CAR-T细胞靶向整合膜蛋白减少小鼠模型脑部的原位胶质母细胞瘤

技术资料下载地址: http://www.ncbi.nlm.nih.gov/pubmed/26822025
文献来源: Cancer Immunol Res.
CAR T cells targeting podoplanin reduce orthotopic glioblastomas in mouse brains.
Abstract
Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR) transduced T cells can recognize predefined tumor surface antigens independent of major histocompatibility complex (MHC) restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third generation CAR comprising a PDPN-specific antibody [NZ-1-based single chain variable fragment (scFv)] with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes (PBMCs) were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM.
CAR-T细胞靶向整合膜蛋白减少小鼠模型脑部的原位胶质母细胞瘤
摘要：
胶质母细胞瘤（GBM）是成人最常见的致死性原发性恶性脑肿瘤，5年生存率小于10%。Podoplanin（PDPN）是I型跨膜粘蛋白样蛋白，在淋巴管内皮细胞表面表达。有几种实体肿瘤过度表达PDPN，包括GBM间质型，而且是目前已报道的预后最差的GBM亚型。嵌合抗原受体（CAR）转导的T细胞可以识别肿瘤表面抗原独立的主要组织相容性复合体（MHC）的限制，这往往在胶质瘤表面是下调的。我们构建的慢病毒载体，三代CAR-T包括PDPN特异性抗体[ nz-1-为基础的单链可变区片段（scFv）]与CD28和4-1BB，CD3ζ胞内域。CAR转导的外周血单核细胞通过钙黄绿素介导的细胞毒试验、ELISA、肿瘤大小、生存期和总生存期来进行免疫评价。CAR-T细胞特异性和体外抗GBM细胞积极有效。CAR-T细胞注射到免疫缺陷小鼠模型系统在体内抑制脑胶质瘤生长。CAR-T细胞治疗PDPN，将有希望过继免疫细胞治疗间质性GBM。

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