Improving genetically engineered T cells for medulloblastomas
改善髓母细胞瘤基因工程 T 细胞
基本信息
- 批准号:10581552
- 负责人:
- 金额:$ 44.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-15 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAntigensAntitumor ResponseB lymphoid malignancyBrain NeoplasmsCD276 geneCSF1R geneCancerousCell CommunicationCell TherapyCell physiologyCellsChildChildhood Brain NeoplasmChildhood Malignant Brain TumorClinical ResearchCombined Modality TherapyDNADNA Modification MethylasesDioxygenasesERBB2 geneEndowmentEngineered GeneEngineeringEpigenetic ProcessFrequenciesFutureGeneticGenetic EngineeringHealthIL13RA1 geneImmuneImmune responseImmune systemImmunocompetentImmunotherapyInfusion proceduresInnovative TherapyInstitutionKnowledgeLeadLeftMacrophage Colony-Stimulating FactorMalignant NeoplasmsMediatingMediatorMethodsMethyltransferaseModificationMolecularMusNeoplasm MetastasisPatientsPerformancePhase I Clinical TrialsPre-Clinical ModelProductionRecurrenceRecurrent tumorRelapseResistanceResourcesSignal TransductionSpecificityT-Cell Immunologic SpecificityT-LymphocyteTestingTetanus Helper PeptideTextTherapeuticTissuesTumor AntigensTumor PromotionTumor-associated macrophagesXenograft procedureangiogenesisantigen challengeantigen-specific T cellsantitumor effectcancer cellcancer therapychimeric antigen receptorchimeric antigen receptor T cellsconventional therapycytokineeffector T cellengineered T cellsexhaustionexperienceexperimental studyimmunoengineeringimprovedimproved outcomeinhibitorinsightleukemiamedulloblastomamouse modelnegative affectnovel therapeutic interventionpre-clinicalpreclinical studyprogramsreceptorrecruitsafety engineeringside effectsuccesssynergismtooltumortumor microenvironmenttumor progressiontumor-immune system interactions
项目摘要
Title: Improving genetically engineered T cells for medulloblastoma
PROJECT SUMMARY/ABSTRACT
The intent of this project is to develop antigen-specific T cells as an effective immunotherapy for medulloblastoma
(MB), a most common pediatric brain tumor. While recent advances in MB treatment slightly improved the overall
survival, the patients are left with long-term devastating side effects as a result of a treatment. The body’s natural
immune defenses against cancer often fail because the cancer either does not provoke or actively inhibits
immune responses. However, genetic modification of the patient’s own immune system can be used to endow
T cells with improved ability to recognize and kill cancerous cells that would not otherwise respond to
conventional therapies. Cancer treatments consisting of the infusion of T cells that are engineered to recognize
tumor antigens, molecules present only on cancers cells, have shown dramatic success in clinical studies against
leukemia. We now propose to develop such approach for MB. In our method, we will target two antigens called
IL13Ra2 and B7-H3 which are present on MB cells. Next, we will improve our approach by deleting epigenetic
regulators that are known to suppress T cell effector function. Finally, we will use an immunocompetent MB
mouse model to ask which immune cells within brain tumor microenvironment (TME) control CAR T cell efficacy.
Brain tumors are notorious for having an immunosuppressive TME, yet its effect on engineered immune cells
are poorly understood. Thus, the use of mouse models with functional immune system will allow us to accurately
evaluate the function and safety of engineered T cells as well as understand the brain TME. In summary, we
propose to first establish CAR T cells targeting two antigens in order to improve their specificity (Aim 1). We will
then improve their persistence through ablation of epigenetic programs (Aim 2). We will also perform a detailed
mechanistic study to determine how epigenetic regulators control effector function of engineered CAR T cells.
Finally, we will investigate if elimination of key inhibitory immune cells within the brain TME will enhance anti-
tumor effects of CAR T cells (Aim 3). We expect that our proposed studies using gene engineered bi-specific
CAR T cells and immunocompetent mouse model will provide mechanistic insight and superior understanding
on how engineered T cells function and interact with the brain TME. We believe that such knowledge will lead
not only to the creation of improved immune cell-based approaches but also to potential novel therapeutic
approaches for brain tumors in the future. If our pre-clinical approach is successful, we have the resources to
develop a Phase I clinical trial at our institution.
标题:改善基因工程T细胞治疗髓母细胞瘤
项目总结/摘要
本项目的目的是开发抗原特异性T细胞作为髓母细胞瘤的有效免疫疗法
(MB)是最常见的小儿脑肿瘤。虽然MB治疗的最新进展略微改善了整体
为了生存,患者会因治疗而留下长期的破坏性副作用。身体的自然
对癌症的免疫防御经常失败,因为癌症要么不激发,要么主动抑制,
免疫反应。然而,对患者自身免疫系统的基因改造可以用来赋予
T细胞识别和杀死癌细胞的能力提高,否则这些癌细胞不会对免疫应答。
传统疗法。癌症治疗包括输注T细胞,这些T细胞被设计为识别
肿瘤抗原,仅存在于癌细胞上的分子,在临床研究中显示出巨大的成功,
白血病我们现在建议为MB开发这种方法。在我们的方法中,我们将靶向两种抗原,
IL 13 Ra 2和B7-H3,其存在于MB细胞上。接下来,我们将通过删除表观遗传来改进我们的方法。
已知抑制T细胞效应子功能的调节子。最后,我们将使用免疫活性MB
小鼠模型,以询问脑肿瘤微环境(TME)中的哪些免疫细胞控制CAR T细胞功效。
脑肿瘤因具有免疫抑制性TME而臭名昭著,但其对工程免疫细胞的影响
我们对此知之甚少。因此,使用具有功能性免疫系统的小鼠模型将使我们能够准确地
评估工程化T细胞的功能和安全性,并了解大脑TME。总之,我们
提出首先建立靶向两种抗原的CAR T细胞,以提高其特异性(目标1)。我们将
然后通过消除表观遗传程序来提高其持久性(目标2)。我们还将进行详细的
这是一项机制研究,以确定表观遗传调节剂如何控制工程化CAR T细胞的效应子功能。
最后,我们将研究消除脑TME内的关键抑制性免疫细胞是否会增强抗TME的作用。
CAR T细胞的肿瘤效应(Aim 3)。我们希望我们提出的使用基因工程双特异性
CAR T细胞和免疫活性小鼠模型将提供机制洞察和上级理解
关于工程化T细胞如何发挥作用并与大脑TME相互作用。我们相信,这些知识将导致
这不仅有助于建立改进的基于免疫细胞的方法,
脑肿瘤的治疗方法。如果我们的临床前方法成功,我们就有资源
在我们的机构开展I期临床试验。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Giedre Krenciute其他文献
Giedre Krenciute的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Giedre Krenciute', 18)}}的其他基金
Targeting tumor and T cell DNA methylomes to improve CAR T cell therapies for diffuse midline glioma
靶向肿瘤和 T 细胞 DNA 甲基化组以改善弥漫性中线神经胶质瘤的 CAR T 细胞疗法
- 批准号:
10715739 - 财政年份:2023
- 资助金额:
$ 44.48万 - 项目类别:
Improving genetically engineered T cells for medulloblastomas
改善髓母细胞瘤基因工程 T 细胞
- 批准号:
10390362 - 财政年份:2021
- 资助金额:
$ 44.48万 - 项目类别:
Improving genetically engineered T cells for medulloblastomas
改善髓母细胞瘤基因工程 T 细胞
- 批准号:
10181761 - 财政年份:2021
- 资助金额:
$ 44.48万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 44.48万 - 项目类别:
Research Grant