Targeting the adenosine A2A receptor immune checkpoint in lung cancer patients

晚期非小细胞肺癌是无法治愈的，中位生存期为12个月。循序渐进的进步 在过去的20年里，中位生存期只有9个月。一个主要的进步是 驱动器突变的发现和针对这些的药物已经非常成功，尽管只是一个很小的 符合条件的患者比例。最近发现，免疫疗法在临床上对 NSCLC，随着Medium OS的显著改进，其影响似乎非常显著，并且许多 反应保持耐用。这一重大进展是通过破坏单一的免疫调节途径来实现的。 (PD1检查点)。继续改进这种方式的前景是巨大的，因为肿瘤 以无数种不同的方式逃避免疫排斥。在这里，我们第一次提议将另一个目标 在肿瘤内产生免疫抑制的免疫检查点蛋白，腺苷A2a受体。这 人肺癌TIL上蛋白表达频繁，肿瘤微环境高 其配体腺苷的浓度。我们将使用腺苷A2a受体拮抗剂来预防T细胞 通过这一途径抑制。单剂抗PD1耐受性良好并且在非小细胞肺癌中产生15%的RR， 因此，我们将以此为平台，添加A2AR拮抗剂PBF-509。安全和 初步临床疗效将在第一阶段和第二阶段进行评估(免疫疗法--天真，和 免疫治疗耐药组)Ib期临床试验。 免疫治疗无效者目前尚不清楚。我们将在治疗前和治疗中对 患者，这将使我们能够表征临床应答者的生产性免疫反应，以及 临床无应答者中耐药机制的本质。 肿瘤辅助的免疫抑制机制，以及这些机制中哪些是可操作的异质性 在个别患者中，临床反应预测试验是必要的，但目前还不存在 免疫疗法。因此，我们还建议检测多种免疫相关基因的表达 作为临床反应预测因子的初步表现的基因。

Advanced non-small cell lung cancer is incurable with a median survival of 12 mo. Incremental advances have been made over the past 20 years when the median survival was only 9 months. A major advance was the discovery of driver mutations and agents targeting these have been highly successful, however a small percentage of patients qualify. Recently it was found that immunotherapy produces clinical responses in NSCLC, and the impact appears dramatic with significant improvements of median OS, and many of the responses remaining durable. This major advance came by disrupting a single immunomodulatory pathway (PD1 checkpoint). The prospects for continuing to improve this modality are great given the fact that tumors evade immune rejection in a myriad of different ways. Here we propose for the first time to target another immune checkpoint protein that produces immunosuppression within tumors, the adenosine A2A receptor. This protein is frequently expressed on human lung cancer TILs, and the tumor microenvironment has high concentrations of its ligand, adenosine. We will utilize an adenosine A2A receptor antagonist to prevent T cell inhibition through this pathway. Single agent anti-PD1 is well tolerated and produces a RR of 15% in NSCLC, therefore we will use this as the platform onto which we will add PBF-509, an A2AR antagonist. Safety and preliminary clinical efficacy will be assessed in phase I and two arm (immunotherapy-naïve, and immunotherapy resistant groups) phase Ib clinical trials.The resistance mechanisms operational in immunotherapy non-responders are currently unknown. We will perform pre- and on-treatment biopsies of the patients which will allow us to characterize the productive immune response in the clinical responders, and the nature of the resistance mechanisms in the clinical non-responders.Given the multitude of potential immunoinhibitory mechanisms co-opted by tumors, and the heterogeneity as to which of these are operational in individual patients, clinical response predictive tests are neceassary but do not currently exist for immunotherapeutics. Therefore we also propose to examine the expression of a variety of immune-related genes for preliminary performance as clinical response predictors.