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CAR Macrophages for SARS-CoV-2 Immunotherapy
Wenyan Fu1,2,3, Changhai Lei1,2, Zetong Ma1
1Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China.
Abstract:
Targeted therapeutics for the treatment of coronavirus disease 2019 (COVID-19), especially severe cases, are currently lacking. As macrophages have unique effector functions as a first-line defense against invading pathogens, we genetically armed human macrophages with chimeric antigen receptors (CARs) to reprogram their phagocytic activity against SARS-CoV-2. After investigation of CAR constructs with different intracellular receptor domains, we found that although cytosolic domains from MERTK (CARMERTK) did not trigger antigen-specific cellular phagocytosis or killing effects, unlike those from MEGF10, FcRγ and CD3ζ did, these CARs all mediated similar SARS-CoV-2 clearance in vitro. Notably, we showed that CARMERTK macrophages reduced the virion load without upregulation of proinflammatory cytokine expression. These results suggest that CARMERTK drives an 'immunologically silent' scavenger effect in macrophages and pave the way for further investigation of CARs for the treatment of individuals with COVID-19, particularly those with severe cases at a high risk of hyperinflammation.
Insights
Genetically engineered macrophages using chimeric antigen receptors (CARs) effectively clear SARS-CoV-2. CAR-MERTK macrophages offer a promising COVID-19 therapy by reducing viral load without causing inflammation.
Area of Science:
- Immunology
- Cellular and Molecular Medicine
- Infectious Diseases
Background:
- Targeted therapies for severe COVID-19 are limited.
- Macrophages are key immune cells in pathogen defense.
- Chimeric antigen receptors (CARs) can reprogram immune cells.
Purpose of the Study:
- To genetically engineer human macrophages with CARs to target SARS-CoV-2.
- To investigate the efficacy of different CAR constructs in clearing the virus.
- To evaluate the inflammatory response associated with CAR-modified macrophages.
Main Methods:
- Genetic engineering of human macrophages with CARs containing various intracellular domains (MERTK, MEGF10, FcRγ, CD3ζ).
- In vitro assessment of CAR-mediated phagocytosis, viral clearance, and cytokine expression.
- Comparison of CARMERTK efficacy against other CAR constructs.
Main Results:
- All tested CARs mediated SARS-CoV-2 clearance in vitro.
- CARMERTK macrophages reduced viral load without increasing pro-inflammatory cytokines.
- CARMERTK demonstrated an 'immunologically silent' scavenger effect.
Conclusions:
- CAR-engineered macrophages show potential for treating COVID-19.
- CARMERTK offers a novel therapeutic strategy for severe COVID-19, particularly in cases with hyperinflammation risk.
- Further research into CARs for COVID-19 treatment is warranted.
