Immunotherapeutic targeting of gangliosides in Ewing Sarcoma

尤文肉瘤中神经节苷脂的免疫治疗靶向

• 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
• 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' 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

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.

项目摘要 尤文肉瘤(EWS)是儿童和年轻人中第二常见的骨肿瘤，是 在大多数转移性或复发性疾病患者中是致命的。幸存下来的患者将面临晚年的生活 他们所接受的毒性治疗的效果。还没有新的、成功的靶向药物被开发出来 治疗EWS近40年，我们已经达到了可以加强化疗的限度 治疗。为了防止复发和治愈更多的患者，新的治疗方法是必要的。 免疫疗法已经改变了许多成人实体瘤的治疗格局，但尚未发挥作用 对患有EWS的儿童有实质性的好处。嵌合抗原受体(CAR)T细胞已经彻底改变了 儿童复发性白血病和淋巴瘤的治疗。最近，我们发现CAR T细胞靶向GD2， 一种在许多儿科癌症表面表达的糖，在患有无法治愈的脑瘤的儿童中很活跃。 这项提案的重点是将GD2 CAR T细胞应用于EWS。因为GD2是异质表达在 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)靶向紧密的 相关神经节苷脂，在GD2低时高表达，以及2)利用表观遗传抑制物显著 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 神经节苷脂及其相关的合成酶在患者组织上的变化，并与替代方案进行CARS测试 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对EWS肿瘤的GD2。在……里面 目的3，我们将测试CAR T细胞和表观遗传抑制物的组合方法。成功完成 这些研究将为尤文肉瘤儿童带来新的治疗选择。