School of Pharmacy, Quanzhou Medical College, Quanzhou, Fujian, China.
Institute of Immunotherapy, Fujian Medical University, Fuzhou, Fujian, China.
PLoS One. 2024 Oct 1;19(10):e0310430. doi: 10.1371/journal.pone.0310430. eCollection 2024.
Over the years, CAR-T cell therapy has achieved remarkable success in treating hematological malignancies. However, this efficacy has not been replicated in the context of glioblastoma (GBM). In this study, a PD1CD28 chimeric molecule was introduced into EGFRvⅢ-directed CAR-T cells, generating EGFRvⅢ-P2A-PD1CD28 CAR-T cells. Notably, this modification significantly increased IL-2 secretion and enhanced antigen-dependent activation of CAR-T cells, especially when programmed cell death ligand 1 (PD-L1) was present in vitro. In addition, the in vivo xenograft experiments revealed that the PD1CD28 chimeric molecule played a pivotal role in reducing recurrence rates, effectively controlling recurrent tumor volume, and ultimately prolonging the survival of mice. Collectively, these findings suggest that EGFRvⅢ-directed CAR-T cells co-expressing the PD1CD28 chimeric molecule have the potential to significantly enhance the treatment efficacy against GBM.
多年来，嵌合抗原受体 T 细胞（CAR-T）疗法在治疗血液系统恶性肿瘤方面取得了显著的成功。然而，这种疗效在胶质母细胞瘤（GBM）中并未得到复制。在这项研究中，我们将 PD1CD28 嵌合分子引入到 EGFRvⅢ 导向的 CAR-T 细胞中，生成了 EGFRvⅢ-P2A-PD1CD28 CAR-T 细胞。值得注意的是，这种修饰显著增加了 IL-2 的分泌，并增强了 CAR-T 细胞的抗原依赖性激活，尤其是在体外存在程序性细胞死亡配体 1（PD-L1）的情况下。此外，体内异种移植实验表明，PD1CD28 嵌合分子在降低复发率、有效控制复发性肿瘤体积以及最终延长小鼠生存时间方面发挥了关键作用。总之，这些发现表明，共表达 PD1CD28 嵌合分子的 EGFRvⅢ 导向的 CAR-T 细胞有可能显著增强针对 GBM 的治疗效果。
