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Mechanisms of resistance to CAR-T cell therapy of B-cell malignancies and reversal strategies
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Abstract:
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 nonHodgkin 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.
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