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; Cristina Puig-Saus

doi:10.1038/s41467-024-45221-2

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

Nat Commun. 2024 Feb 9;15(1):1244. doi: 10.1038/s41467-024-45221-2.

Authors

Sameeha Jilani^#¹, Justin D Saco^#¹, Edurne Mugarza^#¹, Aleida Pujol-Morcillo¹, Jeffrey Chokry¹, Clement Ng¹, Gabriel Abril-Rodriguez^{1

2}, David Berger-Manerio¹, Ami Pant³, Jane Hu³, Rubi Gupta¹, Agustin Vega-Crespo¹, Ignacio Baselga-Carretero¹, Jia M Chen^{1

2}, Daniel Sanghoon Shin^{4

5

6}, Philip Scumpia^{7

8}, Roxana A Radu³, Yvonne Chen^{2

6

9

10}, Antoni Ribas^{1

2

6

10}, Cristina Puig-Saus^{11

12

13

14}

Affiliations

¹ Department of Hematology-Oncology, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles, CA, USA.
² Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA, USA.
³ UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁴ Division of Hematology/Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁵ Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
⁶ Jonsson Comprehensive Cancer Center-UCLA, Los Angeles, CA, USA.
⁷ Division of Dermatology, Department of Medicine, UCLA, Los Angeles, CA, USA.
⁸ Department of Dermatology, VA Greater Los Angeles Healthcare System-West Los Angeles, Los Angeles, CA, USA.
⁹ Department of Microbiology, Immunology, and Molecular Genetics at UCLA, Los Angeles, CA, USA.
¹⁰ Broad Stem Cell Research Center-UCLA, Los Angeles, CA, USA.
¹¹ Department of Hematology-Oncology, David Geffen School of Medicine at the University of California Los Angeles (UCLA), Los Angeles, CA, USA. [email protected].
¹² Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA, USA. [email protected].
¹³ Jonsson Comprehensive Cancer Center-UCLA, Los Angeles, CA, USA. [email protected].
¹⁴ Broad Stem Cell Research Center-UCLA, Los Angeles, CA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Animals
Cell- and Tissue-Based Therapy
Humans
Immunotherapy, Adoptive
Melanoma* / drug therapy
Melanoma* / therapy
Membrane Glycoproteins
Mice
Oxidoreductases
Receptors, Chimeric Antigen*
Uveal Neoplasms* / drug therapy
Uveal Neoplasms* / therapy

Substances

Receptors, Chimeric Antigen
TYRP1 protein, human
Membrane Glycoproteins
Oxidoreductases

Abstract

MeSH terms

Substances

Grants and funding