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

• Published in: Nature communications 2022-05, Vol.13 (1), p.2576-2576, Article 2576
• Main Authors: Lu, Ting, Ma, Rui, Dong, Wenjuan, Teng, Kun-Yu, Kollath, Daniel S., Li, Zhiyao, Yi, Jinhee, Bustillos, Christian, Ma, Shoubao, Tian, Lei, Mansour, Anthony G., Li, Zhenlong, Settles, Erik W., Zhang, Jianying, Keim, Paul S., Barker, Bridget M., Caligiuri, Michael A., Yu, Jianhua
• Format: Article
• Language: English
• Subjects: 13/109; 13/31; 38/88; 42/44; 59/5; 631/250/2152/1566/1618; 631/250/251; 631/326/596/4130; 64/60; 692/699/255/2514; ACE2; Angiotensin-Converting Enzyme 2; Animals; Antigens; Biocompatibility; Body weight; Chimeric antigen receptors; Coronaviruses; COVID-19; COVID-19 - therapy; Cryopreservation; Cytokines; Cytotoxicity; Humanities and Social Sciences; Humans; Interleukin 15; Interleukin-15 - metabolism; Killer Cells, Natural; Mice; multidisciplinary; Natural killer cells; Proteins; Receptors; Receptors, Chimeric Antigen; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus; Spike protein; Survival; Toxicity; Transgenic mice; Tumor necrosis factor-α; Viral diseases; Weight reduction; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• 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. Severe COVID-19 requires immediate and targeted intervention that is efficient against SARS-CoV-2 and its variants. Authors show here the therapeutic potential of engineered natural killer cells that simultaneously express a chimeric antigen receptor targeting the spike protein of SARS-CoV-2, and IL-15, a cytokine that enhances the function and survival of their own.