Targeting monocytes using C-miR146a mimic alleviates CRS induced by CD19 CAR T cells without compromising antitumor effects. (A-B) C-miR146a does not affect cytotoxic activity of CD19 CAR T cells against target leukemia cells. Mock- or CD19 CAR-transduced T cells were cocultured at a 1:1:1 ratio with donor-matched CD14⁺ monocytes and target CD19⁺ Nalm6 B-cell leukemia for 48 hours in the presence of 500 nM of C-miR146a or control C-scrRNA. (A) Shown are the percentages of live CD19⁺ target cells (left) or CAR T cells (right) vs untreated control. (B) The IL-1 and IL-6 levels in cultured supernatants as measured by using ELISA. Shown are results combined from 4 different peripheral blood mononuclear cell donors. (C) The experimental design for in vivo studies on the CAR T-cell–induced CRS using a xenotransplanted lymphoma model. SCID-Beige mice were engrafted with luciferase-expressing Raji lymphoma cells (intraperitoneally [IP]), and after 2 weeks were injected daily by using 5 mg/kg (IP) of C-miR146a or PBS. A total of 12.5 × 10⁶ mock or CD19 CAR T cells were injected IP on day 18 before euthanizing mice on day 22. (D-E) Tumor progression was monitored by using bioluminescent imaging; means ± SEM. (F) The intracellular miR-146a levels were measured by using qPCR in CD11b⁺ myeloid and CD11b^– nonmyeloid cells derived from peritoneal lavage. (G) Serum human cytokine levels and mouse IL-6 and G-CSF were measured by using ELISA after 24 hours from CAR T-cell transfer. Representative results from at least 2 independent experiments are shown as means ± SEM (n = 4). ***P < .001; **P < .01; and *P < .05 compared to untreated or as indicated. mG-CSF, mouse G-CSF; p/s, photons per second; ROI, regions of interest.