CAR Macrophages for SARS-CoV-2 Immunotherapy

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 notably 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.

Effective chimeric antigen receptor T cells against SARS-CoV-2

“…During the final preparation of this paper, two groups reported the successful generation of natural killer and macrophage CARs in in vitro assays (Fu et al, 2021;Ma et al, 2021). Unlike T cells of the adaptive immune system, these cells are part of the innate immune system with distinct co-receptors that regulate function.…”

Integrative Metabolomic and Proteomic Signatures Define Clinical Outcomes in Severe COVID-19

“…The modules identified various proteins and metabolites involved in inflammatory and vascular injury processes, such as MMP 12, Cathepsin D and RAGE which, to the best of our knowledge, have not yet been studied as targets for therapeutic intervention in COVID-19. Of note, our modules contained IL-6, which is already a mainstay of treatment for severe disease(50), and several other molecules such as carnitine, niacinamide and IFN-gamma which others have been studying in the context of COVID-19 therapies(51-53).…”

Cancer Immunotherapy and Cytotoxicity: Current Advances and Challenges

“…State-of-the-art updates have indicated the feasibility of CAR-Ms for solid tumor management and virion load reduction [129,130]. Differ from the other CARtransduced immune cells, CAR-Ms are important sources of matrix metalloproteinase (MMPs), which can enter tumor tissue and degrade almost all extracellular matrix (ECM) components and thus destroy malignant tumor progression [130].…”