Abstract
Purpose: To evaluate the safety, efficacy, and immunobiolo-gical 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 linCD34þCD123þCD45RAþ blast cells in responders had increased total HLA class I and HLA-E expression. Responding patients displayed less pronounced activation of CD8þ 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-67þCD127FoxP3þCD25hiCD4þ 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1834-1844 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 15 2018 |
Bibliographical note
Funding Information:This clinical trial would not have been possible without generous support from the Tobias Foundation, which funded a significant part. In addition, the authors are supported by grants from the Swedish Research Council, the Swedish Children's Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Cancer Society, the Swedish Society for Medical Research, the Jeansson's Foundations, Radiumhemmets Research Foundation, the Knut and Alice Wallenberg Foundation, Marianne and Marcus Wallenberg Foundation, the Karolinska Institutet, the Karolinska University Hospital, the Norwegian Research Council, the Norwegian Cancer Society, the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, the KG Jebsen Center for Cancer Immunotherapy, and the European Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
This clinical trial would not have been possible without generous support from the Tobias Foundation, which funded a significant part. In addition, the authors are supported by grants from the Swedish Research Council, the Swedish Children's Cancer Society, the Swedish Foundation for Strategic Research, the Swedish Cancer Society, the Swedish Society for Medical Research, the Jeansson's Foundations, Radiumhemmets Research Foundation, the Knut and Alice Wallenberg Foundation, Marianne and Marcus Wallenberg Foundation, the Karo-linska Institutet, the Karolinska University Hospital, the Norwegian Research Council, the Norwegian Cancer Society, the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, the KG Jebsen Center for Cancer Immunotherapy, and the European Research Council.
Publisher Copyright:
© 2018 American Association for Cancer Research.
