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Clin Cancer Res. 2018 Apr 15;24(8):1834-1844. doi: 10.1158/1078-0432.CCR-17-3196. Epub 2018 Feb 14.

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

Author information

1
Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
2
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
3
Department. of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden.
4
Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
5
Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
6
The KG Jebsen Centre for Cancer Immunotherapy, University of Oslo, Oslo, Norway.
7
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
8
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
9
Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
10
Vecura, Karolinska Center for Cell Therapy Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden.
11
Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden.
12
Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
13
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. k.j.malmberg@medisin.uio.no hans-gustaf.ljunggren@ki.se.

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.

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