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Oncoimmunology. 2015 Apr 1;4(7):e1017701. eCollection 2015 Jul.

Combined IL-15 and IL-12 drives the generation of CD34+-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer.

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Department of Laboratory Medicine; Laboratory of Hematology; Radboud University Medical Center (Radboudumc); Nijmegen, The Netherlands.
Glycostem Therapeutics; 's-Hertogenbosch , The Netherlands.
Department of Hematology; Radboudumc ; Nijmegen, The Netherlands.


Adoptive transfer of allogeneic natural killer (NK) cells represents a promising treatment approach against cancer, including acute myeloid leukemia (AML). Previously, we reported a cytokine-based culture method for the generation of NK cell products with high cell number and purity. In this system, CD34+ hematopoietic progenitor cells (HPC) were expanded and differentiated into NK cells under stroma-free conditions in the presence of IL-15 and IL-2. We show that combining IL-15 with IL-12 drives the generation of more mature and highly functional NK cells. In particular, replacement of IL-2 by IL-12 enhanced the cytolytic activity and IFNγ production of HPC-NK cells toward cultured and primary AML cells in vitro, and improved antileukemic responses in NOD/SCID-IL2Rγnull (NSG) mice bearing human AML cells. Phenotypically, IL-12 increased the frequency of HPC-NK cells expressing NKG2A and killer immunoglobulin-like receptor (KIR), which were more responsive to target cell stimulation. In addition, NK15/12 cell products demonstrated superior maturation potential, resulting in >70% positivity for CD16 and/or KIR within 2 weeks after infusion into NSG mice. We predict that higher functionality and faster in vivo maturation will favor HPC-NK cell alloreactivity toward malignant cells in patients, making this cytokine combination an attractive strategy to generate clinical HPC-NK cell products for cancer adoptive immunotherapy.


AML, acute myeloid leukemia; BM, bone marrow; HPC, hematopoietic progenitor cell; HSCT, hematopoietic stem cell transplantation; KIR, killer immunoglobulin-like receptor; NK, natural killer; NSG, NOD/SCID-IL2Rγnull; UCB, umbilical cord blood; acute myeloid leukemia; adoptive immunotherapy; interferon-gamma; interleukin-12; killer immunoglobulin-like receptor; natural killer cell

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