大约一半的神经母细胞瘤患者会发展为高风险神经母细胞瘤。目前的治疗涉及多模式策略，包括使用靶向 GD2 的 dinutuximab (IgG ch14.18) 进行免疫治疗。尽管取得了有希望的结果，但复发率仍然很高，生存率仍然很低。 Dinutuximab 的治疗效果因中性粒细胞活化欠佳和严重神经性疼痛而受到影响，部分由补体活化引起。为了增强中性粒细胞的细胞毒性，IgG ch14.18 被转化为 IgA 同种型，从而产生有效的中性粒细胞介导的抗体依赖性细胞-介导的细胞毒性（ADCC），无需补体激活。然而，骨髓检查点分子会阻碍中性粒细胞的细胞毒性，例如通过在神经母细胞瘤上过度表达的 CD47，并在与中性粒细胞表达的信号调节蛋白 α (SIRPα) 连接后协调免疫抑制环境。在这项研究中，我们将 IgA 疗法与 CD47 阻断相结合。体外杀伤试验显示，与 IgG 相比，中性粒细胞靶向神经母细胞瘤细胞系和类器官的 IgA 介导的 ADCC 增强。值得注意的是，当与 CD47 阻断联合使用时，IgG 和 IgA 治疗均得到增强，尽管与 IgA 联合使用导致 ADCC 的改善最大。此外，在神经母细胞瘤异种移植模型中，我们用含有消除的 IgG1 Fc 的 SIRPα 融合蛋白系统性阻断 CD47，并将 IgA 疗法与 IgG 疗法进行比较。只有 IgA 疗法与 CD47 阻断相结合才能增加中性粒细胞流入肿瘤微环境。此外，IgA 组合策略最有效地抑制肿瘤生长并延长肿瘤特异性生存。这些有希望的结果凸显了通过将 IgA 疗法与 CD47 阻断相结合改善中性粒细胞细胞毒性来增强针对高危神经母细胞瘤的免疫疗法疗效的潜力。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。由英国医学杂志出版。

Approximately half of the neuroblastoma patients develop high-risk neuroblastoma. Current treatment involves a multimodal strategy, including immunotherapy with dinutuximab (IgG ch14.18) targeting GD2. Despite achieving promising results, the recurrence rate remains high and poor survival persists. The therapeutic efficacy of dinutuximab is compromised by suboptimal activation of neutrophils and severe neuropathic pain, partially induced by complement activation.To enhance neutrophil cytotoxicity, IgG ch14.18 was converted to the IgA isotype, resulting in potent neutrophil-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), without complement activation. However, myeloid checkpoint molecules hamper neutrophil cytotoxicity, for example through CD47 that is overexpressed on neuroblastomas and orchestrates an immunosuppressive environment upon ligation to signal regulatory protein alpha (SIRPα) expressed on neutrophils. In this study, we combined IgA therapy with CD47 blockade.In vitro killing assays showed enhanced IgA-mediated ADCC by neutrophils targeting neuroblastoma cell lines and organoids in comparison to IgG. Notably, when combined with CD47 blockade, both IgG and IgA therapy were enhanced, though the combination with IgA resulted in the greatest improvement of ADCC. Furthermore, in a neuroblastoma xenograft model, we systemically blocked CD47 with a SIRPα fusion protein containing an ablated IgG1 Fc, and compared IgA therapy to IgG therapy. Only IgA therapy combined with CD47 blockade increased neutrophil influx to the tumor microenvironment. Moreover, the IgA combination strategy hampered tumor outgrowth most effectively and prolonged tumor-specific survival.These promising results highlight the potential to enhance immunotherapy efficacy against high-risk neuroblastoma through improved neutrophil cytotoxicity by combining IgA therapy with CD47 blockade.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.