Characterizing the immune infiltrate in muscle-invasive urothelial carcinoma

肌层浸润性尿路上皮癌免疫浸润的特征

• 批准号: 10738992
• 负责人: Katharine A. Collier
• 金额: $ 27.36万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-04 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738992
• 关键词: Achievement; Address; Adjuvant Chemotherapy; Affect; Aftercare; Award; Biological Assay; Bladder; Bladder Neoplasm; CD8-Positive T-Lymphocytes; CD8B1 gene; Chemical Engineering; Cisplatin; Clinical; Clinical Trials; Clinical Trials Design; Complement; Comprehensive Cancer Center; Cystectomy; Data; Data Analyses; Disease; Doctor of Philosophy; Ensure; Environment; Excision; FOXP3 gene; Future; Gene Expression Profile; Genes; Goals; Grant; Immune; Immune checkpoint inhibitor; In complete remission; Individual; Institution; Investigation; Investments; Knowledge; Leadership; Malignant Neoplasms; Measures; Medical Oncology; Mentors; Mentorship; Methods; Modernization; Molecular Analysis; Muscle; Neoadjuvant Therapy; Ohio; Outcome; Pathologic; Patient Selection; Patient-Focused Outcomes; Patients; Performance; Perioperative; Phase II Clinical Trials; Physicians; Preclinical Testing; Proteins; Proteomics; Radical Cystectomy; Regimen; Regulatory T-Lymphocyte; Research; Residual Neoplasm; Resources; Sampling; Scientist; Specimen; Stromal Cells; Systemic Therapy; T cell infiltration; Techniques; Time; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Training; Transitional Cell Carcinoma; Treatment Protocols; Tumor-infiltrating immune cells; Universities; Urethra; Urogenital Cancer; Writing; biomarker development; biomarker driven; biomarker performance; biomarker validation; career development; chemotherapy; clinical training; cohort; design; differential expression; experience; gemcitabine; high dimensionality; immune cell infiltrate; improved; improved outcome; multiple omics; novel; overtreatment; phase II trial; preclinical study; predictive marker; prevent; prospective; protein expression; rational design; research and development; responders and non-responders; response; response biomarker; skills; standard of care; therapy resistant; transcriptomics; translational physician; translational scientist; treatment response; treatment stratification; tumor; tumor immunology; tumor microenvironment

Project Summary Urothelial carcinoma is a common, aggressive, morbid, and understudied disease. Many patients are not cured with the current standard of care for localized muscle-invasive urothelial carcinoma, which is neoadjuvant combination cisplatin-based chemotherapy followed by radical cystectomy. But overall survival is significantly longer in patients who obtain a pathologic complete response to neoadjuvant chemotherapy, suggesting that intensification of systemic therapy will improve survival. It is critical that we develop reliable predictive biomarkers that can select patients that will or will not have a complete pathologic response to receive, respectively, either chemotherapy or an intensified peri-operative regimen. Preliminary evidence in urothelial carcinoma and other cancers suggests that infiltrating immune cells play a role in treatment response, but this has not been rigorously studied in muscle-invasive urothelial carcinoma. In this study, we will interrogate pre- and post-treatment samples from a completed, pivotal phase II clinical trial, harnessing our expertise in spatial transcriptomics and proteomics to interrogate differential gene and protein expression in tumor, immune, and stromal cells in annotated tissue specimens before and after neoadjuvant chemotherapy with or without a checkpoint inhibitor. Specifically, we will evaluate baseline CD8:FOXP3 ratio and responses to therapy (Aim 1), determine the effect of neoadjuvant therapy on CD8:FOXP3 ratio (Aim 2), and leverage the full capacity of spatial transcriptomic/proteomic assays to develop and evaluate the performance of novel predictive biomarkers of response to neoadjuvant therapy (Aim 3). This study will result in predictive biomarkers while concurrently profiling the immune infiltrate composition and how it is influenced by treatment. The ultimate goal is to design rational combination or sequential peri-operative regimens for biomarker-driven clinical trials to improve patient survival and cure rates. The project will provide the candidate, Katharine Collier, MD, MSc, MSE, MS, with training in rigorous quantitative methods, cutting-edge spatial molecular analyses, and high-dimensional biomarker development. The proposal capitalizes on Dr. Collier’s quantitative background in Chemical Engineering, clinical training in Medical Oncology, and formal training in clinical trial design, while providing an opportunity to gain additional skills and knowledge in multi-omics techniques and data analyses, preclinical studies, leadership, presentations, and grant writing. Dr. Collier is committed long-term to improving outcomes for patients with genitourinary cancers as a translational physician-scientist. Dr. Collier will be supported by an experienced mentorship team (Amir Mortazavi, MD, Zihai Li, MD, PhD, Daniel Stover, MD, Steven Clinton, MD, PhD), skilled collaborators, the rich academic environment of the Ohio State University Comprehensive Cancer Center, and an invested institution committed to providing protected time and resources for career development and research. This award will ensure Dr. Collier’s successful transition to independence as a physician-scientist and translational researcher improving outcomes for patients with genitourinary cancers.

项目概要 尿路上皮癌是一种常见、侵袭性、病态且尚未得到充分研究的疾病。 目前局部肌肉浸润性尿路上皮癌的护理标准是新辅助治疗 以顺铂为基础的联合化疗，然后进行根治性膀胱切除术，但总生存率显着提高。 对新辅助化疗获得病理完全缓解的患者的时间更长，这表明 强化全身治疗将提高生存率，因此开发可靠的预测生物标志物至关重要。 可以分别选择将或不会有完全病理反应的患者接受 尿路上皮癌和其他疾病的化疗或强化围手术期治疗方案的初步证据。 癌症表明浸润性免疫细胞在治疗反应中发挥作用，但这尚未得到严格证实 在这项研究中，我们将探讨治疗前和治疗后。 来自已完成的关键 II 期临床试验的样本，利用我们在空间转录组学方面的专业知识和 蛋白质组学研究肿瘤、免疫和基质细胞中的差异基因和蛋白质表达 在使用或不使用检查点抑制剂的新辅助化疗之前和之后注释的组织标本。 具体来说，我们将评估基线 CD8:FOXP3 比率和对治疗的反应（目标 1），确定效果 新辅助治疗对 CD8:FOXP3 比率的影响（目标 2），并充分利用空间容量 转录组/蛋白质组检测，用于开发和评估新型预测生物标志物的性能 对新辅助治疗的反应（目标 3）同时产生预测性生物标志物。 分析免疫浸润成分及其如何受到治疗的影响最终目标是设计。 用于生物标志物驱动的临床试验的合理组合或序贯围手术期治疗方案，以改善患者的病情 该项目将为候选人 Katharine Collier（医学博士、理学硕士、MSE、MS）提供生存率和治愈率。 严格的定量方法、尖端空间分子分析和高维方法的培训 该提案利用了 Collier 博士在化学领域的定量背景。 工程、肿瘤内科临床培训以及临床试验设计的正式培训，同时提供 有机会获得多组学技术和数据分析、临床前的额外技能和知识 科利尔博士长期致力于研究、领导力、演讲和资助写作。 作为转化医师科学家，科利尔博士将得到泌尿生殖系统癌症患者的支持。 经验丰富的导师团队（Amir Mortazavi，医学博士，李子海，医学博士，哲学博士，丹尼尔·斯托弗，医学博士，史蒂文·克林顿，医学博士， 博士）、熟练的合作者、俄亥俄州立大学综合癌症中心丰富的学术环境 中心，以及致力于为职业发展提供受保护的时间和资源的投资机构 该奖项将确保科利尔博士成功过渡为一名医师科学家。 和转化研究人员改善泌尿生殖系统癌症患者的治疗结果。