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，膀胱尿路上皮癌 (UC) 是男性第四大最常见的恶性肿瘤， 2019 年约有 80,500 例新发病例和 17,500 例死亡。尽管它是多年来治疗成本最高的癌症在患者的一生中，膀胱癌的资金仍然不足。高级别 (HG)、肌肉浸润性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的 5 年生存率仅为 15%。目前转移性疾病的标准一线治疗是以顺铂为基础的联合化疗或不符合铂类资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，代表了晚期 UC 患者癌症治疗的范式转变然而，在已发表的试验中，只有 15-25% 的患者对单药 IC 抑制有客观反应。在患有临床局限性肌层浸润性膀胱癌 (MIBC) 的患者中，存在高水平的支持使用基于顺铂的新辅助化疗的证据。两种被广泛接受的治疗方案治疗平衡是 MVAC（甲氨蝶呤、长春新碱、阿霉素和顺铂）和 GC （吉西他滨/顺铂）。虽然晚期膀胱癌治疗的试验正在评估以下组合：化疗和免疫治疗，要合理结合这两种治疗方式，必须精确地了解 MVAC 和 GC 如何影响免疫微环境以及如何最好地进行化疗和免疫疗法。 Kim 和 Vincent 实验室的初步研究表明，MVAC 和 GC 具有不同的效果对管腔分子亚型膀胱癌免疫微环境的影响。管腔肿瘤具有低基线免疫浸润的亚型的免疫基因特征显着增加 MVAC 后外周血中肿瘤特异性 T 细胞受体 (TCR) 克隆型的表达和限制但不是GC治疗。相比之下，GC 显着增加了已知可促进耐药性的基因特征。膀胱癌的 IC 疗法（成纤维细胞 TGFB 反应特征 [FTBRS] 和 EMT_Stroma）。这些结果总的来说，在管腔膀胱癌中，MVAC 促进发炎的肿瘤免疫微环境允许 IC 抑制，而 GC 会增加基质扩张，已知与免疫治疗耐药性。总的来说，我们的初步数据表明 MVAC 应该与 IC疗法优于GC。该提案的成功完成将在前瞻性队列中验证这些发现在随机临床试验 (SWOG1314) 中收集的配对前后 MVAC 或 GC 样本，确定哪些特定的抗肿瘤药物可以改变免疫微环境并提高对肿瘤的敏感性免疫疗法，以及概述如何最好地排序抗肿瘤药物和免疫检查点阻断膀胱尿路上皮癌。