Cancer Letters

Cancer Letters

Volume 343, Issue 2, 28 February 2014, Pages 172-178
Cancer Letters

Mini-review
Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells

https://doi.org/10.1016/j.canlet.2013.10.004Get rights and content

Highlights

  • Cytokine release syndrome (CRS) is a fatal complication in CAR-T cell therapy.

  • CRS correlates with CAR structures, underlying diseases and cytokine gene polymorphisms.

  • CRS may be reduced by dose-escalation scheme, designing safer CARs and short-lived CAR-T cell infusion.

  • CRS can be controlled by cytokine-directed therapy using steroid and antagonists of cytokines.

Abstract

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells is a promising therapy for cancers. However, the safety of this approach is concerned. Cytokine release syndrome (CRS) is a common but lethal complication of CAR-T cell therapy. The development of CRS correlates with CAR structures, tumor type and burden, and patients’ genetic polymorphisms. CRS related adverse events may be reduced by designing safer CARs and CAR-T cells and following strict dose-escalation scheme. Timely and effective cytokine-directed treatment with corticosteroid and various cytokine antagonists is important to avoid CRS associated death.

Introduction

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells is a promising new therapy for cancers. Significant progresses have been made in the past decades as the optimization of the CAR design [1], [2], [3]. The results from early clinical trials have revealed a very encouraging therapeutic efficacy of the CAR-mediated immunotherapy in a variety of cancers including lymphoma, chronic lymphocytic leukemia (CLL), acute lymphobastic leukemia (ALL) and neuroblastoma [4], [5], [6], [7], [8], [9].

Although most adverse events with genetically modified T cell infusion are tolerable and acceptable in clinical trials, the safety and toxicity of CAR engineered T cell (CAR-T cell) infusion are of concern, including insertional mutagenesis, off-target effects and systemic inflammatory reaction (cytokine storm and tumor lysis syndrome) [10]. Two cases of serious adverse events following the administration of CAR-T cells were reported in 2010 [11], [12]. Both the deaths seemed related to a systemic cytokine release that has been termed cytokine release syndrome (CRS). According to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAEs) Version 4.0, CRS is a disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath caused by the release of cytokines from the cells [13]. It is caused by an exaggerated systemic immune response mediated by T cells, B cells, NK cells and monocytes/macrophages which release a large amount of inflammatory mediators such as cytokines and chemokines. CRS is not a rare phenomenon in clinical setting. It occurs in graft-versus-host disease (GVHD) after transplantation, severe bacterial and viral infections, hemophagocytic lympohistiocytosis (HLH)/macrophage activation syndrome (MAS) and monoclonal antibody (mAb) therapy [14], [15], [16], [17], [18]. Cytokines trigger an acute inflammatory response and induce endothelial and organ damage, which result in microvascular leakage, heart failure and even death [19], [20], [21].Thus, it is of great importance to timely and properly manage CRS during CAR-T cell therapy. In this review, we will briefly discuss the manifestations, pathophysiology, precaution and treatment of CRS in CAR-T cell infusion.

Section snippets

Cytokine profile and clinical manifestations of CRS

The administration of biologic products resulting in CRS was firstly observed in patients with anti-CD3 mAb OTK3 therapy for organ transplantation [22]. Within 1–4 h following the antibody injection, serum levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2 were markedly elevated. Severe, life-threatening CRS has been reported in six previous healthy volunteers who received intravenously infusion of TGN1412, an anti-CD28 humanized mAb that directly stimulates T

Pathophysiology of CRS

The classic and basic design of a CAR includes a single chain variable fragment (scFv) targeting tumor associated antigen (TAA), an extracellular spacer/hinge region, a trans-membrane domain and an intracellular signaling domain. After the CAR-T cells encountered the tumor cells, the scFv is engaged by the TAA and the activation signal is transduced to the immunoreceptor tyrosine-based activating motif of the CD3ζ chain. The CD3ζ signal provides the requisite ‘signal 1’ resulting in T cell

Differentiation of CRS

In CAR-T cell therapy, some other complications, including tumor lysis syndrome (TLS) and severe sepsis, may mimic CAR-T cell induced CRS. Both of them may cause elevation of cytokines and organ failure, but the managements are different. Thus, it is necessary to differentiate the above conditions and to give proper treatment. TLS is a disease-related emergency which has been reported in CAR-T cell therapy. In TLS, lysed tumor cells release DNA, phosphate, potassium, and cytokines. When the

Potential factors related to CRS

The incidence of CRS varies greatly among different clinical trials and each patient responds differently to CAR-T infusion even when the same protocol is used. The variety of cytokine profiles among different individuals and different clinical trials may be related to various CAR structures, underlying diseases and patients’ genetic polymorphisms.

Precautions of CRS

CRS induced by CAR-T cell infusion shares many common features with that caused by mAb administration. However, unlike mAb-induced side effects could be alleviated following the excretion of the drug, CRS and its related toxicity induced by CAR-T cells could be long-lasting, as proliferating T cells will increase in numbers in vivo and eventually cause CRS. For example, the 4-1BB incorporated anti-CD19 CAR modified T cells can be expanded more than 1000 folds in CLL patients [6]. From this

Treatment of CRS

CRS is an emergent and life-threatening entity. According to the data of rituximab, there were at least 9 fatalities resulting from CRS had occurred by the year of 1999, 2 years after rituximab was approved by U.S. FDA [53]. The clinical data of CAR-T cell therapy are limited as there are only few patients being treated up to now. However, 2 fatalities have been reported shortly after adoptive transfer of CAR-T cells, which were both related to CRS [11], [12]. The two patients both presented

Challenges and perspectives

Adoptive CAR-T cell therapy is an attractive strategy for cancer. While the antitumor effects have been greatly enhanced following the improvement of the CAR design and growth conditions [65], how best to develop a safe approach to implement this new therapeutics becomes a big concern. CRS is a double-edged sword which is closely related to the efficacy of such therapy but does harm to the host if the inflammatory response is overwhelming [10], [25]. Therefore, how to balance the two aspects is

Conflict of Interest

All the authors declare no conflict of interests.

Acknowledgement

This study was supported in part by Grants from the National Natural Science Foundation of China (Nos. 30971283, 31100638 and 81170502), the Zhejiang Provincial Natural Science Foundation of China (Nos. Y2110020 and LZ12H08001), and the PhD Programs Foundation of Ministry of Education of China (No. 20110101120138).

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