Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China.
Cytotherapy. 2023 Jul;25(7):739-749. doi: 10.1016/j.jcyt.2023.03.005. Epub 2023 Apr 17.
Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation.
We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model.
Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype.
Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.
联合治疗正在积极探索中，以提高抗 CD19 嵌合抗原受体 T 细胞（CART19）治疗的疗效和安全性，其中布鲁顿酪氨酸激酶抑制剂（BTKIs）备受期待。BTKIs 可能调节 T 细胞功能并重塑肿瘤微环境（TME），但涉及的确切机制以及将不同 BTKIs 转化为临床应用所需的步骤仍需进一步研究。
我们研究了 BTKIs 对体外 T 细胞和 CART19 表型和功能的影响，并进一步探讨了相关机制。我们评估了 CART19 与 BTKIs 联合应用的体外和体内疗效和安全性。此外，我们还研究了 BTKIs 在同种异体淋巴瘤模型中对 TME 的影响。
我们发现三种 BTKIs（依鲁替尼、泽布替尼和奥雷巴替尼）可减弱由持续信号、T 细胞受体（TCR）激活和抗原刺激引起的 CART19 耗竭。机制上，BTKIs 显著抑制嵌合抗原受体和 TCR 的 CD3-ζ 磷酸化，并下调与 T 细胞激活信号通路相关的基因表达。此外，BTKIs 减少了体外和体内白细胞介素 6 和肿瘤坏死因子-α的释放。在同种异体淋巴瘤模型中，BTKIs 将巨噬细胞重编程为 M1 亚型，并将辅助性 T 细胞（Th）向 Th1 亚型极化。
我们的数据表明，BTKIs 在持续抗原暴露下保持了 T 细胞和 CART19 的功能，进一步证明 BTKI 给药是减轻 CART19 治疗后细胞因子释放综合征的一种潜在策略。我们的研究为 BTKIs 联合 CART19 在临床实践中的合理应用奠定了实验基础。
