TY - JOUR
T1 - CAR-NK Cells Effectively Target SARS-CoV-2-Spike-Expressing Cell Lines In Vitro
AU - Ma, Minh Tuyet
AU - Badeti, Saiaditya
AU - Chen, Chih Hsiung
AU - Kim, James
AU - Choudhary, Alok
AU - Honnen, Bill
AU - Reichman, Charles
AU - Calianese, David
AU - Pinter, Abraham
AU - Jiang, Qingkui
AU - Shi, Lanbo
AU - Zhou, Renping
AU - Xu, Huanbin
AU - Li, Qingsheng
AU - Gause, William
AU - Liu, Dongfang
N1 - Funding Information:
This work was supported in part from HL125018 (DL), AI124769 (DL), AI129594 (DL), AI130197 (DL), and Rutgers-Health Advance Funding (NIH REACH program), U01HL150852 (R. Panettieri, S. Libutti, and R. Pasqualini), S10OD025182 (DL), and Rutgers University-New Jersey Medical School Startup funding for DL Laboratory.
Funding Information:
We would like to thank the members of the Liu laboratory for their comments on the manuscripts. We thank Dr. Rongfu Wang (Houston Methodist Research Institute) for providing pHAGE-FFLuc-GFP plasmid. We also thank AP (Rutgers-Public Health Research Institute) for providing 293T-ACE2 cell line, Dr. Pei-Hui Wang (Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012,?China) and Dr. Yuan Liu (Cornell University) for providing the related SARS-CoV-2 plasmids. We also would like to thank Dr. Gianpietro Dotti for the SFG vectors.
Publisher Copyright:
© Copyright © 2021 Ma, Badeti, Chen, Kim, Choudhary, Honnen, Reichman, Calianese, Pinter, Jiang, Shi, Zhou, Xu, Li, Gause and Liu.
PY - 2021/7/23
Y1 - 2021/7/23
N2 - Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent antitumor response in hematologic cancers with minimal adverse effects in recent studies, however, the potentials of CAR-NK cells in treating COVID-19 has not yet been fully exploited. Here, we improve upon a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2 and its various mutants. CAR-NK cells were generated using the scFv domain of S309 (henceforward, S309-CAR-NK), a SARS-CoV and SARS-CoV-2 neutralizing antibody (NAbs) that targets the highly conserved region of SARS-CoV-2 spike (S) glycoprotein and is therefore more likely to recognize different variants of SARS-CoV-2 isolates. S309-CAR-NK cells can specifically bind to pseudotyped SARS-CoV-2 virus and its D614G, N501Y, and E484K mutants. Furthermore, S309-CAR-NK cells can specifically kill target cells expressing SARS-CoV-2 S protein in vitro and show superior killing activity and cytokine production, compared to that of the recently reported CR3022-CAR-NK cells. Thus, these results pave the way for generating ‘off-the-shelf’ S309-CAR-NK cells for treatment in high-risk individuals as well as provide an alternative strategy for patients unresponsive to current vaccines.
AB - Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly contagious and presents a significant public health issue. Current therapies used to treat coronavirus disease 2019 (COVID-19) include monoclonal antibody cocktail, convalescent plasma, antivirals, immunomodulators, and anticoagulants. The vaccines from Pfizer and Moderna have recently been authorized for emergency use, which are invaluable for the prevention of SARS-CoV-2 infection. However, their long-term side effects are not yet documented, and populations with immunocompromised conditions (e.g., organ-transplantation and immunodeficient patients) may not be able to mount an effective immune response. In addition, there are concerns that wide-scale immunity to SARS-CoV-2 may introduce immune pressure that could select for escape mutants to the existing vaccines and monoclonal antibody therapies. Emerging evidence has shown that chimeric antigen receptor (CAR)- natural killer (NK) immunotherapy has potent antitumor response in hematologic cancers with minimal adverse effects in recent studies, however, the potentials of CAR-NK cells in treating COVID-19 has not yet been fully exploited. Here, we improve upon a novel approach for the generation of CAR-NK cells for targeting SARS-CoV-2 and its various mutants. CAR-NK cells were generated using the scFv domain of S309 (henceforward, S309-CAR-NK), a SARS-CoV and SARS-CoV-2 neutralizing antibody (NAbs) that targets the highly conserved region of SARS-CoV-2 spike (S) glycoprotein and is therefore more likely to recognize different variants of SARS-CoV-2 isolates. S309-CAR-NK cells can specifically bind to pseudotyped SARS-CoV-2 virus and its D614G, N501Y, and E484K mutants. Furthermore, S309-CAR-NK cells can specifically kill target cells expressing SARS-CoV-2 S protein in vitro and show superior killing activity and cytokine production, compared to that of the recently reported CR3022-CAR-NK cells. Thus, these results pave the way for generating ‘off-the-shelf’ S309-CAR-NK cells for treatment in high-risk individuals as well as provide an alternative strategy for patients unresponsive to current vaccines.
KW - CAR (chimeric antigen receptor)
KW - COVID-19
KW - E484K variant
KW - N501Y variant
KW - NK cells
KW - SARS-CoV-2
KW - off-the-shelf
UR - http://www.scopus.com/inward/record.url?scp=85112594274&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112594274&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.652223
DO - 10.3389/fimmu.2021.652223
M3 - Article
C2 - 34367128
AN - SCOPUS:85112594274
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 652223
ER -