Overcoming Resistance to CD19 CAR-T Cell Therapy in B-cell Malignancies: Mechanisms and Emerging Strategies

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy, especially CD19-targeted therapy, has revolutionized B-cell malignancy treatment, achieving unprecedented remission in relapsed/refractory patients—many of whom previously had limited therapeutic options. However, disease recurrence and drug resistance remain major challenges, necessitating deeper understanding of resistance mechanisms and effective solutions. This paper outlines key CD19 CAR-T resistance mechanisms: CD19 loss via genetic (e.g., deletions) or epigenetic (e.g., promoter methylation) changes, CAR-T cell exhaustion from sustained stimulation (marked by reduced cytokine secretion), immunosuppressive tumor microenvironments (with Tregs/MDSCs and TGF-β/IL-10), and abnormal activation of JAK/STAT3 or PI3K/AKT/mTOR pathways (enhancing tumor survival/immune escape). Proposed strategies to overcome resistance include dual/multi-target CARs, combining immune checkpoint inhibitors (e.g., anti-PD-1), CRISPR-engineered "armored" CAR-T cells, optimizing T-cell metabolism/memory, and regulating the tumor microenvironment. Future research should address long-term toxicity (e.g., neurotoxicity), develop predictive biomarkers, and advance allogeneic universal CAR-T platforms, with solid tumor CAR-T experience providing references. These findings lay a foundation for next-generation cellular immunotherapy.