In the clinic, chimeric antigen receptor–modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell–mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.
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We thank G. Dotti (University of North Carolina) and H. Abken (University of Cologne) for providing the original CAR constructs, F. Falkenburg (Leiden University Medical Center) for providing ALL-CM leukemic cells and L. Naldini (San Raffaele-Telethon Institute for Gene Therapy) for providing lentiviral vectors. We thank R. Norato (San Raffaele Scientific Institute) for histology technical support. This work was supported by the Italian Association for Cancer Research (AIRC) (MFAG grant no. 13390 and Investigator grant no. 17706 to B.A.; MFAG grant no. 20247 to O.R.).
C.T. and C. Bordignon are employees of Molmed Spa, whose potential product is studied in this work. F.C. and C. Bonini are consultants of Molmed Spa.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–19
Datasets generated in this study and sequencing information
List of differentially expressed genes for each scRNA-seq
List of differentially expressed genes in scRNA-seq clusters 5, 7, 11, 12 (monocyte and DC populations)
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Norelli, M., Camisa, B., Barbiera, G. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 24, 739–748 (2018). https://doi.org/10.1038/s41591-018-0036-4
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