In vivo Assessment of Chemotherapy Remodeling of the Bladder Cancer Immune Microenvironment

膀胱癌免疫微环境化疗重塑的体内评估

基本信息

批准号：
10819107
负责人：
WILLIAM Y. KIM
金额：
$ 7.5万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10819107
关键词：
Adjuvant Chemotherapy Adriamycin PFS Antineoplastic Agents Bladder Neoplasm Cancer Biology Cessation of life Cisplatin Clinical Clonality Data Development Plans Disease Dose Educational process of instructing Equipoise FGFR3 gene Fellowship Fibroblasts Gene Expression Profile Generations Genetically Engineered Mouse Immune Immunotherapy Institution Laboratories Learning Level of Evidence Malignant Neoplasms Malignant neoplasm of urinary bladder Methotrexate Modality Modeling Muscle Neoadjuvant Therapy Operative Surgical Procedures Oral Patients Postdoctoral Fellow Pre-Clinical Model Process Professional Competence Regimen Research Research Project Grants Resistance Resolution Schedule Survival Rate T-Cell Receptor TGFB1 gene Therapeutic Training Programs United States Urothelium Validation Vincristine Work Writing anti-PD1 therapy anticancer research bladder transitional cell carcinoma cancer therapy career career development checkpoint inhibition chemotherapy cost drug development gemcitabine genetic signature genomic platform immune cell infiltrate improved in vivo men molecular subtypes muscle invasive bladder cancer novel peripheral blood permissiveness research and development response responsible research conduct single cell analysis single-cell RNA sequencing skills tumor tumor microenvironment tumor-immune system interactions

项目摘要

ABSTRACT In the United States urothelial carcinoma (UC) of the bladder is the 4th most frequent malignancy in men, and there will be an estimated 80,500 new cases and 17,500 deaths in 2019. Despite being the most costly cancer to treat over a patient’s lifetime, bladder cancer remains underfunded. High-grade (HG), muscle invasive bladder tumors account for the majority of these deaths as patients with metastatic disease have a 5-year survival rate of only 15%. In patients with clinically localized, muscle-invasive bladder cancer (MIBC), there is a high level of evidence to support the use of cisplatin-based neoadjuvant chemotherapy. Two widely accepted regimens with therapeutic equipoise are MVAC (methotrexate, vincristine, adriamycin, and cisplatin) and GC (gemcitabine, cisplatin). While trials in advanced bladder cancer therapy are evaluating the combination of chemo and immunotherapy, to rationally combine these two therapeutic modalities it is imperative to precisely understand how MVAC and GC impact the immune microenvironment and how to best sequence chemo and immunotherapy. Preliminary studies from the Kim and Vincent laboratories show that MVAC and GC have differing effects on the immune microenvironment in bladder cancers of the luminal molecular subtype. Tumors of the luminal subtype, which have low baseline immune infiltration, have a significant increase in immune gene signature expression and clonality of tumor-specific T cell receptor (TCR) clonotypes in the peripheral blood after MVAC but not GC treatment. In contrast, GC significantly increases gene signatures known to promote resistance to IC therapy in bladder cancer (Fibroblast TGFB Response Signature [FTBRS] and EMT-Stroma). These results suggest that in luminal bladder cancers, MVAC promotes an inflamed tumor immune microenvironment permissive to IC inhibition, while GC increases stromal activation, known to correlate with IC resistance. The diversity supplement candidate will leverage a novel, faithful, genetically engineered murine (GEM) model of bladder cancer of the luminal molecular subtype as well as single cell RNA sequencing (scRNAseq) to examine the effect of MVAC and GC at high resolution on the tumor microenvironment. Moreover, he will determine the best sequence of administration of chemo and immunotherapy in these faithful models. The comprehensive career development plan will teach presentation, writing, and networking skills to leverage for the next steps in his career. Successful completion of this scientific work and training program will poise the candidate for a selective, academic post-doctoral fellowship and an effective academic career. 1

抽象的在美国，膀胱的尿路上皮癌（UC）是男性最常见的恶性肿瘤， 2019年估计有80,500例新病例和17,500例死亡。为了治疗患者的一生，膀胱癌仍然不足。高级（HG），肌肉侵入性由于转移性疾病患者有5年存活率仅为15％。在患有临床局部肌肉侵入性膀胱癌（MIBC）的患者中，有支持基于顺铂的新辅助化疗的高度证据。两个广泛具有治疗能力的接受方案是MVAC（甲氨蝶呤，长春新碱，阿霉素和顺铂）和GC（吉西他滨，顺铂）。虽然晚期膀胱癌疗法的试验正在评估化学疗法和免疫疗法的结合，合理地结合了这两种治疗方式必须精确理解MVAC和GC如何影响免疫微环境以及如何最佳序列化学疗法和免疫疗法。 Kim和Vincent实验室的初步研究表明，MVAC和GC有不同的对腔分子亚型的膀胱癌中免疫微环境的影响。肿瘤基线免疫泄露较低的腔内亚型的免疫原子显着增加外周血中肿瘤特异性T细胞受体（TCR）克隆的签名表达和克隆性 MVAC之后，但没有GC治疗。相反，GC显着增加了已知促进的基因特征对膀胱癌（成纤维细胞TGFB反应签名[FTBRS]和EMT-STROMA）的IC治疗抗性。这些结果表明，在腔膀胱癌中，MVAC促进了发炎的肿瘤免疫微环境可以允许进行IC抑制，而GC增加了基质激活，已知与IC相关反抗。多样性补充候选人将利用一种小说，忠实，基因工程的鼠（宝石）腔分子亚型以及单细胞RNA测序（SCRNASEQ）的膀胱癌模型在高分辨率下检查MVAC和GC对肿瘤微环境的影响。而且，他会的在这些忠实模型中确定化学和免疫疗法的最佳施用序列。全面的职业发展计划将教授演讲，写作和网络技能，以利用他职业生涯的下一步。成功完成这项科学工作和培训计划将使选择性，学术后奖学金和有效的学术职业的候选人。 1