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 尤因肉瘤（EWS）是涉及儿童和年轻人骨骼的第二大肿瘤，是 大多数转移性或复发性疾病的患者致命。生存的患者终生剩下 他们接受的有毒疗法的影响。没有开发出新的，成功的针对性药物 治疗EWS已有近四十年的时间，我们已经达到了可以加强化学疗法的限制 治疗。必须采用新的治疗方法来防止复发和治愈更多的患者。 免疫疗法改变了许多成年实体瘤的治疗景观，但尚未介导 EWS儿童的巨大好处。嵌合抗原受体（CAR）T细胞彻底改变了 患有复发性白血病和淋巴瘤儿童的治疗。最近，我们发现针对GD2的汽车T细胞， 在许多儿科癌症表面表达的糖，在无法治愈的脑肿瘤的儿童中活跃。 该建议着重于将GD2 CAR T细胞应用于EWS。因为GD2在 ews，我们将探索多种机制，以有效地应用这种疾病中的CAR T细胞：1）紧密靶向 当GD2低和2）使用表观遗传抑制剂显着表达的相关神经苷高度表达 增加GD2，使CAR T细胞能够更好地识别肿瘤细胞。在AIM 1中，我们将定义表达式 在患者组织和测试汽车上针对替代方案上的神经苷及其相关的合酶 神经节。在AIM 2中，我们将利用表观遗传抑制剂在体外和体内增加EWS肿瘤的GD2。在 AIM 3，我们将测试CAR T细胞和表观遗传抑制剂的组合方法。成功完成 这些研究将为Ewing肉瘤儿童提供新的治疗选择。