CAR-T-centered sequential therapy: current status, challenges, and future clinical perspectives

Over recent years, chimeric antigen receptor T-cell (CAR-T) therapy has markedly improved outcomes for patients with relapsed or refractory hematological malignancies. Nevertheless, a substantial proportion of patients still experience relapse or progression after treatment, driven by factors including antigen escape, suboptimal CAR-T cell expansion and persistence, functional exhaustion, and remodeling of the tumor microenvironment. In the context of managing patients who fail initial CAR-T therapy, CAR-T-centered sequential therapy has been increasingly investigated as a potential therapeutic approach. The selection of therapeutic targets and treatment approaches may be informed by resistance mechanisms, changes in target antigen expression, and disease progression patterns following prior treatment, with the aim of prolonging disease control and improving long-term outcomes. This review summarizes recent progress in CAR-T-centered sequential therapy, with particular emphasis on same-target retreatment, switching to different antigens, multi-target stepwise CAR-T regimens, and the sequential integration of CAR-T with hematopoietic stem cell transplantation, radiotherapy, immune checkpoint inhibitors, and other immunomodulatory approaches. We further discuss the biological rationale and clinical settings of these CAR-T-centered sequential approaches in the context of antigen escape, CAR-T cell functional decline, tumor clonal evolution, and immune microenvironment remodeling. Additionally, we discuss factors that may inform the selection of subsequent regimens, including the initial treatment response, antigen status at relapse, CAR-T cell persistence, and the patient's therapeutic window, as well as the clinical settings in which these sequential approaches have been explored.