Combining hu14.18-IL2 and NK cell infusions to treat neuroblastoma

神经母细胞瘤是儿童最常见的颅外实体瘤， 二唾液酸神经节苷脂GD2。对于患有高风险疾病或疾病复发的患者， 完成治疗后，选择有限。异基因造血干细胞移植（AlloHSCT）是一种 将来自健康供体的造血干细胞输注给接受高剂量治疗的患者 化疗和/或放疗，临床上通常用于白血病或淋巴瘤儿童。但 迄今为止，alloHSCT在利用移植物抗肿瘤（GVT）效应攻击神经母细胞瘤方面的成功有限， 并引入了致命的移植物抗宿主病（GVHD）。这项建议的长远目标是 增强GVT对神经母细胞瘤的作用。该提案探讨了改善GVT效果的3个具体目标 使用alloHSCT的动物模型。首先，我们将探索称为hu14.18-IL2的免疫细胞因子的使用， 人源化GD2单克隆抗体与白细胞介素（IL）-2连接，以增强GVT效应，改善GVT， 移植的功效。这种抗体已经在临床试验中用于神经母细胞瘤儿童 但不具有治愈性，并且尚未在alloHSCT环境中进行测试。第二，我们将激活同种异体天然 杀伤（NK）细胞与IL-15和CD137L表达的人工抗原呈递细胞，并将它们输注用于 首次使用hu14.18-IL2作为进一步改善GVT的组合策略。我们将控制任何潜在的 通过抑制JAK/STAT通路和阻断肿瘤坏死因子-α的产生来治疗GVHD。最后，我们将 用氟的非放射性同位素（UF）标记NK细胞，使这些细胞可以被MRI检测到， 确定hu14.18-IL2在alloHSCT后如何标记NK细胞运输到神经母细胞瘤肿瘤，以及hu14.18-IL2是否可以 进一步将NK细胞吸引到肿瘤上。最终目标是支持国家的研究重点 癌症研究所通过开发研究，将导致新的治疗神经母细胞瘤。任何一个成功 个体目标将是使alloHSCT对神经母细胞瘤更有效的主要进展。成功 整个提案的翻译将导致一个创新的联合免疫治疗平台， 神经母细胞瘤

Neuroblastoma is the most common extracranial solid tumor seen in children, and expresses the disialoganglioside GD2 on its surface. For patients who have high risk disease or whose disease recurs after completing therapy, there are limited options. Allogeneic hematopoietic stem cell transplant (AlloHSCT) is a transfusion of hematopoietic stem cells from a healthy donor to a patient who has been treated with high doses of chemotherapy and/or radiation, and is typically used clinically for children with leukemia or lymphoma. But alloHSCT has had limited success thus far in attacking neuroblastoma with a graft-versus-tumor (GVT) effect, and has introduced lethal graft-versus-host-disease (GVHD). The long term objective of this proposal is to enhance the GVT effect against neuroblastoma. This proposal explores 3 specific aims to improve GVT effects using animal models of alloHSCT. First we will explore usage of an immunocytokine called hu14.18-IL2, a humanized GD2 monoclonal antibody linked to interleukin (IL)-2, to enhance the GVT effect, improving the efficacy of the transplant. This antibody has already been given to children with neuroblastoma in clinical trials but is not curative, and has not been tested in the alloHSCT setting. Second, we will activate allogeneic natural killer (NK) cells with IL-15 and CD137L-expressing artificial antigen presenting cells, and infuse them for the first time with hu14.18-IL2 as a combination strategy for improving GVT further. We will control any potential GVHD by inhibiting the JAK/STAT pathway and blocking tumor necrosis factor-alpha production. Lastly, we will label NK cells with a nonradioactive isotope of fluorine (¹⁹F) that will make these cells detectable by MRI, determine how ¹⁹F-labeled NK cells traffic to neuroblastoma tumors after alloHSCT and if hu14.18-IL2 can further attract NK cells to the tumor. The ultimate goal is to support the research priorities of the National Cancer Institute by developing research that will lead to novel therapies for neuroblastoma. Success of any of the individual aims will be a major advance in making alloHSCT more effective for neuroblastoma. Successful translation of the entire proposal will lead to an innovative combination immunotherapy platform for treating neuroblastoma.