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基因修饰的T细胞治疗白血病

一个在三名病人中进行的新的研究报告说,经过基因修饰的免疫细胞在转移到3个病人的体内后可对肿瘤发动攻击并促进癌症的缓解。 这些有设计标识的T细胞会表达一种人造的受体,而该受体可特异性地以白血病细胞作为标靶。 通过对身体的抗感染T细胞进行重新编程来寻找并摧毁癌症细胞,研究人员正在尝试研发可利用身体自身免疫系统治疗潜力的新型的“智能”抗癌疗法。 在理想的情况下,这些治疗可杀灭癌症但却不会损害机体的健康细胞,而这正是诸如放疗和化疗等疗法的主要缺陷。 然而,训练T细胞来发现肿瘤并在病人体内维持这些细胞仍然是一种挑战。 如今,Michael Kalos及其同事修饰了T细胞的基因,使其能够表达一种经过设计的可特异性地以慢性淋巴细胞性白血病作为标靶的抗原受体。 这些有设计标识的T细胞在转移到3名病人的体内后会增生,它们在体内可持续6个月的时间,并会攻击肿瘤细胞。 事实上,这3名接受了T细胞治疗的病人中有2人出现了白血病完全的缓解。 然而,在一名患者中,其白细胞看上去就像是无辜的旁观者。该患者出现了低丙球蛋白血症,这是一种让免疫系统很难制造抗体的疾病。 这一早期的临床试验显示,经过基因修饰的T细胞也许可被人们添加到抗癌疗法的武器库中。

 

英文论文摘要:

T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia

Abstract: Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials. We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months. Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex–independent approach for the effective treatment of B cell malignancies.

 

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