eRapa for bladder cancer prevention

eRapa 用于预防膀胱癌

• 批准号: 10434081
• 负责人: Robert Scott Svatek
• 金额: $ 44.84万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434081
• 关键词: Address; Adverse effects; Affect; Age; Antigens; Attention; Autologous; BCG Live; Biopsy; Bladder; Bladder Neoplasm; Bladder Tissue; Cancer Patient; Cells; Cessation of life; Cognition; Data; Development; Diagnosis; Dose; Double-Blind Method; Elderly; Encapsulated; Event; Excision; Exhibits; Formulation; Foundations; Genomic Instability; Growth Factor; Human; Human Resources; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Surveillance; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Medical; Memory; Monitor; Newly Diagnosed; Nutrient; Organ Transplantation; Organism; Outcome; Outcome Measure; Pathologic; Patient Outcomes Assessments; Patients; Phase; Phase II Clinical Trials; Physical Function; Physical Performance; Placebo Control; Placebos; Plant Roots; Population; Pre-Clinical Model; Prevention; Procedures; Production; Property; Public Health; Publishing; Quality of life; Questionnaires; Randomized; Randomized Controlled Trials; Recurrence; Recurrent disease; Relapse; Reporting; Risk; Safety; Secondary Cancer Prevention; Secondary Prevention; Sirolimus; Symptoms; T cell differentiation; T memory cell; T-Lymphocyte; Testing; Training; Transitional Epithelium; Tumor Immunity; Tumor-Derived; Work; age related; antitumor effect; base; bladder cancer prevention; cancer immunotherapy; cancer prevention; cancer risk; chemotherapeutic agent; cognitive function; cost estimate; cytokine; detrusor muscle; early phase clinical trial; exhaust; exhaustion; high risk; immune function; improved; insight; instrument; intravesical; mTOR Inhibitor; mTOR inhibition; men; neoplastic cell; non-muscle invasive bladder cancer; novel; novel strategies; older patient; performance tests; pharmacokinetics and pharmacodynamics; phenotypic biomarker; prevent; primary outcome; relapse patients; response; standard care; standard of care; tumor

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.

膀胱肿瘤起源于移行上皮，很少穿透膀胱逼尿肌。 因此，通常可以使用经尿道器械切除肿瘤，以完全切除肿瘤。 其根部无需完全切除膀胱。不幸的是，基因组不稳定在整个过渡时期普遍存在。 大多数患者的上皮细胞均存在，尽管肿瘤已完全切除，但肿瘤复发仍很常见。结果，患者 需要终生内窥镜监测、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)，并被认为通过直接靶向膀胱发挥作用 肿瘤。虽然这个教条是正确的，但它并不能完整地描述这种疗法在 BC 的潜在活性。 我们的初步数据显示低剂量雷帕霉素在治疗中具有良好的药代动力学和药效活性 膀胱组织。我们还表明，一种新型雷帕霉素胶囊制剂（eRapa）可调节免疫 反应和这些作用有利于提高抗 BC 免疫力和改善对 BCG 的反应，这是 高级别非肌层浸润性膀胱癌 (BC) 的标准护理免疫治疗。我们建议 研究 eRapa 对新诊断的非肌肉侵袭性患者的二级癌症预防 膀胱癌。 Aim 1进行长期（一年）II期双盲随机对照试验 使用 eRapa 与安慰剂进行预防。结果测量包括功效、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情况 并估计无复发生存率。耐受性通过经过验证的 BC 特异性症状来衡量 评估和全球生活质量调查问卷。认知和身体功能的评估 经过验证的执行/记忆功能测试和物理性能测试。目标 2 检验假设 eRapa 通过检查 eRapa 对循环免疫的影响来改善 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 膀胱内注射 BCG，测试了 eRapa 增强 BCG 特异性免疫力的能力。如果成功，该项目将 促进针对 BC 患者的新型二级预防药物的 III 期注册试验。另外，这部作品 为老年 BC 患者的免疫事件提供基础见解，这有助于发展其他疾病 癌症免疫疗法。