Harnessing CAR T-cell Insights to Develop Treatments for Hyperinflammatory Responses in Patients with COVID-19

Abstract

Cytokine release and macrophage activation contribute to immunopathology after SARS-CoV-2 infection. We discuss approaches to decrease the morbidity and mortality in patients with COVID-19 by repurposing existing drugs previously developed for cancer therapy.

Figure 1.

SARS-CoV-2 infection disables cross-talk between immune cells, causing CRS and HLH. The virus entry begins by infecting pneumocytes expressing the ACE2 receptor that recruits antigen-presenting cells (dendritic cells and macrophages) to the lungs. This activates the NLRC4 inflammasome that leads to overproduction of both IL1β and IL18, leading to IL6 and ferritin secretion by macrophages. Liver damage leads to upregulation of CRP and subsequently IL8 secretion. In addition, inadequate processing and presentation of viral proteins leads to formation of dysfunctional T-cell responses, that is, limited production of perforin and granzyme B but constant production of IFNγ and TNFα, which furthers disease progression. Upregulation of all these cytokines leads to a disorder called “cytokine release syndrome” and the recruitment of macrophages to the lungs, contributing to ARDS. CTL, cytotoxic T lymphocyte; NK cell, natural killer cell.