Chimeric antigen receptors containing the OX40 signalling domain enhance the persistence of T cells even under repeated stimulation with multiple myeloma target cells

作者：Tan, Jingwen; Jia, Yujie; Zhou, Meixia; Fu, Chengcheng; Tuhin, Israth Jahan; Ye, Jing; Monty, Masuma Akter; Xu, Nan; Kang, Liqing; Li, Minghao; Shao, Jiaqi; Fang, Xiaoyan; Zhu, Hongjia; Yan, Lingzhi; Qu, Changju; Xue, Shengli; Jin, Zhengming; Chen, Suning; Huang, Haiwen; Xu, Yang; Chen, Jia; Miao, Miao; Tang, Xiaowen; Li, Caixia; Yan, Zhiqiang^*; Wu, Depei^*; Yu, Lei^*

来源：Journal of Hematology & Oncology, 2022, 15(1): 39.

DOI：10.1186/s13045-022-01244-0

• Chimeric antigen receptor T cells
• Multiple myeloma
• Persistence
• Costimulatory molecules
• OX40
• CD28
• 41BB

Persistence of CAR-T cell function is associated with relapse rate after CAR-T therapy, while co-stimulatory agents are highly concerned with the persistence of CAR-T cells. In this study, we designed and constructed a series of BCMA-targeting second-generation CAR constructs containing CD28, 41BB, and OX40 molecules, respectively, to identify the costimulatory domains most favorable for persistence. The results of routine in vitro studies showed that OX40-CAR-T and 41BB-CAR-T had similar antitumor effects and were superior to CD28-CAR-T in terms of proliferation and cytotoxicity. Although difficult to distinguish by conventional functional assays, OX40-CAR-T cells exhibited greater proliferation and enhanced immune memory than 41BB-CAR-T cells with the repeated stimulation assay by BCMA-expressing target cells. In vivo studies further demonstrated that OX40-CAR-T cells had stronger proliferative activity than 41BB-CAR-T cells, which was highly consistent with the in vitro antitumor activity and proliferation results. Our study provides for the first time a scientific basis for designing OX40-CAR-T cell therapy to improve relapse in patients with MM after CAR-T treatment.

• 单位
  1; 苏州大学