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Haematologica 2018 Volume 103(10):1720-1729
Ferrata Storti Foundation
Cell Therapy & Immunotherapy
CD16+NK-92 and anti-CD123 monoclonal antibody prolongs survival in primary human acute myeloid leukemia xenografted mice
Brent A. Williams,1,2 Xing-Hua Wang,1 Jeffrey V. Leyton,3 Sonam Maghera,1,2 Bishoy Deif,1 Raymond M. Reilly,4,5,6 Mark D. Minden7,8
and Armand Keating1,2,8,9,10
1Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, Ontario; 2Institute of Medical Science, University of Toronto, Ontario; 3Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Quebec; 4Department of Medical Imaging, University of Toronto, Ontario; 5Department of Pharmaceutical Sciences, University of Toronto, Ontario; 6Toronto General Research Institute, University Health Network, Toronto, Ontario; 7Department of Medical Biophysics, University of Toronto, Ontario; 8Department of Medicine, University of Toronto, Ontario; 9Institute of Biomaterials and Biomedical Engineering, University of Toronto and 10Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
ABSTRACT
Patients with acute myeloid leukemia (AML) often relapse after ini- tial therapy because of persistence of leukemic stem cells that fre- quently express the IL-3 receptor alpha chain CD123. Natural killer (NK) cell-based therapeutic strategies for AML show promise and we explore the NK cell lines, NK-92 and CD16+NK-92, as a treatment for AML. NK-92 has been tested in phase I clinical trials with minimal toxi- city; irradiation prior to infusion prevents risk of engraftment. The CD16 negative NK-92 parental line was genetically modified to express the high affinity Fc gamma receptor, enabling antibody-dependent cell- mediated cytotoxicity, which we utilized in combination with an anti- CD123 antibody to target leukemic stem cells. NK-92 was preferentially cytotoxic against leukemic stem and progenitor cells compared with bulk leukemia in in vitro assays, while CD16+NK-92 in combination with an anti-CD123 mAb mediated antibody-dependent cell-mediated cyto- toxicity against CD123+ leukemic targets. Furthermore, NK-92 infusions (with or without prior irradiation) improved survival in a primary AML xenograft model. Mice xenografted with primary human AML cells had a superior survival when treated with irradiated CD16+NK-92 cells and an anti-CD123 monoclonal antibody (7G3) versus treatment with irradi- ated CD16+NK-92 cells combined with an isotype control antibody. In this proof-of-principle study, we show for the first time that a CD16+NK- 92 cell line combined with an antibody that targets a leukemic stem cell antigen can lead to improved survival in a relevant pre-clinical model of AML.
Introduction
Acute myeloid leukemia (AML) accounts for the majority of acute leukemias in adults and a minority in children.1,2 While up to 70-85% of AML patients treated with current chemotherapy protocols achieve morphological remission,1,3 many relapse because of recurrence from residual leukemic stem cells (LSCs) resulting in an overall 5-year survival of approximately 40%.2 AML was the first malignancy with clear evidence of a stem cell hierarchy, with the LSCs being enriched in the CD34+CD38– fraction.4,5 In addition, they often express the IL-3 receptor alpha chain (CD123), a marker not highly expressed on normal hematopoietic stem cells.6 AML patients with a greater than 1% burden of CD34+CD38–CD123+ LSCs at diag- nosis have a reduced disease-free and overall survival rate, directly implicating CD123 as a relevant target antigen.7 Natural killer (NK)-cell-based approaches are under development for the treatment of AML, such as the use of haploidentical NK-cell infusions.8,9 While this shows promise, there is inherent variability in the
Correspondence:
brentw@uhnres.utoronto.ca or brentwilliams.brent@gmail.com
Received: January 17, 2018. Accepted: July 3, 2018. Pre-published: July 5, 2018.
doi:10.3324/haematol.2017.187385
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1720
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