1区 · 综合性期刊
ArticleOA
作者: Scumpia, Philip ; Puig-Saus, Cristina ; Jilani, Sameeha ; Chen, Jia M ; Chen, Yvonne ; Saco, Justin D ; Radu, Roxana A ; Berger-Manerio, David ; Shin, Daniel Sanghoon ; Vega-Crespo, Agustin ; Pujol-Morcillo, Aleida ; Chokry, Jeffrey ; Gupta, Rubi ; Hu, Jane ; Pant, Ami ; Baselga-Carretero, Ignacio ; Ng, Clement ; Abril-Rodriguez, Gabriel ; Ribas, Antoni ; Mugarza, Edurne
AbstractA 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.
