Overcoming Antigen Escape and T-Cell Exhaustion in CAR-T Therapy for Leukemia

Abstract

Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients' T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we examine the mechanisms of T-cell exhaustion and strategies to enhance CAR-T persistence and effectiveness. Despite remarkable clinical successes, CAR-T therapy poses risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our findings highlight the need for ongoing research to optimize CAR-T applications, reduce toxicities, and extend this innovative therapy to a broader range of hematologic malignancies. This comprehensive review aims to provide valuable insights for improving leukemia treatment and advancing the field of cancer immunotherapy.

Keywords: CAR-T therapy; T-cell exhaustion; acute lymphoblastic leukemia; acute myeloid leukemia; antigen escape; cytokine release syndrome; dual-targeting CAR-Ts; immune effector cell-associated neurotoxicity syndrome; leukemia; pediatric oncology.

Figure 1

Chimeric antigen receptor T-cell (CAR-T) therapy. CAR-T therapy involves a multi-step process that begins with extracting T cells from the patient’s peripheral blood. These T cells are genetically engineered using a viral vector to express chimeric antigen receptors (CARs). Following genetic modification, the T cells are expanded ex vivo, meaning they are cultivated and multiplied outside the body under controlled laboratory conditions. Once a sufficient number of modified T cells are obtained, they are reinfused into the patient to serve as a therapeutic intervention.

Figure 2

Mechanisms of antigen escape resulting in CAR-T therapy ineffectiveness.