A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis.
A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis.
复制标题
靶向PD-L1的嵌合开关受体增强CAR-T细胞对胸膜和腹膜转移的疗效
DOI：
10.1038/s41392-022-01198-2
复制
发表时间：
2022-11-19
影响因子：
39.3
通讯作者：
Wang, Yongsheng
中科院分区：
文献类型：
--
作者：
Ma, Qizhi;He, Xia;Zhang, Benxia;Guo, Fuchun;Ou, Xuejin;Yang, Qiyu;Shu, Pei;Chen, Yue;Li, Kai;Gao, Ge;Zhu, Yajuan;Qin, Diyuan;Tang, Jie;Li, Xiaoyu;Jing, Meng;Zhao, Jian;Mo, Zeming;Liu, Ning;Zeng, Yao;Zhou, Kexun;Feng, Mingyang;Liao, Weiting;Lei, Wanting;Li, Qiu;Li, Dan;Wang, Yongsheng
胸膜和腹膜转移伴恶性胸腔积液（MPE）或恶性腹水（MA）在源自肺、乳腺、胃肠道和卵巢的晚期实体瘤患者中很常见。CAR-T细胞的区域递送代表了控制肿瘤在浆膜腔中传播的新策略。然而，恶性积液构成了可能诱导CAR-T细胞功能障碍的免疫抑制环境。在这里，我们证明了常规第二代CAR-T细胞的抗肿瘤细胞毒性被MPE/MA的细胞和非细胞组分显著抑制，这主要归因于MPE/MA环境中CAR-T细胞增殖和细胞因子产生受损。有趣的是，我们发现PD-L1在新鲜分离的MPE/MA细胞上广泛表达。基于这一特性，设计了一种新型的PD-L1靶向嵌合开关受体（PD-L1.BB CSR），它可以与PD-L1结合，将抑制信号转换为额外的4-1BB信号。当与第二代CAR共表达时，PD-L1.BB CSR修饰的CAR-T细胞在培养基和MPE/MA环境中均显示出上级适应性和增强的功能，从而在异种移植模型中快速持久地根除胸膜和腹膜转移性肿瘤。进一步的研究显示T细胞活化、增殖和细胞毒性相关基因的表达升高，我们证实PD-L1 scFv和4-1BB胞内结构域（PD-L1.BB CSR的两个重要组成部分）对于CAR-T细胞的功能改善都是必需的。总的来说，我们的研究阐明了PD-L1.BB CSR修饰的双重靶向CAR-T细胞的临床应用。基于该研究，在胸膜或腹膜转移患者中启动了I期临床试验（NCT 04684459）。
Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).
登录
查看更多内容
影响因子：
10
作者：
Clive AO;Kahan BC;Hooper CE;Bhatnagar R;Morley AJ;Zahan-Evans N;Bintcliffe OJ;Boshuizen RC;Fysh ET;Tobin CL;Medford AR;Harvey JE;van den Heuvel MM;Lee YC;Maskell NA
通讯作者：
Maskell NA
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA
影响因子：
3.4
作者：
Kostron, Arthur;Friess, Martina;Opitz, Isabelle
通讯作者：
Opitz, Isabelle
影响因子：
5.3
作者：
Ikematsu, Yuki;Tanaka, Kentaro;Okamoto, Isamu
通讯作者：
Okamoto, Isamu
影响因子：
4.6
作者：
Jiwangga, Dhihintia;Cho, Sukki;Jheon, Sanghoon
通讯作者：
Jheon, Sanghoon