Clinical and Biological Correlates of Resistance and Relapse After CD19-Directed CAR T-Cell Therapy in Large B-Cell Lymphoma: A Structured Narrative Review

Background/Objectives: CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory large B-cell lymphoma (r/r LBCL), yet primary resistance and relapse remain common. We evaluated how recent clinical and translational evidence refines established resistance frameworks and which knowledge gaps prevent the relative contribution of individual mechanisms from being determined. Methods: We conducted a structured narrative review of 14 selected clinical and translational studies addressing tumor-, product-, host-, and microenvironment-related dimensions of treatment failure, synthesized across four interpretive domains and compared with nine previous reviews. Results: Durable benefit was associated with favorable tumor and immune transcriptional programs and greater CAR T-cell fitness, expansion, or persistence. Treatment failure was associated with tumor-intrinsic resistance programs, exhausted T-cell states, systemic inflammatory signals, and suppressive tumor-microenvironment features, including PD-L1-expressing macrophages. Antigen escape remained relevant, but incomplete serial CD19 assessment precluded conclusions about its relative contribution. Comparison with earlier reviews showed continuity rather than replacement, with LBCL-focused evidence adding biological resolution. Conclusions: Resistance and relapse after CD19 CAR T-cell therapy in LBCL are multifactorial. Prospective longitudinal studies integrating tumor tissue, apheresis and manufactured products, peripheral blood, and matched relapse samples are needed to validate predictive biomarkers and guide rational treatment strategies.