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Effective chimeric antigen receptor T cells against SARS-CoV-2
Xueyang Guo1,2,3, Alexandra Kazanova1,2,3, Stephanie Thurmond1,2,3
1Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
Abstract:
Current therapies to treat coronavirus disease 2019 (COVID-19) involve vaccines against the spike protein S1 of SARS-CoV-2. Here, we outline an alternative approach involving chimeric antigen receptors (CARs) in T cells (CAR-Ts). CAR-T recognition of the SARS-CoV-2 receptor-binding domain (RBD) peptide induced ribosomal protein S6 phosphorylation, the increased expression of activation antigen, CD69 and effectors, interferon-γ, granzyme B, perforin, and Fas-ligand on overlapping subsets of CAR-Ts. CAR-Ts further showed potent in vitro killing of target cells loaded with RBD, S1 peptide, or expressing the S1 protein. The efficacy of killing varied with different sized hinge regions, whereas time-lapse microscopy showed CAR-T cluster formation around RBD-expressing targets. Cytolysis of targets was mediated primarily by the GZMB/perforin pathway. Lastly, we showed in vivo killing of S1-expressing cells by our SARS-CoV-2 CAR-Ts in mice. The successful generation of SARS-CoV-2 CAR-Ts represents a living vaccine approach for the treatment of COVID-19.
Insights
This study introduces chimeric antigen receptor T-cells (CAR-Ts) as a novel "living vaccine" to combat COVID-19. These engineered T-cells effectively target and destroy SARS-CoV-2 infected cells, offering a new therapeutic avenue.
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- Current COVID-19 treatments primarily rely on vaccines targeting the SARS-CoV-2 spike protein S1.
- There is a need for alternative therapeutic strategies to combat SARS-CoV-2 infection.
Purpose of the Study:
- To investigate the potential of chimeric antigen receptors (CARs) engineered into T-cells (CAR-Ts) as a novel therapeutic approach for COVID-19.
- To evaluate the efficacy of SARS-CoV-2 specific CAR-Ts in recognizing and eliminating infected cells.
Main Methods:
- Generation of CAR-T cells targeting the SARS-CoV-2 receptor-binding domain (RBD) and S1 protein.
- In vitro assessment of CAR-T cell activation, effector function, and target cell killing.
- In vivo evaluation of CAR-T cell efficacy in a mouse model.
Main Results:
- CAR-T recognition of SARS-CoV-2 antigens induced T-cell activation and effector molecule release (IFN-γ, granzyme B, perforin, Fas-ligand).
- CAR-Ts demonstrated potent in vitro killing of target cells expressing RBD, S1 peptide, or S1 protein.
- Cytolysis was primarily mediated by the granzyme B/perforin pathway, with varying efficacy based on CAR hinge region length.
- In vivo studies confirmed CAR-T mediated killing of S1-expressing cells in mice.
Conclusions:
- The development of SARS-CoV-2 specific CAR-Ts represents a promising "living vaccine" strategy for COVID-19 treatment.
- CAR-T cell therapy offers a potential alternative or adjunct to current vaccination and treatment modalities.
