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.

Background/Objectives: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (axi-cel) improves outcomes in relapsed/refractory large B-cell lymphoma (LBCL), but many patients relapse despite retained CD19 expression. We explored baseline tumor transcriptional features associated with event-free survival (EFS) after axi-cel. Methods: We reanalyzed baseline NanoString IO 360 profiles from the randomized ZUMA-7 trial (axi-cel, n = 134; standard of care [SOC], n = 122) using differential expression, gene set enrichment, MCP-counter deconvolution, Kaplan–Meier and Cox models adjusted for tumor burden and cell of origin, and gene-by-treatment interaction models. Results: T-cell exhaustion and HLA transcripts were not associated with response in either arm, and no transcript passed FDR correction in differential expression. In the axi-cel arm, 13 of 14 modeled transcripts remained associated with EFS after adjustment; eight (MS4A1, CD19, TNFRSF17, HLA-DOB, CD45RA, DUSP5, KLRD1 and WNT11) were FDR-supported at every survival-analysis stage within the 25 prioritized candidates, but not panel-wide. Consistent with the primary ZUMA-7 report, higher B-cell transcript expression was associated with longer EFS. Interaction testing gave borderline support for a differential association between arms only for KLRD1 and DUSP5 (FDR = 0.049), robust to arm-stratified models; other candidates showed no or only nominal specificity. Apart from the B-lineage score (FDR = 0.029), no estimated immune or stromal population was associated with response. Conclusions: Baseline B-cell transcriptional programs and a small set of gene-level candidates are associated with EFS after axi-cel in ZUMA-7. These exploratory findings do not establish predictive value and require independent validation.