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，完全切除肿瘤通常是可能的，使用经尿路器械切除肿瘤。 其根部不需全膀胱切除。不幸的是，基因组的不稳定性在整个过渡期都很猖獗。 大多数患者的上皮细胞和肿瘤复发是常见的，尽管完全切除了肿瘤。因此，患者 需要终生内窥镜监测、多次活检和重复的膀胱内治疗。MTOR抑制 在临床前模型中治疗和预防膀胱癌(BC)，并被认为通过直接靶向膀胱发挥作用 肿瘤。虽然这一信条是正确的，但它提供了这种疗法在不列颠哥伦比亚省潜在活动的不完整图景。 我们的初步数据显示低剂量雷帕霉素在人体内具有良好的药代动力学和药效学活性。 膀胱组织。我们还发现了一种新的雷帕霉素胶囊制剂(ERapa)可以调节免疫。 反应和这些效应有利于提高抗BC免疫和对卡介苗的反应，即 高级别非肌肉浸润性膀胱癌(BC)的标准免疫治疗。我们建议 ERAPA在新诊断的非肌肉侵袭性肿瘤二级预防中的应用研究 膀胱癌。目的1进行长期(一年)的II期双盲随机对照试验 与安慰剂相比，使用eRapa预防。结果测量包括疗效、耐受性和对认知的影响。 和身体机能。通过标准护理监测来评估疗效，以捕获复发 并估计无复发存活率。耐受性是通过经过验证的BC特定症状来衡量的 评估和全球生活质量调查问卷。认知和身体功能用 经过验证的执行/内存功能测试和物理性能测试。目标2检验假设 ERapa通过检测eRapa对循环免疫的影响改善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。对于同时接受治疗的患者 在膀胱内注射卡介苗，检测eRapa增强卡介苗特异性免疫的能力。如果成功，这个项目将 促进一种用于BC患者的新二级预防药剂的第三阶段注册试验。此外，这项工作 提供对老年BC患者免疫事件的基础性见解，有助于开发其他 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.