Targeting the adenosine A2A receptor immune checkpoint in lung cancer patients

靶向肺癌患者的腺苷 A2A 受体免疫检查点

基本信息

批准号：
9175600
负责人：
SCOTT J. ANTONIA
金额：
$ 32.17万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-26 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9175600
关键词：
ADORA2A gene Adenosine Antigens Biopsy Cancer Patient Cell physiology Cell surface Cleaved cell Clinical Clinical Trials Enrollment Fibroblasts Gene Expression Profile Genes Growth Histology Human Hypoxia Immune Immune response Immunologic Surveillance Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Infiltration Inflammatory Inflammatory Response Ligands Long-Term Survivors Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Modality Nature Nodal Non-Small-Cell Lung Carcinoma Normal tissue morphology Outcome PDCD1LG1 gene Pathway interactions Patients Performance Phase Physiological Proteins Qualifying Randomized Receptor Signaling Resected Resistance Safety Signal Transduction Site Staging Surface System T-Lymphocyte Tail Testing Therapeutic Time Tissues Warburg Effect actionable mutation arm clinical efficacy cytokine experience extracellular gene discovery improved individual patient injured nano-string neoplastic cell novel phase I trial phase III trial predicting response prevent receptor resistance mechanism response targeted agent treatment response tumor tumor heterogeneity tumor microenvironment

项目摘要

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.

晚期非小细胞肺癌的中位存活率为12 mo。增量进步在过去的20年中，中位生存只有9个月。一个重大进步是发现驾驶员突变和针对性的代理一直非常成功，但是很小患者的百分比有资格。最近发现，免疫疗法在 NSCLC，影响似乎具有显着改善的OS，许多影响似乎很大，许多响应保持耐用。这一重大进展是破坏了单个免疫调节途径（PD1检查点）。鉴于肿瘤的事实，继续改善这种方式的前景很棒以多种不同的方式逃避免疫拒绝。在这里，我们首次提出针对另一个免疫检查点蛋白，可在肿瘤内产生免疫抑制，即腺苷A2A接收器。这蛋白质经常在人肺癌泰尔（TIL）上表达，肿瘤微环境高其配体的浓度，腺苷。我们将利用腺苷A2A受体拮抗剂来防止T细胞通过这一途径抑制。单药抗PD1的耐受性很好，在NSCLC中产生15％的RR，因此，我们将使用它作为A2AR拮抗剂PBF-509的平台。安全和初步的临床效率将在I期和两个ARM（免疫疗法，没有）和抗免疫疗法组）IB期临床试验。抗药性机制在免疫疗法目前未知。我们将执行前后的研究前和治疗活检这将使我们能够表征临床反应者中产品免疫响应的患者，并临床非反应器中电阻机制的性质。由肿瘤采用的免疫抑制机制，以及其中哪些是运行的异质性在个别患者中，需要进行临床反应预测测试，但目前不存在免疫治疗药。因此，我们还建议检查各种免疫相关的表达初步性能作为临床反应预测因子的基因。