Abstract / Summary
Abstract CD19-directed chimeric antigen receptor (CAR)-T-cell therapy has improved the outcome of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet the biologic determinants underlying differences among CAR-T products remain incompletely understood. We prospectively studied 67 patients treated with tisagenlecleucel (tisa-cel; n = 28) or axicabtagene ciloleucel (axi-cel; n = 39), integrating baseline inflammatory variables with longitudinal flow cytometry, stimulated intracellular cytokine production, plasma cytokines, and infusion-product phenotyping. A lower pre-infusion inflammatory profile, reflected by reduced ferritin, LDH levels and CAR-HEMATOTOX score, was associated with early complete response and improved hematologic recovery, supporting baseline immune fitness as a key determinant of treatment outcome. Following infusion, immune kinetics were shaped by both tumor burden and CAR construct. In patients with low tumor burden, tisa-cel induced a greater expansion of circulating T cells without translating into superior tumor control, whereas axi-cel achieved more durable responses despite lower peripheral lymphocyte counts, suggesting a qualitative immune advantage. Axi-cel induced a rapid in vivo CAR⁺ expansion, a more balanced CD4⁺/CD8⁺ CAR-T ratio, a differentiation towards effector and exhausted phenotypes, and a pronounced bystander activation of endogenous CAR⁻ T cells. Cytokine profiling identified IL-8 as an important mediator, associated with neurotoxicity, reduced circulating lymphocytes and inferior clinical outcomes. Collectively, these findings define distinct biologic programs associated with axi-cel and tisa-cel administration and support a model in which CAR-T-cell efficacy in R/R LBCL is driven by qualitative immune remodeling integrating host inflammatory fitness with construct-specific immune reprogramming.