CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade
Open accessAbstract
Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) 1 . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2-4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden 2-4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity 2-9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2-3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.
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Therapy for cytokine release syndrome and its neurological toxicity chiefly targets IL-6, which probably originates from monocytes or activated endothelial cells.
“Treatment for CRS and associated neurotoxicity primarily targets IL-6, likely arising from monocytes or activated endothelium [1, 6, 11–17].”
From Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm (2021) · cites this paper as [12]
The paper’s main text (indexed under Abstract; page unavailable) says CRS may respond to IL-6 receptor blockade and identifies recipient macrophages as the main overall source of IL-6, while also finding IL-6 transcripts in monocytes. It does not establish activated endothelial cells as an IL-6 source or say that treatment of associated neurotoxicity primarily targets IL-6; instead, it discusses IL-1 blockade as a potential way to reduce neurotoxicity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIL-1 and IL-6 are involved in the lethal cytokine storm sometimes seen in CAR-T treatment.
“IL-1 and IL-6 are involved in the lethal cytokine storm sometimes seen in CAR-T treatment (353, 354).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [354]
Recent studies in mice suggest that cytokines and factors mediating the severity of CAR T-cell-induced cytokine storm are produced by macrophages, not CAR T cells, and can be reversed by interleukin-6 and interleukin-1 blockade.
“recent studies in mice suggest that the cytokines and factors mediating the severity of cytokine storm are produced not by the CAR T cells but by macrophages and can be reversed by interleukin-6 and interleukin-1 blockade.52-54”
From Cytokine storm (2020) · cites this paper as [53]
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“IL-1 and IL-6 are involved in the lethal cytokine storm sometimes seen in CAR-T treatment (353, 354).”
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- Authors
- Giavridis, T., van der Stegen, S. J. C., Eyquem, J., Hamieh, M., Piersigilli, A., & Sadelain, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Sadelain, Michel
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-05-28
- Volume
- 24
- Issue
- 6
- Pages
- 731-738
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6410714
- OpenAlex
- W2803430447
- Cited by
- 1,272
- References
- 44
- Citations by year
- 2026: 120 · 2025: 126 · 2024: 165 · 2023: 172 · 2022: 159 · 2021: 188 · 2020: 186 · 2019: 113 · 2018: 42
- FWCI
- 49.80
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center
- Alexander S. Onassis Public Benefit Foundation
- Juno Therapeutics
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cytokine release syndrome, CAR T-cell therapy, CD19, acute lymphoblastic leukemia, macrophages, interleukin-1, interleukin-6, nitric oxide, inducible nitric oxide synthase, IL-1 blockade, IL-6 receptor inhibition, mouse model, B-cell malignancies
- MeSH terms
- Animals, Humans, Interleukin-1, Macrophages, Neoplasms, Syndrome, Cytokines, Immunotherapy, Adoptive, Myeloid Cells, Mice, Interleukin 1 Receptor Antagonist Protein
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Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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