Targeting immunosuppressive adenosine in patients with metastatic non-small cell lung cancer
靶向免疫抑制腺苷治疗转移性非小细胞肺癌患者
基本信息
- 批准号:10593117
- 负责人:
- 金额:$ 38.05万
- 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:2021-02-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdenosineAdenosine A2B ReceptorAdverse effectsAffectAffinityAnimal ModelAnimalsApplications GrantsBiologyBiopsyCancer ModelCancer PatientCatabolismCell Differentiation processCell FractionCellsClinical ResearchClinical TrialsCollaborationsCombination immunotherapyCombined Modality TherapyDataDendritic CellsDiseaseDoseEffectivenessEnzymesEvaluationGenerationsGeneticGrowthImmuneImmune checkpoint inhibitorImmunityImmunologicsImmunosuppressionImmunotherapeutic agentImmunotherapyImpairmentInstitutionMagnetic Resonance ImagingMalignant NeoplasmsMalignant neoplasm of lungMaximum Tolerated DoseMediatingMetabolicMetabolic stressMethodsModelingMolecularMyelogenousMyeloid-derived suppressor cellsNatural Killer CellsNivolumabNon-Small-Cell Lung CarcinomaOutcomePD-1 inhibitorsPathologicPatientsPeripheral Blood Mononuclear CellPhasePhase Ib Clinical TrialPhase Ib TrialPhenotypePreclinical Drug EvaluationProbabilityProductivityProteinsPurinergic P1 ReceptorsReceptor InhibitionReceptor SignalingRecommendationRegulationRegulatory T-LymphocyteResistanceRoleSafetySamplingShapesSignal TransductionSpainT cell responseT-LymphocyteTestingTissuesTumor Immunityantagonistanti-PD-1anti-PD1 antibodiesanti-tumor immune responseblood treatmentcheckpoint inhibitionchemotherapyclinical applicationcohortdesignecto-nucleotidaseefficacy evaluationextracellularimaging approachimaging modalityimmunoregulationimprovednovelnovel strategiesnovel therapeutic interventionpharmacologicphenotypic biomarkerpre-clinicalpreclinical studyprogrammed cell death protein 1receptorresponsesafety assessmentstress reductiontherapeutic targettumortumor growthtumor microenvironment
项目摘要
SUMMARY/ABSTRACT
Immune checkpoint inhibitors (ICIs) have transformed the management of patients with metastatic non-small cell
lung cancer (NSCLC). Unfortunately, over 50% of patients do not respond to these therapies. Combination
strategies with chemotherapy-ICIs show progress, but long-term responses remain rare, pointing to the role for
other tumor-associated mechanisms affecting functionality of immune cells. Adenosinergic signaling has recently
emerged as a powerful immuno-metabolic regulator within the tumor microenvironment (TME) exploited by
tumors to promote their growth and suppress immunity. Preclinical studies on interference with adenosine
generation or signaling through A2A and A2B adenosine receptors (A2BAR) have demonstrated efficacy in relieving
this immunosuppression by reducing stress in the TME and decreasing expression of key adenosine-generating
enzymes, thereby enhancing efficacy of immune checkpoint inhibition. A2BAR blockade in particular enhanced
anti-tumor immunity through both a reduction in myeloid-derived suppressor cell differentiation and an
enhancement of the capacity of dendritic cells to evoke anti-tumor T cell responses. These findings provide
strong rationale for clinical applications of A2BAR antagonists in combination with current ICIs. To determine
whether disruption of A2BAR signaling has the potential to improve upon single agent PD-1 immunotherapy, we
propose a phase Ib clinical trial testing the A2BAR antagonist PBF-1129 in combination with nivolumab in
patients with metastatic NSCLC. The primary objective of the clinical study is to evaluate the safety and
tolerability of combination PBF-1129 with nivolumab; preliminary evidence of efficacy will be evaluated in an
expansion cohort. Analysis of pre- and on- treatment blood and tumor samples will be conducted to evaluate the
correlation between and immunological parameters and adenosine generation and signaling, and to evaluate
the efficacy of PBF-1129 in targeting adenosine-mediated immunosuppression. Finally, we intend to further
elucidate mechanisms of metabolic TME and immune regulation by adenosine in pre-clinical cancer models and
test the combined PBF-1129/anti-PD-1 approach to ameliorate metabolic TME using a novel imaging modality.
Together, we expect that A2BAR antagonist treatment combined with nivolumab will be a safe, effective
approach targeting different mechanisms of immunosuppression and tumor growth in metastatic
NSCLC patients, that we will uncover immunological profiles reflective of adenosinergic signaling
disruption in these patients, and that we will demonstrate the utility of a novel combined imaging
approach for evaluation of adenosine targeting in the TME.
总结/摘要
免疫检查点抑制剂(ICI)已经改变了转移性非小细胞肺癌患者的管理,
肺癌(NSCLC)。不幸的是,超过50%的患者对这些治疗没有反应。组合
化疗-ICIs策略显示出进展,但长期反应仍然罕见,指出了ICIs的作用。
影响免疫细胞功能的其他肿瘤相关机制。最近,
在肿瘤微环境(TME)中作为一种强大的免疫代谢调节剂出现,
促进肿瘤生长,抑制免疫力。腺苷干扰的临床前研究
通过A2 A和A2 B腺苷受体(A2 BAR)的产生或信号传导已经证明了在缓解
这种免疫抑制通过减少TME中的应激和减少关键的腺苷生成因子的表达来实现。
酶,从而增强免疫检查点抑制的功效。A2 BAR阻断作用特别增强
通过骨髓来源的抑制细胞分化的减少和
增强树突状细胞诱发抗肿瘤T细胞应答的能力。这些发现提供
A2 BAR拮抗剂与当前ICI组合的临床应用的强有力的理由。以确定
A2 BAR信号传导的破坏是否有可能改善单药PD-1免疫治疗,我们
提出一项Ib期临床试验,测试A2 BAR拮抗剂PBF-1129与纳武利尤单抗联合治疗
转移性NSCLC患者。临床研究的主要目的是评价安全性和
PBF-1129与纳武单抗的组合的耐受性;将在一项研究中评估疗效的初步证据。
扩展队列。将对治疗前和治疗中的血液和肿瘤样本进行分析,以评估
免疫学参数与腺苷生成和信号传导之间的相关性,并评估
PBF-1129在靶向腺苷介导的免疫抑制中的功效。最后,我们打算进一步
阐明代谢TME和腺苷在临床前癌症模型中的免疫调节机制,
使用新的成像方式测试组合的PBF-1129/抗PD-1方法以改善代谢性TME。
总之,我们预计A2 BAR拮抗剂治疗与纳武单抗联合将是一种安全、有效的治疗方法。
针对转移性肿瘤中免疫抑制和肿瘤生长不同机制的方法
NSCLC患者,我们将揭示反映腺苷能信号传导的免疫学特征
我们将证明一种新的联合成像技术的实用性,
TME中腺苷靶向评价的方法。
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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DAVID P. CARBONE其他文献
DAVID P. CARBONE的其他文献
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{{ truncateString('DAVID P. CARBONE', 18)}}的其他基金
Targeting immunosuppressive adenosine in patients with metastatic non-small cell lung cancer
靶向免疫抑制腺苷治疗转移性非小细胞肺癌患者
- 批准号:
10350636 - 财政年份:2021
- 资助金额:
$ 38.05万 - 项目类别:
OSU as a Network Lead Academic Participating Site for the NCI NCTN
OSU 作为 NCI NCTN 网络主导学术参与网站
- 批准号:
9902398 - 财政年份:2019
- 资助金额:
$ 38.05万 - 项目类别:
ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center
ECOG-ACRIN 胸部恶性肿瘤综合转化科学中心
- 批准号:
10374819 - 财政年份:2019
- 资助金额:
$ 38.05万 - 项目类别:
ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center
ECOG-ACRIN 胸部恶性肿瘤综合转化科学中心
- 批准号:
9894764 - 财政年份:2019
- 资助金额:
$ 38.05万 - 项目类别:
OSU as a Network Lead Academic Participating Site for the NCI NCTN
OSU 作为 NCI NCTN 网络主导学术参与网站
- 批准号:
10581614 - 财政年份:2019
- 资助金额:
$ 38.05万 - 项目类别:
ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center
ECOG-ACRIN 胸部恶性肿瘤综合转化科学中心
- 批准号:
10133005 - 财政年份:2019
- 资助金额:
$ 38.05万 - 项目类别:
OSU as a Network Lead Academic Participating Site for the NCI NCTN
OSU 作为 NCI NCTN 网络主导学术参与网站
- 批准号:
10356923 - 财政年份:2019
- 资助金额:
$ 38.05万 - 项目类别:
ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center
ECOG-ACRIN 胸部恶性肿瘤综合转化科学中心
- 批准号:
10582677 - 财政年份:2019
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$ 38.05万 - 项目类别:
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- 批准号:
8743193 - 财政年份:2013
- 资助金额:
$ 38.05万 - 项目类别:
Notch ligands in regulation of anti-cancer immunity
Notch配体在抗癌免疫调节中的作用
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9130120 - 财政年份:2013
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