Endothelial Injury Following CAR-T Cell Immunotherapy for Hematological Malignancies

Abstract

Chimeric antigen receptor-T (CAR-T) cell immunotherapy constitutes a cornerstone in the management of patients with relapsed/refractory B-cell lineage lymphoid malignancies. Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity (ICAHT) have been recognized in the post-infusion period. The initial interplay between CAR-T cells and tumor cells, followed by cytokine release and the bystander activation of the innate immunity cells, result in endothelial cell injury. In the current review, the ongoing research regarding endothelial injury in CAR-T cell recipients is summarized. Various markers of endothelial injury have been investigated in CAR-T cell recipients, including markers of complement activation, such as soluble C5b-9, endothelial dysfunction (angiopoietin-2, VCAM1, ICAM-1), inflammation, and thrombosis (von Willebrand antigen, ADAMTS13, thrombomodulin). The expression level of these endothelial injury markers has been identified as impaired in CAR-T cell recipients, not only when compared with healthy controls but also among patients with severe CRS/ICANS and those with mild toxicities or without toxicities. Furthermore, the Endothelial Activation and Stress Index (EASIX) and modified versions of this score, calculated in the pre- and early post-infusion period, seem to predict development of severe toxicities, ICAHT, and, thus, poor overall survival in CAR-T cell patients. More data concerning the role of these endothelial injury markers and clinical outcomes in CAR-T cell settings are essential.

Keywords: CAR-T; CRS; ICANS; complement; endothelium; lymphoma; myeloma.

Figure 1

Endothelial injury in CAR-T cell recipients. Various markers of endothelial injury have been investigated in CAR-T cell recipients, including markers of complement activation, such as soluble C5b-9, endothelial dysfunction (Ang-2, VCAM1, ICAM-1, E-selectin), inflammation, and thrombosis (VWF, ADAMTS13). The expression of these endothelial injury markers has been identified as impaired in CAR-T cell recipients, not only when compared with healthy controls but also when compared between patients with severe CRS/ICANS and those with mild toxicities or without toxicities. ↑: increased; ↓: decreased; ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13; CAR-T = chimeric antigen receptor-T; ICAM-1 = intercellular adhesion molecule; IL-6 = interleukin-6; IL-1 = interleukin-1; sC5b-9 = soluble C5b-9. TNF-α = tumor necrosis factor-α; VCAM-1 = vascular adhesion molecule; VWF: von Willebrand factor (created in BioRender. Evangelidis, P. (2025) https://BioRender.com/bwzsi9g, accessed on 11 May 2025).