CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes

• Published in: Nature communications Vol. 15; no. 1; pp. 1244 - 19
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.02.2024; Nature Portfolio
• Subjects: Animal models; Animals; Anticancer properties; Antitumor activity; Cell culture; Cell surface; Cell therapy; Cell- and Tissue-Based Therapy; Chimeric antigen receptors; Humans; Immune checkpoint inhibitors; Immunotherapy, Adoptive; Lymphocytes; Lymphocytes T; Melanoma; Melanoma - drug therapy; Melanoma - therapy; Melanosomes; Membrane Glycoproteins; Mice; Oxidoreductases; Proteins; Receptors, Chimeric Antigen; Solid tumors; Therapy; Tumor cells; Tumors; Tyrosinase; Uveal Neoplasms - drug therapy; Uveal Neoplasms - therapy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45221-2

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.