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

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 immunocom-petent model of anti-CD19 CART cell therapy, we report that CD4+, but not CD8+, CART cells elicit physiolog-ical CRS-like manifestations associated with the release of inflammatory cytokines. In CAR T cell-treated pa-tients, CRS occurrence and severity are significantly associated with high absolute values of CD4+ CART cells in the blood. CRS in mice occurs independently of CART cell-derived interferon g (IFN-g) 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.