Reprogramming the Tumor Microenvironment to Improve Immunotherapy of Glioblastoma by Co-Targeting VEGF and Ang2
通过共同靶向 VEGF 和 Ang2 重新编程肿瘤微环境以改善胶质母细胞瘤的免疫治疗
基本信息
- 批准号:10582613
- 负责人:
- 金额:$ 40.34万
- 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:2021-05-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AbbreviationsAdverse effectsAdverse eventAngiopoietin-2AntibodiesAntigen-Presenting CellsAutoimmuneBispecific AntibodiesBlood VesselsBrain NeoplasmsCD8-Positive T-LymphocytesCell Adhesion MoleculesCell CommunicationCellsCervicalClinical ResearchClinical Trials DesignCombined Modality TherapyComplexCytolysisCytotoxic T-LymphocytesDataDevelopmentDrug Delivery SystemsEdemaEndothelial CellsExclusionFDA approvedFailureGlioblastomaGliomaHemorrhageHypoxiaImaging TechniquesImmuneImmune EvasionImmunoglobulin GImmunohistochemistryImmunologic SurveillanceImmunosuppressionImmunotherapyImpairmentInfiltrationInflammationInflammatory ResponseLiteratureLong-Term SurvivorsLymphocyte FunctionLymphocytic InfiltrateMacrophageMalignant neoplasm of lungMeasuresMediatingMemoryMusMyeloid CellsOperative Surgical ProceduresOrganPatientsPerfusionPeripheralPhase III Clinical TrialsPhenotypePilot ProjectsProliferatingPublishingQuality of lifeReactionRegulatory T-LymphocyteResistanceRiskSpleenSurgical ModelsT-LymphocyteTestingToxic effectTreatment EfficacyTumor AntigensTumor BurdenTumor ImmunityTumor-infiltrating immune cellsUp-RegulationVascular Endothelial Growth Factorsanti-PD-1anti-PD1 therapyantibody testantibody-dependent cell cytotoxicitybevacizumabcancer cellcell killingchemoradiationcomorbiditycytokinedosageimmune checkpoint blockersimprovedimproved outcomein vivoin vivo imaginginsightintravital imaginglymph nodeslymphocyte traffickingmelanomaneoantigensneoplastic cellnovel strategiesnovel therapeuticspreclinical studyreceptorrepairedresistance mechanismresponsestandard of caretraffickingtumortumor microenvironmenttumor-immune system interactionsvascular abnormality
项目摘要
SUMMARY
Glioblastoma (GBM) is a universally fatal brain tumor. Immune checkpoint blockers (ICBs), such as anti-
programmed cell death-1 protein (aPD1), alone or in combination with bevacizumab - an anti-vascular endothelial
growth factor antibody (aVEGF), failed to improve survival in phase III clinical trials in GBM. This failure is, in
part, due to the formidable barriers that the GBM tumor microenvironment (TME) creates. First, GBM tumor cells
are highly proliferative and invasive with low neoantigen load, and thus, can easily evade immune surveillance.
Second, GBM vessels are abnormal, and thus, they create a leaky, hypoxic and edematous TME and limit the
delivery of drugs and the access of antitumor immune cells such as cytotoxic T lymphocytes (CTLs) into the tumor
resulting in a cold CTL-excluded TME. Moreover, limited number of CTLs that accrue within GBM TME are
dysfunctional. In contrast, pro-tumor immune cells such as regulatory T cells (Tregs) and “M2-like” macrophages
preferentially accumulate in GBM. Unlike CTLs, Tregs and “M2-like” macrophages do not require intact vessels
for trafficking to the tumor and thrive and proliferate in the GBM TME. Third, our pilot studies indicate that aPD1
aggravates vascular abnormalities and inflammatory responses in GBM, causing toxicities. Collectively, these
features give rise to a strongly immunosuppressive TME in GBM that resists both the standard of care (SoC) and
immunotherapy. Our preclinical and clinical studies and those of others indicate that angiopoietin-2 (Ang-2) can
shorten the duration of aVEGF-induced vascular normalization. Thus, we hypothesize that normalizing tumor
vasculature by co-targeting angiopoietin-2 (Ang-2) and aVEGF (abbreviated as aA2V) can both overcome
resistance to aPD1 and reduce toxicities in patients with GBM. We will test if aA2V+aPD1 can durably
normalize tumor vessels and improve their function. At cellular level, we will test if aA2V+aPD1 can repair the
dysfunctional endothelial cells to express adhesion molecules, which are required for CTL cell trafficking, convert
them to non-canonical antigen presenting cells to present tumor antigens to CTLs, and collectively result in
improved CTL infiltration and function (Aim 1). We will further determine the involvement of antibody-
dependent cell cytotoxicity (ADCC) in aPD1-induced adverse events and their alleviation by aA2V (Aim 2).
Finally, we will use our newly developed surgical model that faithfully recapitulates GBM therapy in mice
including SoC (surgery and chemo radiation) to test whether combining SoC with aA2V+aPD1 can promote
durable responses (longer survival and memory responses) (Aim 3). Our findings will provide unprecedented
insights into the mechanisms of resistance to immunotherapy in GBM, establish a novel strategy to overcome this
resistance while abrogating putative adverse effects, and directly inform the design of clinical trials of GBM
patients with combination aA2V+aPD1 therapy and SoC.
总结
胶质母细胞瘤(GBM)是一种普遍致命的脑肿瘤。免疫检查点阻断剂(ICB),如抗-
程序性细胞死亡-1蛋白(aPD 1),单独或与贝伐单抗(一种抗血管内皮
生长因子抗体(aVEGF)在GBM的III期临床试验中未能改善存活率。这一失败,在
部分原因是由于GBM肿瘤微环境(TME)产生的强大屏障。首先,GBM肿瘤细胞
是高度增殖性和侵袭性的,具有低的新抗原负荷,因此可以容易地逃避免疫监视。
其次,GBM血管是异常的,因此,它们产生渗漏、缺氧和水肿的TME,并限制了TME的生长。
药物的递送和抗肿瘤免疫细胞如细胞毒性T淋巴细胞(CTL)进入肿瘤
导致冷的CTL排除的TME。此外,GBM TME内累积的CTL数量有限,
功能失调相比之下,促肿瘤免疫细胞如调节性T细胞(Tcells)和“M2样”巨噬细胞(M2-like macrophages)可被免疫细胞(如巨噬细胞)激活。
优先在GBM中积累。与CTL不同的是,TCFs和“M2样”巨噬细胞不需要完整的血管
用于运输到肿瘤并在GBM TME中茁壮成长和增殖。第三,我们的初步研究表明,aPD 1
加重GBM中的血管异常和炎症反应,导致毒性。总的来说,这些
这些特征导致GBM中出现强烈的免疫抑制性TME,既抵抗标准治疗(SoC),
免疫疗法。我们的临床前和临床研究以及其他研究表明,血管生成素-2(Ang-2)可以
缩短aVEGF诱导的血管正常化的持续时间。因此,我们假设正常化肿瘤
通过共靶向血管生成素-2(Ang-2)和aVEGF(缩写为aA 2 V)来抑制血管生成,
抗aPD 1和减少GBM患者的毒性。我们将测试aA 2 V + aPD 1是否可以持久
使肿瘤血管正常化并改善其功能。在细胞水平上,我们将测试aA 2 V + aPD 1是否可以修复
功能障碍的内皮细胞表达CTL细胞运输所需的粘附分子,
将它们递送至非典型抗原呈递细胞,以将肿瘤抗原呈递至CTL,并且共同导致
改善CTL的浸润和功能(目的1)。我们将进一步确定抗体的参与-
在aPD 1诱导的不良事件中的依赖性细胞毒性(ADCC)和aA 2 V的缓解(目的2)。
最后,我们将使用我们新开发的手术模型,忠实地概括了小鼠GBM治疗
包括SoC(手术和化疗),以测试SoC与aA 2 V + aPD 1的组合是否可以促进
持久的反应(更长的生存和记忆反应)(目标3)。我们的发现将提供前所未有的
深入了解GBM对免疫治疗的耐药机制,建立一种新的策略来克服这一点
同时消除假定的不良反应,并直接告知GBM临床试验的设计
aA 2 V + aPD 1联合治疗和SoC的患者。
项目成果
期刊论文数量(0)
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Dai Fukumura其他文献
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{{ truncateString('Dai Fukumura', 18)}}的其他基金
Reprogramming the tumor microenvironment to improve immunotherapy of glioblastoma by co-targeting VEGF and Ang2
通过共同靶向 VEGF 和 Ang2 重新编程肿瘤微环境以改善胶质母细胞瘤的免疫治疗
- 批准号:
10394968 - 财政年份:2021
- 资助金额:
$ 40.34万 - 项目类别:
Reengineering obesity-induced abnormal microenvironment to improve PDAC treatment
重新设计肥胖引起的异常微环境以改善 PDAC 治疗
- 批准号:
9403496 - 财政年份:2017
- 资助金额:
$ 40.34万 - 项目类别:
Overcoming Resistance to Anti-VEGF Treatment of Colorectal Cancers
克服结直肠癌抗 VEGF 治疗的耐药性
- 批准号:
8463132 - 财政年份:2013
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$ 40.34万 - 项目类别:
Doppler Optical Frequency Domain Imaging Instrument
多普勒光频域成像仪
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7793981 - 财政年份:2010
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Vascular Normalization: Rolse of Perivascular Cells
血管正常化:血管周围细胞的旋转
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7118413 - 财政年份:2006
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NO in Tumor Angiogenesis,Microcirculation & Rad.Therapy
NO在肿瘤血管生成、微循环中的作用
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7071781 - 财政年份:2002
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$ 40.34万 - 项目类别:
Nitric Oxide in Tumor Angiogenesis, Microcirculation and Radiation Therapy
一氧化氮在肿瘤血管生成、微循环和放射治疗中的作用
- 批准号:
7618192 - 财政年份:2002
- 资助金额:
$ 40.34万 - 项目类别:
NO in Tumor Angiogenesis,Microcirculation & Rad.Therapy
NO在肿瘤血管生成、微循环中的作用
- 批准号:
6522149 - 财政年份:2002
- 资助金额:
$ 40.34万 - 项目类别:
Nitric Oxide in Tumor Angiogenesis, Microcirculation and Radiation Therapy
一氧化氮在肿瘤血管生成、微循环和放射治疗中的作用
- 批准号:
7812092 - 财政年份:2002
- 资助金额:
$ 40.34万 - 项目类别:
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