Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15
Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15
复制标题
DOI：
10.1038/nm827
复制
发表时间：
2003-03-01
期刊：
影响因子：
82.9
通讯作者：
Sadelain, M
中科院分区：
文献类型：
--
作者：
Brentjens, RJ;Latouche, JB;Sadelain, M
抗原受体的遗传转移提供了一种快速产生自体肿瘤反应性T淋巴细胞的方法。然而，细胞毒性 T 细胞识别肿瘤抗原只是有效癌症免疫治疗的第一步。必须满足其他重要的生物学先决条件才能扩展保留功能表型的肿瘤反应性 T 细胞，包括体内细胞溶解活性和前往肿瘤部位而不过早屈服于细胞凋亡的能力。我们证明，在 CD80 和白细胞介素 15 (IL-15) 存在的情况下，通过扩增基因靶向 CD19 抗原的外周血 T 细胞，可以满足这些要求。在 IL-15 存在下，T 细胞在荷瘤严重联合免疫缺陷 (SCID) 米色小鼠中独特地持续扩增，并根除播散性髓内肿瘤。它们的抗肿瘤活性通过体内共刺激进一步增强。此外，来自慢性淋巴细胞白血病 (CLL) 患者的转导 T 细胞可有效裂解自体肿瘤细胞。这些发现有力地支持了这种治疗策略的临床可行性。
The genetic transfer of antigen receptors provides a means to rapidly generate autologous tumor-reactive T lymphocytes. However, recognition of tumor antigens by cytotoxic T cells is only one step towards effective cancer immunotherapy. Other crucial biological prerequisites must be fulfilled to expand tumor-reactive T cells that retain a functional phenotype, including in vivo cytolytic activity and the ability to travel to tumor sites without prematurely succumbing to apoptosis. We show that these requirements are met by expanding peripheral blood T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15). T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors. Their anti-tumor activity is further enhanced by in vivo co-stimulation. In addition, transduced T cells from patients with chronic lymphocytic leukemia (CLL) effectively lyse autologous tumor cells. These findings strongly support the clinical feasibility of this therapeutic strategy.