Development of irreversible electroporation-based rational combinations to potentiate the activity of cancer immunotherapy against pancreatic ductal adenocarcinoma
开发基于不可逆电穿孔的合理组合以增强癌症免疫疗法对胰腺导管腺癌的活性
基本信息
- 批准号:10559607
- 负责人:
- 金额:$ 56.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AnabolismAntibodiesAntidiabetic DrugsAntigensAttenuatedBioenergeticsC57BL/6 MouseCD8-Positive T-LymphocytesCTLA4 geneCell MaturationCell membraneCellsClinicClinicalClinical TrialsCoagulative necrosisCompensationCross PresentationCytometryCytotoxic T-LymphocytesDataDendritic CellsDevelopmentDiseaseElectroporationFlow CytometryGlutamatesGlutaminaseGlutamineGlycolysisHumanIL8RB geneITGAM geneImmuneImmunocompetentImmunologicsImmunosuppressionImmunotherapyInfiltrationInflammatory InfiltrateInflammatory ResponseIonizing radiationKRASG12DKnowledgeLymphocyte ActivationLymphocytic InfiltrateMalignant NeoplasmsMetabolicMetabolismMetastatic Neoplasm to the LiverMetforminMitochondriaModelingMusMutationMyeloid-derived suppressor cellsOperative Surgical ProceduresOxidative PhosphorylationPTPRC genePancreatic Ductal AdenocarcinomaPathway AnalysisPathway interactionsPatientsPenetrationPhasePhenforminPhysiologic pulseProductionPrognosisProtein Array AnalysisQuality of lifeRecurrent tumorResistanceRespirationRoleSignal TransductionSurvival RateT-LymphocyteTechniquesTestingTimeTumor AntigensTumor ImmunityUp-Regulationadvanced diseaseanaloganti-PD-1attenuationcancer immunotherapycell injurychemoradiationclinically relevantcytokineeffective therapyimmune cell infiltrateimmune checkpoint blockadeimmunogenic cell deathimprovedinhibitorinnovationmouse modelneoplastic cellnovelnovel therapeuticspancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpharmacologicprogrammed cell death protein 1programsrecruitresponsesingle-cell RNA sequencingsmall hairpin RNAsuccesstheranosticstranscriptome sequencingtumortumor ablationtumor eradicationtumor microenvironmenttumor-immune system interactionsvoltage
项目摘要
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers, with a 5-year overall survival
(OS) rate of 7% for metastatic disease and less than 20% for locally advanced disease. Benefit from current
therapies including chemoradiation and surgery is often modest and transient. The significant challenge in the
field is how to turn immunologically cold PDAC into hot tumors that respond to immune checkpoint blockade
(ICB) therapy. We recently showed that irreversible electroporation (IRE), a tumor ablative technique currently
used in the clinics, significantly sensitized PDAC to anti-PD-1 ICB, leading to long-term survival in ~40% mice in
an aggressive orthotopic PDAC model. The remarkable anti-PDAC activity was attributed to efficient induction
of immunogenic cell death and stromal perturbation in favor of tumor infiltration of CTLs. As part of an effort to
define approaches to further enhance the efficacy of IRE + anti-PD-1 combination against PDAC, we uncovered
novel immune suppressive mechanism through time-of-flight mass cytometry (CyTOF) immune profiling and
single cell RNAseq of PDACs, which showed significant infiltration of CXCR2-expressing myeloid suppressive
cells (MDSCs). Furthermore, we found that IRE collapsed glycolysis and oxidative phosphorylation (OxPhos)
while upregulated glutaminase and glutamate, suggesting glutaminolysis as a compensatory mechanism to
satisfy energy and biosynthesis needs of IRE-treated cells. These data, taken together with the known critical
role of MDSCs and heightened glutamine metabolism in immune suppression, the findings by others that the
anti-diabetic drugs metformin and phenformin fundamentally change the tumor metabolic program to sensitize
tumors to ICB therapy, and our preliminary findings that both IRE and Re-Phen, a newly developed analogue of
phenformin, downregulated the OxPhos pathway while displaying an opposite effect on glutamate production,
lead us to hypothesize that attenuation of the immunosuppressive TME by depletion of MDSCs or suppression
of glutaminolysis by Re-Phen potentiates IRE + ICB to further prolong overall survival and increase the rate of
durable response. To test our hypothesis, we will pursue the following specific aims: 1) To identify
immunosuppressive factors associated with long-term versus short-term response to IRE + ICB. We will use
CyTOF immune profiling, scRNAseq, and cytokine array analyses to fully characterize the impact of IRE in the
presence and absence of anti-PD-1 on the immunosuppressive TME. 2) To determine the extent to which
therapies directed at MDSCs potentiate IRE + ICB. 3) To determine the extent to which disruption of the
metabolic program by theranostic agent Re-Phen potentiates IRE + ICB. The findings from this project are
expected to reveal previously undefined roles of MDSCs and deregulated metabolic programming in immune
suppression in the context of combined IRE + ICB therapy. Success of this project will have exceptional impact
because it will offer a potentially effective therapy for PDAC.
项目摘要
胰腺导管腺癌(PDAC)是人类最致命的癌症之一,其5年总生存率为
(OS)转移性疾病的发生率为7%,局部晚期疾病的发生率低于20%。受益于当前
包括放化疗和手术的治疗通常是温和和短暂的。2010年的重大挑战
如何将免疫学上的冷PDAC转化为对免疫检查点阻断有反应的热肿瘤
(ICB)疗法我们最近表明,不可逆电穿孔(IRE),目前的肿瘤消融技术,
在临床中使用,PDAC对抗PD-1 ICB显着致敏,导致约40%的小鼠长期存活,
一个积极的原位PDAC模型。显著的抗PDAC活性归因于有效的诱导
免疫原性细胞死亡和间质扰动有利于CTL的肿瘤浸润。作为努力的一部分,
定义进一步增强IRE +抗PD-1联合治疗PDAC疗效的方法,我们发现
通过飞行时间质谱细胞术(CyTOF)免疫分析的新的免疫抑制机制,
PDAC的单细胞RNAseq,其显示表达CXCR 2的髓样抑制细胞的显著浸润,
细胞(MDSC)。此外,我们发现IRE破坏糖酵解和氧化磷酸化(OxPhos)
而上调谷氨酰胺酶和谷氨酸,表明谷氨酰胺分解是一种代偿机制,
满足IRE处理的细胞的能量和生物合成需要。这些数据与已知的关键数据一起,
MDSC和谷氨酰胺代谢在免疫抑制中的作用,
抗糖尿病药物二甲双胍和苯丙氨酸从根本上改变肿瘤代谢程序,
我们的初步发现,IRE和Re-Phen,一种新开发的ICB类似物,
苯丙氨酸,下调OxPhos途径,同时显示对谷氨酸产生的相反作用,
导致我们假设通过MDSC耗竭或抑制免疫抑制性TME的减弱
通过Re-Phen增强IRE + ICB以进一步延长总生存期并增加
持久的反应。为了验证我们的假设,我们将追求以下具体目标:1)识别
与IRE + ICB的长期和短期反应相关的免疫抑制因素。我们将使用
CyTOF免疫谱分析、scRNAseq和细胞因子阵列分析,以充分表征IRE在免疫缺陷病毒中的影响。
免疫抑制性TME上抗PD-1的存在和不存在。2)为了确定在多大程度上
针对MDSC的治疗增强IRE + ICB。3)为了确定在多大程度上破坏了
通过治疗诊断剂Re-Phen的代谢程序增强IRE + ICB。该项目的结果是
预计将揭示以前未定义的MDSC的作用和免疫调节中代谢编程的失调。
在IRE + ICB联合治疗的背景下抑制。该项目的成功将产生特殊的影响
因为它将为PDAC提供一种潜在的有效疗法。
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 }}
CHUN LI其他文献
CHUN LI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('CHUN LI', 18)}}的其他基金
Development of irreversible electroporation-based rational combinations to potentiate the activity of cancer immunotherapy against pancreatic ductal adenocarcinoma
开发基于不可逆电穿孔的合理组合以增强癌症免疫疗法对胰腺导管腺癌的活性
- 批准号:
10363932 - 财政年份:2022
- 资助金额:
$ 56.97万 - 项目类别:
GS-441524 is Pharmacodynamically Equivalent to Remdesivir and Pharmacokinetically Superior Drug for the Treatment of COVID-19
GS-441524在药效学上与瑞德西韦相当,是治疗COVID-19的药代动力学优越的药物
- 批准号:
10199288 - 财政年份:2021
- 资助金额:
$ 56.97万 - 项目类别:
Multifunctional Hollow Gold Nanospheres for Concurrent Photothermal-Chemotherapy
用于同步光热化疗的多功能空心金纳米球
- 批准号:
9039018 - 财政年份:2015
- 资助金额:
$ 56.97万 - 项目类别:
MEASUREMENT OF SPECTRAL SHIFT AND LIFETIME CHANGES OF NOVEL DYES
新型染料的光谱偏移和寿命变化的测量
- 批准号:
8361774 - 财政年份:2011
- 资助金额:
$ 56.97万 - 项目类别:
MEASUREMENT OF SPECTRAL SHIFT AND LIFETIME CHANGES OF NOVEL DYES
新型染料的光谱偏移和寿命变化的测量
- 批准号:
8169410 - 财政年份:2010
- 资助金额:
$ 56.97万 - 项目类别:
Near-Infrared Fluorescence Nanoparticles for Targeted O*
用于靶向 O* 的近红外荧光纳米颗粒
- 批准号:
7919135 - 财政年份:2009
- 资助金额:
$ 56.97万 - 项目类别:
MEASUREMENT OF SPECTRAL SHIFT AND LIFETIME CHANGES OF NOVEL DYES
新型染料的光谱偏移和寿命变化的测量
- 批准号:
7956793 - 财政年份:2009
- 资助金额:
$ 56.97万 - 项目类别:
MEASUREMENT OF SPECTRAL SHIFT AND LIFETIME CHANGES OF NOVEL DYES
新型染料的光谱偏移和寿命变化的测量
- 批准号:
7724272 - 财政年份:2008
- 资助金额:
$ 56.97万 - 项目类别:
Near-Infrared Fluorescence Nanoparticles for Targeted Optical Imaging
用于靶向光学成像的近红外荧光纳米颗粒
- 批准号:
7478768 - 财政年份:2005
- 资助金额:
$ 56.97万 - 项目类别:
Near-Infrared Fluorescence Nanoparticles for Targeted O*
用于靶向 O* 的近红外荧光纳米颗粒
- 批准号:
7127285 - 财政年份:2005
- 资助金额:
$ 56.97万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 56.97万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 56.97万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 56.97万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 56.97万 - 项目类别:
Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 56.97万 - 项目类别:
Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 56.97万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 56.97万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
- 批准号:
10639161 - 财政年份:2023
- 资助金额:
$ 56.97万 - 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
- 批准号:
10752441 - 财政年份:2023
- 资助金额:
$ 56.97万 - 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
- 批准号:
10867639 - 财政年份:2023
- 资助金额:
$ 56.97万 - 项目类别: