Relapse and progression after CAR-T cell therapy in large B-cell lymphoma: Patterns, mechanisms, and salvage...

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for large B-cell lymphoma (LBCL), particularly in the relapsed or refractory. However, relapse after CAR-T cell therapy remains a major barrier to durable remission and long-term survival because post-CAR-T relapse is biologically and clinically heterogeneous and lacks standardized management strategies. In this narrative review, we provide a clinically oriented synthesis of the current evidence on relapse or progression after CAR-T cell therapy in LBCL, focusing on relapse patterns, underlying biological mechanisms, risk factors, and evolving salvage strategies. Evidence from other B-cell lymphoma subtypes is included selectively when it provides relevant biological or clinical context, but it is not considered directly interchangeable with findings from LBCL. We delineate the heterogeneity of post-CAR-T cell recurrence across lymphoma subtypes, emphasizing differences in the timing, patterns of progression, and antigen expression. We then discuss the principal determinants of treatment failure, including patient-related factors, tumor-intrinsic features, impaired CAR-T cell expansion and persistence, an immunosuppressive tumor microenvironment, and treatment-induced selective pressures. We also summarize current salvage strategies, including bispecific antibodies, CAR-T cell reinfusion, allogeneic hematopoietic stem cell transplantation, and investigational approaches under clinical evaluation. Among these, bispecific antibodies have demonstrated promising efficacy in real-world settings and are increasingly being incorporated into post-CAR-T cell treatment algorithms. Overall, post-CAR-T cell relapse is a multifactorial process with important clinical implications. Integrating mechanistic insights with emerging therapeutic advances may enable more individualized salvage strategies. Future research should focus on improved risk stratification, biomarker-guided surveillance, optimization of treatment sequencing, and the development of next-generation cellular and combinatorial immunotherapies to improve long-term outcomes.