Biotherapy Center, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450003, China.
Stem Cell Research Center, People's Hospital of Henan Province, Zhengzhou University, Zhengzhou, 450003, China.
Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):59-66. doi: 10.1016/j.bbrc.2018.10.151. Epub 2018 Nov 6.
Adoptive immunotherapy using chimeric antigen receptors-modified T cells (CAR-T) is a promising approach for cancer treatment. However, CARs currently applied in the clinics cannot be effectively regulated and the safety of CAR-T cell therapies remains a major concern. To improve the safety of CAR-T cells, we designed a synthetic splitting CAR (ssCAR) that can regulate T cell functions exogenously. Epidermal growth factor receptor variant III (EGFRvIII) was used as a molecular target for ssCAR. Our results indicate that both EGFRvIII and small molecule are needed for the activation of the ssCAR-T cells. AP21967 dose-dependently increased the expression of T cell activation, production of cytokines and extent of cell lysis. In conclusion, the gene switch designed in this study allows for temporal and spatial control over engineered T cells in a dose-and time-dependent manner by AP21967. Our work demonstrates the feasibility and improved safety profile of this novel treatment approach.
嵌合抗原受体修饰 T 细胞（CAR-T）的过继免疫疗法是一种很有前途的癌症治疗方法。然而，目前应用于临床的 CAR 不能有效地被调控，CAR-T 细胞疗法的安全性仍然是一个主要关注点。为了提高 CAR-T 细胞的安全性，我们设计了一种可以外源性调控 T 细胞功能的合成分裂 CAR（ssCAR）。表皮生长因子受体变异 III（EGFRvIII）被用作 ssCAR 的分子靶标。我们的结果表明，ssCAR-T 细胞的激活需要 EGFRvIII 和小分子。AP21967 呈剂量依赖性地增加 T 细胞激活、细胞因子产生和细胞裂解的程度。总之，本研究设计的基因开关可以通过 AP21967 实现工程化 T 细胞的时间和空间控制，具有剂量和时间依赖性。我们的工作证明了这种新型治疗方法的可行性和安全性的提高。
