Plasma Cytokine and Chemokine Profiles Predict Efficacy and Toxicity of Anti-CD19 CAR-T Cell Therapy in Large B-Cell Lymphoma.

Abstract

Background: Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising treatment for large B-cell lymphoma (LBCL); however, durable complete responses are achieved in only 30% to 40% of patients. Additionally, CAR-T therapy is frequently associated with significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

Patients and methods: We explored the translational potential of cytokines and chemokines as predictive biomarkers for CAR-T outcomes by analyzing 47 plasma cytokines/chemokines in serial blood samples from 24 LBCL patients undergoing CAR-T therapy. Blood samples were collected at multiple times: prelymphodepletion, day of CAR-T infusion (Day 0), and post-infusion. We investigated the association between cytokine levels and key clinical outcomes using machine learning models, including treatment response at 3 months, CRS, and ICANS.

Results: Higher day 0 IL-7, day 7 IL-21, and day 0 CCL8 levels correlated with improved remission rates. Conversely, elevated CRS risk was linked to higher day 0 CCL17 and day 3 CCL13, IL-6, and IFN-γ levels. ICANS development was associated with increased day 0 TGF-β1, and day 3 IL-5 and IL-7 levels, while lower day 0 CCL19 and day 3 VIP levels were inversely related to ICANS risk. Additionally, patients who received higher-intensity lymphodepletion had elevated day 0 CCL2 and IL-15 levels.

Conclusion: These findings highlight the role of plasma cytokines and chemokines as biomarkers for predicting both the therapeutic efficacy and toxicity of CART, with the potential to guide more personalized, safer, and effective immunotherapies for B cell lymphoma.