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Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy

Author

Listed:
  • Vipul Bhatia

    (Fred Hutchinson Cancer Center)

  • Nikhil V. Kamat

    (University of Washington)

  • Tiffany E. Pariva

    (Fred Hutchinson Cancer Center)

  • Li-Ting Wu

    (Fred Hutchinson Cancer Center)

  • Annabelle Tsao

    (Fred Hutchinson Cancer Center)

  • Koichi Sasaki

    (Imperial College London)

  • Huiyun Sun

    (Fred Hutchinson Cancer Center)

  • Gerardo Javier

    (Fred Hutchinson Cancer Center)

  • Sam Nutt

    (Fred Hutchinson Cancer Center)

  • Ilsa Coleman

    (Fred Hutchinson Cancer Center)

  • Lauren Hitchcock

    (Fred Hutchinson Cancer Center)

  • Ailin Zhang

    (Fred Hutchinson Cancer Center)

  • Dmytro Rudoy

    (Fred Hutchinson Cancer Center)

  • Roman Gulati

    (Fred Hutchinson Cancer Center)

  • Radhika A. Patel

    (Fred Hutchinson Cancer Center)

  • Martine P. Roudier

    (University of Washington)

  • Lawrence D. True

    (University of Washington)

  • Shivani Srivastava

    (Fred Hutchinson Cancer Center)

  • Colm M. Morrissey

    (University of Washington)

  • Michael C. Haffner

    (Fred Hutchinson Cancer Center
    University of Washington
    Fred Hutchinson Cancer Center)

  • Peter S. Nelson

    (Fred Hutchinson Cancer Center
    University of Washington
    Fred Hutchinson Cancer Center
    University of Washington)

  • Saul J. Priceman

    (City of Hope
    Beckman Research Institute of City of Hope)

  • Jun Ishihara

    (Imperial College London)

  • John K. Lee

    (Fred Hutchinson Cancer Center
    University of Washington
    University of Washington
    Fred Hutchinson Cancer Center)

Abstract

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Suggested Citation

  • Vipul Bhatia & Nikhil V. Kamat & Tiffany E. Pariva & Li-Ting Wu & Annabelle Tsao & Koichi Sasaki & Huiyun Sun & Gerardo Javier & Sam Nutt & Ilsa Coleman & Lauren Hitchcock & Ailin Zhang & Dmytro Rudoy, 2023. "Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37874-2
    DOI: 10.1038/s41467-023-37874-2
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