Clin Cancer Res; 24(8); 1834–44. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • A.T. Björklund, M. Carlsten, and E. Sohlberg are the co-first authors of this article.

  • H.-G. Ljunggren and K.-J. Malmberg are the co-last authors of this article.

  • Received October 29, 2017.
  • Revision received January 8, 2018.
  • Accepted January 30, 2018.
  • Published first February 14, 2018.
  • ©2018 American Association for Cancer Research.
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Clinical Cancer Research: 24 (8)
April 2018
Volume 24, Issue 8
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Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML
Andreas T. Björklund, Mattias Carlsten, Ebba Sohlberg, Lisa L. Liu, Trevor Clancy, Mohsen Karimi, Sarah Cooley, Jeffrey S. Miller, Monika Klimkowska, Marie Schaffer, Emma Watz, Kristina Wikström, Pontus Blomberg, Björn Engelbrekt Wahlin, Marzia Palma, Lotta Hansson, Per Ljungman, Eva Hellström-Lindberg, Hans-Gustaf Ljunggren and Karl-Johan Malmberg
Clin Cancer Res April 15 2018 (24) (8) 1834-1844; DOI: 10.1158/1078-0432.CCR-17-3196

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Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML
Andreas T. Björklund, Mattias Carlsten, Ebba Sohlberg, Lisa L. Liu, Trevor Clancy, Mohsen Karimi, Sarah Cooley, Jeffrey S. Miller, Monika Klimkowska, Marie Schaffer, Emma Watz, Kristina Wikström, Pontus Blomberg, Björn Engelbrekt Wahlin, Marzia Palma, Lotta Hansson, Per Ljungman, Eva Hellström-Lindberg, Hans-Gustaf Ljunggren and Karl-Johan Malmberg
Clin Cancer Res April 15 2018 (24) (8) 1834-1844; DOI: 10.1158/1078-0432.CCR-17-3196
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Clinical Cancer Research
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