Modulation of the human pancreatic microenvironment by combined cytokine and immune checkpoint blockade
通过联合细胞因子和免疫检查点阻断来调节人胰腺微环境
基本信息
- 批准号:10544304
- 负责人:
- 金额:$ 17.93万
- 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:2022-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressApplications GrantsBiologyBiopsyBiopsy SpecimenBlocking AntibodiesBloodBlood specimenCCRCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCellsCirculationClinicalClinical ResearchClinical TrialsCombined Modality TherapyComplementCorrelative StudyCoupledCytometryDataData SetDendritic CellsDiseaseEquilibriumFibroblastsFunctional disorderFutureGoalsHormone secretionHumanImmuneImmunityImmunofluorescence ImmunologicImmunologic FactorsImmunologic MarkersImmunologicsImmunotherapyInflammatoryInterleukin-6MaintenanceMalignant NeoplasmsMeasuresMediatorModelingMusMyelogenousMyeloid CellsMyeloid-derived suppressor cellsMyristica fragransNeoplasm MetastasisPD-1 blockadePancreasPancreatic Ductal AdenocarcinomaPatientsPhase Ib/II Clinical TrialPhenotypePopulationPre-Clinical ModelProteinsPublicationsPublishingRegimenReportingResearchResistanceRoleSamplingSourceSpecimenT cell infiltrationT-LymphocyteTestingTissuesTranslatingTreatment outcomeTumor PromotionWorkanti-PD-1anti-tumor immune responsecytokineeffector T cellfirst-in-humanimmune checkpointimmune checkpoint blockadeimprovedin vivoinnovationmouse modelnovelpancreatic ductal adenocarcinoma modelpancreatic neoplasmpancreatic stellate cellperipheral bloodpre-clinicalpreclinical studyprogrammed cell death ligand 1programmed cell death protein 1programsresidenceresponserestraintstemtranslational approachtumortumor microenvironment
项目摘要
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) harbors significant barriers restraining immunity. One notable factor
is the fibrotic stroma, driven by cancer associated fibroblast (CAF) subsets. Another is the myeloid-skewed
immune composition of TIL in PDAC tumors, which lack robust effector T cell infiltration. We postulate that
interleukin-6 (IL-6) is a critical factor that promotes inflammatory CAF, enables suppressive myeloid cell
residence, along with T cell dysfunction in PDAC. Using innovative translational approaches and patient
specimens, we will address relationships between IL-6, CAF and the balance of myeloid and T cells in metastatic
human PDAC. Studies in pre-clinical models support a role for these factors in both primary and metastatic
PDAC tumors, and our work will invigorate further discovery by studying tumor and blood samples from patients
where IL-6, a key cytokine mediator, is blocked along with the PD-1 immune checkpoint. This data will enhance
our understanding of how CAF interact with cytokines and immune cells in metastatic foci. This proposal
addresses the scientific premise that IL-6 acting directly on CAF and immune cells are key mechanisms for
maintaining an immunologically “cold” tumor microenvironment (TME) in metastatic PDAC and contributes to
immunotherapy resistance. We will test our overall hypothesis that IL-6 restrains immunity against PDAC,
through its effects on CAF and immune cells, and that targeting it reprograms the TME to enhance
efficacy of immunotherapy. Prior publications from our group have demonstrated a role for IL-6 in PDAC and
shown in mouse models how targeting it can improve efficacy of immune checkpoint blockade. These extensive
efforts have culminated in this proposal, which will translate into patients a first-in-human trial of IL-6 and PD-1
blockade in PDAC. This trial provides a needed study of how IL-6 and CAF are related to balance of immune
cells in metastatic tumors. This proposal represents an important opportunity to uncover connections between
CAF, immune cells and IL-6 in metastatic disease in patients. We will conduct two specific aims. First, we will
determine how dual blockade of IL-6 and PD-1 orchestrates the balance of CAF populations in tumors from
metastatic PDAC patients. In this aim, we will generate foundational data using human samples from paired pre-
and on-treatment biopsies of PDAC metastases from the clinical trial. Composition of CAF will be measured via
multiplex immunofluorescence (IF) to uncover how therapy modulates fibroblast subsets in metastatic PDAC.
Second, we will determine how targeting IL-6 and PD-1 influences the balance of T and myeloid cells in
metastatic PDAC tumors and systemic circulation. We will utilize single cell mass cytometry approaches on
paired biopsies and blood to study immune phenotype reprogramming in metastases and systemic longitudinal
changes during treatment and relationship to clinical response. This study will impact our understanding of how
immunotherapy can be improved and provide a rich dataset related to both stroma and immune markers in
metastatic PDAC to facilitate subsequent treatment opportunities.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Bassel El-Rayes其他文献
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{{ truncateString('Bassel El-Rayes', 18)}}的其他基金
Modulation of the human pancreatic microenvironment by combined cytokine and immune checkpoint blockade
通过联合细胞因子和免疫检查点阻断来调节人胰腺微环境
- 批准号:
10339958 - 财政年份:2022
- 资助金额:
$ 17.93万 - 项目类别:
Targeting immune stroma interactions in pancreatic cancer
靶向胰腺癌中的免疫基质相互作用
- 批准号:
10448352 - 财政年份:2019
- 资助金额:
$ 17.93万 - 项目类别:
Targeting immune stroma interactions in pancreatic cancer
靶向胰腺癌中的免疫基质相互作用
- 批准号:
10661565 - 财政年份:2019
- 资助金额:
$ 17.93万 - 项目类别:
Targeting immune stroma interactions in pancreatic cancer
靶向胰腺癌中的免疫基质相互作用
- 批准号:
10219189 - 财政年份:2019
- 资助金额:
$ 17.93万 - 项目类别:
Targeting immune stroma interactions in pancreatic cancer
靶向胰腺癌中的免疫基质相互作用
- 批准号:
9977988 - 财政年份:2019
- 资助金额:
$ 17.93万 - 项目类别:
Targeting immune stroma interactions in pancreatic cancer
靶向胰腺癌中的免疫基质相互作用
- 批准号:
9765906 - 财政年份:2019
- 资助金额:
$ 17.93万 - 项目类别: