Development of personalized surgical algorithms for muscle-invasive bladder cancer patients

为肌层浸润性膀胱癌患者开发个性化手术流程

• 批准号: 9503703
• 负责人: Philip Abbosh
• 金额: $ 23.88万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-09 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9503703
• 关键词: Aftercare; Algorithms; Biological; Biological Assay; Biological Markers; Biopsy; Bladder; Bladder Neoplasm; Body Fluids; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Cisplatin; Clinic; Clinical Trials; Computational algorithm; Consult; Cost Savings; Cystectomy; Cytotoxic T-Lymphocytes; DNA; Data; Detection; Development; Disease; Disease Marker; Endoscopic Biopsy; Enrollment; Excision; Fox Chase Cancer Center; Frameshift Mutation; Future; Genes; Goals; Immune; Immune system; Immunotherapy; In complete remission; Left; Life; Literature; Malignant neoplasm of urinary bladder; Measures; Mediating; Methods; Missense Mutation; Modality; Molecular; Muscle; Mutation; Neoadjuvant Therapy; Operative Surgical Procedures; Pathologic; Patients; Peptides; Peripheral; Population; Procedures; Radical Cystectomy; Receptor Cell; Residual Tumors; Residual state; Role; Sampling; Somatic Mutation; Source; Technology; Testing; Transurethral Resection; Tumor-Infiltrating Lymphocytes; United States; Urine; Urologic Oncology; Variant; base; biomarker-driven; cancer surgery; cell free DNA; chemotherapy; cohort; cytotoxic; density; design; exome; exome sequencing; hospital readmission; interest; method development; mutant; neoantigens; neoplastic cell; next generation sequencing; novel; prospective; receptor; response; screening; single molecule; standard of care; survival outcome; targeted exome sequencing; transcriptome sequencing; tumor; urinary

PROJECT SUMMARY Radical cystectomy is the cornerstone of treatment for patients with muscle-invasive bladder cancer and is among the most complicated oncologic procedures performed in the United States. Along with neoadjuvant chemotherapy, these two modalities comprise the current standard of care for the disease. Approximately 1/3 of patients who undergo radical cystectomy after neoadjuvant chemotherapy will have no residual disease left in the bladder. Retrospective literature supports the use of cystectomy deferral in patients who undergo endoscopic biopsy showing no residual disease. However, this algorithm is prone to a high false negative rate necessitating salvage cystectomy, delay of which may result in worse survival outcomes. The first aim of the proposal will explore the phenomenon of mutation clearance and persistence in urine-derived cell-free DNA as a marker for disease absence or persistence, respectively, after endoscopic resection and chemotherapy. In preliminary studies, combination of single molecule tags and next generation sequencing resulted in high sensitivity detection of somatic variants previously identified in tumor whole exomes in prechemotherapy urine samples. At least one variant persisted in postchemotherapy urine samples from two of two nonresponders, and no variants were detected in urine samples from two of two complete responders. This preliminary data shows that the assay is feasible, reliable, and merits further exploration. The assay will be used on banked samples collected on a previously completed trial (NCT01031420) and on samples from a prospective clinical trial opening now at Fox Chase Cancer Center. Localized bladder cancer demonstrates a relatively high rate of pathological complete chemoresponse, but the mechanism of chemosensitivity remains incompletely understood. Data described herein suggests that the immune infiltrate is driven by CD8+ cells and high neoantigen density. Neoantigens are the non-self peptides that result from somatic missense or frameshift mutations that can be recognized by the immune system. Aim 2 of the proposal seeks to clinch a role for the immune system in this context by identifying tumor-specific cytotoxic T-cells which recognize tumor neoantigens. Expressed neoantigens will be identified using whole exome sequencing and RNA-seq of tumors and available computational algorithms. These mutant peptides will then be synthesized and used to screen live patient-derived CD8+ cells for neoantigen- specific cytotoxic responses. Samples to be used in this study will be obtained from a prospective clinical trial opening now at Fox Chase Cancer Center. This hypothesis-driven molecular and cellular biological study can potentially identify a new and unexpected mechanism for chemoresponse mediated by the immune system. If successful, these aims will go hand-in-hand in the future to prospectively and retrospectively identify responders and provide a framework to manipulate the immune system to achieve chemoresponse with the long term goal of safe radical cystectomy avoidance.

项目摘要 根治性膀胱切除术是肌层浸润性膀胱癌患者治疗的基石 并且是在美国进行的最复杂的肿瘤手术之一。沿着 新辅助化疗，这两种方式构成了目前的标准护理的疾病。 在新辅助化疗后接受根治性膀胱癌的患者中，约有1/3的患者将不会出现复发。 残留在膀胱里的疾病。回顾性文献支持在患者中使用环磷酰胺延迟治疗 接受内窥镜活检显示无残留病变。但是，这种算法容易出现较高的错误 阴性率需要进行挽救性手术，延误可能导致生存结局更差。 该提案的第一个目标将探讨突变清除和持续存在的现象， 尿源性细胞游离DNA分别作为内镜检查后疾病不存在或持续存在的标志物 切除和化疗。在初步研究中，单分子标签和下一代标签的组合 测序导致先前在肿瘤整体中鉴定的体细胞变体的高灵敏度检测。 化疗前尿液样本中的外显子。化疗后尿液样本中至少有一种变异持续存在 两个无应答者中的两个，两个完整的尿液样本中没有检测到变异。 响应者。初步数据表明，该方法可行、可靠，值得进一步探索。 该检测试剂盒将用于先前完成的试验（NCT 01031420）和 来自福克斯蔡斯癌症中心正在进行的前瞻性临床试验的样本。 局限性膀胱癌表现出相对较高的病理完全化学反应率， 但化学敏感性的机制仍不完全清楚。本文描述的数据表明， 免疫浸润由CD 8+细胞和高新抗原密度驱动。新抗原是非自我的 由体细胞错义或移码突变产生的肽，可被免疫系统识别 系统该提案的目标2旨在通过识别免疫系统在这方面的作用， 识别肿瘤新抗原的肿瘤特异性细胞毒性T细胞。将鉴定表达的新抗原 使用肿瘤的全外显子组测序和RNA-seq以及可用的计算算法。这些 然后合成突变肽，并用于筛选活的患者来源的CD 8+细胞的新抗原- 特异性细胞毒性反应。本研究中使用的样本将从前瞻性临床试验中获得 现已在福克斯蔡斯癌症中心开业。这项假设驱动的分子和细胞生物学研究可以 潜在地确定了免疫系统介导的化学反应的新的和意想不到的机制。 如果成功，这些目标将在未来齐头并进，以前瞻性和回顾性地确定 反应者，并提供一个框架，以操纵免疫系统，以实现与化疗反应。 长期目标是安全避免根治性化疗。