Elevated Serum IL-10 in the Setting of Relapsed B-ALL in Patients Previously Treated with CART

Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor T-cell therapy (CART) for B-cell acute lymphoblastic leukemia (B-ALL). Lower rates of severe CRS are reported in patients treated with CD22-directed CART (CART22) compared to those treated with CD19-directed CART (CART19). Here, we identify interleukin-10 (IL-10) as a critical endogenous modulator of CRS and demonstrate that previous treatment with CART is associated with increased serum IL-10 in the setting of subsequent relapse. Mechanistically, IL-10 induced higher interferon gamma (IFNγ) expression and SOCS3 upregulation in both CART19 and CART22 cells. IL-10 differentially impacted the CART immune synapse, prolonging the CART19 but shortening the CART22 immune synapse. Using single cell RNA sequencing (scRNAseq) we demonstrate upregulation of SOCS3 in CART22 patient CD4 T-cells, potentially suppressing gp130-mediated IL-6 signaling. These findings reveal IL-10 as a potent CRS‐mitigating factor and support IL-10 enhancement strategies to improve the safety of CART.