title: Combined IL-15 and IL-12 drives the generation of CD34+-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer.
abstract: 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 cellsin 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 fasterin vivomaturation 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.
authors.affiliation: Department of Laboratory Medicine; Laboratory of Hematology; Radboud University Medical Center (Radboudumc); Nijmegen, The Netherlands.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Cany
authors.affiliation: Department of Laboratory Medicine; Laboratory of Hematology; Radboud University Medical Center (Radboudumc); Nijmegen, The Netherlands.
authors.forename: Anniek B
authors.initials: AB
authors.lastname: van der Waart
authors.affiliation: Glycostem Therapeutics; 's-Hertogenbosch , The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Spanholtz
authors.affiliation: Glycostem Therapeutics; 's-Hertogenbosch , The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Tordoir
authors.affiliation: Department of Laboratory Medicine; Laboratory of Hematology; Radboud University Medical Center (Radboudumc); Nijmegen, The Netherlands.
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Department of Laboratory Medicine; Laboratory of Hematology; Radboud University Medical Center (Radboudumc); Nijmegen, The Netherlands.
authors.forename: Robbert
authors.initials: R
authors.lastname: van der Voort
authors.affiliation: Department of Hematology; Radboudumc ; Nijmegen, The Netherlands.
authors.forename: Nicolaas M
authors.initials: NM
authors.lastname: Schaap
authors.affiliation: Department of Laboratory Medicine; Laboratory of Hematology; Radboud University Medical Center (Radboudumc); Nijmegen, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
keywords: 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