Lymphodepletion in Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors: A Focus on Brain Tumors

Abstract

Chimeric antigen receptor (CAR)-T cell therapy, which has demonstrated remarkable efficacy in hematologic malignancies, is being extended to the treatment of refractory solid tumors, including brain tu-mors. Lymphodepletion (LD) is an essential preconditioning process that enhances CAR-T efficacy by promoting CAR-T cell expansion and persistence in the body, and has become a standard regimen for hematologic cancers. Recent clinical results of CAR-T therapy for solid tumors, including brain tumors, have shown that cyclophosphamide/fludarabine-based preconditioning has potential benefits and is gradually becoming adopted in solid tumor CAR-T trials. Furthermore, some CAR-T trials for solid tumors are attempting to develop LD regimens optimized specifically for solid tumors, distinct from the standard LD regimens used in hematologic cancers. In contrast, CAR-T therapy targeting brain tumors frequently employs locoregionally repeated administration in tumors or cerebrospinal fluid, resulting in less frequent use of LD compared to other solid tumors. Nevertheless, several clinical studies suggest that LD may still provide potential benefits for CAR-T expansion and improvement in clinical responses in systemic CAR-T administration. The studies presented in this review suggest that while LD can be beneficial for enhancing CAR-T efficacy, considerations must be made regarding its compatibility with the CAR-T administration route, potential excessive activation based on CAR-T structural characteris-tics, and target expression in normal organs. Additionally, given the unique characteristics of brain tu-mors, optimized selection of LD agents, as well as dosing and regimens, may be required, highlighting the need for further research.