Purpose: Cluster of differentiation 40 (CD40) is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases. However, the effect of CD40 activation on B-ALL cells has never been tested in vivo. Experimental Design: The aim of our preclinical study was to investigate the therapeutic potential of a CD40 agonist in the treatment of B-ALL using patient-derived xenograft (PDX) mouse models. Results: Intravenous administration of the CD40 agonist significantly impeded B-ALL cell proliferation and growth in vivo, accompanied by rapid activation of the extracellular signal-regulated kinase (ERK) pathway, leading to the induction of apoptosis and disruption of cell cycle progression. Co-treatment with a specific inhibitor of ERK further demonstrated that CD40 stimulation induced the pro-apoptosis of B-ALL cells in an ERK-dependent manner. Proteomic analysis revealed alterations in key signaling pathways associated with B-ALL expansion and maintenance. Moreover, the CD40 agonist markedly reduced the frequency of leukemia-initiating cells and leukemia development in PDX mice. Our study showed that the CD40 agonist can be associated with chemotherapeutic agents such as vincristine and dexamethasone, and this combination showed improved effectiveness. Additionally, the CD40 agonist was more effective on pre-B-ALL (EGIL B-III) that expressed CD40, than on common B-ALL (EGIL B-II) that lacked CD40 expression. Conclusion: These findings suggest that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL, warranting further clinical investigations to improve patient outcomes in CD40-expressing B-ALL.

中文翻译：

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CD40 激动剂治疗 B 细胞急性淋巴细胞白血病


目的：分化簇 40 （CD40） 在 B 细胞急性淋巴细胞白血病 （B-ALL） 病例中表达。然而，CD40 激活对 B-ALL 细胞的影响从未在体内测试过。实验设计：我们的临床前研究的目的是使用患者来源的异种移植物 （PDX） 小鼠模型研究 CD40 激动剂治疗 B-ALL 的治疗潜力。结果： 静脉内给予 CD40 激动剂显着阻碍 B-ALL 细胞体内增殖和生长，并伴有细胞外信号调节激酶 （ERK） 通路的快速激活，导致细胞凋亡的诱导和细胞周期进程的破坏。与 ERK 特异性抑制剂的共同处理进一步表明，CD40 刺激以 ERK 依赖性方式诱导 B-ALL 细胞的促凋亡。蛋白质组学分析揭示了与 B-ALL 扩增和维持相关的关键信号通路的改变。此外，CD40 激动剂显著降低了 PDX 小鼠白血病起始细胞的频率和白血病的发展。我们的研究表明，CD40 激动剂可以与长春新碱和地塞米松等化疗药物相关，并且这种组合显示出更高的疗效。此外，CD40 激动剂对表达 CD40 的前 B-ALL （EGIL B-III） 比对缺乏 CD40 表达的常见 B-ALL （EGIL B-II） 更有效。结论： 这些发现表明 CD40 激动剂是儿科 B-ALL 的有前途的免疫治疗候选者，需要进一步的临床研究以改善 CD40 表达 B-ALL 的患者预后。