Optimizing CAR-T Therapy in Diffuse Large B-Cell Lymphoma: Biological Determinants and Translational Strategies Across the Therapeutic Continuum.
Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), yet a substantial proportion of patients fail to achieve durable remission. These limitations arise from both inadequate initial response and subsequent disease relapse. Despite the availability of multiple optimization strategies, their clinical implementation remains challenging, partly because these approaches act at different points along the therapeutic continuum and address distinct biological or clinical barriers, resulting in a fragmented clinical implementation landscape that lacks a unified framework. In this review, we provide a clinically oriented synthesis of strategies to improve CAR-T efficacy in DLBCL, focusing on two interconnected objectives: enhancing initial remission and sustaining long-term disease control. We discuss how interventions before leukapheresis, during manufacturing, before infusion, during in vivo expansion, and after remission may shape clinical outcomes. We also discuss in vivo CAR-T technologies as an emerging platform with the potential to expand the therapeutic landscape and improve accessibility. By integrating evidence across studies, this review provides a comprehensive and systematic perspective on optimizing CAR-T efficacy in DLBCL while highlighting current evidence gaps and challenges to clinical implementation.