RP-3: Elucidating Mechanisms of Sensitivity and Resistance to Checkpoint Blockade Therapy for Rational Multi-Drug Immunotherapy in Urothelial Cancers

项目摘要/摘要 检查点阻断免疫疗法(ICB)可提高部分转移性患者的总存活率 尿路上皮癌。阿替唑单抗是一种程序性死亡配体-1(PD-L1)靶向剂，于#年获得FDA批准 2017年顺铂不合格的尿路上皮癌患者的应答率为24%，中位数为 存活期15.9个月。然而，只有一小部分患者有反应，一些人在一次治疗后出现耐药性 最初的响应期。尽管有无数研究探索免疫的长期临床益处 这些癌症的调节正在进行中或正在开发中，这是新疗法的机制基础 转移性尿路上皮癌的联合用药尚不多见。研究项目3(RP-3)试图确定，在 一项前瞻性、随机、多中心研究的背景下，是否将抗血管生成治疗添加到 抗PD-L1治疗可提高不符合顺铂化疗条件的患者的存活率。那次审判 是基于这样一个假设，即与PD-L1和血管内皮生长因子靶向抗体联合治疗将具有抗肿瘤作用 通过改变肿瘤微环境，部分通过耗尽免疫抑制细胞类型，如 髓系来源的抑制细胞(MDSCs)。肿瘤微环境的变化(T细胞受体[TCR]) 克隆性、MDSC水平)和内在肿瘤因素(肿瘤突变负荷、新抗原负荷和克隆性、PD-L1 染色等)与ICB的临床收益相关，但最优临床决策的统一模型是 缺乏。我们提出了一种系统的方法，采用前瞻性临床试验，大规模的血液分析 和来自ICB治疗患者的肿瘤样本具有不同的临床结果，大规模解剖 分子决定因素，以及治疗过程中发生的微环境变化的特征。这个 这项建议的目标是：1)评估肿瘤和血液免疫标记物，以预测ICB反应；2) 表征肿瘤微环境在治疗过程中的适应性变化；以及3)确定 对ICB的获得性耐药。RP-3的具体目的是比较阿替唑单抗和阿替唑单抗的疗效 贝伐单抗与阿替唑单抗比较，同时研究反应和耐药性的生物标记物 这一背景(目标1)；检查治疗诱导的肿瘤的躯体和微环境适应 发现联合治疗的疾病特异性靶点(目标2)；并剖析获得性 参与试验的患者和接受标准ICB治疗的患者的耐药性(目标3)。这些项目的目标是 分析将是开发更强大的免疫治疗反应的生物标志物，确定合理的靶点 有效的联合治疗，了解尿路上皮癌患者对ICB的获得性耐药性。

Project Summary/Abstract Checkpoint blockade immunotherapy (ICB) improves overall survival in a subset of patients with metastatic urothelial cancer. Atezolizumab, a programmed death ligand-1 (PD-L1) targeting agent, was FDA-approved in 2017 for cisplatin-ineligible patients with urothelial cancer based on a response rate of 24% and a median survival of 15.9 months. However, only a minority of patients responds, and some develop resistance after an initial period of response. Though myriad studies exploring the long-term clinical benefits of immune modulation in these cancers are ongoing or under development, a mechanistic rationale for novel therapeutic combinations in metastatic urothelial cancer is lacking. Research Project 3 (RP-3) seeks to determine, within the context of a prospective, randomized, multicenter study, whether the addition of antiangiogenic therapy to anti-PD-L1 therapy improves survival in patients who are ineligible for cisplatin-based chemotherapy. That trial is based on the hypothesis that co-treatment with PD-L1 and VEGF-targeting antibodies will have antitumor effects by altering the tumor microenvironment, in part by depleting immunosuppressive cell types such as myeloid-derived suppressor cells (MDSCs). Changes in the tumor microenvironment (T-cell receptor [TCR] clonality, MDSC levels) and intrinsic tumor factors (tumor mutation load, neoantigen load and clonality, PD-L1 staining, etc.) correlate with clinical benefit from ICB, but a unified model for optimal clinical decision making is lacking. We propose a systematic approach employing a prospective clinical trial, large-scale analysis of blood and tumor samples from ICB-treated patients with diverse clinical outcomes, large-scale dissection of molecular determinants, and characterization of microenvironmental changes that occur from treatment. The objectives of this proposal are to 1) assess tumor and blood immune markers to predict ICB response; 2) characterize adaptive changes in the tumor microenvironment on treatment; and 3) identify mechanisms of acquired resistance to ICB. The Specific Aims of RP-3 are to compare the efficacy of atezolizumab plus bevacizumab as compared to atezolizumab alone, while studying biomarkers of response and resistance in this context (Aim 1); examine treatment-induced somatic and microenvironmental adaptations in the tumor to discover disease-specific targets for combination therapy (Aim 2); and dissect mechanisms of acquired resistance in patients on this trial and patients receiving standard-of-care ICB (Aim 3). The goal of these analyses will be to develop more robust biomarkers of immunotherapy response, identify rational targets for effective combinatorial therapies, and understand acquired resistance to ICB in patients with urothelial cancer.