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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

摘要在美国，膀胱尿路上皮癌(UC)是男性第四常见的恶性肿瘤，据估计，2019年将有80,500例新病例和17,500例死亡。尽管它是成本最高的癌症要在患者的一生中进行治疗，膀胱癌的资金仍然不足。高级别(HG)，肌肉侵袭性膀胱癌是这些死亡的主要原因，因为患有转移性疾病的患者有5年的存活率只有15%。在临床局限的肌肉浸润性膀胱癌(MIBC)患者中，有高水平的证据支持使用以顺铂为基础的新辅助化疗。两个广泛的公认的平衡治疗方案是MVAC(甲氨蝶呤、长春新碱、阿霉素和顺铂)。和GC(吉西他滨、顺铂)。虽然先进的膀胱癌治疗试验正在评估化疗和免疫治疗相结合，要将这两种治疗方式合理结合起来必须准确了解MVAC和GC如何影响免疫微环境，以及如何最好地顺序化疗和免疫治疗。来自Kim和文森特实验室的初步研究表明，MVAC和GC具有不同的腔分子亚型对膀胱癌免疫微环境的影响。颌骨肿瘤免疫浸润率低的腔型，其免疫基因显著增加。肿瘤特异性T细胞受体(TCR)在外周血中的特征表达和克隆性在MVAC治疗后，而不是GC治疗后。相比之下，GC显著增加了已知的促进膀胱癌对IC治疗的抵抗(成纤维细胞TGFb反应信号[FTBRS]和EMT-Stroma)。这些结果表明，在腔性膀胱癌中，MVAC促进了炎症的肿瘤免疫微环境允许抑制IC，而GC增加间质激活，已知与IC相关抵抗。多样性补充剂候选者将利用一种新颖、忠诚、基因工程的小鼠(GEM) 腔内分子亚型膀胱癌模型及单细胞RNA测序(ScRNAseq) 探讨高分辨率MVAC和GC对肿瘤微环境的影响。此外，他还会在这些忠实的模型中确定化疗和免疫治疗的最佳给药顺序。这个全面的职业发展计划将教授演示、写作和网络技能，以供他职业生涯的下一步。这项科学工作和培训计划的圆满完成将使有选择地申请学术博士后奖学金和有效的学术生涯的候选人。 1