title: Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells.
abstract: Reprogramming of NK cells with a chimeric antigen receptor (CAR) proved an effective strategy to increase NK cell reactivity and recognition specificity toward tumor cells. To enhance the cytotoxicity of NK cells against CD138-positive multiple myeloma (MM) cells, we generated genetically modified NK-92MI cells carrying a CAR that consists of an anti-CD138 single-chain variable fragment (scFv) fused to the CD3ζ chain as a signaling moiety. The genetic modification through a lentiviral vector did not affect the intrinsic cytolytic activity of NK-92MI toward human erythroleukemic cell line K562 cells or CD138-negative targets. However, these retargeted NK-92MI (NK-92MI-scFv) displayed markedly enhanced cytotoxicity against CD138-positive human MM cell lines (RPMI8226, U266 and NCI-H929) and primary MM cells at various effector-to-target ratios (E:T) as compared to the empty vector-transfected NK-92MI (NK-92MI-mock). In line with the enhanced cytotoxicity of NK-92MI-scFv, significant elevations in the secretion of granzyme B, interferon-γ and proportion of CD107a expression were also found in NK-92MI-scFv in response to CD138-positive targets compared with NK-92MI-mock. Most importantly, the enhancement in the cytotoxicity of NK-92MI-scFv did not attenuate with 10Gy-irradiation that sufficiently blocked cell proliferation. Moreover, the irradiated NK-92MI-scFv exerted definitely intensified anti-tumor activity toward CD138-positive MM cells than NK-92MI-mock in the xenograft NOD-SCID mouse model. This study provides the rationale and feasibility for adoptive immunotherapy with CD138-specific CAR-modified NK cells in CD138-positive plasmacytic malignancies, which potentially further improves remission quality and prolongs the remission duration of patients with MM after upfront chemotherapy.
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Shang
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Tianmei
authors.initials: T
authors.lastname: Zeng
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China.
authors.forename: Hejing
authors.initials: H
authors.lastname: Huang
authors.affiliation: Institute of Biotechnology and Clinical Immunology, Research Laboratory of Jiangsu Province, Soochow University, Suzhou 215007, China.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Biotechnology and Clinical Immunology, Research Laboratory of Jiangsu Province, Soochow University, Suzhou 215007, China.
authors.forename: Wanping
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region.
authors.forename: Daniel
authors.initials: D
authors.lastname: Man-Yuen Sze
authors.affiliation: Department of Lymphoma/Myeloma, Division of Cancer Medicine, and Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.affiliation: Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Rd, Shanghai 200003, China. Electronic address: houjian167@sohu.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Hou
mesh_terms: D000328:Adult; D000818:Animals; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D053668:Syndecan-1 / Q000235:genetics / Q000276:immunology; D014162:Transfection
chemical_list: D000912:Antibodies, Neoplasm; D009363:Neoplasm Proteins; C508241:SDC1 protein, human; D057127:Single-Chain Antibodies; D053668:Syndecan-1
keywords: Adoptive immunotherapy; CD138 (syndecan-1); Chimeric antigen receptor; Multiple myeloma; NK cells