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：
DAVID P. CARBONE
金额：
$ 38.05万
依托单位：
OHIO STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10593117
关键词：
Ablation Adenosine Adenosine A2B Receptor Adverse effects Affect Affinity Animal Model Animals Applications Grants Biology Biopsy Cancer Model Cancer Patient Catabolism Cell Differentiation process Cell Fraction Cells Clinical Research Clinical Trials Collaborations Combination immunotherapy Combined Modality Therapy Data Dendritic Cells Disease Dose Effectiveness Enzymes Evaluation Generations Genetic Growth Immune Immune checkpoint inhibitor Immunity Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Impairment Institution Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Maximum Tolerated Dose Mediating Metabolic Metabolic stress Methods Modeling Molecular Myelogenous Myeloid-derived suppressor cells Natural Killer Cells Nivolumab Non-Small-Cell Lung Carcinoma Outcome PD-1 inhibitors Pathologic Patients Peripheral Blood Mononuclear Cell Phase Phase Ib Clinical Trial Phase Ib Trial Phenotype Preclinical Drug Evaluation Probability Productivity Proteins Purinergic P1 Receptors Receptor Inhibition Receptor Signaling Recommendation Regulation Regulatory T-Lymphocyte Resistance Role Safety Sampling Shapes Signal Transduction Spain T cell response T-Lymphocyte Testing Tissues Tumor Immunity antagonist anti-PD-1 anti-PD1 antibodies anti-tumor immune response blood treatment checkpoint inhibition chemotherapy clinical application cohort design ecto-nucleotidase efficacy evaluation extracellular imaging approach imaging modality immunoregulation improved novel novel strategies novel therapeutic intervention pharmacologic phenotypic biomarker pre-clinical preclinical study programmed cell death protein 1 receptor response safety assessment stress reduction therapeutic target tumor tumor growth tumor 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.

摘要/摘要免疫检查点抑制剂（ICI）已转化了转移性非小细胞患者的管理肺癌（NSCLC）。不幸的是，超过50％的患者对这些疗法没有反应。组合化学疗法 - ICIS的策略显示出进步，但长期反应仍然很少见，这表明了影响免疫细胞功能的其他肿瘤相关机制。腺苷能信号最近有在肿瘤微环境（TME）内的强大免疫代谢调节剂中出现肿瘤促进其生长并抑制免疫力。干涉腺苷的临床前研究通过A2A和A2B腺苷受体（A2BAR）发电或发信号已证明有效缓解通过减少TME的应力并降低钥匙腺苷生成的表达来进行免疫抑制酶，从而增强了免疫检查点抑制的功效。 A2BAR封锁特别增强通过降低髓样衍生的抑制细胞分化和A的抗肿瘤免疫力树突状细胞唤起抗肿瘤T细胞反应的能力的增强。这些发现提供了 A2BAR拮抗剂与当前ICI结合使用的临床应用的良好基本原理。确定 A2BAR信号的破坏是否有可能改善单药PD-1免疫疗法，我们提出一项IB期临床试验，对A2BAR拮抗剂PBF-1129与Nivolumab结合使用转移性NSCLC患者。临床研究的主要目的是评估安全性和 Nivolumab组合PBF-1129的耐受性；有效性的初步证据将在扩展队列。将对前后治疗血液和肿瘤样品进行分析以评估免疫学参数与腺苷的产生和信号之间的相关性，并评估 PBF-1129在靶向腺苷介导的免疫抑制方面的功效。最后，我们打算进一步阐明腺苷前临床癌模型中腺苷的代谢TME和免疫调节机制使用新型的成像方式测试合并的PBF-1129/抗PD-1方法，以改善代谢TME。我们预计，A2BAR拮抗剂与Nivolumab结合在一起将是安全，有效的靶向转移性免疫抑制和肿瘤生长的不同机制的方法 NSCLC患者，我们将发现反映腺苷能信号传导的免疫学特征这些患者的破坏，我们将证明新型组合成像的实用性评估TME中腺苷靶向的方法。