Mechanisms of resistance to CAR-T cell therapy of B-cell malignancies and reversal strategies
Chimeric antigen receptor gene-modified T-cell (CAR-T cell),represented by the target CD19,has achieved breakthrough progress in the treatment of B-cell malignancies. However,with the increasing number of patients undergoing CAR-T cell therapy,the issue of relapse and resistance has become particularly prominent and is now a major clinical challenge and a research hotspot in the field. In recent years,in addition to immune escape due to antigen loss and treatment insensitivity caused by CAR-T cells dysfunction,progress has been made in understanding resistance mechanisms caused by intrinsic factors of tumor cells. Using high throughput screening system,resistance mechanisms mediated by downregulation or deficient expression of pro-apoptotic molecules (such as NOXA,FADD) and adhesion molecules (such as CD58,ICAM1) have been identified. Several strategies have been developed to reverse these resistance mechanisms,such as HDAC inhibitors combined with CAR-T cell therapy to treat NOXA-low expressing non-Hodgkin lymphoma;pretreatment of CAR-T cells with epigenetic drugs to enhance their antitumor efficacy and persistence;using gene editing technologies to relieve gene suppression and enhance CAR-T cell activity;and overexpressing cytokines to improve tumor microenvironment. Some of these strategies have already been clinically validated. This review aims to summarize the existing resistance mechanisms to CAR-T cell therapy and their targeted reversal strategies,analyze the clinical outcomes of related studies,and provide new insights into enhancing CAR-T cell efficacy in B-cell malignancies.
万方数据
维普
