Therapeutic Potential of TNFα and IL1β Blockade for CRS/ICANS in CAR-T Therapy via Ameliorating Endothelial Activation.

Yunshuo Chen,Xuejiao Yang,Ranran Li,Wenbo Wang,Siqi Shang,Yueying Wang,Lei Li

doi:10.3389/fimmu.2021.623610

Abstract

Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) strongly hampered the broad clinical applicability of chimeric antigen receptor T cell (CAR-T) therapy. Vascular endothelial activation has been suggested to contribute to the development of CRS and ICANS after CAR-T therapy. However, therapeutic strategies targeting endothelial dysfunction during CAR-T therapy have not been well studied yet. Here, we found that tumor necrosis factor α (TNFα) produced by CAR-T cells upon tumor recognition and interleukin 1β (IL1β) secreted by activated myeloid cells were the main cytokines in inducing endothelial activation. Therefore, we investigated the potential effectiveness of TNFα and IL1β signaling blockade on endothelial activation in CAR-T therapy. The blockade of TNFα and IL1β with adalimumab and anti-IL1β antibody respectively, as well as the application of focal adhesion kinase (FAK) inhibitor, effectively ameliorated endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Moreover, adalimumab and anti-IL1β antibody exerted synergistic effect on the prevention of endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Our results indicate that TNFα and IL1β blockade might have therapeutic potential for the treatment of CAR-T therapy-associated CRS and neurotoxicity.

Highlights

Chimeric antigen receptor T cell (CAR-T) therapy following lymphodepletion has shown unprecedented prospect in the field of tumor treatment, especially in hematological malignancies
We found that tumor necrosis factor a (TNFa) was among the most abundant cytokines secreted by engaged CAR-T cells and identified a remarkable TNFa signaling pathway activation based on the analysis of transcriptome of treated endothelial cells
We found that the level of engaged CAR-T-induced endothelial activation was inhibited by knocking down TNF receptor 1 (TNFR1) in human umbilical vein endothelial cells (HUVEC) (Supplementary Figure 5), indicating that TNFR1 mediates, at least partially, endothelial activation induced by engaged CAR-T cells

Summary

Introduction

Chimeric antigen receptor T cell (CAR-T) therapy following lymphodepletion has shown unprecedented prospect in the field of tumor treatment, especially in hematological malignancies. In the clinical trials of CAR-T therapy, the complete remission rate of pediatric/adult patients with relapsed/refractory B-cell acute lymphoblastic. EC Activation in CAR-T Toxicities leukemia (B-ALL) and adult patients with relapsed/refractory Bcell non-Hodgkin lymphomas (B-NHL) is about 70%~90% and 43%~54%, respectively [5,6,7]. Current treatments effectively abated the severity of CRS and substantially extended event-free survival [14, 15], there are still patients unresolved, in the most severe cases. This seriously limited the efficacy and the clinical applicability of CAR-T therapy. Understanding the mechanisms of CAR-T-induced CRS and ICANS is urgent for effective identification and intervention

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Conclusion