CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade

Abstract

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)2,3,4, 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 burden2,3,4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2,3,4,5,6,7,8,9. 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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Fig. 1: A mouse model of CRS recapitulates clinical CAR T cell–induced CRS.
Fig. 2: Tumor–CAR T cell interactions trigger myeloid cell recruitment and activation.
Fig. 3: Modulation of macrophage function determines CRS severity.
Fig. 4: IL-1Ra protects from severe CRS without compromising antitumor efficacy.

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Acknowledgements

We thank the Alexander S. Onassis Public Benefit Foundation for their support (T.G.). We thank the following MSK core facilities for their outstanding support: flow cytometry core facility, laboratory of comparative pathology, animal facility, integrated genomics operation and bioinformatics core. We thank G. Gunset, Z. Zhao, A. Dobrin and P. Lindenbergh for their assistance with some experiments. This study was supported by Juno Therapeutics and the MSK Cancer Center Support Grant/Core Grant (P30 CA008748).

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T.G. designed the study, performed experiments, analyzed and interpreted the data and wrote the manuscript. S.J.C.v.d.S. helped design and perform in vivo experiments. J.E. performed in vivo experiments. M.H. performed in vivo experiments. A.P. performed and interpreted histopathological studies. M.S. designed the study, analyzed and interpreted the data and wrote the manuscript.

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Correspondence to Michel Sadelain.

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A patent application on CRS prevention listing T.G. and M.S. as co-inventors has been filed by MSK.

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Giavridis, T., van der Stegen, S.J.C., Eyquem, J. et al. CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med 24, 731–738 (2018). https://doi.org/10.1038/s41591-018-0041-7

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