Immunologic Targeting of Developmentally-Regulated Antigens for the Treatment of High-Risk Medulloblastoma

发育调节抗原的免疫靶向治疗高风险髓母细胞瘤

基本信息

  • 批准号:
    9397160
  • 负责人:
  • 金额:
    $ 3.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-01 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Pediatric brain tumors have recently surpassed leukemia as the most common cause of cancer-related death in children. Immunotherapies leveraging the specificity of cytotoxic T cells have demonstrated unprecedented treatment responses for some malignancies; however, a lack of known targets prevents its application to the treatment of pediatric brain tumors. Medulloblastoma (MB) is the most common malignant pediatric brain tumor and is now understood to include at least four distinct molecular variants. Group 3 MB is the deadliest and among the most prevalent subtypes. Despite the use of aggressive treatments, the overall survival of patients with Group 3 MB remains below 50%. Serious long-term side effects and high relapse rates indicate that more targeted and effective therapies are desperately needed. Thus, the long-term goal of this proposal is to develop an immunologic strategy for treating high-risk MB. In melanoma, the most commonly appreciated immunologic targets are mutated proteins that generate immunogenic epitopes unique to tumor cells (neoantigens). In contrast to melanoma, the prevalence of mutations in pediatric brain tumors is paltry. Epigenetic modifiers predominate the few recurrently mutated genes. In MB, aberrant epigenetic gene regulation is shown to drive transcription patterns reminiscent of pluripotent stem cells and developing neural precursors. Pluripotent stem cells and neural stem cells therefore represent potential cellular sources of developmentally-regulated antigens (Dev Ags) that can be used to prime immune responses. The central hypothesis of this proposal portends that immunologic targeting of aberrantly expressed developmental proteins in Group 3 MB will provide a novel therapeutic platform with enhanced curative potential for these patients. This hypothesis will be tested through three specific aims: 1) Evaluate the capacity of induced pluripotent stem cells (iPSCs) and their spatiotemporally distinct neural progeny to serve as sources of antigen for immunologic targeting of Group 3 MB; 2) Determine the effect of chemotherapy, radiation, and epigenetic modifiers on the expression and anti-tumor efficacy of Dev Ags in Group 3 MB tumors; and 3) Demonstrate the ability of human Dev Ag specific T cells to target human MB tumors in vitro and in a patient-derived xenograft model of Group 3 MB. Aim 1, will utilize an in vitro model of neurodevelopment to analyze the transcriptional overlap of iPSCs and distinct iPSC-derived neural stem and progenitors (iNSPCs) with Group 3 MB and will evaluate the specificity and efficacy for targeting MB using Dev Ag T cells. Aim 2 will evaluate changes in gene expression, T cell specificity, and anti-tumor efficacy following exposure of MB tumors to radiation, chemotherapy, and epigenetic modifiers. Finally, using autologous iPSCs, iNSPCs, immune cells, and MB tumors, the efficacy of Dev Ag T cells in patient-derived xenografts of Group 3 MB will be evaluated. This research is significant in that it will provide an innovative strategy for deriving antigens with the capacity to immunologically target MB and demonstrate the effectiveness of these antigens at directing cytotoxic T cell responses against mouse and human tumors.
项目总结/文摘

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 }}

Kyle Dyson其他文献

Kyle Dyson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('Kyle Dyson', 18)}}的其他基金

Immunologic Targeting of Developmentally-Regulated Antigens for the Treatment of High-Risk Medulloblastoma
发育调节抗原的免疫靶向治疗高风险髓母细胞瘤
  • 批准号:
    10246430
  • 财政年份:
    2017
  • 资助金额:
    $ 3.81万
  • 项目类别:
Immunologic Targeting of Developmentally-Regulated Antigens for the Treatment of High-Risk Medulloblastoma
发育调节抗原的免疫靶向治疗高风险髓母细胞瘤
  • 批准号:
    9767728
  • 财政年份:
    2017
  • 资助金额:
    $ 3.81万
  • 项目类别:

相似海外基金

Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
  • 批准号:
    10591918
  • 财政年份:
    2023
  • 资助金额:
    $ 3.81万
  • 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
  • 批准号:
    23K15383
  • 财政年份:
    2023
  • 资助金额:
    $ 3.81万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
  • 批准号:
    23H03556
  • 财政年份:
    2023
  • 资助金额:
    $ 3.81万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
  • 批准号:
    23K17212
  • 财政年份:
    2023
  • 资助金额:
    $ 3.81万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
  • 批准号:
    22H03519
  • 财政年份:
    2022
  • 资助金额:
    $ 3.81万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
  • 批准号:
    563657-2021
  • 财政年份:
    2022
  • 资助金额:
    $ 3.81万
  • 项目类别:
    Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10521849
  • 财政年份:
    2022
  • 资助金额:
    $ 3.81万
  • 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10671022
  • 财政年份:
    2022
  • 资助金额:
    $ 3.81万
  • 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
  • 批准号:
    10670918
  • 财政年份:
    2022
  • 资助金额:
    $ 3.81万
  • 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
  • 批准号:
    2706416
  • 财政年份:
    2022
  • 资助金额:
    $ 3.81万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了