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:
- 金额:$ 79.52万
- 依托单位:
- 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:
- 关键词:AdolescentAdultAntibodiesAntigensBiologicalBone neoplasmsBrain NeoplasmsCaringCell TherapyCellsChildChildhood LeukemiaChildhood Solid NeoplasmChromatinClinicalClinical TrialsCombination Drug TherapyCommon NeoplasmCredentialingDataDevelopmentDiagnosisDiffuse intrinsic pontine gliomaDiseaseDrug TargetingEngineeringEnzymesEpigenetic ProcessEwings sarcomaFailureG(M2) GangliosideGanglioside GD2GangliosidesGenetic EngineeringGenetic TranscriptionGlycolipidsGoalsHeterogeneityImmune checkpoint inhibitorImmune responseImmunotherapeutic agentImmunotherapyIn VitroLate EffectsLeftLinkMalignant Childhood NeoplasmMalignant NeoplasmsMediatingMetastatic Ewing&aposs SarcomaMethodsModelingMolecularMutationNeuroblastomaOperative Surgical ProceduresPathway interactionsPatientsRadiation therapyReceptor SignalingRecurrenceRecurrent diseaseRegulationRelapseRepressionSafetySamplingSignal TransductionSolid NeoplasmSurfaceSurvival RateT cell responseT-LymphocyteTestingTissuesToxic effectTranslatingZAP-70 Geneadvanced diseasebonecancer cellchemotherapychimeric antigen receptorchimeric antigen receptor T cellscombinatorialexhaustiongene translocationimprovedin vivoinhibitorinsightleukemia relapseleukemia/lymphomamouse modelneoplastic cellnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionpostnatalprimary bone cancerrelapse preventionresistance mechanismresponsesialogangliosidessugartumoryoung 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.
项目摘要
尤文肉瘤(EWS)是儿童和年轻人中第二常见的累及骨的肿瘤,
在大多数转移性或复发性疾病患者中是致命的。活下来的病人,
他们接受的毒性治疗的影响。目前还没有新的、成功的靶向药物被开发出来,
我们治疗EWS已经将近四十年了,我们已经达到了加强化疗的极限
治疗。新的治疗方法是必要的,以防止复发和治愈更多的患者。
免疫疗法已经改变了许多成人实体瘤的治疗前景,但尚未介导
为患有EWS的儿童提供大量福利。嵌合抗原受体(CAR)T细胞已经彻底改变了免疫系统。
治疗儿童复发性白血病和淋巴瘤。最近,我们发现靶向GD2的CAR T细胞,
许多儿科癌症表面表达的一种糖,在患有无法治愈的脑肿瘤的儿童中活跃。
该提案的重点是将GD2 CAR T细胞应用于EWS。由于GD2在细胞表面不均一表达,
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)靶向密切相关的
相关神经节苷脂,当GD2低时高度表达,和2)利用表观遗传抑制剂,
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合酶在患者组织上的表达,并针对替代物测试汽车
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。成功完成
这些研究将为患有尤文肉瘤的儿童提供新的治疗选择。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robbie G. Majzner其他文献
Programming CAR-T cells to kill cancer
编程嵌合抗原受体 T 细胞以杀死癌症
- DOI:
10.1038/s41551-018-0235-9 - 发表时间:
2018-06-11 - 期刊:
- 影响因子:26.600
- 作者:
Louai Labanieh;Robbie G. Majzner;Crystal L. Mackall - 通讯作者:
Crystal L. Mackall
IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies
IKAROS 水平与 B 细胞恶性肿瘤的 CD19 和 CD22 靶向治疗中的抗原逃逸相关
- DOI:
10.1038/s41467-025-58868-2 - 发表时间:
2025-04-23 - 期刊:
- 影响因子:15.700
- 作者:
Pablo Domizi;Jolanda Sarno;Astraea Jager;Milton Merchant;Kaithlen Zen B. Pacheco;Sean A. Yamada-Hunter;Maria Caterina Rotiroti;Yuxuan Liu;Reema Baskar;Warren D. Reynolds;Brian J. Sworder;Bita Sahaf;Sean C. Bendall;Charles G. Mullighan;Ash A. Alizadeh;Allison B. Leahy;Regina M. Myers;Bonnie Yates;Hao-Wei Wang;Nirali N. Shah;Robbie G. Majzner;Crystal L. Mackall;Stephan A. Grupp;David M. Barrett;Elena Sotillo;Kara L. Davis - 通讯作者:
Kara L. Davis
Clinical lessons learned from the first leg of the CAR T cell journey
从嵌合抗原受体 T 细胞之旅的第一阶段中汲取的临床经验教训
- DOI:
10.1038/s41591-019-0564-6 - 发表时间:
2019-09-09 - 期刊:
- 影响因子:50.000
- 作者:
Robbie G. Majzner;Crystal L. Mackall - 通讯作者:
Crystal L. Mackall
Long-Term Follow-up of CD19/22 CAR Therapy in Children and Young Adults with B-ALL Reveals Efficacy, Tolerability and High Survival Rates When Coupled with Hematopoietic Stem Cell Transplantation
- DOI:
10.1182/blood-2022-167789 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Liora M. Schultz;Sneha Ramakrishna;Reema Baskar;Rebecca M Richards;Jennifer Moon;Christina Baggott;Michelle Fujimoto;Michael Kunicki;Amy Li;Sneha Jariwala;Courtney Erickson;Ashley Jacobs;Karen Yamabe;Valentin Barsan;Robbie G. Majzner;Emily L. Egeler;Sharon Mavroukakis;Zachary Ehlinger;Warren D. Reynolds;Bita Sahaf - 通讯作者:
Bita Sahaf
Robbie G. Majzner的其他文献
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{{ truncateString('Robbie G. Majzner', 18)}}的其他基金
Hijacking the T cell machinery for logic-gated CAR T cell control
劫持 T 细胞机器以进行逻辑门控 CAR T 细胞控制
- 批准号:
10246119 - 财政年份:2021
- 资助金额:
$ 79.52万 - 项目类别:
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