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Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19.
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.
  • Lu T; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Ma R; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Dong W; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Teng KY; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Kollath DS; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Li Z; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA.
  • Yi J; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Bustillos C; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA.
  • Ma S; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Tian L; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Mansour AG; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Li Z; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Settles EW; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Zhang J; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA.
  • Keim PS; Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
  • Barker BM; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA.
  • Caligiuri MA; Division of Pathogen and Microbiome, TGen North, Flagstaff, AZ, 86011, USA.
  • Yu J; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA.
Nat Commun ; 13(1): 2576, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1931386
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Chimeric Antigen / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2022 Document Type: Article Affiliation country: S41467-022-30216-8

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Receptors, Chimeric Antigen / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2022 Document Type: Article Affiliation country: S41467-022-30216-8