Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Clin Cancer Res. 2010 Jan 15;16(2):474-85. doi: 10.1158/1078-0432.CCR-09-1322. Epub 2010 Jan 12.
Glioblastoma multiforme (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 GBM patients 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. 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-gamma and interleukin-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 autologous GBM xenografts established in the brain of severe combined immunodeficient 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.
多形性胶质母细胞瘤（GBM）是最具侵袭性的人类原发性脑肿瘤，目前尚无治愈方法。免疫疗法有可能针对GBM 干细胞，这些干细胞对常规疗法具有抗性。人类表皮生长因子受体 2（HER2）是一个经过验证的免疫治疗靶点，我们确定是否可以从 GBM 患者中产生针对自体 HER2 阳性 GBM 及其 CD133 阳性干细胞区室的 HER2 特异性 T 细胞。
通过转导编码 HER2 特异性嵌合抗原受体的逆转录病毒载体，从 10 例连续 GBM 患者中生成 HER2 特异性 T 细胞。评估 HER2 特异性 T 细胞对自体 GBM 细胞（包括 CD133 阳性干细胞）的效应功能，包括在体外和在原位啮齿动物异种移植模型中。
用 HER2 阳性自体 GBM 细胞刺激 HER2 特异性 T 细胞，导致 T 细胞增殖，并以 HER2 依赖性方式分泌 IFN-γ和白细胞介素-2。患者的 HER2 特异性 T 细胞杀伤源自原发性 HER2 阳性 GBM 的 CD133 阳性和 CD133 阴性细胞，而 HER2 阴性肿瘤细胞则不被杀伤。注射 HER2 特异性 T 细胞可诱导自体 GBM 异种移植在严重联合免疫缺陷小鼠脑内的持续消退。
基因转移允许从 GBM 患者中可靠地产生 HER2 特异性 T 细胞，这些 T 细胞对自体 HER2 阳性肿瘤（包括其假定的干细胞）具有强大的抗肿瘤活性。因此，HER2 重定向 T 细胞的过继转移可能是 GBM 的一种有前途的免疫治疗方法。
