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 (ICIs) 改变了转移性非小细胞患者的治疗肺癌（NSCLC）。不幸的是，超过 50% 的患者对这些疗法没有反应。组合化疗-ICIs 策略显示出进展，但长期缓解仍然很少，这表明化疗的作用其他影响免疫细胞功能的肿瘤相关机制。最近，腺苷能信号传导成为肿瘤微环境（TME）中强大的免疫代谢调节剂肿瘤促进其生长并抑制免疫力。干扰腺苷的临床前研究通过 A2A 和 A2B 腺苷受体 (A2BAR) 产生或信号传导已被证明能够有效缓解这种免疫抑制是通过减少 TME 中的应激和减少关键腺苷生成的表达来实现的酶，从而增强免疫检查点抑制的功效。 A2BAR封锁特别增强通过减少骨髓源性抑制细胞分化和抗肿瘤免疫增强树突状细胞引发抗肿瘤 T 细胞反应的能力。这些发现提供了 A2BAR 拮抗剂与当前 ICI 联合临床应用的有力理由。确定 A2BAR 信号传导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，测试 A2BAR 拮抗剂 PBF-1129 与纳武单抗 (nivolumab) 的联合治疗转移性非小细胞肺癌患者。临床研究的主要目的是评估安全性和 PBF-1129 与纳武单抗联合用药的耐受性；有效性的初步证据将在扩展队列。将分析治疗前和治疗中的血液和肿瘤样本，以评估免疫学参数与腺苷生成和信号传导之间的相关性，并进行评估 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临床前癌症模型中腺苷代谢 TME 和免疫调节的机制使用新型成像方式测试 PBF-1129/抗 PD-1 联合方法改善代谢性 TME 的效果。我们共同期望 A2BAR 拮抗剂联合纳武单抗治疗将是一种安全、有效的治疗方法。针对转移性免疫抑制和肿瘤生长的不同机制的方法 NSCLC 患者，我们将揭示反映腺苷能信号传导的免疫学特征对这些患者的干扰，我们将展示一种新型组合成像的实用性评估 TME 中腺苷靶向的方法。