嵌合抗原受体
细胞毒性T细胞
免疫疗法
NK-92
癌症研究
克隆(Java方法)
生物
癌症免疫疗法
CD28
抗原
淋巴因子激活杀伤细胞
白细胞介素21
免疫学
免疫系统
CD8型
体外
DNA
生物化学
遗传学
作者
J. P. Steinbach,C. Zhang,Michael C. Burger,Lukas Jennewein,Kurt Schönfeld,Sabrina Genßler,Christiane Sahm,Christian Brendel,Sonja Naundorf,Marcus Odendahl,Ulrike Koehl,Paulina Nowakowska,Erhard Seifried,Halvard Bönig,Torsten Tonn,Manuel Grez,Michel Mittelbronn,Winfried S. Wels
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2014-07-01
卷期号:16 (suppl 3): iii44-iii44
被引量:2
标识
DOI:10.1093/neuonc/nou209.9
摘要
BACKGROUND: While EGFRvIII appears a logical target for immunotherapy, only a subpopulation of tumor cells express EGFRvIII and immune escape has been demonstrated. ErbB2 is overexpressed in a substantial proportion of glioblastomas and has been successfully utilized in immunotherapies. Natural killer (NK) cells are the first line of defense against viral infections and malignant cells. The continuously growing cytotoxic cell line NK-92 holds promise for cancer immunotherapy. Safety of infusion of high doses of NK-92 was established in previous phase I clinical trials utilizing irradiated cells to prevent permanent engraftment. METHODS: To provide NK-92 cells with pre-determined tumor-cell specificity, we generated a lentiviral second generation chimeric antigen receptor (CAR) construct (5.28.z) employing the ErbB2 (HER2)-specific scFv(FRP5) antibody fragment for target cell recognition, and human CD28-CD3 ζ as a composite signaling moiety. An ErbB2-specific single cell clone (NK-92/5.28.z) was isolated, which showed high and selective cytotoxicity towards ErbB2-expressing tumor cells of various origins in vitro. We evaluated the cytotoxicity of NK-93/5.28.z cells against a panel of glioblastoma cell lines and primary glioblastoma cultures with different levels of Erb2 expression in vitro and in vivo. RESULTS: To provide NK-92 cells with pre-determined tumor-cell specificity, we generated a lentiviral second generation chimeric antigen receptor (CAR) construct (5.28.z) employing the ErbB2 (HER2)-specific scFv(FRP5) antibody fragment for target cell recognition, and human CD28-CD3 ζ as a composite signaling moiety. An ErbB2-specific single cell clone (NK-92/5.28.z) was isolated, which showed high and selective cytotoxicity towards ErbB2-expressing tumor cells of various origins in vitro. We evaluated the cytotoxicity of NK-93/5.28.z cells against a panel of glioblastoma cell lines and primary glioblastoma cultures with different levels of Erb2 expression in vitro and in vivo. CONCLUSIONS: Adoptive immunotherapy with application of ErbB2-specific NK-92/5.28.z cells may be a promising new immunotherapy approach for ErB2 positive glioblastoma. A phase I trial for glioblastoma patients with local injections of NK-92/5.28.z cells is in preparation. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
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