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

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.

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

“…TNF-α blockade (adalimumab) exerted separated and synergistic effects on preventing endothelial activation induced by CAR-T, myeloid cells, and tumor cells. 138 Besides, adalimumab prevents macrophage activation and effectively mitigates CRS in anti-CD3 bispecific antibody therapy. 61 Furthermore, in SARS-CoV and MERS cases, excessive TNF-α represented a poor prognosis and inhibition of NF-κB can increase survival in SARS-CoV-infected mice.…”

“… 143 Anti-IL1β antibody exerted separated and synergistic effects in preventing endothelial activation induced by tumor cells, CAR-T, and myeloid cells. 138 In severe COVID-19, it was proposed that NLRP3 activation and IL-1β precursor cleavage potentially aggravate CRS. 144 …”

Investigation of CRS-associated cytokines in CAR-T therapy with meta-GNN and pathway crosstalk

“…When CAR-T cells enter the human body, they directly cause the tumor cells to burn out, so that ATP, the energy molecule in the cells, is released in large quantities, and ATP can strongly activate macrophages [ 31 ]. Macrophages promote assembly of signaling complexes by inducing activation of TCR adjacent to tyrosine kinases, thereby activating downstream signaling pathways such as MAPK, PKC, and calcium ions.…”

Management of haemostatic complications of chimaeric antigen receptor T‐cell therapy

“…Treatment of CRS itself with corticosteroids and the anti‐IL6 receptor antibody tocilizumab, following international guidelines, is likely to ameliorate the prothombotic and haemorrhagic phenotype that may accompany severe CRS 18,20 . Preclinical studies using TNF‐α and IL‐1 antagonists have shown the ability to dampen endothelial activation and features of CRS and ICANS, which may be of clinical utility pending results of future clinical trials 67 . However, anticoagulation may also provide additional benefit, with the limited data currently published suggesting an acceptable bleeding risk amongst selected patients.…”

“…18,20 Preclinical studies using TNF-α and IL-1 antagonists have shown the ability to dampen endothelial activation and features of CRS and ICANS, which may be of clinical utility pending results of future clinical trials. 67 However, anticoagulation may also provide additional benefit, with the limited data currently published suggesting an acceptable bleeding risk amongst selected patients.…”