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

Nat Commun. 2022 May 11;13(1):2576. doi: 10.1038/s41467-022-30216-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • COVID-19* / therapy
  • Humans
  • Interleukin-15 / metabolism
  • Killer Cells, Natural
  • Mice
  • Receptors, Chimeric Antigen*
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus


  • Interleukin-15
  • Receptors, Chimeric Antigen
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2