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

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Publication Year:
2024
Authors:
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
PubMed ID:
38336975
Funding Grants:
Public Summary:
An important challenge in creating CAR-T cell therapies for solid tumors is finding surface proteins that are abundant in tumors but not in healthy tissues. In this study, we identify a protein called TYRP1 as a potential target for CAR-T cell therapy to treat patients with cutaneous and rare melanoma subtypes that do not respond to existing immune therapies. While TYRP1 is mostly found intracellularly in the melanosomes, a fraction localizes on cell surface, making it detectable by our CAR-T cells. We develop a highly sensitive CAR-T cell therapy that can recognizes and attacks tumor cells with high levels of TYRP1. Our therapy shows effectiveness in in vitro model systems and in animal models, including immunocompetent murine models and patient-derived models of cutaneous, acral, and uveal melanoma in immunodeficient mice. Importantly, the TYRP1 CAR-T cell therapy does not cause serious side effects in mice. These promising results support the preparation for a phase I clinical trial to further test the therapy's safety and effectiveness in patients.
Scientific 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.