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

Abstract

Simple Summary CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of large B-cell lymphoma (LBCL), but many patients either do not respond or subsequently relapse. This structured narrative review examines clinical outcomes and biological factors associated with resistance and relapse. Across 14 studies, treatment failure could not be attributed to loss of CD19 alone, although incomplete assessment of CD19 at relapse limits this interpretation. Tumor-intrinsic programs, impaired CAR T-cell fitness and persistence, systemic inflammation, and an immunosuppressive tumor microenvironment also contributed, although differences in study design and incomplete testing at relapse prevented determination of the relative importance of each mechanism. Comparison with previous reviews shows continuity with earlier frameworks, with greater biological resolution in LBCL rather than replacement of the antigen-escape model. These findings support longitudinal assessment of the tumor, infused cell product, and peripheral immune response, and integrated biomarkers to identify high-risk patients and guide rational treatment strategies.