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.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CD44/CD133 双靶向 IL7Rα 装甲 CAR-T 细胞抗胶质母细胞瘤的开发与强效抗肿瘤疗效
英文原题：The development and potent antitumor efficacy of CD44/CD133 dual-targeting IL7Rα-armored CAR-T cells against glioblastoma.
查看英文原题
The development and potent antitumor efficacy of CD44/CD133 dual-targeting IL7Rα-armored CAR-T cells against glioblastoma.
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中文摘要
肿瘤异质性和免疫抑制微环境对实体瘤的免疫治疗构成重大挑战，尤其是多形性胶质母细胞瘤（GBM）。近期研究强调了胶质瘤干细胞（GSCs）在肿瘤复发和治疗耐药中的关键作用。
在此背景下，我们开发了一种靶向 CD44 和 CD133（PROM1）的串联嵌合抗原受体（CAR）-T 细胞，其在 CD28 共刺激受体和 CD3 信号链之间包含一个截短的 IL-7 受体 α 胞内结构域（7R）（Tan -T28- 7R）。
我们使用 GSCs、GBM 患者样本及相应测序数据进行了靶点识别和验证。在患者来源的 GSCs、颅内异种移植模型、患者来源的异种移植模型和胶质母细胞瘤类器官（GBOs）中评估了 CAR-T 细胞的抗肿瘤疗效。使用单细胞 RNA 测序和质谱流式细胞术测定 CAR-T 细胞的免疫表型。
我们发现，局部区域给药的 Tan -T28- 7R CAR-T 细胞诱导了长期肿瘤消退，并具有理想的安全性结局。患者来源的自体 Tan -T28- 7R CAR-T 细胞对 GBOs 表现出强效抗肿瘤活性。
我们的临床前数据证明了 Tan -T28- 7R CAR-T 细胞针对 GBM 的转化潜力。
展开英文摘要原文
Tumor heterogeneity and an immunosuppressive microenvironment pose significant challenges for immunotherapy against solid tumors, particularly glioblastoma multiforme (GBM). Recent studies have highlighted the crucial role of glioma stem cells (GSCs) in tumor recurrence and therapeutic resistance.
In this context, we developed a tandem chimeric antigen receptor (CAR)-T cell targeting CD44 and CD133 (PROM1), containing a truncated IL-7 receptor alpha intracellular domain ( 7R) between the CD28 costimulatory receptor and the CD3 signaling chain (Tan -T28- 7R).
Our target identification and validation were carried out using GSCs, samples from GBM patients, and the corresponding sequencing data. The antitumor efficacy of CAR-T cells was evaluated in patient-derived GSCs, intracranial xenograft models, patient-derived xenograft models, and glioblastoma organoids (GBOs). Single-cell RNA sequencing and mass cytometry were used to determine the immune phenotypes of CAR-T cells.
We showed that locoregionally administered Tan -T28- 7R CAR-T cells induced long-term tumor regression with the desired safety outcomes. Patient-derived autologous Tan -T28- 7R CAR-T cells showed robust antitumor activity against GBOs.
Our pre-clinical data has demonstrated the translational potential of Tan -T28- 7R CAR-T cell against GBM.
论文信息
- 作者
- Zhai Y、Li G、Pan C、Yu M、Hu H、Wang D、Shi Z、Jiang T
- 第一作者单位
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, PR China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China. Electronic address: ttyyzhaiyou@163.com.China
- 通讯作者单位
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China; China National Clinical Research Center for Neurological Diseases, Beijing, PR China; Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing, PR China; Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, PR China; Beijing Engineering Research Center of Targeted Drugs and Cell Therapy for CNS Tumors, Beijing, PR China. Electronic address: zhangwei_vincent@mail.ccmu.edu.cn.China
- 期刊
- Cancer letters2025 Apr 1
- 原文标识
- PubMed 39952598 · DOI 10.1016/j.canlet.2025.217541