Immunotherapeutic targeting of gangliosides in Ewing Sarcoma

尤文肉瘤中神经节苷脂的免疫治疗靶向

基本信息

批准号：
10715119
负责人：
Robbie G. Majzner
金额：
$ 79.52万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715119
关键词：
Adolescent Adult Antibodies Antigens Biological Bone neoplasms Brain Neoplasms Caring Cell Therapy Cells Child Childhood Leukemia Childhood Solid Neoplasm Chromatin Clinical Clinical Trials Combination Drug Therapy Common Neoplasm Credentialing Data Development Diagnosis Diffuse intrinsic pontine glioma Disease Drug Targeting Engineering Enzymes Epigenetic Process Ewings sarcoma Failure G(M2) Ganglioside Ganglioside GD2 Gangliosides Genetic Engineering Genetic Transcription Glycolipids Goals Heterogeneity Immune checkpoint inhibitor Immune response Immunotherapeutic agent Immunotherapy In Vitro Late Effects Left Link Malignant Childhood Neoplasm Malignant Neoplasms Mediating Metastatic Ewing&apos s Sarcoma Methods Modeling Molecular Mutation Neuroblastoma Operative Surgical Procedures Pathway interactions Patients Radiation therapy Receptor Signaling Recurrence Recurrent disease Regulation Relapse Repression Safety Sampling Signal Transduction Solid Neoplasm Surface Survival Rate T cell response T-Lymphocyte Testing Tissues Toxic effect Translating ZAP-70 Gene advanced disease bone cancer cell chemotherapy chimeric antigen receptor chimeric antigen receptor T cells combinatorial exhaustion gene translocation improved in vivo inhibitor insight leukemia relapse leukemia/lymphoma mouse model neoplastic cell novel novel strategies novel therapeutic intervention novel therapeutics overexpression postnatal primary bone cancer relapse prevention resistance mechanism response sialogangliosides sugar tumor young adult

项目摘要

Project Summary Ewing sarcoma (EWS) is the second most common tumor involving bone in children and young adults and is fatal in most patients with metastatic or relapsed disease. Patients who survive are left with a lifetime of late effects from the toxic therapy they receive. There have been no new, successful targeted drugs developed to treat EWS for nearly forty years, and we have reached the limit on how much we can intensify chemotherapy treatments. New therapeutic approaches are necessary to prevent relapse and cure more patients. Immunotherapy has altered the treatment landscape for many adult solid tumors but has not yet mediated substantial benefit for children with EWS. Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of children with relapsed leukemia and lymphoma. Recently, we found that CAR T cells targeting GD2, a sugar expressed on the surface of many pediatric cancers, are active in children with incurable brain tumors. This proposal focuses on applying GD2 CAR T cells to EWS. Because GD2 is heterogeneously expressed on EWS, we will explore multiple mechanisms to effectively apply CAR T cells in this disease: 1) targeting a closely related ganglioside that is highly expressed when GD2 is low and 2) utilizing epigenetic inhibitors to significantly increase GD2, making CAR T cells better able to recognize tumor cells. In Aim 1, we will define the expression of gangliosides and their related synthase enzymes on patient tissues and test CARs against an alternative ganglioside. In Aim 2, we will utilize epigenetic inhibitors to increase GD2 on EWS tumors in vitro and in vivo. In Aim 3, we will test combinatorial approaches of CAR T cells and epigenetic inhibitors. Successful completion of these studies will result in new therapeutic options for children with Ewing sarcoma.

项目概要尤文肉瘤 (EWS) 是儿童和年轻人中第二常见的骨肿瘤，对于大多数患有转移性或复发性疾病的患者来说是致命的。幸存的患者将剩下一生他们接受的毒性治疗的影响。目前尚未开发出新的、成功的靶向药物治疗EWS近四十年，强化化疗已经到了极限治疗。需要新的治疗方法来预防复发并治愈更多患者。免疫疗法已经改变了许多成人实体瘤的治疗格局，但尚未介导为患有 EWS 的儿童带来巨大益处。嵌合抗原受体 (CAR) T 细胞彻底改变了治疗患有复发性白血病和淋巴瘤的儿童。最近，我们发现靶向GD2的CAR T细胞，一种在许多儿科癌症表面表达的糖，在患有无法治愈的脑肿瘤的儿童中很活跃。该提案重点是将GD2 CAR T细胞应用于EWS。因为 GD2 的表达异质性 EWS，我们将探索多种机制来有效地将CAR T细胞应用于这种疾病：1）紧密靶向相关神经节苷脂在 GD2 较低时高度表达，并且 2) 利用表观遗传抑制剂显着增加GD2，使CAR T细胞能够更好地识别肿瘤细胞。在目标 1 中，我们将定义表达式在患者组织上检测神经节苷脂及其相关合酶，并针对替代方案测试 CAR 神经节苷脂。在目标 2 中，我们将利用表观遗传抑制剂在体外和体内增加 EWS 肿瘤上的 GD2。在目标 3，我们将测试 CAR T 细胞和表观遗传抑制剂的组合方法。顺利完成这些研究将为患有尤文肉瘤的儿童带来新的治疗选择。