CCSG Supplement: Early-stage Surgeon Scientist Program (ESSP) - Chibawanye Ene
CCSG 增刊:早期外科医生科学家计划 (ESSP) - Chibawanye Ene
基本信息
- 批准号:10748481
- 负责人:
- 金额:$ 20.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-08-28 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAftercareAntsAttentionAutomobile DrivingBiologicalBloodCD14 geneCD3 AntigensCD8-Positive T-LymphocytesCancer CenterCancer Center Support GrantCell CommunicationCell secretionChemotherapy and/or radiationCirculationClinicalClinical TrialsDataEngineeringEnvironmentEvaluationGenesGlioblastomaGliomaGrantGranzymeHigh PrevalenceHumanImmuneImmune checkpoint inhibitorImmune responseImmunomodulatorsImmunosuppressionImmunotherapeutic agentImmunotherapyImpairmentIn complete remissionInfectionInfiltrationInterleukin-12Knockout MiceKnowledgeLinkLong-Term SurvivorsMART-1 Tumor AntigenMacrophageMalignant NeoplasmsMediatingModelingMusMyelogenousMyeloid CellsMyeloid-derived suppressor cellsOncolytic virusesOperative Surgical ProceduresOutcomePatient SelectionPatientsPhase I Clinical TrialsPredispositionPrimary Brain NeoplasmsRecurrenceResearch PersonnelResistanceScientistStandard ModelSurgeonSurvival RateSurvivorsT cell responseT-Cell ActivationT-LymphocyteTestingTherapeuticTimeTumor AntigensVaccinesViralanti-tumor immune responsecell mediated immune responsechimeric antigen receptorconditional knockoutcytokineeffector T cellexperienceimmune healthimmunosuppressedimprovedinterestmonocytemouse modelnew therapeutic targetnovel strategiesoncolytic virotherapypre-clinicalprogrammed cell death ligand 1programsresponsesynergismtumor
项目摘要
SUMMARY AND ABSTRACT
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-
21-100.
Glioblastoma (GBM), the most common primary brain tumor in adults has a median survival of only 14.6months
despite aggressive surgery, radiation and chemotherapy. This outcome has not changed in the past 20 years as
many of the newer targeted therapies and even immunotherapies, which have been highly effective in other
cancers, have proven ineffective in GBM. Delta-24RGD oncolytic virus is a form of immunotherapy that has
shown efficacy with complete responses in 15% of GBM patients (or long-term survivors) as part of a clinical trial
performed here at MD Anderson Cancer Center. Short term survivors, however, showed no clinical response
following Delta-24RGD oncolytic virus treatment. Virally induced anti-glioma CD8+ T-cell responses were
observed in some long-term survivors following treatment, indicating that Delta-24RGD elicits an ant-tumor
immune response in GBM. It is unclear why short-term survivors lacked an anti-tumor immune response. Recent
studies have shown that patients with GBM have some of the highest levels of circulating immunosuppressive
myeloid cells, particularly PD-L1+ myeloid-derived suppressor cells (MDSCs), and that the levels of these PD-
L1+ immunosuppressive myeloid cells correlate with poor outcomes in GBM patients receiving immunotherapies.
Our preliminary data showed that Delta-24RGD oncolytic virus long term survivors have higher levels of the
potent polyfunctional and anti-tumor T-cell sub-population in circulation after treatment. It remains unclear
whether immunosuppressive PD-L1+ MDSCs modulate the levels of polyfunctional T-cells resulting in a lack of
expansion following Delta-24RGD oncolytic virus treatment especially in short-term survivors. We hypothesize
that circulating immunosuppressive myeloid cells inhibit circulating T-cell activation and polyfunctionality
resulting in resistance of GBM patients to Delta-24RGD oncolytic virus. To assess our hypothesis, we will
compare the levels of PD-L1+ MDSCs in Delta-24RGD responders to non-responders. In a mouse GBM model
that re-capitulates the high levels of PD-L1+ MDSCs in circulation, we will evaluate whether Delta-24RGD
oncolytic virus is more effective following selectively depletion of circulating PD-L1+ MDSCs. Finally, we propose
a therapeutic strategy to overcome systemic myeloid mediated immunosuppression by administering genetically
modified macrophages expressing T-cell activating cytokine IL-12 prior to Delta-24RGD oncolytic virus
treatment.
摘要和摘要
本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的
21比100。
胶质母细胞瘤(GBM)是成人最常见的原发脑肿瘤,中位生存期仅为14.6个月
尽管进行了积极的手术、放疗和化疗。这一结果在过去20年里没有改变,因为
许多较新的靶向疗法,甚至免疫疗法,对其他疾病都非常有效
癌症,已被证明在GBM中无效。Delta-24RGD溶瘤病毒是一种免疫疗法,具有
作为临床试验的一部分,在15%的GBM患者(或长期幸存者)中显示出完全有效的疗效
在MD安德森癌症中心演出。然而,短期存活者没有表现出临床反应。
在Delta-24RGD溶瘤病毒治疗后。病毒诱导的抗胶质瘤CD8+T细胞应答
在一些长期存活者的治疗后观察,表明Delta-24RGD诱发了一种抗肿瘤
基底膜的免疫反应。目前尚不清楚为什么短期幸存者缺乏抗肿瘤免疫反应。近期
研究表明,GBM患者的循环免疫抑制水平最高。
髓系细胞,特别是PD-L1+髓系来源的抑制细胞(MDSCs),这些PD-L1+的水平。
在接受免疫治疗的GBM患者中,L1+免疫抑制髓系细胞与不良预后相关。
我们的初步数据显示,长期存活的Delta-24RGD溶瘤病毒患者体内的
治疗后循环中强大的多功能和抗肿瘤T细胞亚群。目前仍不清楚
免疫抑制PD-L1+MDSCs是否调节多功能T细胞水平导致缺乏
在Delta-24RGD溶瘤病毒治疗后扩大,特别是在短期幸存者中。我们假设
循环免疫抑制髓系细胞抑制循环T细胞活化和多功能
导致GBM患者对Delta-24RGD溶瘤病毒产生耐药性。为了评估我们的假设,我们将
比较Delta-24RGD应答者与非应答者PD-L1+MDSCs水平。在小鼠GBM模型中
使循环中高水平的PD-L1+MDSCs重新屈服,我们将评估Delta-24RGD
溶瘤病毒在选择性耗尽循环中的PD-L1+MDSCs后更有效。最后,我们建议
基因给药克服全身性髓系免疫抑制的治疗策略
Delta-24RGD溶瘤病毒前表达T细胞激活因子IL-12的修饰巨噬细胞
治疗。
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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Giulio Francesco Draetta其他文献
Giulio Francesco Draetta的其他文献
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{{ truncateString('Giulio Francesco Draetta', 18)}}的其他基金
Project 5: Targeting Oxidative Phosphorylation in AML
项目 5:针对 AML 中的氧化磷酸化
- 批准号:
10931070 - 财政年份:2023
- 资助金额:
$ 20.25万 - 项目类别:
Medium-chain acyl-coenzyme A dehydrogenase as an essential feeder of glioblastoma multiforme
中链酰基辅酶 A 脱氢酶作为多形性胶质母细胞瘤的重要饲养者
- 批准号:
10094200 - 财政年份:2018
- 资助金额:
$ 20.25万 - 项目类别:
Medium-chain acyl-coenzyme A dehydrogenase as an essential feeder of glioblastoma multiforme
中链酰基辅酶 A 脱氢酶作为多形性胶质母细胞瘤的重要饲养者
- 批准号:
10335175 - 财政年份:2018
- 资助金额:
$ 20.25万 - 项目类别:
Project 5: Targeting Oxidative Phosphorylation in AML
项目 5:针对 AML 中的氧化磷酸化
- 批准号:
10006817 - 财政年份:2003
- 资助金额:
$ 20.25万 - 项目类别:
Project 5: Targeting Oxidative Phosphorylation in AML
项目 5:针对 AML 中的氧化磷酸化
- 批准号:
10247507 - 财政年份:2003
- 资助金额:
$ 20.25万 - 项目类别:
CCSG Supplement: Strengthen the Research, Training, and Outreach Capacity
CCSG 补充:加强研究、培训和推广能力
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- 资助金额:
$ 20.25万 - 项目类别:
Project 5: Targeting Oxidative Phosphorylation in AML
项目 5:针对 AML 中的氧化磷酸化
- 批准号:
9762859 - 财政年份:
- 资助金额:
$ 20.25万 - 项目类别:
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