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Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

Nature Reviews Immunology volume 22, pages 85–96 (2022)Cite this article

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Abstract

A paradigm shift has recently occurred in the field of cancer therapeutics. Traditional anticancer agents, such as chemotherapy, radiotherapy and small-molecule drugs targeting specific signalling pathways, have been joined by cellular immunotherapies based on T cell engineering. The rapid adoption of novel, patient-specific cellular therapies builds on scientific developments in tumour immunology, genetic engineering and cell manufacturing, best illustrated by the curative potential of chimeric antigen receptor (CAR) T cell therapy targeting CD19-expressing malignancies. However, the clinical benefit observed in many patients may come at a cost. In up to one-third of patients, significant toxicities occur that are directly associated with the induction of powerful immune effector responses. The most frequently observed immune-mediated toxicities are cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This Review discusses our current understanding of their pathophysiology and clinical features, as well as the development of novel therapeutics for their prevention and/or management.

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Fig. 1: Schematic diagram showing a relative timescale for the onset and duration of CRS and ICANS.
Fig. 2: Working model of the pathophysiological mechanisms of CRS.
Fig. 3: Schematic representation of current and potential therapeutic interventions for CRS.
Fig. 4: Pathophysiology of ICANS.

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Acknowledgements

E.C.M. was supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre.

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Authors and Affiliations

  1. Department of Immunology, Institute of Immunity and Transplantation, University College London, London, UK

    Emma C. Morris

  2. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sattva S. Neelapu

  3. Center for Cell Engineering, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Theodoros Giavridis & Michel Sadelain

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  1. Emma C. Morris
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  2. Sattva S. Neelapu
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  3. Theodoros Giavridis
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  4. Michel Sadelain
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The authors contributed equally to all aspects of the article.

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Correspondence to Emma C. Morris.

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Competing interests

M.S. and T.G. are listed as inventors in a Memorial Sloan Kettering-held patent application related to treatment of cytokine release syndrome: ‘Methods and compositions for alleviating cytokine release syndrome’ (WO2019099993A1). E.C.M. is scientific co-founder of Quell Therapeutics Ltd, which is developing chimeric antigen receptor (CAR)-modified regulatory T cells, and has served as a consultant to Kite, a Gilead company. S.S.N. served as consultant to Kite, a Gilead Company, Merck, Bristol-Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr and Unum Therapeutics; received research support from Kite, a Gilead Company, Bristol-Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics, Allogene Therapeutics, Precision Biosciences and Acerta; received royalties from Takeda Pharmaceuticals; and has intellectual property related to cell therapy.

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Nature Reviews Immunology thanks A. Bondanza, S. Grupp and C. Jacobson for their contribution to the peer review of this work.

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Glossary

Poor-risk malignant disease

Subtypes of malignancy (cancer) that have a poor prognosis with conventional therapies.

Blood–brain barrier

(BBB). A network of blood vessels and tissues that form a functional barrier to prevent harmful substances from entering the brain.

Activation-induced cell death

In peripheral T cells, death that is often the result of engagement of cell death pathways (for example, CD95–CD95L) that are upregulated during immune activation.

CD19+ lymphoma xenograft model

A lymphoma model in which immunodeficient mice are engrafted with human lymphoma cells positive for the CD19 surface antigen.

Humanized NSG mice

An immunodeficient mouse strain (NSG) reconstituted with human immune cells; in some iterations of this model, mice are engineered with transgenes encoding human haematopoietic cytokines.

Acute phase response

An early-onset, innate, systemic inflammatory reaction that results from various insults such as infection and tissue injury.

SCID–beige xenograft model

Severe combined immunodeficient (SCID)–beige mice lack mature B cells and T cells and exhibit defective natural killer cell responses, which makes them permissive to engraftment with human tumour tissue.

Human PBMC xenograft model

An immunodeficient mouse strain with an immune system reconstituted with human peripheral blood mononuclear cells (PBMCs) that can be engrafted with human tumour tissue.

Disseminated intravascular coagulation

A rare condition in which abnormal blood clotting occurs throughout the body’s blood vessels in response to various triggers that activate coagulation pathways.

Conditioning therapy

Chemotherapy and/or radiotherapy delivered prior to the infusion of chimeric antigen receptor (CAR) T cells, with the aim of increasing the expansion of the infused T cell population.

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Morris, E.C., Neelapu, S.S., Giavridis, T. et al. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol 22, 85–96 (2022). https://doi.org/10.1038/s41577-021-00547-6

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