title: Antibody-dependent cell-mediated cytotoxicity overcomes NK cell resistance in MLL-rearranged leukemia expressing inhibitory KIR ligands but not activating ligands.
abstract: OBJECTIVE
  Leukemias with MLL gene rearrangement are associated with a poor prognosis. Natural killer (NK) cell therapy is a potential treatment, but leukemia cells may be resistant. Here, we sought to determine the susceptibility of MLL-rearranged leukemia cells to NK cell lysis and to develop a novel immunotherapeutic approach to optimize NK cell therapy, including the use of an antibody against leukemia-associated antigen and the elimination of killer-cell immunoglobulin-like receptor (KIR)-mediated inhibition.
  
  
  METHODS
  Three MLL-rearranged leukemia cell lines (RS4;11, SEM, and MV4-11) and primary leukemia blasts were assessed for surface phenotype and susceptibility to NK cell lysis with or without antibodies against CD19 (XmAb5574), CD33 (lintuzumab), or KIR ligands.
  
  
  RESULTS
  All three cell lines were resistant to NK cell lysis, had some inhibitory KIR ligands and protease inhibitor-9, and expressed low levels of NKG2D activating ligands and adhesion molecules. After treatment with XmAb5574 or lintuzumab, MLL-rearranged leukemia cells were efficiently killed by NK cells. The addition of pan-major histocompatibility complex class I antibody, which blocked inhibitory KIR-HLA interaction, further augmented degranulation in all three KIR2DL1, KIR2DL2/3, and KIR3DL1 subsets of NK cells based on the rule of missing-self recognition. A mouse model showed a decreased rate of leukemia progression in vivo as monitored by bioluminescence imaging and longer survival after antibody treatment.
  
  
  CONCLUSIONS
  Our data support the use of a triple immunotherapy approach, including an antibody directed against tumor-associated antigen, KIR-mismatched NK cell transplantation, and inhibitory KIR blockade, for the treatment of NK cell-resistant MLL-rearranged leukemias.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
authors.forename: Wing Keung
authors.initials: WK
authors.lastname: Chan
authors.forename: May
authors.initials: M
authors.lastname: Kung Sutherland
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zalevsky
authors.forename: Sarah
authors.initials: S
authors.lastname: Schell
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015235:HLA-B Antigens / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007694:Killer Cells, Natural / Q000637:transplantation*; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics; D054340:Receptors, KIR / Q000378:metabolism; D014178:Translocation, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C496124:FCGR3A protein, human; D015235:HLA-B Antigens; C497422:KMT2A protein, human; D017452:Receptors, IgG; D054340:Receptors, KIR; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C477390:lintuzumab