IFN-γ and TNF-α aggravate endothelial damage caused by CD123-targeted CAR T cell

Abstract

Background: CD123-targeted chimeric antigen receptor (CAR) T cell (CART123) for the treatment of acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm has exhibited potential in clinical trials. However, capillary leakage syndrome, which is associated with endothelial cells damage, is under intensive focus in CART123 therapy. Purpose: The present study aimed to explore the change in CD123 in endothelial cells and the injury to endothelial cells caused by CART123. Methods: The expression of CD123 and cytotoxicity were assessed by flow cytometry. Cytokine release was assessed by ELISA. An in vitro co-culture model was designed to mimic the status, wherein CART123 was stimulated and cytokines were released. Results: In the current study, CART123 exhibited cytotoxicity and the effects of cytokine production on endothelium, and the upregulation of CD123 enhanced the cytotoxicity. The addition of interferon (IFN)-γ and tumor necrosis factor (TNF)-α neutralizing antibodies can effectively reverse the upregulation of CD123 on the endothelial cells caused by CART123, while the cytotoxicity of CART123 in AML cell lines was not affected in vitro. Second, we proved that CD123 expresses in CART123 and would be upregulated after activation, putatively causing an overactivated and fratricide effect. Conclusion: In summary, this study identified that the expression of CD123 on endothelial cells could be upregulated when co-cultured with CART123. Furthermore, IFN-γ and TNF-α could aggravate endothelial damage caused by CART123 in vitro.