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

Author

Listed:
  • 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)
    Parker Institute for Cancer Immunotherapy Center at 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)
    Parker Institute for Cancer Immunotherapy Center at UCLA)

  • Daniel Sanghoon Shin

    (VA Greater Los Angeles Healthcare System
    UCLA
    Jonsson Comprehensive Cancer Center—UCLA)

  • Philip Scumpia

    (UCLA
    VA Greater Los Angeles Healthcare System-West Los Angeles)

  • Roxana A. Radu

    (David Geffen School of Medicine at UCLA)

  • Yvonne Chen

    (Parker Institute for Cancer Immunotherapy Center at UCLA
    Jonsson Comprehensive Cancer Center—UCLA
    Immunology, and Molecular Genetics at UCLA
    Broad Stem Cell Research Center—UCLA)

  • Antoni Ribas

    (David Geffen School of Medicine at the University of California Los Angeles (UCLA)
    Parker Institute for Cancer Immunotherapy Center at UCLA
    Jonsson Comprehensive Cancer Center—UCLA
    Broad Stem Cell Research Center—UCLA)

  • Cristina Puig-Saus

    (David Geffen School of Medicine at the University of California Los Angeles (UCLA)
    Parker Institute for Cancer Immunotherapy Center at UCLA
    Jonsson Comprehensive Cancer Center—UCLA
    Broad Stem Cell Research Center—UCLA)

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.

Suggested Citation

  • 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, 2024. "CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45221-2
    DOI: 10.1038/s41467-024-45221-2
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    References listed on IDEAS

    as
    1. Louai Labanieh & Crystal L. Mackall, 2023. "CAR immune cells: design principles, resistance and the next generation," Nature, Nature, vol. 614(7949), pages 635-648, February.
    2. Robbie G. Majzner & Sneha Ramakrishna & Kristen W. Yeom & Shabnum Patel & Harshini Chinnasamy & Liora M. Schultz & Rebecca M. Richards & Li Jiang & Valentin Barsan & Rebecca Mancusi & Anna C. Geraghty, 2022. "GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas," Nature, Nature, vol. 603(7903), pages 934-941, March.
    Full references (including those not matched with items on IDEAS)

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