• CAR-T疗法在实体瘤领域的突破；
• 免疫耐药的黑色素瘤（含皮肤、肢端、黏膜和葡萄膜）治疗的新曙光。

Nature Communications (IF 16.6) Pub Date: 2024-02-09, DOI: 10.1038/s41467-024-45221-2

Sameeha Jilani ,  Justin D. Saco ,  Edurne Mugarza ,  Aleida Pujol-Morcillo ,  Jeffrey Chokry ,  Clement Ng ,  Gabriel Abril-Rodriguez ,  David Berger-Manerio ,  Ami Pant ,  Jane Hu ,  Rubi Gupta ,  Agustin Vega-Crespo ,  Ignacio Baselga-Carretero ,  Jia M. Chen ,  Daniel Sanghoon Shin ,  Philip Scumpia ,  Roxana A. Radu ,  Yvonne Chen ,  Antoni Ribas  &  Cristina Puig-Saus  

最近，来自美国加利福尼亚大学洛杉矶分校的研究者发现，一种在黑色素瘤表面表达的酪氨酸酶相关蛋白 1 ( TYRP1， Tyrosinase Related Protein 1   )   可以成为CAR-T细胞的有效靶标，经过改造能针对TYRP1的CAR-T细胞能够有效清除黑色素瘤并且不会产生副作用。并且改 黑色素瘤的CAR-T疗法已经开启一期临床试验。

该研究已发表在《自然-通讯》（Nature Communications），文章题为《CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes》（靶向TYRP1表面表达的CAR-T细胞治疗皮肤型和罕见亚型黑色素瘤（注：包括肢端、黏膜、葡萄膜型））

研究摘要

开发用于实体瘤的 CAR-T 细胞疗法的一个主要限制是识别在肿瘤中高度表达但在正常组织中不表达的表面蛋白（identifying surface proteins highly expressed in tumors but not in normal tissues）。在这里，研究人员将酪氨酸酶相关蛋白1（TYRP1）确定为CAR-T细胞治疗靶点，用于治疗对免疫检查点阻断无反应的皮肤和罕见黑色素瘤亚型患者。TYRP1主要位于黑色素体的细胞内，一小部分通过囊泡运输被运输到细胞表面。研究人员开发了一种高度灵敏的CAR-T细胞疗法，该疗法可检测TYRP1高表达的肿瘤细胞中的表面TYRP1，并在小鼠和患者来源的皮肤、肢端和葡萄膜黑色素瘤模型中呈现体外和体内抗肿瘤活性。此外，在免疫活性小鼠模型中未观察到全身或肿瘤外严重毒性。TYRP1 CAR-T细胞疗法的疗效和安全性支持正在进行的I期临床试验的准备工作。

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.