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
• 负责人: DAVID P. CARBONE
• 金额: $ 55.98万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10350636
• 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; Nonmetastatic; PD-1 inhibitors; Pathologic; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phase; Phase Ib Clinical Trial; Phase Ib Trial; Phenotype; Preclinical Drug Evaluation; Probability; Proteins; Purinergic P1 Receptors; Receptor Inhibition; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Resistance; Role; Safety; Sampling; Shapes; Signal Transduction; Spain; Stress; 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; immune function; immunoregulation; improved; novel; novel strategies; novel therapeutic intervention; phenotypic biomarker; pre-clinical; preclinical study; programmed cell death protein 1; receptor; response; therapeutic target; therapy outcome; tumor; tumor growth; tumor microenvironment

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 增强树突状细胞激发抗肿瘤 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 这些患者的干扰，我们将展示一种新颖的组合成像的实用性 评估 TME 中腺苷靶向的方法。