Immune reconstitution following allogeneic hematopoietic cell transplantation and CAR-T therapy: dynamics, determinants, and directions

Abstract

Immune reconstitution (IR) is a dynamic and sequential process that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) and cellular therapies, involving the gradual recovery of both innate and adaptive immune compartments. The success of IR is a critical determinant of clinical outcomes, including the risk of graft-versus-host disease and graft-versus-leukemia effects. In the context of allo-HCT, IR shaped by various factors, including transplantation modalities, conditioning regimens, therapeutic interventions, and post-transplant strategies. The kinetics and quality of IR following chimeric antigen receptor T-cell (CAR-T) therapy are also shaped by several factors, such as lymphodepleting chemotherapy, CAR construct design, and the patient's baseline immune status. In particular, B-cell–targeted CAR-T therapy frequently results in B-cell aplasia, hypogammaglobulinemia, and immune exhaustion, necessitating improved monitoring and post-treatment interventions. These immunologic effects highlight the need for improved post-treatment monitoring and supportive interventions to reduce infection risk and ensure sustained immune recovery. To better characterize IR across both allo-HCT and CAR-T settings, advanced immune profiling technologies, such as flow cytometry and single-cell RNA sequencing, are providing new insights into the dynamics of immune recovery. Here, we summarize current knowledge on IR kinetics and evaluate the impact of different transplant and CAR-T settings. We then discuss personalized strategies to optimize immune monitoring and therapeutic approaches for recipients of allo-HCT and CAR-T therapies.