Targeting immunosuppressive adenosine in patients with metastatic non-small cell lung cancer

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的策略显示出进展，但长期反应仍然很少，这表明了 影响免疫细胞功能的其他肿瘤相关机制。腺苷能信号转导最近 作为一种强大的免疫代谢调节剂出现在肿瘤微环境(TME)中，由 促进肿瘤生长，抑制免疫力。腺苷干扰的临床前研究 通过A2A型和A2B型腺苷受体(A2BAR)产生或传递信号已显示出缓解高血压的疗效 这种免疫抑制是通过减少TME中的压力和减少关键的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封锁特别加强 通过减少髓系来源的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拮抗剂结合目前的ICIS临床应用有很强的理据。要确定 A2BAR信号的中断是否有可能改善单剂PD-1免疫治疗，我们 建议进行一项测试A2BAR拮抗剂PBF-1129与尼伏鲁单抗联合试验的Ib期临床试验 转移性非小细胞肺癌患者。临床研究的主要目的是评估该药的安全性和安全性。 PBF-1129与nivolumab的联合耐受性；疗效的初步证据将在 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转导的相关性及评价 PBF-1129靶向性腺苷介导的免疫抑制作用最后，我们打算进一步 阐明临床前肿瘤模型及腺苷对TME代谢和免疫调节的机制 使用一种新的成像方式测试PBF-1129/抗PD-1联合方法来改善代谢性TME。 总之，我们期待A2BAR拮抗剂联合尼伏卢单抗治疗将是一种安全、有效的方法 针对不同免疫抑制机制与转移性肿瘤生长的探讨 NSCLC患者，我们将发现反映腺苷能信号的免疫学特征 我们将展示一种新的联合成像的实用价值 TME中腺苷靶向性的评价方法。

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.