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

联合 hu14.18-IL2 和 NK 细胞输注治疗神经母细胞瘤

基本信息

批准号：
10403986
负责人：
Christian Capitini
金额：
$ 34.71万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403986
关键词：
Activated Natural Killer Cell Allogenic Animal Model Antibodies Antigen-Presenting Cells Antigens Autologous Biological Cells Chemotherapy and/or radiation Child Childhood Childhood Leukemia Clinical Clinical Trials Combination immunotherapy Detection Disease Effector Cell Environment Fluorine Goals Graft-Versus-Tumor Induction Granulocyte-Macrophage Colony-Stimulating Factor Hematopoietic Stem Cell Transplantation Hematopoietic stem cells High Dose Chemotherapy IL2 gene Immune Immune system Immunologics Immunomodulators Immunotherapy In Vitro Individual Infusion procedures Injections Interleukin-15 Interleukin-2 Isotopes Label Lead Life Ligands Link Lymphoma Magnetic Resonance Imaging Mediating Methods Modeling Monoclonal Antibodies Mus National Cancer Institute Natural Killer Cells Neuroblastoma Operative Surgical Procedures Pathway interactions Patients Production Radiation Refractory Relapse Reporting Research Research Priority Research Support Residual Neoplasm Role Route STAT1 gene Sensitivity and Specificity Solid Neoplasm Stem cell transplant Surface TNF gene Testing Time Toxic effect Transfusion Translating Translations Transplantation antitumor effect chemotherapy clinical application clinically translatable detection platform disorder risk graft vs host disease high risk humanized monoclonal antibodies immunological synapse immunoregulation improved in vivo innovation killer immunoglobulin-like receptor novel novel strategies novel therapeutics patient response phase II trial pre-clinical research clinical testing response sialogangliosides standard of care success trafficking tumor

项目摘要

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.

神经母细胞瘤是儿童中最常见的颅外实体瘤，并表达表面上的dialoganglioside gd2。对于患有高风险疾病或疾病后复发的患者完成治疗，选择有限。同种异体造血干细胞移植（AlloHSCT）是一个造血干细胞从健康供体的输血给接受高剂量治疗的患者化学疗法和/或放射线的疗法，通常用于白血病或淋巴瘤儿童的临床上。迄今并引入了致命的移植物抗宿主 - 疾病（GVHD）。该提议的长期目标是增强针对神经母细胞瘤的GVT效应。该建议探讨了3个特定旨在改善GVT效果的目的使用AlloHSCT的动物模型。首先，我们将探索一种称为HU14.18-IL2的免疫细胞因子的用法与白介素（IL）-2相关的人源化GD2单克隆抗体，以增强GVT效果，改善移植的功效。在临床试验中，该抗体已经给予神经母细胞瘤儿童但不是治愈性的，尚未在AllOHSCT设置中进行测试。第二，我们将激活同种异体自然具有IL-15和CD137L表达人工抗原的细胞的杀伤（NK）细胞，并将其注入首次以HU14.18-IL2作为进一步改善GVT的组合策略。我们将控制任何潜力 GVHD通过抑制JAK/STAT途径并阻止肿瘤坏死因子-Alpha产生。最后，我们会的标记NK细胞具有非放射性氟（F）的非放射性同位素，该同位素将使这些细胞可通过MRI检测到这些细胞，确定α标记的NK细胞如何在AllOHSCT后与神经母细胞瘤肿瘤流动，以及HU14.18-IL2是否可以进一步吸引NK细胞到肿瘤中。最终目标是支持国家的研究优先事项癌症研究所通过开发将导致神经母细胞瘤的新疗法的研究。任何一项成功个体目标将是使AlloHSCT对神经母细胞瘤更有效的重大进步。成功的整个建议的翻译将导致一个创新的治疗疗法平台用于治疗成神经细胞瘤。