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

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Boulch, Morgane | Cazaux, Marine | Cuffel, Alexis | Ruggiu, Mathilde | Allain, Vincent | Corre, Béatrice | Loe-Mie, Yann | Hosten, Benoit | Cisternino, Salvatore | Auvity, Sylvain | Thieblemont, Catherine | Caillat-Zucman, Sophie | Bousso, Philippe

Edité par CCSD ; Cell Press -

International audience. 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.

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