HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.
HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.
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DOI：
10.1158/1078-0432.ccr-09-1322
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Gottschalk S
中科院分区：
文献类型：
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作者：
Ahmed N;Salsman VS;Kew Y;Shaffer D;Powell S;Zhang YJ;Grossman RG;Heslop HE;Gottschalk S
胶质母细胞瘤（GBM）是最具侵袭性的人类原发性脑肿瘤，目前无法治愈。免疫疗法具有靶向GBM干细胞的潜力，GBM干细胞对常规疗法具有抗性。人表皮生长因子受体2（HER 2）是一种经过验证的免疫治疗靶点，我们确定了HER 2特异性T细胞是否可以从患有靶向自体HER 2阳性GBM及其CD 133阳性干细胞区室的疾病的患者中产生。通过用编码HER 2特异性嵌合抗原受体（CAR）的逆转录病毒载体转导来产生来自10个连续GBM患者的HER 2特异性T细胞。在体外和原位鼠异种移植模型中评价了HER 2特异性T细胞对自体GBM细胞（包括CD 133阳性干细胞）的效应子功能。用HER 2阳性自体GBM细胞刺激HER 2特异性T细胞导致T细胞增殖并以HER 2依赖性方式分泌IFN-γ和IL-2。患者的HER 2特异性T细胞杀死源自原发性HER 2阳性GBM的CD 133阳性和CD 133阴性细胞，而HER 2阴性肿瘤细胞未被杀死。注射HER 2特异性T细胞诱导在SCID小鼠脑中建立的自体GBM异种移植物的持续消退。基因转移允许从GBM患者中可靠地产生HER 2特异性T细胞，其对自体HER 2阳性肿瘤（包括其推定的干细胞）具有有效的抗肿瘤活性。因此，HER 2重定向的T细胞的过继转移可能是GBM的有希望的免疫方法。
Glioblastoma (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target and we determined if HER2-specific T cells can be generated from patients with disease that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment. HER2-specific T cells from 10 consecutive GBM patients were generated by transduction with a retroviral vector encoding a HER2-specific chimeric antigen receptor (CAR). The effector function of HER2-specific T cells against autologous GBM cells, including CD133-positive stem cells, was evaluated in vitro and in an orthotopic murine xenograft model. Stimulation of HER2-specific T cells with HER2-positive autologous GBM cells resulted in T-cell proliferation and secretion of IFN-γ and IL-2 in a HER2-dependent manner. Patients’ HER2-specific T cells killed CD133-positive and CD133-negative cells derived from primary HER2-positive GBMs, whereas HER2-negative tumor cells were not killed. Injection of HER2-specific T cells induced sustained regression of established autologous GBM xenografts established in the brain of SCID mice. Gene transfer allows the reliable generation of HER2-specific T cells from GBM patients, which have potent antitumor activity against autologous HER2-positive tumors including their putative stem cells. Hence, the adoptive transfer of HER2-redirected T-cells may be a promising immunotherapeutic approach for GBM.