title: IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, In Vivo Expansion, and Enhanced Function.
abstract: The effectiveness of NK cell infusions to induce leukemic remission is limited by lack of both antigen specificity and in vivo expansion. To address the first issue, we previously generated a bispecific killer engager (BiKE) containing single-chain scFv against CD16 and CD33 to create an immunologic synapse between NK cells and CD33(+) myeloid targets. We have now incorporated a novel modified human IL15 crosslinker, producing a 161533 trispecific killer engager (TriKE) to induce expansion, priming, and survival, which we hypothesize will enhance clinical efficacy.
  
  
  
  Reagents were tested in proliferation and functional assays and in an in vivo xenograft model of AML.
  
  
  
  When compared with the 1633 BiKE, the 161533 TriKE induced superior NK cell cytotoxicity, degranulation, and cytokine production against CD33(+) HL-60 targets and increased NK survival and proliferation. Specificity was shown by the ability of a 1615EpCAM TriKE to kill CD33-EpCAM(+) targets. Using NK cells from patients after allogeneic stem cell transplantation when NK cell function is defective, the 161533 TriKE restored potent NK function against primary AML targets and induced specific NK cell proliferation. These results were confirmed in an immunodeficient mouse HL-60-Luc tumor model where the 161533 TriKE exhibited superior antitumor activity and induced in vivo persistence and survival of human NK cells for at least 3 weeks.
  
  
  
  Off-the-shelf 161533 TriKE imparts antigen specificity and promotes in vivo persistence, activation, and survival of NK cells. These qualities are ideal for NK cell therapy of myeloid malignancies or targeting antigens of solid tumors. Clin Cancer Res; 22(14); 3440-50. ©2016 AACRSee related commentary by Talmadge, p. 3419.
authors: Masonic Cancer Center, Laboratory of Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. valle001@umn.edu.
authors: Daniel A
authors: DA
authors: Vallera
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Martin
authors: M
authors: Felices
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Ron
authors: R
authors: McElmurry
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Valarie
authors: V
authors: McCullar
authors: New York Medical College, New York, New York.
authors: Xianzheng
authors: X
authors: Zhou
authors: Masonic Cancer Center, Laboratory of Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, Minnesota.
authors: Joerg Uwe
authors: JU
authors: Schmohl
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Bin
authors: B
authors: Zhang
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Alexander J
authors: AJ
authors: Lenvik
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Angela
authors: A
authors: Panoskaltsis-Mortari
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Michael R
authors: MR
authors: Verneris
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Jakub
authors: J
authors: Tolar
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Sarah
authors: S
authors: Cooley
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Daniel J
authors: DJ
authors: Weisdorf
authors: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors: Bruce R
authors: BR
authors: Blazar
authors: Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors: Jeffrey S
authors: JS
authors: Miller
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D000071858:Epithelial Cell Adhesion Molecule / Q000276:immunology; D018922:HL-60 Cells; D019073:HT29 Cells; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology*; D013234:Stem Cells / Q000276:immunology; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: C571163:CD33 protein, human; D000071858:Epithelial Cell Adhesion Molecule; C569274:IL15 protein, human; D019409:Interleukin-15; D063268:Sialic Acid Binding Ig-like Lectin 3