A major role for CD4 ⁺ T cells in driving cytokine release syndrome during CAR T cell therapy

Summary

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy represents a breakthrough for the treatment of B cell malignancies. Yet, it can lead to severe adverse events, including cytokine release syndrome (CRS), which may require urgent clinical management. Whether interpatient variability in CAR T cell subsets contributes to CRS is unclear. Here, we show that CD4 ⁺ CAR T cells are the main drivers of CRS. Using an immunocompetent model of anti-CD19 CAR T cell therapy, we report that CD4 ⁺, but not CD8 ⁺, CAR T cells elicit physiological CRS-like manifestations associated with the release of inflammatory cytokines. In CAR T cell-treated patients, CRS occurrence and severity are significantly associated with high absolute values of CD4 ⁺ CAR T cells in the blood. CRS in mice occurs independently of CAR T cell-derived interferon γ (IFN-γ) but requires elevated tumor burden. Thus, adjusting the CD4:CD8 CAR T cell ratio to patient tumor load may help mitigate CAR T cell-associated toxicities.

Graphical abstract

Highlights

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  CD4 ⁺ CAR T cells play a major role in eliciting CRS in mice

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  CD4 ⁺ CAR T cells are elevated in the blood of CAR T cell patients experiencing CRS

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  CRS appears independent of CAR T cell-derived IFN-γ but requires high tumor burden

Abstract

Boulch et al. report that CD4 ⁺ CAR T cells play a more important role than their CD8 ⁺ counterparts in triggering cytokine release syndrome, a life-threatening complication of CAR T cell therapy. Fine-tuning of the CD4:CD8 CAR T cell ratio may therefore help mitigate CAR T cell-associated toxicities.