Phase 1/2 Study of Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder - (ADAPT-BLADDER)

项目摘要：每年有超过81,000名新患者被诊断为尿路上皮癌 (UC)，17,000人将死于他们的疾病。大多数人患有非肌肉侵袭性疾病 (NMIBC)。尽管用活的、减毒的分枝杆菌菌株进行标准治疗 卡介苗(BCG)注入膀胱，三分之二的NMIBC患者会复发 卡介苗治疗后的肿瘤。虽然膀胱切除术是治愈的，但它与改变生活质量有关 影响，在许多情况下是不可行的，或者被拒绝。卡介苗复发NMIBC的非手术治疗选择 病人很少。在转移性UC中，观察到了低毒副作用的持久反应 针对程序性细胞死亡蛋白1(PD-1)的检查点抑制(CPI)疗法 死亡配体1(PD-L1)途径导致FDA批准了五种药物。审视新奇组合 在卡介苗复发的NMIBC中包括CPIs的方法是自然的下一步。在这项提案中，我们 计划定义安全性和临床活性，评估以下几种基因组的护理点诊断潜力 生物标记物平台，并对CPI治疗的新组合进行初步机制研究 在多臂、多阶段适应膀胱1b/2期临床试验中同时应用卡介苗和放射治疗， 长期目标是为未来改变做法的第三阶段试验的设计提供信息。 目的：1)论证免疫治疗联合方案的安全性和临床疗效 卡介苗复发的NMIBC患者；2)确定与以下相关的保守候选基因组特征 新免疫治疗方案对NMIBC复发患者的临床益处和/或治疗耐药性 BCG治疗后的肿瘤；3)证明肿瘤抗原特异性T细胞反应的存在和 NMIBC患者的这种反应与新的免疫治疗方案的临床结果相关 既往卡介苗治疗后肿瘤复发。 方法：我们将通过多中心阶段1 b/2适应对每个目标进行前瞻性评估。 170多例卡介苗复发NMIBC患者的膀胱试验。具体地说，我们将记录安全性 每种方案在第一阶段和第二阶段的临床疗效。我们将相关基线和治疗后 治疗具有临床益处的基因组生物标记物签名。最后，我们将审问一下 个性化的新抗原肽库，以扩大抗原特异性T细胞克隆。 我们假设免疫治疗联合方案将是安全有效的。此外，我们 预期识别可区分患者的护理点基因组生物标记物签名 最有可能受益的是；我们希望识别预测治疗的新基因表达特征 反应和耐药性；我们怀疑计划中的功能性肿瘤免疫学研究将 产生了启发性的发现。

Project Summary: Over 81,000 new individuals are diagnosed each year with urothelial carcinoma (UC) of the bladder and 17,000 will die from their disease. Most have non-muscle invasive disease (NMIBC) at diagnosis. Despite standard treatment with the live, attenuated mycobacterial strain Bacillus Calmette-Guerin (BCG) instilled into the bladder, two-thirds of NMIBC patients will develop relapsed tumors after BCG treatment. While curative, cystectomy is associated with life-altering quality of life impact and is not feasible, or is refused, in many. Nonsurgical curative options for BCG-relapsing NMIBC patients are lacking. In metastatic UC, durable responses with low toxicity rates have been observed with checkpoint inhibitor (CPI) therapies aimed at the programmed cell death protein 1 (PD-1) / programmed death-ligand 1 (PD-L1) pathway leading to the FDA approval of five agents. Examining novel combination approaches including CPIs in BCG-relapsing NMIBC represents a natural next step. In this proposal, we plan to define the safety and clinical activity, assess the point-of-care diagnostic potential of several genomic biomarker platforms, and perform initial mechanistic investigations of novel combinations of CPI therapy with both BCG and radiation in the multi-arm, multi-stage ADAPT-BLADDER phase 1b/2 clinical trial, with the long-term goal of informing the design of future practice-changing phase 3 trials. Objectives: 1) To demonstrate safety and clinical efficacy of immunotherapy combination regimens in patients with BCG-relapsing NMIBC; 2) To identify conserved candidate genomic signatures associated with clinical benefit and/or treatment resistance to novel immunotherapy regimens in NMIBC patients with recurrent tumors after prior BCG therapy; 3) To demonstrate the existence of tumor antigen-specific T-cell responses and correlate such responses with clinical outcomes to novel immunotherapy regimens in NMIBC patients with recurrent tumors after prior BCG therapy. Methods: We will assess each objective prospectively through the multi-center phase 1 b / 2 ADAPT- BLADDER trial in over 170 patients with BCG-relapsing NMIBC. Specifically, we will document the safety of each regimen in phase 1 and clinical efficacy in phase 2. We will correlate baseline and post- treatment genomic biomarker signatures with clinical benefit. Lastly, we will interrogate the ability of personalized neoantigen peptide libraries to expand antigen-specific T-cell clones. We hypothesize that immunotherapy combination regimens will be safe and effective. Moreover, we anticipate the identification of point-of-care genomic biomarker signatures that can distinguish patients most likely to benefit; we expect to identify novel gene expression signatures predictive of therapy response and resistance; and we suspect the planned functional tumor immunology investigations will yield illuminating discoveries.