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Review
. 2018 Jan 22:6:4.
doi: 10.1186/s40364-018-0116-0. eCollection 2018.

Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy

Zhenguang Wang  1 , Weidong Han  1
Affiliations
Review

Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy

Zhenguang Wang et al. Biomark Res. .

Abstract

Severe cytokine release syndrome (CRS) and neurotoxicity following chimeric antigen receptor T cell (CAR-T) therapy can be life-threatening in some cases, and management of those toxicities is still a great challenge for physicians. Researchers hope to understand the pathophysiology of CRS and neurotoxicity, and identify predictive biomarkers that can forecast those toxicities in advance. Some risk factors for severe CRS and/or neurotoxicity including patient and treatment characteristics have been identified in multiple clinical trials of CAR-T cell therapy. Moreover, several groups have identified some predictive biomarkers that are able to determine beforehand which patients may suffer severe CRS and/or neurotoxicity during CAR-T cell therapy, facilitating testing of early intervention strategies for those toxicities. However, further studies are needed to better understand the biology and related risk factors for CRS and/or neurotoxicity, and determine if those identified predictors can be extrapolated to other series. Herein, we review the pathophysiology of CRS and neurotoxicity, and summarize the progress of predictive biomarkers to improve CAR-T cell therapy in cancer.

Keywords: Biomarker; CAR-T; CRS; Chimeric antigen receptor; Neurotoxicity.

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Conflict of interest statement

This is not applicable for this review.This is not applicable for this review.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Risk factors for CRS and neurotoxicity. Disease burden and infused CAR-T cell dose have a direct impact on the in vivo CAR-T cell expansion. Enhanced in vivo CAR-T cell expansion also correlates with the high-intensity lymphodepletion with fludarabine, which can result in greater lymphodepletion and prevention of the anti-CAR immune responses. The level of IL-15, one of the cytokines that can improve T cell activation and function, is elevated due to the greater lymphodepletion. Patients with preexisting endothelial cell activation are prone to develop severe CRS and/or neurotoxicity. VWF released by the activated endothelial cell can bind activated endothelium and sequesters platelets. Ang-2, another endothelial cell activation biomarker, can promote the capillary leak. Moreover, activated endothelial cell is a key resource of IL-6 in CRS, and then secreted IL-6 can further facilitate endothelial cell activation, increasing the risk of CRS and/or neurotoxicity. CRS: cytokine release syndrome; CAR-T: chimeric antigen receptor T cell; IL: interleukin; VWF: von Willebrand Factor; Ang:angiopoietin
See this image and copyright information in PMC

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