CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains
CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains
复制标题
DOI：
10.1158/2326-6066.cir-15-0060
复制
发表时间：
2016-03-01
影响因子：
10.1
通讯作者：
Natsume, Atsushi
中科院分区：
文献类型：
--
作者：
Shiina, Satoshi;Ohno, Masasuke;Natsume, Atsushi
胶质母细胞瘤（GBM）是成人最常见、最致命的原发性恶性脑肿瘤，5年总生存率不到10%。Podoplanin （PDPN）是一种I型跨膜黏液样糖蛋白，在淋巴内皮中表达。一些实体肿瘤过度表达PDPN，包括GBM的间充质型，据报道在GBM亚型中预后最差。嵌合抗原受体（CAR）转导的T细胞可以识别预定义的肿瘤表面抗原，不依赖于MHC限制，MHC限制在胶质瘤中经常下调。我们构建了一个慢病毒载体，表达含有pdpn特异性抗体（基于nz -1的单链可变片段）的第三代CAR，具有CD28、4-1BB和CD3 zeta细胞内结构域。通过钙黄蛋白介导的细胞毒性试验、ELISA、肿瘤大小和总生存率对car转导的外周血单核细胞进行免疫评价。生成的CAR - T细胞在体外对pdpn阳性GBM细胞具有特异性和有效性。将CAR - T细胞全身注射到免疫缺陷小鼠模型中，体内抑制了颅内胶质瘤异种移植物的生长。靶向PDPN的CAR - t细胞疗法将是治疗间充质GBM的一种有前途的过继免疫疗法。(c) 2016年aacr。
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 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) with CD28, 4-1BB, and CD3 zeta intracellular domains. CAR-transduced peripheral blood monocytes 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. (C) 2016 AACR.