Abstract
Targeting IL1 attenuates cytokine release syndrome (CRS) without affecting CAR T-cell antitumor activity.
Major finding: Targeting IL1 attenuates cytokine release syndrome (CRS) without affecting CAR T-cell antitumor activity.
Concept: Two mouse models of CAR T cell–mediated CRS suggest that myeloid cell–derived cytokines induce toxicity.
Impact: Identification of IL1 as a cause of CRS and neurotoxicity may enable development of safer CAR T cells.
Adoptive transfer of chimeric antigen receptor (CAR) T cells targeting CD19 induces tumor regression in patients with refractory B-cell malignancies. However, despite potent antitumor activity, the use of CAR T-cell therapies is limited by the occurrence of severe cytokine release syndrome (CRS) and neurotoxicity. In two related studies, mouse models of CAR T cell–mediated toxicity were developed to better understand and predict the clinical behavior of CAR T cells. To recapitulate CRS in mice with B-cell malignancies, Giavridis and colleagues injected human 1928z CAR T cells into lymphoma-bearing SCID-bg/bg mice. CRS developed within 2–3 days of CAR T-cell infusion, and interactions between the tumor and CAR T cells induced the recruitment and activation of myeloid cells. Specifically, macrophage function determined the severity of CRS via production of IL6, IL1, and nitric oxide. Consistent with these findings, treatment with an IL1 receptor (IL1R) antagonist or transfer of CAR T cells engineered to produce an IL1R antagonist protected against CRS-related mortality, without interfering with therapeutic efficacy. In a related study, Norelli and colleagues developed a mouse model of CAR T-cell toxicity by transplanting human cord blood hematopoietic stem and progenitor cells into sublethally irradiated newborn mice transgenic for cytokines supporting human hematopoiesis. These CAR T cells were not xenoreactive, but induced CRS in leukemia-bearing mice. Mechanistically, monocytes released IL1 and IL6 to induce CRS, and the severity correlated with leukemia burden. Monocyte ablation protected mice from CRS, and an IL1R antagonist reduced neurotoxicity and CRS-mediated mortality, whereas an IL6R antagonist did not reduce neurotoxicity. Further, IL1R inhibition did not diminish the antileukemic activity of CAR T cells. Taken together, these studies indicate that monocyte-mediated IL1 release underlies CAR T-cell toxicity and suggest the potential for therapeutic targeting of IL1 or design of safer CAR T cells.
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