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

项目概要/摘要 检查点阻断免疫疗法（ICB）可改善转移性乳腺癌患者亚组的总生存期 尿路上皮癌Atezolizumab是一种程序性死亡配体-1（PD-L1）靶向药物， 根据24%的缓解率和中位数，2017年不符合顺铂条件的尿路上皮癌患者 存活15.9个月。然而，只有少数患者有反应，有些人在治疗后会产生耐药性。 第一反应期。尽管无数的研究探索了免疫治疗的长期临床益处， 这些癌症的调节正在进行或正在开发中，这是新的治疗方法的机制原理。 在转移性尿路上皮癌中缺乏联合治疗。研究项目3（RP-3）旨在确定， 在一项前瞻性、随机、多中心研究的背景下， 抗PD-L1治疗可改善不适合接受顺铂化疗的患者的生存率。审判 基于PD-L1和VEGF靶向抗体的联合治疗将具有抗肿瘤作用的假设。 通过改变肿瘤微环境，部分通过消耗免疫抑制细胞类型， 骨髓源性抑制细胞（MDSC）。肿瘤微环境（T细胞受体[TCR]）的变化 克隆性、MDSC水平）和内在肿瘤因子（肿瘤突变负荷、新抗原负荷和克隆性、PD-L1 染色等）与ICB的临床获益相关，但最佳临床决策的统一模型是 缺乏我们提出了一个系统的方法，采用前瞻性临床试验，大规模的血液分析， ICB治疗患者的肿瘤样本具有不同的临床结局， 分子决定因素和治疗引起的微环境变化的特征。的 该提案的目的是1）评估肿瘤和血液免疫标志物以预测ICB反应; 2） 表征治疗时肿瘤微环境的适应性变化;以及3）识别 对ICB产生耐药性。RP-3的具体目的是比较atezolizumab + 贝伐珠单抗与atezolizumab单药相比，同时研究了 本背景（目标1）;检查肿瘤中治疗诱导的体细胞和微环境适应， 发现联合治疗的疾病特异性靶点（目标2）; 本试验患者和接受标准治疗ICB患者的耐药性（目标3）。这些目标 分析将开发更强大的免疫治疗反应生物标志物，确定合理的靶点， 有效的组合疗法，并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.