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通过CD47阻断增强IgA介导的中性粒细胞对神经母细胞瘤的毒性

Chilam Chan¹, Marjolein Stip¹, Maaike Nederend¹

¹Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.

Journal for immunotherapy of cancer

|May 23, 2024

概括

将IgA免疫疗法与CD47阻断相结合,显著增强了对高风险神经母细胞瘤的中性粒细胞抗瘤活性. 这种新的策略改善了抗体依赖细胞介导的细胞毒性,并减少了瘤的生长,为患者提供了新的希望.

科学领域:

免疫治疗是一种免疫疗法.
在瘤学瘤学.
癌症免疫学癌症免疫学

背景情况:

高风险神经母细胞瘤的生存率很低,尽管目前的多模式治疗.
现有的免疫疗法 (dinutuximab,IgG ch14.18) 由于中性粒细胞的低最佳激活和补充诱导的副作用,显示出局限性.
神经母细胞瘤上的髓质检查点分子CD47阻碍了中性粒细胞的抗瘤功能.

研究的目的:

为了增强中性粒细胞介导的抗体依赖细胞介导的细胞毒性 (ADCC) 对神经母细胞瘤.
为了研究将IgA免疫疗法与CD47阻断相结合的疗效.
为了克服瘤微环境中的免疫抑制机制.

主要方法:

将IgG ch14.18转换为IgA同型,以在没有补体激活的情况下促进中性粒细胞ADCC.
通过SIRPα融合蛋白利用CD47阻断来抵消髓质检查点.
在体外评估ADCC与神经母细胞瘤细胞系和有机体相比.
在神经母细胞瘤异种移植模型中评估治疗疗效.

主要成果:

与IgG相比,IgA疗法在体外显示了中性粒细胞介导ADCC的优势.
结合IgA治疗和CD47阻断,ADCC得到了最大的改善.
系统性CD47阻断与IgA疗法增加了中性粒细胞透到瘤中,并最有效地抑制了瘤外生长.
这种组合策略显著延长了瘤特异性存活率.

结论:

与CD47阻断相结合的IgA免疫疗法是增强抗神经母细胞瘤免疫力的有希望的策略.
改善中性粒细胞毒性是克服高风险神经母细胞瘤治疗耐药性的关键.
针对CD47与IgA治疗结合,需要进一步的临床研究.

关键词:

免疫检查点抑制剂免疫检查点抑制剂免疫疗法免疫疗法神经母细胞瘤的神经母细胞瘤中性粒细胞的透透.

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