title: Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: implications for clinical therapy.
abstract: Natural killer (NK) cell efficacy correlates with in vivo proliferation, and we hypothesize that NK cell product manipulations may optimize this endpoint. Xenotransplantation was used to compare good manufacturing practice (GMP) grade freshly activated NK cells (FA-NK) and ex vivo expanded NK cells (Ex-NK). Cells were infused into NOD scid IL2 receptor gamma chain knockout (NSG) mice followed by IL-2, IL-15, or no cytokines. Evaluation of blood, spleen, and marrow showed that persistence and expansion was cytokine dependent, IL-15 being superior to IL-2. Cryopreservation and immediate infusion resulted in less cytotoxicity and fewer NK cells in vivo, and this could be rescued in FA-NK by overnight culture and testing the next day. Marked differences in the kinetics and homing of FA-NK versus Ex-NK were apparent: FA-NK cells preferentially homed to spleen and persisted longer after cytokine withdrawal. These data suggest that cryopreservation of FA-NK and Ex-NK is detrimental and that culture conditions profoundly affect homing, persistence, and expansion of NK cells in vivo. The NSG mouse model is an adjuvant to in vitro assays before clinical testing.
authors.affiliation: Blood and Marrow Transplant Program, Department of Medicine, Minneapolis, Minnesota. Electronic address: mille011@umn.edu.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.affiliation: Blood and Marrow Transplant Program, Department of Medicine, Minneapolis, Minnesota.
authors.forename: Julie
authors.initials: J
authors.lastname: Curtsinger
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Ron
authors.initials: R
authors.lastname: McElmurry
authors.affiliation: Blood and Marrow Transplant Program, Department of Medicine, Minneapolis, Minnesota.
authors.forename: Valarie
authors.initials: V
authors.lastname: McCullar
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lapteva
authors.affiliation: Molecular & Cellular Therapeutics, University of Minnesota, Saint Paul, Minnesota.
authors.forename: David
authors.initials: D
authors.lastname: McKenna
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: John E
authors.initials: JE
authors.lastname: Wagner
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014183:Transplantation, Heterologous
chemical_list: D016207:Cytokines
keywords: Human; Immunotherapy; NK cells; Xenogeneic