BACKGROUND: Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. DESIGN AND METHODS: The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. RESULTS: Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. CONCLUSIONS: This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted.
BACKGROUND: Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. DESIGN AND METHODS: The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. RESULTS: Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. CONCLUSIONS: This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted.
Authors: Yasser M El-Sherbiny; Josephine L Meade; Tim D Holmes; Dennis McGonagle; Sarah L Mackie; Ann W Morgan; Gordon Cook; Sylvia Feyler; Stephen J Richards; Faith E Davies; Gareth J Morgan; Graham P Cook Journal: Cancer Res Date: 2007-09-15 Impact factor: 12.701
Authors: Kimberly Noonan; William Matsui; Paolo Serafini; Rebecca Carbley; Gladys Tan; Jahan Khalili; Mark Bonyhadi; Hyam Levitsky; Katie Whartenby; Ivan Borrello Journal: Cancer Res Date: 2005-03-01 Impact factor: 12.701
Authors: William Matsui; Qiuju Wang; James P Barber; Sarah Brennan; B Douglas Smith; Ivan Borrello; Ian McNiece; Lan Lin; Richard F Ambinder; Craig Peacock; D Neil Watkins; Carol Ann Huff; Richard J Jones Journal: Cancer Res Date: 2008-01-01 Impact factor: 12.701
Authors: Elke Pogge von Strandmann; Venkateswara Rao Simhadri; Bastian von Tresckow; Stephanie Sasse; Katrin S Reiners; Hinrich P Hansen; Achim Rothe; Boris Böll; Vijaya Lakshmi Simhadri; Peter Borchmann; Peter J McKinnon; Michael Hallek; Andreas Engert Journal: Immunity Date: 2007-12-06 Impact factor: 31.745
Authors: B Martin-Antonio; A Najjar; S N Robinson; C Chew; S Li; E Yvon; M W Thomas; I Mc Niece; R Orlowski; C Muñoz-Pinedo; C Bueno; P Menendez; C Fernández de Larrea; A Urbano-Ispizua; E J Shpall; N Shah Journal: Cell Death Differ Date: 2014-08-29 Impact factor: 15.828