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

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A2A和A2B腺苷受体（A2BAR）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。A2BAR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 A2BAR拮抗剂与当前ICI组合的临床应用的强有力的理由。以确定 A2BAR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A2BAR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A2BAR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。 靶向转移性肿瘤中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 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。

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.