Table_4_Therapeutic Potential of TNFα and IL1β Blockade for CRS/ICANS in CAR-T Therapy via Ameliorating Endothelial Activation.xls

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.

重度细胞因子释放综合征（CRS）与免疫效应细胞相关神经毒性综合征（ICANS）严重阻碍了嵌合抗原受体T细胞（CAR-T）疗法的临床推广应用。已有研究表明，血管内皮激活与CAR-T治疗后CRS及ICANS的发生发展存在关联。然而，目前针对CAR-T治疗过程中内皮功能障碍的治疗策略尚未得到充分研究。本研究发现，CAR-T细胞识别肿瘤后产生的肿瘤坏死因子α（TNFα），以及活化髓系细胞分泌的白细胞介素1β（IL1β），是诱导内皮激活的核心细胞因子。据此，本研究探讨了阻断TNFα与IL1β信号通路对CAR-T治疗中内皮激活的潜在干预价值。分别使用阿达木单抗（adalimumab）与抗IL1β抗体阻断TNFα、IL1β，联合黏着斑激酶（FAK）抑制剂，可有效改善CAR-T细胞、肿瘤细胞与髓系细胞共同诱导的内皮激活。此外，阿达木单抗与抗IL1β抗体在预防CAR-T、肿瘤细胞及髓系细胞诱导的内皮激活方面具有协同效应。本研究结果显示，阻断TNFα与IL1β信号通路或可用于治疗CAR-T疗法相关的CRS与神经毒性。