分泌 PD-L1 阻断 scFv 的间皮素 CAR-T 细胞用于胰腺癌治疗。
Mesothelin CAR-T cells secreting PD-L1 blocking scFv for pancreatic cancer treatment.
机构信息
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.
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.
出版信息
Cancer Genet. 2022 Nov;268-269:103-110. doi: 10.1016/j.cancergen.2022.10.003. Epub 2022 Oct 18.
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-γ 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.
PD-1/PD-L1 通路引起的免疫抑制至少部分解释了嵌合抗原受体 T（CAR-T）对实体瘤治疗效果不佳的原因。在这项研究中，我们设计并制备了能够分泌 PD-L1 阻断抗体并靶向间皮素抗原（Sec-MesoCAR-T）的 CAR-T 细胞，以消除肿瘤对 CAR-T 细胞的免疫抑制作用，从而提高 CAR-T 细胞对胰腺癌的治疗效果。未分泌 PD-L1 阻断抗体的 CAR-T 细胞（MesoCAR-T）被用作对照。Sec-MesoCAR-T 细胞在体外和体内对 BxPC-3 肿瘤的抑制作用均强于 MesoCAR-T 细胞。此外，Sec-MesoCAR-T 细胞在体外分泌的细胞因子（包括 IL-2、IL-6 和 IFN-γ）水平高于 MesoCAR-T 细胞。注射后，Sec-MesoCAR-T 组外周血中的 CAR-T 细胞明显多于 MesoCAR-T 组。这项工作表明，Sec-MesoCAR-T 细胞分泌的 PD-L1 抗体缓解了胰腺癌对 CAR-T 细胞的免疫抑制作用，提高了 CAR-T 细胞的抗肿瘤活性，这对 CAR-T 细胞在治疗实体瘤中的临床应用具有很好的指导意义。
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