Intravesical Gene Therapy for BCG Refractory Bladder Cancer

卡介苗难治性膀胱癌膀胱内基因治疗

• 批准号: 8230256
• 负责人: WILLIAM Francis BENEDICT
• 金额: $ 20.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230256
• 关键词: Adenoviruses; Apoptosis; Apoptotic; Biological Markers; Biological Markers; Bystander Effect; Cell Death; Cells; Cleaved cell; Clinical; Cystectomy; Cytokeratin 18; Disease remission; Dose; Dose-Limiting; Effectiveness; Exclusion; Funding; Future; Gene Transfer; Goals; Human; In complete remission; Interferons; Lead; Malignant neoplasm of urinary bladder; Mass Spectrum Analysis; Measures; Mediating; Methods; Monitor; Necrosis; Outcome; Patients; Pharmacodynamics; Phase; Phase II Clinical Trials; Proteins; Recombinants; Recurrence; Refractory; Resistance; Schedule; Specimen; Stress; TNF-related apoptosis-inducing ligand; Tissues; Toxic effect; Urine; Urogenital Cancer; Urothelial Cell; Urothelium; adenoviral-mediated; base; cancer cell; cancer therapy; caspase-3; clinical efficacy; cost; disease natural history; effective therapy; extracellular; fast protein liquid chromatography; gene therapy; improved; intravesical; killings; neoplastic cell; novel therapeutics; phase 1 study; phase 2 study; phase 3 study; preclinical study; response; transgene expression; tumor

The overall goal of these studies is to improve the treatment of non-muscle invasive bladder cancer by identifying second line agents that are effective in the scenario of BCG resistance and hopefully for all nonmuscle invasive bladder cancer in future years. During the course of the last cycle of SPORE funding, we provided strong evidence for effective gene transfer and potential clinical efficacy when intravesical adenoviral-mediated interferona(IFNa) gene therapy was administered with Syn3 (Ad-IFNa/Syn3). Approximately 50% of the treated patients, all of which were BCG resistant, obtained a complete remission (CR). We also found that Ad-IFNa induces cancer cell death in human bladder cancer cells that are insensitive to the recombinant IFNa protein itself, and that cell death occurs via direct and indirect (bystander) mechanisms. Moreover, normal urothelial cells appear to be resistant to Ad-IFNa. In this renewal we plan to complete a Phase IB study of intravesical Ad-IFNa/Syn3 to optimize the schedule by determining whether therapy on Day 1 and an additional instillation on Day 4 will enhance gene transfer and result in higher and more sustained urine IFNa levels than were achieved with a single treatment In patients achieving a CR at 90 days we will repeat treatment on Day 1 and 4 to determine whether redosing with this schedule will provide for effective gene transfer. TRAIL, M30 and M65 levels will also be measured in the urine as possible markers of clinical efficacy and tumor cell death. Subsequently we plan to participate in and lead a multicenter Phase II trial based upon the results of Phase IB study. The isolation and identification of the soluble factor(s) responsible for the Ad-IFNa produced bystander cell death on cancer cells will also be a focus. In addition to its obvious value as a biomarker of Ad-IFN activity, the bystander factor(s) could itself have clinical utility. Various methods will be utilized in these studies, including size exclusion concentration, size-exclusion FPLC column subfractionation and mass spectroscopy.

这些研究的总体目标是改善非肌层浸润性膀胱癌的治疗， 确定在BCG耐药情况下有效的二线药物， 浸润性膀胱癌在未来几年。在上一轮SPORE融资期间，我们 为膀胱内注射时有效的基因转移和潜在的临床疗效提供了强有力的证据。 腺病毒介导的干扰素（IFN α）基因治疗与Syn 3一起施用（Ad-IFN α/Syn 3）。 大约50%的治疗患者，所有这些都是卡介苗耐药，获得了完全缓解 的双曲余切值。我们还发现Ad-IFNa诱导人膀胱癌细胞的癌细胞死亡， 对重组IFNa蛋白本身不敏感，并且细胞死亡通过直接和间接的 （旁观者）机制。此外，正常的尿路上皮细胞似乎对Ad-IFNa具有抗性。在这次更新中， 我们计划完成膀胱内Ad-IFNa/Syn 3的IB期研究，通过确定 第1天的治疗和第4天的额外滴注是否会增强基因转移并导致 与单次治疗相比， 如果在第90天达到CR，我们将在第1天和第4天重复治疗，以确定是否重新给药 时间表将提供有效的基因转移。TRAIL、M30和M65水平也将在 尿液作为临床疗效和肿瘤细胞死亡的可能标志物。随后，我们计划参加和 根据IB期研究的结果，领导一项多中心II期试验。 分泌Ad-IFN α的旁观者细胞可溶性因子的分离与鉴定 癌细胞的死亡也将是一个焦点。除了作为Ad-IFN活性的生物标志物的明显价值外， 旁观者因子本身可以具有临床效用。在这些研究中将使用各种方法， 包括尺寸排阻浓缩、尺寸排阻FPLC柱亚分级和质量 谱