实体瘤患者的外周血衍生的PD-1/CD28-CD19 CAR修饰的PD-1+ T细胞治疗
Peripheral Blood-Derived PD-1/CD28-CD19 CAR-Modified PD-1+ T-Cell Therapy in Patients with Solid Tumors
影响因子:8.20000
分区:医学1区 Top / 免疫学2区 肿瘤学2区
发表日期:2024 Dec 03
作者:
Zhen Zhang, Xuan Zhao, Qitai Zhao, Xinfeng Chen, Congcong Li, Yaqing Liu, Chunyi Shen, Lijie Song, Lijun Miao, Fuyou Guo, Xiaoning Mou, Jie Zhao, Weiyue Gu, Yi Zhang
摘要
肿瘤患者的外周血（PB）中表达编程细胞死亡1（PD-1）的T细胞具有治疗潜力；但是，PD-1+ T细胞的免疫抑制，PD-1触发的信号传导途径和有限的增殖能力对其治疗应用带来了挑战。在这里，我们观察到在克隆重叠方面，PD-1+和PD-1-T细胞之间没有明显的区别。但是，来自Pb和肿瘤组织的CD8+ PD-1+ T细胞根据克隆大小表现出更严格的聚类。单细胞RNA测序分析表明，来自PB高度表达的细胞毒性基因的PD-1+ T细胞与与PB或肿瘤组织的PD-1-T细胞相比，用T细胞激活相关的途径富含T细胞激活相关的途径。与此相一致，PB来源的PD-1+ T细胞对自体肿瘤细胞和肿瘤细胞系表现出强大的细胞毒性。为了增强对体内实体瘤的PD-1+ T细胞活性，我们引入了PD-1/CD28融合受体与CD19嵌合抗原受体结合到PD-1+ T细胞中，然后在体外扩展。修饰的PD-1+ T细胞在体外表现出优异的增殖和抗肿瘤能力。此外，将四名癌症患者注入自体PD-1/CD28-CD19嵌合抗原受体PD-1+ T细胞。这些患者均未发生严重的副作用，一名黑色素瘤患者达到了6.7个月的完全反应。另外三名患者患有稳定的疾病。总的来说，这些结果表明，使用经过修饰的PB衍生的PD-1+ T细胞的细胞疗法既安全有效，又可能构成针对癌症患者的有前途的治疗策略。
Abstract
T cells expressing programmed cell death 1 (PD-1) in the peripheral blood (PB) of patients with tumors possess therapeutic potential; however, the immunosuppressive, PD-1-triggered signaling pathway and limited proliferative capacity of PD-1+ T cells present challenges to their therapeutic application. Here, we observed no discernible distinction between PD-1+ and PD-1- T cells in terms of clonal overlap. However, CD8+PD-1+ T cells from PB and tumor tissues exhibited tighter clustering based on clone size. Single-cell RNA sequencing analysis showed that PD-1+ T cells from PB highly expressed cytotoxicity-related genes and were enriched for T-cell activation-related pathways compared with PD-1- T cells from PB or tumor tissues. Consistent with this, PB-derived PD-1+ T cells exhibited strong cytotoxicity toward autologous tumor cells and tumor cell lines. To augment PD-1+ T-cell activity against solid tumors in vivo, we introduced a PD-1/CD28 fusion receptor combined with a CD19 chimeric antigen receptor into PD-1+ T cells, which were then expanded in vitro. The modified PD-1+ T cells exhibited superior proliferation and antitumor abilities in vitro. In addition, four patients with cancer were infused with autologous PD-1/CD28-CD19 chimeric antigen receptor PD-1+ T cells. None of these patients experienced severe side effects, and one patient with melanoma achieved a complete response that was maintained for 6.7 months. The three other patients had stable disease. Collectively, these results suggested that cell therapy with modified PB-derived PD-1+ T cells is both safe and effective, and it may constitute a promising treatment strategy for patients with cancer.