In Vivo Expansion and Antitumor Activity of Coinfused CD28-and 4-1BB-Engineered CAR-T Cells in Patients with B Cell Leukemia
In Vivo Expansion and Antitumor Activity of Coinfused CD28-and 4-1BB-Engineered CAR-T Cells in Patients with B Cell Leukemia
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DOI：
10.1016/j.ymthe.2018.01.022
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发表时间：
2018-04-04
影响因子：
12.4
通讯作者：
Wang, Pin
中科院分区：
文献类型：
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作者：
Cheng, Zhi;Wei, Runhong;Wang, Pin
最近的几项临床试验已经成功地将源自CD 28或4-1BB的共刺激结构域与原始CD 3 zeta T细胞活化结构域结合，以形成第二代嵌合抗原受体（汽车），其可以增加CAR工程化T（CAR-T）细胞的反应性和存活。然而，仍然缺乏对这些共刺激组分相对于患者中输注的T细胞的体内性能的个体益处的严格评估。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。B细胞白血病患者输注了两种类型的CD 19特异性CAR-T细胞的混合物，分别携带CD 28（28 zeta）和4-1BB（BB zeta）共刺激信号结构域。我们发现这种临床手术是可行和安全的。在7名入组患者中的5名中观察到完全缓解（CR），其中2名患者表现出持续超过15个月的持久CR。28 z和BBz CAR-T细胞的体内扩增模式在个体患者中差异显著。这些结果证实了在个体患者中比较不同CAR设计的可行方法，可能提供客观的见解，可能有助于开发最佳的基于CAR-T细胞的免疫疗法。
Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3 zeta 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 (28 zeta) and 4-1BB (BB zeta) 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 28z and BBz 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.