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：
9462266
负责人：
SCOTT J. ANTONIA
金额：
$ 18.92万
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/9462266
关键词：
ADORA2A gene Adenosine Antigens Biopsy Cancer Patient Cell physiology Cleaved cell Clinical Clinical Trials Enrollment Extranodal 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 Non-Small-Cell Lung Carcinoma Normal tissue morphology Outcome PDCD1LG1 gene Pathway interactions Patients Performance Phase Physiological Proteins Randomized Receptor Signaling Resected Resistance Safety Signal Transduction Site Surface System T-Lymphocyte Tail Testing Therapeutic Time Tissues Warburg Effect actionable mutation arm clinical efficacy cytokine experience extracellular gene discovery immune checkpoint immune checkpoint blockade immunoregulation improved individual patient inhibitory surface receptor injured nano-string neoplastic cell novel phase I trial phase III trial predicting response predictive signature prevent 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.

晚期非小细胞肺癌无法治愈，中位生存期已延长至 12 个月。过去 20 年来，中位生存期仅为 9 个月，取得了重大进展。驱动突变和针对这些突变的药物的发现非常成功，但是很小最近发现免疫疗法在以下患者中产生了临床反应。 NSCLC，随着中位 OS 的显着改善，其影响似乎非常显着，而且许多这一重大进步来自于破坏单一的免疫调节途径。（PD1检查点）鉴于肿瘤的事实，继续改进这种方式的前景是巨大的。在这里，我们首次提出以多种不同的方式逃避免疫排斥。免疫检查点蛋白，在肿瘤内产生免疫抑制，即腺苷 A2A 受体。该蛋白在人肺癌TILs上频繁表达，肿瘤微环境具有高我们将利用腺苷 A2A 受体拮抗剂来阻止 T 细胞。通过该途径进行的单药抗 PD1 抑制具有良好的耐受性，并且在 NSCLC 中产生 15% 的 RR。因此，我们将以此为平台添加 A2AR 拮抗剂 PBF-509。初步临床疗效将在 I 期和两组（未接受免疫治疗，以及免疫治疗耐药组） Ib 期临床试验。耐药机制在目前尚不清楚免疫治疗无反应者，我们将对治疗前和治疗中进行活检。患者，这将使我们能够表征临床反应者的有效免疫反应，以及临床无反应者耐药机制的性质。考虑到多种潜在的肿瘤所选择的免疫抑制机制，以及其中哪些机制发挥作用的异质性对于个体患者，临床反应预测测试是必要的，但目前尚不存在因此我们还建议检查多种免疫相关的表达。作为临床反应预测因子的初步性能的基因。