Strategies for Reducing Toxicity and Enhancing Efficacy of Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies has made great progress, but there are still some problems. First, T cells from tumor patients show an exhaustion phenotype; thus, the persistence and function of the CAR-Ts are poor, and achieving a satisfactory curative effect is difficult. Second, some patients initially respond well but quickly develop antigen-negative tumor recurrence. Thirdly, CAR-T treatment is not effective in some patients and is accompanied by severe side effects, such as cytokine release syndrome (CRS) and neurotoxicity. The solution to these problems is to reduce the toxicity and enhance the efficacy of CAR-T therapy. In this paper, we describe various strategies for reducing the toxicity and enhancing the efficacy of CAR-T therapy in hematological malignancies. In the first section, strategies for modifying CAR-Ts using gene-editing technologies or combining them with other anti-tumor drugs to enhance the efficacy of CAR-T therapy are introduced. The second section describes some methods in which the design and construction of CAR-Ts differ from the conventional process. The aim of these methods is to enhance the anti-tumor activity of CAR-Ts and prevent tumor recurrence. The third section describes modifying the CAR structure or installing safety switches to radically reduce CAR-T toxicity or regulating inflammatory cytokines to control the symptoms of CAR-T-associated toxicity. Together, the knowledge summarized herein will aid in designing better-suited and safer CAR-T treatment strategies.