Chimeric antigen receptor T (CAR-T) cell therapy is limited by cytokine release syndrome (CRS) and neurotoxicity (NT). We sought to use once-daily prophylactic anakinra, an IL-1R antagonist, to prevent CRS/NT that would require hospitalization (grade 2 or higher) in patients receiving axicabtagene ciloleucel for large cell lymphoma, with the goal of facilitating outpatient therapy and management. Our study (ClinicalTrials.gov #NCT04150913), in line with others, demonstrated that once-daily prophylactic anakinra is insufficient to prevent the development of toxicities that would require hospitalization in most of these patients. As part of the initial study design, we prospectively incorporated scRNAseq to gain insight into the molecular immune signaling associated with breakthrough CRS & NT despite anakinra prophylaxis. In patients who developed breakthrough CRS or NT, we found that IFNg pathways and ligand-receptor activities were significantly enriched, as were cytokine levels of IFNg and CXCL10 in CD14+ monocytes. This correlated with increased IFNg and other cytokines in the peripheral blood. In infused CAR-T products, IL-4 and IL-10 anti-inflammatory pathways were negatively associated with grade 2+ toxicities, regardless of anakinra treatment. These data identify IFNg as a potential key mechanism in CAR-T cell-associated toxicities, which is not inhibited by anakinra but may be otherwise targetable.