Department of Hematology, The Second Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
R&D Department, HRAIN Biotechnology Co., Ltd., Shanghai, China.
Mol Ther. 2018 Apr 4;26(4):976-985. doi: 10.1016/j.ymthe.2018.01.022. Epub 2018 Feb 2.
Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3ζ T cell activating domain to form second-generation chimeric antigen receptors (CARs) that can increase the responsiveness and survival of CAR-engineered T (CAR-T) cells. However, a rigorous assessment of the individual benefits of these costimulatory components relative to the in vivo performance of infused T cells in patients is still lacking. Therefore, we have designed a study that allows us to investigate and compare the impact of different costimulatory signal domains on CAR-T cells in vivo. Patients with B cell leukemia were infused with a mixture of two types of CD19-specific CAR-T cells, individually bearing CD28 (28ζ) and 4-1BB (BBζ) costimulatory signaling domains. We found that such a clinical procedure was feasible and safe. Complete remission (CR) was observed in five of seven enrolled patients, with two patients exhibiting durable CR lasting more than 15 months. The in vivo expansion pattern of 28ζ and BBζ CAR-T cells varied significantly among individual patients. These results confirm a feasible method of comparing different CAR designs within individual patients, potentially offering objective insights that may facilitate the development of optimal CAR-T cell-based immunotherapies.
几项最近的临床试验成功地将源自 CD28 或 4-1BB 的共刺激结构域与原始的 CD3ζ T 细胞激活结构域结合在一起，形成了第二代嵌合抗原受体 (CAR)，可以提高 CAR 修饰的 T (CAR-T)细胞的反应性和存活率。然而，对于这些共刺激成分相对于输注 T 细胞在患者体内的体内表现的个体益处，仍然缺乏严格的评估。因此，我们设计了一项研究，使我们能够研究和比较不同共刺激信号结构域对体内 CAR-T 细胞的影响。患有 B 细胞白血病的患者输注了两种类型的 CD19 特异性 CAR-T 细胞的混合物，分别携带 CD28（28ζ）和 4-1BB（BBζ）共刺激信号结构域。我们发现这种临床程序是可行且安全的。在 7 名入组患者中，有 5 名患者观察到完全缓解 (CR)，其中 2 名患者的 CR 持续时间超过 15 个月。28ζ 和 BBζ CAR-T 细胞在体内的扩增模式在个体患者之间存在显著差异。这些结果证实了在个体患者内比较不同 CAR 设计的可行方法，可能为开发最佳的基于 CAR-T 细胞的免疫疗法提供客观的见解。
