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Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19

Author

Listed:
  • Ting Lu

    (City of Hope National Medical Center
    City of Hope National Medical Center)

  • Rui Ma

    (City of Hope National Medical Center)

  • Wenjuan Dong

    (City of Hope National Medical Center)

  • Kun-Yu Teng

    (City of Hope National Medical Center)

  • Daniel S. Kollath

    (Pathogen and Microbiome Institute, Northern Arizona University)

  • Zhiyao Li

    (City of Hope National Medical Center)

  • Jinhee Yi

    (Pathogen and Microbiome Institute, Northern Arizona University)

  • Christian Bustillos

    (City of Hope National Medical Center)

  • Shoubao Ma

    (City of Hope National Medical Center)

  • Lei Tian

    (City of Hope National Medical Center)

  • Anthony G. Mansour

    (City of Hope National Medical Center)

  • Zhenlong Li

    (City of Hope National Medical Center)

  • Erik W. Settles

    (Pathogen and Microbiome Institute, Northern Arizona University)

  • Jianying Zhang

    (City of Hope National Medical Center)

  • Paul S. Keim

    (Pathogen and Microbiome Institute, Northern Arizona University
    Division of Pathogen and Microbiome, TGen North)

  • Bridget M. Barker

    (Pathogen and Microbiome Institute, Northern Arizona University)

  • Michael A. Caligiuri

    (City of Hope National Medical Center
    City of Hope National Medical Center
    City of Hope Comprehensive Cancer Center)

  • Jianhua Yu

    (City of Hope National Medical Center
    City of Hope National Medical Center
    City of Hope Comprehensive Cancer Center
    Beckman Research Institute of City of Hope)

Abstract

Engineered natural killer (NK) cells represent a promising option for immune therapy option due to their immediate availability in allogeneic settings. Severe acute diseases, such as COVID-19, require targeted and immediate intervention. Here we show engineering of NK cells to express (1) soluble interleukin-15 (sIL15) for enhancing their survival and (2) a chimeric antigen receptor (CAR) consisting of an extracellular domain of ACE2, targeting the spike protein of SARS-CoV-2. These CAR NK cells (mACE2-CAR_sIL15 NK cells) bind to VSV-SARS-CoV-2 chimeric viral particles as well as the recombinant SARS-CoV-2 spike protein subunit S1 leading to enhanced NK cell production of TNF-α and IFN-γ and increased in vitro and in vivo cytotoxicity against cells expressing the spike protein. Administration of mACE2-CAR_sIL15 NK cells maintains body weight, reduces viral load, and prolongs survival of transgenic mice expressing human ACE2 upon infection with live SARS-CoV-2. These experiments, and the capacity of mACE2-CAR_sIL15 NK cells to retain their activity following cryopreservation, demonstrate their potential as an allogeneic off-the-shelf therapy for COVID-19 patients who are faced with limited treatment options.

Suggested Citation

  • Ting Lu & Rui Ma & Wenjuan Dong & Kun-Yu Teng & Daniel S. Kollath & Zhiyao Li & Jinhee Yi & Christian Bustillos & Shoubao Ma & Lei Tian & Anthony G. Mansour & Zhenlong Li & Erik W. Settles & Jianying , 2022. "Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30216-8
    DOI: 10.1038/s41467-022-30216-8
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    1. Seth J. Zost & Pavlo Gilchuk & James Brett Case & Elad Binshtein & Rita E. Chen & Joseph P. Nkolola & Alexandra Schäfer & Joseph X. Reidy & Andrew Trivette & Rachel S. Nargi & Rachel E. Sutton & Navee, 2020. "Potently neutralizing and protective human antibodies against SARS-CoV-2," Nature, Nature, vol. 584(7821), pages 443-449, August.
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