Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells

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• 作者：Hua Jiang^a ; ¹ ; Wenhao Zhang^a ; ¹ ; Peipei Shang^a ; ¹ ; Hui Zhang^a ; Weijun Fu^a ; Fei Ye^a ; Tianmei Zeng^a ; Hejing Huang^a ; Xueguang Zhang^b ; Wanping Sun^b ; Daniel Man-Yuen Sze^c ; Qing Yi^d ; Jian Hou^a ; ^{houjian167@sohu.com" class="auth_mail}
• 关键词：Multiple myeloma ; Adoptive immunotherapy ; NK cells ; Chimeric antigen receptor ; CD138 (syndecan-1)
• 刊名：Molecular Oncology
• 出版年：March, 2014
• 年：2014
• 卷：8
• 期：2
• 页码：297-310
• 全文大小：3745 K

文摘

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 CD3味 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-纬 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.