Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells.
Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells.
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发表时间：
2010-04
影响因子：
1.4
通讯作者：
Jae H. Park;R. Brentjens
中科院分区：
文献类型：
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作者：
Jae H. Park;R. Brentjens
耐化疗的B细胞恶性血液病可以通过异基因造血干细胞移植(HSCT)治愈，这表明这些肿瘤对供者T细胞介导的免疫反应具有潜在的敏感性。然而，移植相关的高发病率和死亡率限制了这种方法。出于这个原因，迫切需要毒性较低的基于免疫的细胞疗法来治疗这些恶性肿瘤。过继转移基因修饰的自体T细胞以表达针对特定肿瘤相关抗原的嵌合抗原受体(CARS)是克服传统HSCT局限性的一种有吸引力的方法。为此，研究人员已经产生了针对B细胞恶性肿瘤表达的各种抗原的CARS，优化了这些CARS的设计以增强受体介导的T细胞信号，并在体外和体内小鼠肿瘤模型中证明了由此产生的CAR修饰的T细胞具有显著的抗肿瘤效果。这些令人鼓舞的临床前数据证明了将这种方法转化为临床环境的合理性，目前有12项公开临床试验和一项已完成的临床试验，使用针对CD19或CD20 B细胞特异性抗原的CAR修饰T细胞治疗各种B细胞恶性肿瘤。
Chemotherapy-resistant B-cell hematologic malignancies may be cured with allogeneic hematopoietic stem cell transplantation (HSCT), demonstrating the potential susceptibility of these tumors to donor T-cell mediated immune responses. However, high rates of transplant-related morbidity and mortality limit this approach. For this reason, there is an urgent need for less-toxic forms of immune-based cellular therapy to treat these malignancies. Adoptive transfer of autologous T cells genetically modified to express chimeric antigen receptors (CARs) targeted to specific tumor-associated antigens represents an attractive means of overcoming the limitations of conventional HSCT. To this end, investigators have generated CARs targeted to various antigens expressed by B-cell malignancies, optimized the design of these CARs to enhance receptor mediated T cell signaling, and demonstrated significant anti-tumor efficacy of the resulting CAR modified T cells both in vitro and in vivo mouse tumor models. These encouraging preclinical data have justified the translation of this approach to the clinical setting with currently 12 open clinical trials and one completed clinical trial treating various B-cell malignancies utilizing CAR modified T cells targeted to either the CD19 or CD20 B-cell specific antigens.