1 Department of Gynecology and Obstetrics, Hannover Medical School , Hannover, Germany .
2 Institute for Experimental Hematology, Hannover Medical School , Hannover, Germany .
Hum Gene Ther. 2017 Oct;28(10):886-896. doi: 10.1089/hum.2017.168. Epub 2017 Aug 24.
Ovarian cancer represents the most lethal gynecological cancer. Although cytoreductive chemotherapy and surgery lead to complete macroscopic tumor removal, most of the patients in advanced stages suffer from recurrent disease and subsequently die. This may be explained by the activity of cancer stem cells (CSC), which are a subpopulation of cells with an elevated chemoresistance and an increased capacity for self-renewal and metastatic spread. Specifically targeting these cells by adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. This study selected the widely accepted CSC marker CD133 as a target for a chimeric antigen receptor (CAR)-based immunotherapeutic approach to treat ovarian cancer. A lentiviral vector was generated encoding a third-generation anti-CD133-CAR, and clinically used NK92 cells were transduced. These engineered natural killer (NK) cells showed specific killing against CD133-positive ovarian cancer cell lines and primary ovarian cancer cells cultured from sequential ascites harvests. Additionally, specific activation of these engineered NK cells was demonstrated via interferon-gamma secretion assays. To improve clinical efficacy of ovarian cancer treatment, the effect of the chemotherapeutic agent cisplatin was evaluated together with CAR-transduced NK cell treatment. It was demonstrated that NK cells remain cytotoxic and active under cisplatin treatment and, importantly, that sequential treatment with cisplatin followed by CAR-NK cells led to the strongest killing effect. The specific eradication of ovarian CSCs by anti-CD133-CAR expressing NK92 cells represents a promising strategy and, when confirmed in vivo, shall be the basis of future clinical studies with the aim to prevent recurrent disease.
卵巢癌是最致命的妇科癌症。尽管细胞减灭化疗和手术导致完全的宏观肿瘤切除，但大多数晚期患者仍患有复发性疾病，并随后死亡。这可能是由于癌症干细胞 (CSC) 的活性所致，CSC 是具有高化疗耐药性和增强自我更新和转移扩散能力的细胞亚群。通过过继免疫疗法专门针对这些细胞是降低复发性疾病风险的一种有前途的策略。本研究选择了广泛接受的 CSC 标志物 CD133 作为基于嵌合抗原受体 (CAR) 的免疫治疗方法的靶标，用于治疗卵巢癌。生成了编码第三代抗-CD133-CAR 的慢病毒载体，并转导了临床使用的 NK92 细胞。这些工程化的自然杀伤 (NK) 细胞显示出针对 CD133 阳性卵巢癌细胞系和从连续腹水收获中培养的原发性卵巢癌细胞的特异性杀伤作用。此外，通过干扰素-γ分泌测定证明了这些工程化 NK 细胞的特异性激活。为了提高卵巢癌治疗的临床疗效，评估了化疗药物顺铂与 CAR 转导的 NK 细胞治疗一起的效果。结果表明，NK 细胞在顺铂治疗下保持细胞毒性和活性，重要的是，顺铂序贯治疗后再进行 CAR-NK 细胞治疗会导致最强的杀伤效果。表达抗-CD133-CAR 的 NK92 细胞特异性根除卵巢 CSC 代表了一种很有前途的策略，当在体内得到证实后，将成为未来旨在预防复发性疾病的临床研究的基础。
