Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies

Xiao, Xinyi; Huang, Shengkang; Chen, Sifei; Wang, Yazhuo; Sun, Qihang; Xu, Xinjie; Li, Yuhua

doi:10.1186/s13046-021-02148-6

Journal of Experimental & Clinical Cancer Research

Table 3 Summary of potential anticytokine agents for CAR-T associated CRS and/or ICANS

From: Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies

Agent	Target	Application	Mechanism	Stage and clinical trial
Tocilizumab	IL-6	CRS	Blocking IL-6R, inhibiting IL-6, the key cytokine of the CRS	FDA-approved first-line agent for severe CRS [143]
Siltuximab	IL-6	CRS ICANS	Blocking IL-6	Clinical trial [152]
Corticosteroids	NA	CRS ICANS	Non-specific anti-inflammatory effects to suppress immune cells	First-line agent for severe and isolated ICANS [156]
Anakinra	IL-1	CRS ICANS	Blocking IL-1, an important cytokine in CRS and ICANS	Ongoing trials: NCT04148430, NCT04150913, NCT04205838, NCT04432506, NCT04359784, NCT03430011, NCT04227275
Lenzilumab	GM-CSF	CRS ICANS	Blocking GM-CSF and inhibiting myeloid cells and T cells entering CNS	Ongoing trial: NCT04314843
Ruxolitinib	JAK1/2	CRS	Broadly inhibiting JAK-STAT pathways, the downstream of multiple cytokines	Clinical trial [175]
Itacitinib	JAK1	CRS	Selectively inhibiting the JAK-STAT pathways	Ongoing trial: NCT04071366
Dasatinib	TK	CRS	Blocking the adenosine triphosphate binding sites of LCK, reversibly inhibiting the activation of CAR T-cells	Ongoing trial: NCT04603872
Ibrutinib	ITK	CRS ICANS	Inhibiting the ITK-induced cytokine release of T cells, monocytes and tumor cells	Ongoing trials: NCT04234061, NCT03331198, NCT03310619, NCT04640909, NCT03570892
Metyrosine	Catecholamine	CRS	Blocking tyrosine hydroxylase to inhibit the synthesis of catecholamine	Preclinical [28]
ANP	Catecholamine	CRS	Inhibiting cytokine secretion	Preclinical [28]
Etanercept	TNF-α	CRS	Blocking TNF-α, an important cytokine in CRS	Clinical trials [29, 192, 193, 225]
Adalimumab	TNF-α	CRS ICANS	Blocking TNF-α	Preclinical, administered with anti-IL-1β antibody [194]
Extracorporeal cytokine removal Plasma exchange Hemofiltration	NA	CRS ICANS	Removal of pro-inflammatory mediators from the blood	Ongoing trial: NCT04048434
TO-207	mRNA 3′-end	CRS	An mRNA 3′-end processing antagonist, inhibiting the secretion of multiple cytokines	Preclinical [196]
THZ1	CDK7	CRS	Suppressing a set of inflammatory genes, mainly STAT and IL-1	Preclinical [197]

CAR-T Chimeric antigen receptor T cell, CRS Cytokine release syndrome, ICANS Immune effector cell associated neurotoxicity syndrome, IL Interleukin, FDA US Food and Drug Administration, NA Not applicable, GM-CSF Granulocyte-macrophage colony-stimulating factor, JAK Janus kinase, STAT Signal transducer and activator of transcription, TK Tyrosine kinase, LCK Lymphocyte-specific protein tyrosine kinase, ITK IL-2-induced tyrosine kinase, TNF-α Tumor necrosis factor-α, CDK7 Cyclin-dependent kinase 7

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ISSN: 1756-9966

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