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，膀胱尿路上皮癌 (UC) 是男性第四大最常见的恶性肿瘤， 2019 年估计将有 80,500 例新病例和 17,500 例死亡。尽管它是成本最高的癌症为了在患者的一生中进行治疗，膀胱癌的资金仍然不足。膀胱肿瘤占这些死亡的大部分，因为患有转移性疾病的患者有 5 年的生存期临床局限性肌层浸润性膀胱癌 (MIBC) 患者的生存率仅为 15%。高水平的证据支持以顺铂为基础的新辅助化疗的广泛使用。接受的治疗平衡方案是 MVAC（甲氨蝶呤、长春新碱、阿霉素和顺铂）和 GC（吉西他滨、顺铂），而晚期膀胱癌治疗的试验正在评估。化疗与免疫治疗相结合，合理结合这两种治疗方式准确了解 MVAC 和 GC 如何影响免疫微环境以及如何最好地发挥作用至关重要序列化疗和免疫治疗。 Kim 和 Vincent 实验室的初步研究表明，MVAC 和 GC 具有不同的特性对管腔分子亚型膀胱癌免疫微环境的影响。管腔亚型，其基线免疫浸润较低，免疫基因显着增加外周血中肿瘤特异性 T 细胞受体 (TCR) 克隆型的特征表达和克隆性相比之下，经过 MVAC 而不是 GC 处理后，GC 显着增加了已知可促进的基因特征。膀胱癌对 IC 治疗的耐药性（成纤维细胞 TGFB 反应特征 [FTBRS] 和 EMT-Stroma）。这些结果表明发炎的管腔肿瘤免疫细胞，MVAC 促进发炎的管腔肿瘤免疫系统微环境允许 IC 抑制，而 GC 会增加基质活化，已知与 IC 相关反抗。多样性补充剂候选者将利用一种新颖、忠实的基因工程小鼠 (GEM) 管腔分子亚型膀胱癌模型以及单细胞 RNA 测序 (scRNAseq) 以高分辨率检查 MVAC 和 GC 对肿瘤微环境的影响。确定这些忠实模型中化疗和免疫治疗的最佳给药顺序。全面的职业发展计划将教授演讲、写作和网络技能，以利用这些技能成功完成这项科学工作和培训计划将为他职业生涯的下一步做好准备。选择性学术博士后奖学金和有效学术生涯的候选人。 1

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RAF1 amplification: an exemplar of MAPK pathway activation in urothelial carcinoma.

RAF1 扩增：尿路上皮癌中 MAPK 通路激活的一个例子。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Clark;Kim, William Y
通讯作者：
Kim, William Y

Spatial Relationships in the Tumor Microenvironment Demonstrate Association with Pathologic Response to Neoadjuvant Chemoimmunotherapy in Muscle-invasive Bladder Cancer.

肿瘤微环境中的空间关系表明与肌层浸润性膀胱癌新辅助化学免疫治疗的病理反应相关。

DOI：
发表时间：
2024-03
期刊：
影响因子：
23.4
作者：
Beckabir, Wolfgang;Wobker, Sara E;Damrauer, Jeffrey S;Midkiff, Bentley;De la Cruz, Gabriela;Makarov, Vladmir;Flick, Leah;Woodcock, Mark G;Grivas, Petros;Bjurlin, Marc A;Harrison, Michael R;Vincent, Benjamin G;Rose, Tracy L;Gupta, Shilpa;Kim
通讯作者：
Kim

Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer.

吉西他滨和分剂量顺铂加派姆单抗作为肌层浸润性膀胱癌患者根治性膀胱切除术前新辅助治疗的 II 期研究。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Rose, Tracy L;Harrison, Michael R;Deal, Allison M;Ramalingam, Sundhar;Whang, Young E;Brower, Blaine;Dunn, Mary;Osterman, Chelsea K;Heiling, Hillary M;Bjurlin, Marc A;Smith, Angela B;Nielsen, Matthew E;Tan, Hung;Wallen, Eric;Woods, Michae
通讯作者：
Woods, Michae

Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer.

膀胱癌倡导网络的合作研究，用于转移性尿路上皮癌的基因组分析。

DOI：
发表时间：
2022-11-04
期刊：
影响因子：
16.6
作者：
Damrauer, Jeffrey S;Beckabir, Wolfgang;Klomp, Jeff;Zhou, Mi;Plimack, Elizabeth R;Galsky, Matthew D;Grivas, Petros;Hahn, Noah M;O'Donnell, Peter H;Iyer, Gopa;Quinn, David I;Vincent, Benjamin G;Quale, Diane Zipursky;Wobker, Sara E;Hoadley, Kat
通讯作者：
Hoadley, Kat