提吉特
下调和上调
嵌合抗原受体
癌症研究
CD19
T细胞
免疫检查点
免疫学
免疫系统
生物
免疫疗法
生物化学
基因
作者
Young-Ho Lee,Hyeong Ji Lee,Hyung Cheol Kim,Yujean Lee,Su Kyung Nam,Cedric Hupperetz,Jennifer S.Y.,Xinxin Wang,Oded Singer,Won Seog Kim,Seok Jin Kim,Youngil Koh,Inkyung Jung,Chan Hyuk Kim
标识
DOI:10.1016/j.ymthe.2021.10.004
摘要
CD19-targeting chimeric antigen receptor (CAR) T cells have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, a significant portion of patients still do not benefit from the therapy owing to various resistance mechanisms, including high expression of multiple inhibitory immune checkpoint receptors. Here, we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors are downregulated simultaneously by a dual short hairpin RNA cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations-PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT-and found that CAR T cells with PD-1/TIGIT downregulation uniquely exerted synergistic antitumor effects. Importantly, functional and phenotypic analyses suggested that downregulation of PD-1 enhances short-term effector function, whereas downregulation of TIGIT is primarily responsible for maintaining a less differentiated/exhausted state, providing a potential mechanism for the observed synergy. The PD-1/TIGIT-downregulated CAR T cells generated from diffuse large B cell lymphoma patient-derived T cells also showed robust antitumor activity and significantly improved persistence in vivo. The efficacy and safety of PD-1/TIGIT-downregulated CD19-targeting CAR T cells are currently being evaluated in adult patients with relapsed or refractory large B cell lymphoma (ClinicalTrials.gov: NCT04836507).
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