Cytokine release syndrome

Abstract

During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

Keywords: CAR T cells; Cytokine release syndrome; Cytokine storm; Immunotherapy; T cell-engaging therapies.

Fig. 1

Clinical presentation of CRS. Beginning with fever and unspecific symptoms CRS might impact most organ systems. Mild cases can present as flu-like illness. Grade °III to IV shows signs of life threatening cardiovascular, pulmonary and renal involvement. Neurotoxicity can occur concurrent or with delay. Abbreviations: DIC: disseminated intravascular coagulation; INR: international normalized ratio; PTT: partial thromboplastin time

Fig. 2

Reported inducers of CRS. CRS can be induced by direct target cell lysis with consecutive release of cytokines like interferon gamma (IFN-γ) or tumor necrosis factor alpha (TNF-α) or by activation of T cells due to therapeutic stimuli with subsequent cytokine release. These cytokines trigger a chain reaction due to the activation of innate immune cells like macrophages and endothelial cells with further cytokine release. Abbreviations: Ang-2: Angiopoetin 2; CAR: chimeric antigen receptor; DC: dendritic cell; IFN-γ: interferon gamma; MHC-I: major histocompatibility complex I;NK cell: natural killer cell; PD-(L)1: programmed cell death protein (ligand) 1; TCR: T cell receptor.; TNF-α: tumor necrosis factor alpha; vWF: von Willebrand factor

Fig. 3

Proposed pathomechanism of CRS. Activation of manly T cells or lysis of immune cells induces a release of interferon gamma (IFN-γ) or tumor necrosis factor alpha (TNF-α). This leads to the activation of macrophages, dendritic cells, other immune cells and endothelial cells. These cells further release proinflammatory cytokines. Importantly, macrophages and endothelial cells produce large amounts of interleukin 6 (IL-6) which in a positive feedback loop manner activates T cells and other immune cells leading to a cytokine storm. Abbreviations: CAR: chimeric antigen receptor; FiO2: fraction of inspired oxygen; IL-6: interleukin 6; IFN-γ: interferon gamma; TNF-α: tumor necrosis factor alpha