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Chemotherapy and the Bladder Cancer Immune Microenvironment

化疗与膀胱癌免疫微环境

基本信息

批准号：
10401438
负责人：
WILLIAM Y. KIM
金额：
$ 55.48万
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/10401438
关键词：
Adriamycin PFS Affect Antigens Antineoplastic Agents Bladder Neoplasm Bladder Urothelium Blood specimen CD8-Positive T-Lymphocytes Cancer Patient Carboplatin Cells Cessation of life Chemotherapy-Oncologic Procedure Cisplatin Clinical Clonality Combination Drug Therapy Combination immunotherapy Cystectomy Data Disease Dose Equipoise Fibroblasts Gene Expression Profile Immune Immune checkpoint inhibitor Immune response Immunotherapy Individual Laboratories Lead Level of Evidence Malignant Neoplasms Malignant neoplasm of urinary bladder Methotrexate Modality Muscle Neoadjuvant Therapy PD-1/PD-L1 PDL1 inhibitors Patients Platinum Progression-Free Survivals Prospective cohort Publishing Randomized Randomized Clinical Trials Regimen Resistance Sampling Schedule Side Survival Rate T cell response T-Cell Receptor TGFB1 gene Testing Therapeutic Transitional Cell Carcinoma Treatment Protocols Tumor-Derived Tumor-infiltrating immune cells United States Urothelium Vincristine anti-PD-1 anti-PD-L1 anti-PD-L1 antibodies anti-PD1 therapy base bladder transitional cell carcinoma cancer therapy checkpoint inhibition checkpoint therapy chemotherapeutic agent chemotherapy cost gemcitabine genetic signature immune checkpoint blockade improved outcome men molecular subtypes mouse model muscle invasive bladder cancer neoantigens novel peripheral blood phase II trial response transcriptomics tumor tumor-immune system interactions

项目摘要

In the United States urothelial carcinoma (UC) of the bladder is the 4th most frequent malignancy in men, with around 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%. The current standard first line therapy for metastatic disease is cisplatin-based combination chemotherapy or immune checkpoint inhibition in patients who are platinum ineligible. Novel immune checkpoint (IC) inhibitors, including anti-PD1 and anti-PD-L1, represent a paradigm shift in cancer therapy in patients with advanced UC however, only 15-25% of patients treated in published trials had objective responses to single agent IC inhibition. 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 restriction 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 in aggregate suggest that in luminal bladder cancers, MVAC promotes an inflamed tumor immune microenvironment permissive to IC inhibition, while GC increases stromal expansion, known to correlate with immunotherapy resistance. In aggregate our preliminary data suggest that MVAC should combine better with IC therapy than GC. Successful completion of this proposal will validate these findings in a prospective cohort of paired pre and post MVAC or GC samples collected in the context of a randomized clinical trial (SWOG1314), determine which specific anti-neoplastic agents alter the immune microenvironment and promote sensitivity to immunotherapy, as well as outline how to best sequence anti-neoplastic agents and immune checkpoint blockade in urothelial bladder cancer.

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。