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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309375 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Chimeric antigen receptor (CAR) T cell therapy have demonstrated remarkable success in treating B-cell malignancies that are refractory to standard therapies; however, preclinical and clinical studies have demonstrated that CAR T cell efficacy is greatly reduced against antigen-low tumors. This was exemplified in a clinical trial of CD22-directed CAR T cells where post-CAR relapses were driven by a decrease in the surface expression of the CD22 antigen. To address the poor response of CAR T cells to antigen-low tumor cells, we performed global phosphoproteomics using a SILAC/mass spectrometry approach to examine signal transduction events within CAR T cells in response to high- and low-levels of CD22 antigen. Stimulation with low levels of CD22 antigen resulted in decreased activation of several canonical T cell signaling pathways in CAR T cells, suggesting poor utilization of LAT. To overcome this inefficiency of LAT activation, we designed a bicistronic construct consisting of a clinically active 2nd generation CD22-BBz CAR along with a novel Adjunctive LAT Activating CAR incorporating the intracellular signaling domain of LAT (ALA-CART). ALA-CART cells demonstrated enhanced phosphorylation of LAT and restored downstream signaling in response to low levels of CD22. In xenograft models, ALA-CART cells completely eradicated CD22-low leukemia, significantly extending survival of mice in comparison to the clinically-active, standard CD22-BBz CAR T cells. Compared to the standard CD22-BBz CAR T cells, ALA-CART cells exhibited transcriptional differences in the resting state reflecting a less differentiated state, which corresponded to an enrichment of T stem cell memory cells and enhanced in vivo persistence. Thus, through the identification of CAR signaling deficits, we rationally designed the ALA-CART platform which improves the sensitivity and persistence of CAR T cells to target antigen-low cells, overcoming a mechanism of resistance to standard CAR therapies.

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

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