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
靶向 TYRP1 表面表达的 CAR-T 细胞疗法治疗皮肤型与罕见黑色素瘤亚型
英文原题：CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes.
查看英文原题
CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes.
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中文摘要
开发用于实体瘤的嵌合抗原受体 (CAR)-T 细胞疗法的一个主要限制是识别在肿瘤中高表达而在正常组织中不表达的细胞表面蛋白。在此，我们将酪氨酸酶相关蛋白1 (TYRP1) 确定为一种 CAR-T 细胞疗法靶点，用于治疗对免疫检查点阻断无反应的皮肤型和罕见黑色素瘤亚型患者。TYRP1 主要位于细胞内黑素体中，小部分通过囊泡运输转运至细胞表面。我们开发了一种高灵敏度的 CAR-T 细胞疗法，可检测 TYRP1 高过表达肿瘤细胞表面的 TYRP1，并在小鼠和患者来源的皮肤型、肢端型和葡萄膜黑色素瘤模型中表现出体外和体内抗肿瘤活性。此外，在免疫健全的小鼠模型中未观察到全身性或肿瘤外严重毒性。TYRP1 CAR-T 细胞疗法的疗效和安全性特征支持正在进行的 I 期临床试验准备工作。
展开英文摘要原文
A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues.
Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport.
We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models.
Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.
论文信息
- 作者
- Jilani S、Saco JD、Mugarza E、Pujol-Morcillo A、Chokry J、Ng C、Abril-Rodriguez G、Berger-Manerio D
- 第一作者单位
- Department of Hematology-Oncology, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles, CA, USA.United States
- 通讯作者单位
- Department of Hematology-Oncology, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles, CA, USA. CPuigSaus@mednet.ucla.edu.United States
- 文献类型
- 美国 NIH 资助研究
- 期刊
- Nature communications2024 Feb 9
- 原文标识
- PubMed 38336975 · DOI 10.1038/s41467-024-45221-2
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