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

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 and Cristina Puig-Saus ()
Additional contact information
Sameeha Jilani: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Justin D. Saco: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Edurne Mugarza: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Aleida Pujol-Morcillo: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Jeffrey Chokry: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Clement Ng: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Gabriel Abril-Rodriguez: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
David Berger-Manerio: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Ami Pant: David Geffen School of Medicine at UCLA
Jane Hu: David Geffen School of Medicine at UCLA
Rubi Gupta: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Agustin Vega-Crespo: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Ignacio Baselga-Carretero: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Jia M. Chen: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Daniel Sanghoon Shin: VA Greater Los Angeles Healthcare System
Philip Scumpia: UCLA
Roxana A. Radu: David Geffen School of Medicine at UCLA
Yvonne Chen: Parker Institute for Cancer Immunotherapy Center at UCLA
Antoni Ribas: David Geffen School of Medicine at the University of California Los Angeles (UCLA)
Cristina Puig-Saus: David Geffen School of Medicine at the University of California Los Angeles (UCLA)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45221-2

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