학술논문
CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes
Document Type
article
Author
Jilani, Sameeha; Saco, Justin D; Mugarza, Edurne; Pujol-Morcillo, Aleida; Chokry, Jeffrey; Ng, Clement; Abril-Rodriguez, Gabriel; Berger-Manerio, David; Pant, Ami; Hu, Jane; Gupta, Rubi; Vega-Crespo, Agustin; Baselga-Carretero, Ignacio; Chen, Jia M; Shin, Daniel Sanghoon; Scumpia, Philip; Radu, Roxana A; Chen, Yvonne; Ribas, Antoni; Puig-Saus, Cristina
Source
Nature Communications. 15(1)
Subject
Language
Abstract
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.