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：
10606615
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/10606615
关键词：
Adjuvant Chemotherapy 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 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 Regimen Resistance Sampling Schedule Side Specific qualifier value Survival Rate T cell response T-Cell Receptor TGFB1 gene Testing Therapeutic Transitional Cell Carcinoma Treatment Protocols United States Urothelium Vincristine anti-PD-1 anti-PD-L1 anti-PD-L1 antibodies anti-PD1 therapy bladder transitional cell carcinoma cancer therapy checkpoint inhibition checkpoint therapy chemotherapeutic agent chemotherapy cost gemcitabine genetic signature immune cell infiltrate immune checkpoint blockade improved improved outcome men molecular subtypes mouse model muscle invasive bladder cancer neoantigens novel peripheral blood permissiveness phase II trial randomized, clinical trials response transcriptomics tumor tumor microenvironment 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，膀胱的尿路上皮癌（UC）是男性中第四大最常见的恶性肿瘤， 2019年大约有80,500例新病例和17,500例死亡。患者的终生，膀胱癌仍然不足。高级（HG），肌肉侵入性膀胱肿瘤这些死亡中的大多数是转移性疾病患者的生存率仅为5年 15％。当前用于转移性疾病的标准第一线治疗是基于顺铂的组合化疗铂不合格的患者的免疫检查点抑制。新型免疫检查点（IC）抑制剂，包括抗PD1和抗PD-L1，代表晚期UC患者癌症治疗的范式转移但是，在公开试验中接受治疗的患者中，只有15-25％对单一药物IC抑制有客观反应。在患有临床局部肌肉侵入性膀胱癌（MIBC）的患者中，有很高的水平支持使用基于顺铂的新辅助化疗的证据。两个广泛接受的方案治疗能力为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和免疫疗法，以合理地结合这两种治疗方式，必须精确地结合了解MVAC和GC如何影响免疫微环境以及如何最佳序列化学序列和免疫疗法。 KIM和Vincent实验室的初步研究表明，MVAC和GC具有不同的影响在腔分子亚型的膀胱癌中的免疫微环境上。腔的肿瘤基线免疫浸润低的亚型的免疫基因特征显着增加 MVAC后血液中肿瘤特异性T细胞受体（TCR）锁骨的表达和限制但不是GC治疗。相反，GC显着增加了已知促进对抗性的基因特征膀胱癌（成纤维细胞TGFB反应签名[FTBRS]和EMT_STROMA）的IC治疗。这些结果总体表明，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增加了基质扩张，已知与免疫疗法抗性。总体上，我们的初步数据表明MVAC应该更好地与 IC治疗比GC。该提案的成功完成将在潜在的队列中验证这些发现在随机临床试验（SWOG1314）的背景下收集的配对前后MVAC或GC样品确定哪种特定的抗肿瘤剂改变了免疫微环境，并促进对免疫疗法以及概述如何最好地序列抗肿瘤剂和免疫检查点尿路上皮膀胱癌的封锁。