Chemotherapy and the Bladder Cancer Immune Microenvironment

化疗与膀胱癌免疫微环境

• 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
• 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

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)是男性第四常见的恶性肿瘤， 2019年新增病例约80,500例，死亡17,500例。尽管这是一年多来治疗费用最高的癌症 在患者的一生中，膀胱癌仍然资金不足。高级别(HG)肌肉浸润性膀胱肿瘤 占这些死亡的大部分，因为转移性疾病患者的5年存活率仅为 15%。目前转移性疾病的标准一线疗法是以顺铂为基础的联合化疗。 或免疫检查点抑制的患者谁是铂不合格。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%的患者对单一药物IC抑制有客观反应。 在临床局限的肌肉浸润性膀胱癌(MIBC)患者中，有高水平的 支持使用基于顺铂的新辅助化疗的证据。两种被广泛接受的方案 治疗平衡药物为甲氨蝶呤、长春新碱、阿霉素和顺铂。 (吉西他滨/顺铂)。而晚期膀胱癌治疗的试验正在评估联合 化疗和免疫治疗，要合理结合这两种治疗方式，必须准确 了解MVAC和GC如何影响免疫微环境，以及如何对化疗和 免疫疗法。 来自Kim和文森特实验室的初步研究表明，MVAC和GC有不同的作用 腔分子亚型膀胱癌免疫微环境的研究腔内肿瘤 具有低基线免疫渗透的亚型具有显著增加的免疫基因特征 MVAC后外周血中肿瘤特异性T细胞受体(TCR)克隆型的表达及限制 但不是GC治疗。相比之下，GC显著增加已知可促进抗药性的基因签名 膀胱癌的IC治疗(成纤维细胞TGFb反应信号[FTBRS]和EMT_Stroma)。这些结果 总而言之，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IC抑制，而GC增加间质扩张，已知与 免疫治疗耐药。总体而言，我们的初步数据表明，MVAC应该与 IC治疗优于GC治疗。这项建议的成功完成将在未来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的MVAC或GC样本的前后， 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 免疫疗法，以及如何对抗肿瘤药物和免疫检查点进行最佳排序 尿路上皮性膀胱癌的阻断。