eRapa for bladder cancer prevention

膀胱肿瘤起源于移行上皮，很少穿透膀胱逼尿肌。 因此，使用经尿道器械在一定时间内切除肿瘤通常是可能的。 不需要完全切除膀胱不幸的是，基因组的不稳定性在整个过渡时期都很猖獗。 大多数患者的上皮细胞，尽管肿瘤完全切除，但肿瘤复发是常见的。因此，患者 需要终身内窥镜监测、多次活检和重复膀胱内治疗。mTOR抑制 在临床前模型中治疗和预防膀胱癌（BC）， 肿瘤的虽然这一教条是正确的，但它提供了这种疗法在BC中的潜在活动的不完整的画面。 我们的初步数据显示，低剂量雷帕霉素在体内具有良好的药代动力学和药效学活性。 膀胱组织我们还表明，一种新的雷帕霉素胶囊制剂（eRapa）调节免疫反应， 这些效果有利于提高抗BC免疫力和提高对BCG的应答， 高级别非肌肉浸润性膀胱癌（BC）的标准护理免疫疗法。我们提出 研究eRapa用于新诊断的非肌肉浸润性肿瘤患者的二级癌症预防 膀胱癌目的1进行一项长期（1年）的II期双盲随机对照试验 eRapa与安慰剂的预防作用。结果指标包括疗效、耐受性和对认知的影响 和身体功能。通过标准治疗监测来评估疗效，以捕获复发 并估计无复发生存率。耐受性通过经验证的BC特异性症状进行测量 评估和全球生活质量问卷。认知和身体功能评估与 通过执行/存储功能测试和物理性能测试进行确认。目的2检验假设， 通过检查eRapa对循环免疫的影响，eRapa改善了BC患者的免疫功能 细胞，包括记忆T细胞分化和肿瘤特异性免疫。对于同时接受 在膀胱内注射BCG之后，测试eRapa增强BCG特异性免疫的能力。如果成功，该项目将 促进BC患者新的二级预防药物的III期注册试验。此外，这项工作 为老年BC患者的免疫事件提供了基础性见解，这些事件有助于发展其他 癌症免疫疗法

Urinary bladder tumors arise from the transitional epithelium and rarely penetrate the bladder’s detrusor muscle. Thus, complete tumor resection is frequently possible using a transurethral instrument to remove the tumor at its root without total bladder removal. Unfortunately, genomic instability is rampant throughout the transitional epithelium in most patients and tumor relapse is common despite complete tumor removal. As a result, patients require lifelong endoscopic monitoring, multiple biopsies, and repeated intravesical therapies. mTOR inhibition treats and prevents bladder cancer (BC) in preclinical models and is thought to work by directly targeting bladder tumors. While this dogma is true, it provides an incomplete picture of the potential activity of this therapy in BC. Our preliminary data shows favorable pharmacokinetic and pharmacodynamic activity of low dose rapamycin in bladder tissues. We also show that a novel encapsulated formulation of rapamycin (eRapa) modulates immune responses and these effects favor improved anti-BC immunity and improved responses towards BCG, which is standard-of-care immune therapy for high-grade non-muscle invasive bladder cancer (BC). We propose investigating eRapa for secondary cancer prevention in patients with newly diagnosed non-muscle invasive bladder cancer. Aim 1 conducts a phase II double-blind randomized controlled trial of long-term (one year) prevention with eRapa versus placebo. Outcome measures include efficacy, tolerability, and effects on cognition and physical function. Efficacy is assessed through standard-of-care surveillance monitoring to capture relapses and to estimate recurrence-free survival. Tolerability is measured with validated BC-specific symptom assessments and global quality of life questionnaires. Cognition and physical function are assessed with validated executive/memory function testing and by physical performance testing. Aim 2 test the hypothesis that eRapa improves immune function in patients with BC by examining the effects of eRapa on circulating immune cells, including memory T cell differentiation, and tumor-specific immunity. For patients concurrently receiving intravesical BCG, the ability of eRapa to boost BCG-specific immunity is tested. If successful, this project will facilitate a phase III registration trial for a new secondary prevention agent for BC patients. In addition, this work provides foundational insights into immune events in elderly BC patients that are useful to developing other cancer immunotherapies.