Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Biomed Eng. 2021 Nov;5(11):1261-1273. doi: 10.1038/s41551-021-00800-2. Epub 2021 Nov 1.
Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and stimulating CD3-mediated signalling are being used in patients to treat acute B-cell lymphoblastic leukemia. However, the potency of BiTEs in solid tumours is limited by their short half-life and their severe toxicity at relevant therapeutic doses. Here we report the design and in vivo performance of a bispecific antibody that simultaneously targets the murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death ligand 1 (PD-L1). In multiple syngeneic tumour models, the bispecific antibody generated higher antitumour immune responses than conventional BiTEs targeting tumour-associated antigens and CD3ε. We found that the durable antigen-specific T-cell responses resulted from the rejuvenation of CD8 T cells, owing to the blockade of PD-L1 on dendritic cells (but not on tumour cells) and co-stimulation by B7-1&2 (a peripheral membrane protein on dendritic cells). Bispecific T-cell engagers targeting dendritic cells rather than tumour cells may represent a general means of T-cell rejuvenation for durable cancer immunotherapy.
双特异性 T 细胞衔接器（BiTEs）优先靶向肿瘤相关抗原，并刺激 CD3 介导的信号转导，目前正在被用于治疗急性 B 细胞淋巴细胞白血病。然而，BiTEs 在实体瘤中的效力受到其半衰期短和在相关治疗剂量下严重毒性的限制。在这里，我们报告了一种双特异性抗体的设计和体内性能，该抗体同时靶向鼠 T 细胞共受体 CD3ε 和鼠免疫检查点程序性死亡配体 1（PD-L1）。在多种同基因肿瘤模型中，双特异性抗体产生的抗肿瘤免疫反应高于传统靶向肿瘤相关抗原和 CD3ε 的 BiTEs。我们发现，持久的抗原特异性 T 细胞反应是由于树突状细胞上 PD-L1 的阻断（而不是肿瘤细胞上）和 B7-1&2（树突状细胞上的外周膜蛋白）的共刺激作用，导致 CD8 T 细胞的再生。靶向树突状细胞而不是肿瘤细胞的双特异性 T 细胞衔接器可能代表一种用于持久癌症免疫治疗的 T 细胞再生的通用方法。
