2. Academic Validation
  3. A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19

A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19

  • Cell Mol Immunol. 2023 Mar 2;1-14. doi: 10.1038/s41423-023-00985-3.
Lin Xia # 1 2 3,  Lun-Zhi Yuan # 3,  Ya-Hong Hu # 1 2,  Jun-Yi Liu # 3,  Guo-Sheng Hu # 1 2,  Ruo-Yao Qi # 3,  Tian-Ying Zhang 3,  Hua-Long Xiong 3,  Zao-Zao Zheng 1 2,  Hong-Wei Lin 3,  Jia-Mo Zhang 1 2,  Chao Yu 3,  Ming Zhou 3,  Jian Ma 3,  Tong Cheng 3,  Ri-Rong Chen 4,  Yi Guan 4,  Ning-Shao Xia 5,  Wen Liu 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
  • 2 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
  • 3 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
  • 4 State Key Laboratory of Emerging Infectious Diseases, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 5 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China. nsxia@xmu.edu.cn.
  • 6 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China. w2liu@xmu.edu.cn.
  • 7 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China. w2liu@xmu.edu.cn.
  • # Contributed equally.
PMID: 36864189 DOI: 10.1038/s41423-023-00985-3
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this "two-cell" (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.

Keywords

CAR-T; COVID-19; NF-κB pathway; SARS-CoV-2; anti-inflammation.

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