Ahmed Nabil, Ratnayake Maheshika, Savoldo Barbara, Perlaky Laszlo, Dotti Gianpietro, Wels Winfried S, Bhattacharjee Meenakshi B, Gilbertson Richard J, Shine H David, Weiss Heidi L, Rooney Cliona M, Heslop Helen E, Gottschalk Stephen
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, Texas 77030, USA.
Cancer Res. 2007 Jun 15;67(12):5957-64. doi: 10.1158/0008-5472.CAN-06-4309.
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 HER2-specific chimeric antigen receptor (CAR; HER2-specific T cells) recognized and killed HER2-positive medulloblastomas. 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 HER2-dependent 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 immunotherapeutic approach for medulloblastoma.
髓母细胞瘤是儿童期常见的恶性脑肿瘤。40%的髓母细胞瘤表达人类表皮生长因子受体2（HER2），并且是当前积极的多模式治疗中预后不良的一个危险因素。与乳腺癌不同，HER2在髓母细胞瘤中仅低水平表达，使得单克隆抗体无效。我们确定了移植有HER2特异性嵌合抗原受体的T细胞（CAR；HER2特异性T细胞）是否能识别并杀死HER2阳性的髓母细胞瘤。在体外，用HER2阳性的髓母细胞瘤刺激HER2特异性T细胞会导致T细胞增殖，并以HER2依赖的方式分泌γ干扰素和白细胞介素2（IL-2）。在细胞毒性试验中，HER2特异性T细胞杀死了自体HER2阳性的原发性髓母细胞瘤细胞和髓母细胞瘤细胞系，而HER2阴性肿瘤细胞未被杀死。在由髓母细胞瘤患者和健康供体产生的HER2特异性T细胞之间未观察到功能差异。在体内，在原位异种基因严重联合免疫缺陷模型中，HER2特异性T细胞的过继转移导致已建立的髓母细胞瘤持续消退。相比之下，递送未转导的T细胞并未改变肿瘤生长模式。HER2特异性T细胞过继转移可能是一种有前景的髓母细胞瘤免疫治疗方法。
