Regression of experimental medulloblastoma following transfer of HER2-specific T cells
Regression of experimental medulloblastoma following transfer of HER2-specific T cells
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DOI：
10.1158/0008-5472.can-06-4309
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发表时间：
2007-06-15
期刊：
影响因子：
11.2
通讯作者：
Gottschalk, Stephen
中科院分区：
文献类型：
--
作者：
Ahmed, Nabil;Ratnayake, Maheshika;Gottschalk, Stephen
髓母细胞瘤是儿童常见的恶性脑肿瘤。人表皮生长因子受体2 （HER2）在40%的髓母细胞瘤中表达，是目前积极的多模式治疗预后不良的危险因素。与乳腺癌相比，HER2仅在髓母细胞瘤中低水平表达，使得单克隆抗体无效。我们确定了移植了her2特异性嵌合抗原受体（CAR； her2特异性T细胞）的T细胞能否识别并杀死her2阳性髓母细胞瘤。在体外，her2阳性髓母细胞瘤刺激her2特异性T细胞可导致T细胞增殖，并以her2依赖的方式分泌ifn - γ和白细胞介素2 （IL-2）。在细胞毒性实验中，her2特异性T细胞杀死了自体her2阳性的原发髓母细胞瘤细胞和髓母细胞瘤细胞系，而her2阴性的肿瘤细胞没有被杀死。髓母细胞瘤患者和健康供体产生的her2特异性T细胞在功能上没有差异。在体内，her2特异性T细胞的过继性转移导致原位、异种严重联合免疫缺陷模型中已建立的髓母细胞瘤持续消退。相反，传递非转导T细胞不会改变肿瘤的生长模式。her2特异性T细胞的过继性转移可能是髓母细胞瘤的一种有前途的免疫治疗方法。
Medulloblastoma is a common malignant brain tumor of childhood. Human epidermal growth factor receptor 2 (HER2) is expressed by 40% of medulloblastomas and is a risk factor for poor outcome with current aggressive multimodal therapy. In contrast to breast cancer, HER2 is expressed only at low levels in medulloblastomas, rendering monoclonal antibodies ineffective. We determined if T cells grafted with a HER2specific chimeric antigen receptor (CAR; HER2-specific T cells) recognized and killed HER2-positive medullohlastomas. Ex vivo, stimulation of HER2-specific T cells with HER2-positive medulloblastomas resulted in T-cell proliferation and secretion of IFN-gamma and interleukin 2 (IL-2) in a HER2dependent manner. HER2-specific T cells killed autologous HER2-positive primary medulloblastoma cells and medulloblastoma cell lines in cytotoxicity assays, whereas HER2-negative tumor cells were not killed. No functional difference was observed between HER2-specific T cells generated from medulloblastoma patients and healthy donors. In vivo, the adoptive transfer of HER2-specific T cells resulted in sustained regression of established medulloblastomas in an orthotopic, xenogenic severe combined immunodeficiency model. In contrast, delivery of nontransduced T cells did not change the tumor growth pattern. Adoptive transfer of HER2-specific T cells may represent a promising immunotherapentic approach for medulloblastoma.