CART19 and CART22 therapies exhibit distinct cytokine profiles, with IL-10 identified as a critical CRS-mitigating factor

Chimeric antigen receptor T-cell (CART) therapy has revolutionized treatment for B-cell acute lymphoblastic leukemia (B-ALL), but it carries a significant risk of Cytokine Release Syndrome (CRS), a life-threatening toxicity. While CD19-directed CART (CART19) is effective, it's associated with higher rates of severe CRS compared to CD22-directed CART (CART22). Understanding the differential cytokine responses between these two CART modalities is crucial for developing safer and more effective therapeutic strategies, addressing a key gap in current CRS management.

Researchers investigated cytokine profiles in 40 patients treated with either CART19 or CART22. Over 1,000 serum proteins were measured using a proximity extension assay to compare cytokine architectures. Single-cell RNA-sequencing (scRNAseq) was employed to identify cellular and transcriptional differences between patient groups. Furthermore, in vitro models were used to study the interactions at the immune synapse (IS) between CART19-blast and CART22-blast cells, providing mechanistic insights.

Interleukin-10 (IL-10) was identified as a critical endogenous modulator of CRS, with previous CART treatment associated with increased serum IL-10 in the context of subsequent relapse. Mechanistically, IL-10 induced higher interferon gamma expression and SOCS3 upregulation in both CART19 and CART22 cells, indicating a broad immunomodulatory role. Importantly, IL-10 differentially impacted the CART immune synapse (IS): it prolonged the CART19 IS but shortened the CART22 IS, suggesting distinct regulatory mechanisms. Using scRNAseq, the study demonstrated SOCS3 upregulation in CART22 patient CD4 T-cells, which potentially suppresses trans-IL-6 signaling, contributing to the observed lower CRS rates.

These findings reveal IL-10 as a potent CRS-mitigating factor, highlighting its crucial role in modulating CART-induced inflammation.