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

By Theodoros Giavridis, Sjoukje J. C. van der Stegen, Justin Eyquem, Mohamad Hamieh, A. Piersigilli, Michel Sadelain. Nature Medicine, 2018

1,122 citations recorded by the source corpus.

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 burden2–4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2–9. 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. Blocking IL-1 and iNOS prevents CAR T cell–induced cytokine release syndrome.

Subfields: Genetics, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/1ef6d6e28328236c57258b7481f6c7c805e983b3

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Citations in the corpus

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, background): “Hematologic toxicity associated neurotoxicity (33, 34).”
IL-6 in inflammation, autoimmunity and cancer (2020, background): “IL-1 and IL-6 are involved in the lethal cytokine storm sometimes seen in CAR-T treatment (353, 354).”
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19 (2020, positive): “It is also noteworthy that two of the cytokines uniquely elevated in response to SARS-CoV-2 are IL-6 and IL1RA, suggesting that there might be a parallel between COVID-19 and cytokine release syndrome (CRS), a complication commonly seen following CAR T-cell treatment (Giavridis et al., 2018) .”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “Accordingly, IL-1 receptor antagonists, either administered systemically or secreted from engineered CAR T cells, ameliorate CRS and neurotoxicity in mouse models of leukaemia or lymphoma treated with anti-CD19 CAR T cells 71,72 .”
ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells (2018, background): “The pathophysiology of the syndrome is unclear, because no animal models of CRS existed until recently [18,19].”
Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients (2020, background): “Cytokine storms are associated with a wide variety of infectious and noninfectious diseases including graft-versus-host disease, autoimmune disease, severe virus infection, multiple organ dysfunction syndromes and chimeric antigen receptor (CAR)-T cell therapy 12, 13 .”