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) . 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), 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). 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. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity. 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.

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

“…None of these factors had significant difference between the groups in our study. The difference could be explained partially by the fact that autoCAR T cells had more robust [26,27]. However, Tcell function was suppressed by monocytes post-HSCT [28], which may result in less severe CRS.…”

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

“…2 for additional technical details on CAR T cell production multifocal vascular lesions, resulting in disruption of the blood-brain barrier, were reported in patients experiencing neurotoxicity within 28 days of infusion with CD19 CAR T cells in B cell ALL and NHL (44). Humanized mice model studies have shown a role for IL-1 and IL-6 derived from host monocytes in neurotoxicity, thereby providing a rationale for the use of anakinara (IL-1 receptor antagonist) in this indication (41). Additionally, the direct inhibition of IL-6 by siltuximab justifies its use over tocilizumab for the treatment of CRS, as it reduces the likelihood of IL-6 passive diffusion into the CNS and its related neurotoxicity (45).…”

“…More recently, studies in murine models of CRS have demonstrated that the severity of CRS does not only depend on CAR T cell-derived cytokines but also on IL-1, IL-6, and nitric oxide release by host macrophages (41). This…”

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…The frequency and severity of each symptom varies widely: CRS has been reported in 18-100% of patients, with severe CRS noted in 27-53% of patients [112]; neurotoxicity in 25-47% of patients [113,114]; and B-cell aplasia in 86-100% of patients [115]. As CRs to CARs are invariably accompanied by severe toxicity, recently developed animal models have shown mechanistic dissection and prevention of toxicity without hampering therapeutic efficacy by using IL-6-receptor and IL-1-receptor antagonists [116,117]. Algorithms and grading scales have been developed to aid the clinical management of these patients and include administration of steroids [118] and the interleukin six blocking antibodies, tocilizumab (FDA approved) [119 & ] and siltuximab [120].…”