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.
内容和摘要
本申请是为了响应被标识为NOT-CA的特别利益通知(NOSI)而提交的-
21-100.
胶质母细胞瘤(GBM)是成人最常见的原发性脑肿瘤,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,
许多较新的靶向治疗,甚至免疫治疗,在其他疾病中非常有效,
癌症,已经证明对GBM无效。Delta-24 RGD溶瘤病毒是一种免疫疗法,
作为临床试验的一部分,在15%的GBM患者(或长期存活者)中显示出完全缓解的疗效
在MD安德森癌症中心进行。然而,短期存活者没有表现出临床反应
在Delta-24 RGD溶瘤病毒处理后。病毒诱导的抗神经胶质瘤CD 8 + T细胞应答是
在治疗后的一些长期存活者中观察到,表明Delta-24 RGD具有抗肿瘤作用,
GBM中的免疫应答。目前尚不清楚为什么短期存活者缺乏抗肿瘤免疫反应。最近
研究表明,GBM患者的循环免疫抑制水平最高,
骨髓细胞,特别是PD-L1+骨髓来源的抑制细胞(MDSC),以及这些PD-L1的水平,
L1+免疫抑制性骨髓细胞与接受免疫治疗的GBM患者的不良结局相关。
我们的初步数据显示,Delta-24 RGD溶瘤病毒的长期存活者具有更高水平的
治疗后循环中有效的多功能和抗肿瘤T细胞亚群。目前还不清楚
免疫抑制性PD-L1+ MDSC是否调节多功能T细胞的水平,导致缺乏免疫抑制性T细胞,
在Delta-24 RGD溶瘤病毒治疗后的扩增,特别是在短期存活者中。我们假设
循环免疫抑制性骨髓细胞抑制循环T细胞活化和多功能性
导致GBM患者对Delta-24 RGD溶瘤病毒的抗性。为了评估我们的假设,我们将
比较Delta-24 RGD应答者与无应答者中的PD-L1+ MDSC水平。在小鼠GBM模型中,
我们将评估Delta-24 RGD是否能在循环中重新发现高水平的PD-L1+ MDSC,
溶瘤病毒在选择性消耗循环PD-L1+ MDSC后更有效。最后提出
通过遗传给药克服系统性骨髓介导的免疫抑制的治疗策略
在Delta-24 RGD溶瘤病毒之前表达T细胞活化细胞因子IL-12的修饰的巨噬细胞
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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10891139 - 财政年份:1996
- 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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