Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells
Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells
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DOI：
10.1016/j.ccell.2019.01.002
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发表时间：
2019-02-11
期刊：
影响因子：
50.3
通讯作者：
Dotti, Gianpietro
中科院分区：
文献类型：
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作者：
Du, Hongwei;Hirabayashi, Koichi;Dotti, Gianpietro
B7-H3 在多种肿瘤类型中的高表达和在正常组织中的有限表达使得 B7-H3 成为免疫治疗的有吸引力的靶点。我们生成了靶向 B7-H3 (B7-H3.CAR-Ts) 的嵌合抗原受体 (CAR) T 细胞，并发现 B7-H3.CAR-Ts 在体外以及原位和转移性异种移植小鼠模型（包括患者来源的异种移植物）中控制胰腺导管腺癌、卵巢癌和神经母细胞瘤的生长。我们还发现，4-1BB 共刺激可促进 B7-H3.CAR-T 中 PD-1 的表达降低，并且在靶向组成型表达 PD-L1 的肿瘤细胞时具有优异的抗肿瘤活性。我们利用 B7-H3.CAR 与小鼠 B7-H3 的交叉反应性，发现 B7-H3.CAR-T 在同基因肿瘤模型中显着控制肿瘤生长，且没有明显毒性。这些发现支持 B7-H3.CAR-T 的临床开发。
The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.CAR-Ts controlled the growth of pancreatic ductal adenocarcinoma, ovarian cancer and neuroblastoma in vitro and in orthotopic and metastatic xenograft mouse models, which included patient-derived xenograft. We also found that 4-1BB co-stimulation promotes lower PD-1 expression in B7-H3.CAR-Ts, and superior antitumor activity when targeting tumor cells that constitutively expressed PD-L1. We took advantage of the cross-reactivity of the B7-H3.CAR with murine B7-H3, and found that B7-H3.CAR-Ts significantly controlled tumor growth in a syngeneic tumor model without evident toxicity. These findings support the clinical development of B7-H3.CAR-Ts.