CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
分泌 PD-L1 阻断 scFv 的间皮素 CAR-T 细胞用于胰腺癌治疗
英文原题：Mesothelin CAR-T cells secreting PD-L1 blocking scFv for pancreatic cancer treatment.
查看英文原题
Mesothelin CAR-T cells secreting PD-L1 blocking scFv for pancreatic cancer treatment.
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中文摘要
PD-1/PD-L1通路引发的免疫抑制至少部分解释了CAR-T（CAR-T）细胞治疗实体瘤疗效较差。本研究设计并制备了能够分泌PD-L1阻断抗体且靶向间皮素抗原的CAR-T 细胞（Sec-MesoCAR-T），以消除肿瘤对CAR-T 细胞的免疫抑制作用，进而提高CAR-T 细胞治疗胰腺癌的疗效。将不能分泌PD-L1阻断抗体的CAR-T 细胞（MesoCAR-T）作为对照。体内外实验中，与MesoCAR-T 相比，Sec-MesoCAR-T 对BxPC-3肿瘤的抑制作用更强。
此外，Sec-MesoCAR-T 体外分泌的IL-2、IL-6和IFN-γ等细胞因子水平高于MesoCAR-T。注射后，Sec-MesoCAR-T 组外周血CAR-T 细胞数量显著高于MesoCAR-T 组。
本研究证明，Sec-MesoCAR-T 分泌的PD-L1抗体减轻了胰腺癌对CAR-T 细胞的免疫抑制作用，并提高其抗肿瘤活性，对CAR-T 细胞治疗实体瘤的临床应用具有良好指导意义。
展开英文摘要原文
PD-1/PD-L1 pathway caused immunosuppression accounts, at least partly, for the poor therapeutic effect of Chimeric Antigen Receptor T (CAR-T) on solid tumors. In this study, we designed and prepared CAR-T cells that could secrete PD-L1 blocking antibody and target Mesothelin antigen (Sec-MesoCAR-T), to remove the immunosuppressive effect of tumor on CAR-T cells, thereby increasing the therapeutic effect of CAR-T cells on pancreatic cancer. The CAR-T cells that could not secret PD-L1 blocking antibodies (MesoCAR-T) were used as a control. Sec-MesoCAR-T cells showed an enhanced inhibitory effect on BxPC-3 tumor than MesoCAR-T cells in vitro and in vivo.
Besides, Sec-MesoCAR-T cells secreted higher level of cytokines including IL-2, IL-6 and IFN- in vitro than MesoCAR-T cells. Following injection, there were significantly more CAR-T cells in the peripheral blood of Sec-MesoCAR-T group than that of MesoCAR-T group.
This work demonstrated that the PD-L1 antibody secreted by Sec-MesoCAR-T cells relieved the immunosuppressive effect of pancreatic cancer on CAR-T cells and improved the anti-tumor activity of CAR-T cells, which has a good guiding significance for the clinical application of CAR-T cells in treating solid tumors.
论文信息
- 作者
- Wang Y、Fang X、Li M、Ye J、Zhao S、Yu L、Wang J、Wang Y
- 第一作者单位
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P R China; Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Lanzhou 730000, P R China.China
- 通讯作者单位
- Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P R China. Electronic address: zqyan@sat.ecnu.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Cancer genetics2022 Nov
- 原文标识
- PubMed 36288641 · DOI 10.1016/j.cancergen.2022.10.003