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1、Armed and accurate: engineering cytotoxic T cells for eradication of leukemia装备并确认：工程细胞毒性 T 细胞 根除白血病Marko RadicCorrespondence: Marko Radic mradicuthsc.eduAuthor AffiliationsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http:/creativecommons.o
2、rg/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractTranslational medicine depends on a rapid and efficient exchange of results between the bench and the bedside. A recent example from the field of ca
3、ncer immunotherapy highlights the essential nature of this exchange. Methods have been developed to convert a patients cytotoxic T cells into efficient and specific killers of cancer cells in patients with leukemia. By using recombinant DNA techniques, a lentiviral vector was constructed to express
4、chimeric antigen receptors in cytotoxic T cells from patients with advanced chronic lymphocytic leukemia. The purpose of the chimeric receptors was to direct the cytotoxic T cell activity against cells causing the cancer. The effect of infusing the engineered T cells back into the cancer patients wa
5、s tested in a Phase I trial at the University of Pennsylvania, and the initial results were described in two articles from the research team of Dr. Carl June. The remarkable success of this trial should energize further applications of biotechnology in the development of new cancer immunotherapies.转
6、化医学取决于工作台和病床间的快速，高效的转换的结果。最近的一个例子，从癌症的免疫疗法领域突出这种交换的本质。方法已被开发是将患者的细胞毒性 T 细胞转换成高效特异的癌细胞杀手。通过使用重组 DNA 技术，慢病毒载体构建从先进的慢性淋巴细胞白血病的患者的细胞毒性 T 细胞中表达嵌合抗原受体。嵌合受体的目的是指导细胞毒性 T 细胞对抗致癌细胞。 I 期临床试验在美国宾夕法尼亚大学设计的工程 T 细胞注入到癌症患者的影响进行了测试，卡尔博士的研究小组的两篇文章中描述了初步的结果。这项试验非凡的成功，应该激励在新的癌症免疫疗法的发展中进一步应用生物技术 Main TextRecent advances
7、 in cancer immunotherapy have allowed the conversion of T cells from leukemia patients into efficient and specific killers of their own cancer cells. The new technique has been recently tested with remarkable results. The outward signs of the successful therapy were dramatic and clear. The cancer pa
8、tients shook with fever, chills and pain; their blood pressure precipitously dropped. They drifted in and out of sleep for days following the infusion of their own engineered killer T cells. The internal struggle peaked between two and three weeks after T cell reinfusion. The load of lysed cancer ce
9、lls stressed and nearly poisoned the patients kidneys. Their immune systems, reinvigorated by the immunotherapy, had destroyed nearly 1 kg of cancer cells. No other available treatment could have achieved a comparable therapeutic success. The new treatment, administered by Dr. Carl June and his coll
10、eagues of the Abrahamson Cancer Center at the University of Pennsylvania, achieved an unprecedented complete eradication of the cancer in two of the three chronic lymphocytic leukemia (CLL) patients in whom it was tried. It had been a dream of many: the harnessing of the immune systems ferocious pow
11、er to eliminate an advanced metastatic cancer.在肿瘤免疫治疗的最新进展已经可以转换白血病患者 T 细胞变成自己的癌细胞的高效特异的细胞杀手。这项新技术最近已测试成效显着。成功治疗的外在表现是显着的，明确的。因发烧，发冷和疼痛而颤抖的癌症患者，他们的血压会急剧下降。在注入他们自己的工程杀伤性 T 细胞会使他们在睡醒之间辗转反侧好几天。 T 细胞回输后的内部斗争在两至三个星期间达到高峰。裂解肿瘤细胞的负荷加大了病人的肾脏压力并几乎肾中毒。通过免疫治疗恢复活力的免疫系统已经摧毁了近1 公斤的肿瘤细胞。没有其他可供选择的治疗已经取得了类似的治疗成功。由卡尔
12、博士和他的在美国宾夕法尼亚大学的亚伯拉罕森癌症研究中心的同事共同执行的新的治疗方法，在试验的3个慢性淋巴细胞白血病（CLL ）患者其中两个实现了前所未有的彻底根除癌症。它曾是许多人的梦想：利用免疫系统的惊人的治理力量消除晚期转移性癌症。The stunning results were published in two simultaneous journal articles 1,2, one of the reports presenting data from a single patient 1. The success was beyond expectation. This, af
13、ter all, was a Phase I clinical trial, one in which the primary objective was to test different doses of the engineered cytotoxic lymphocytes (CTL). Technically, the success could be traced to the fusion of extracellular and intracellular domains into a new, synthetic receptor for the CD8+ T cells 3
14、. In immunotherapy jargon, this type of recombinant protein is called a chimeric antigen receptor (CAR). In this case, the extracellular domain was derived from a mouse monoclonal antibody specific for the CD19 surface protein of human B cells. Because CLL is a B cell cancer, CLL cells express CD19.
15、 The anti-CD19 antibody was reduced to its smallest active form, a single-chain variable fragment (scFv), and grafted onto a T cell receptor transmembrane domain. On the inside of the cell, the construct was fused to the cytoplasmic signaling domains of CD137 (41BB) and the chain of CD3 (Figure 1).
16、This particular combination of functional domains is credited for achieving the spectacular success of the therapy令人惊叹的研究结果发表在两个同时进行的期刊文章，其中一个报告数据来自一个单身病人。这个成功的研究是出乎意料的。毕竟，这是第一期临床试验，其主要目的之一是测试不同剂量的工程细胞毒性 T 细胞（CTL） 。从技术上讲，这次成功可以追溯到融合细胞外和细胞内结构域成一个新的，合成受体的CD8+ T 细胞。在免疫治疗术语中，这种类型的重组蛋白被称为嵌合抗原受体（CAR） 。在这种案例中，胞外结构域是来自特定的人类 B 细胞 CD19表面蛋白的小鼠单克隆抗体。由于 CLL 是一种 B 细胞癌，所以白血病细胞表达 CD19蛋白。抗-CD19 抗体被减少到最小的活性形式，单链可变区片段（scFv ） ，并且被移植到 T 细胞受体的跨膜结构域。在细胞的里面，该结构被融合到胞质信号域CD137（41BB）和 CD3 链（图1） 。这种
