泽布替尼通过抑制 BTK 磷酸化、调控 PI3K/AKT/mTOR 通路和促进自噬增强 CD19 CAR-T 对 B 细胞淋巴瘤的杀伤

Anti-CD19 chimeric antigen receptor T cells (CAR T) still have many limitations, including insufficient clinical efficacy. Zanubrutinib is a second-generation Bruton tyrosine kinase (BTK) inhibitor with higher drug potency, and it is not clear whether it has an enhanced killing effect of CD19 CAR T on B-cell lymphoma.

Therefore, this study will investigate the role and mechanism of zanubrutinib in CD19 CAR T therapy against B-cell lymphoma. B-cell lymphoma cells Daudi were proportionally co-cultured with CD19 CAR T and intervened using different concentrations of zanubrutinib, and the changes of cell viability, apoptosis, autophagy, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway-related factors were assessed using the Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Western blotting, transmission electron microscopy, and immunofluorescence staining.

Also, the effect of zanubrutinib on the sensitivity of B-cell lymphoma mice to CAR T-cell therapy was observed. The results showed that zanubrutinib increased the sensitivity of B-cell lymphoma to CD19 CAR T-cells, promoted apoptosis and autophagy, and inhibited BTK phosphorylation and the PI3K/AKT/mTOR signaling pathway.

Zanubrutinib can promote the killing of B-cell lymphoma by CD19 CAR T. Collectively, zanubrutinib enhances CD19 CAR T killing of B-cell lymphoma by inhibiting BTK phosphorylation, regulating PI3K/AKT/mTOR pathway, and promoting autophagy.