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）是男性中第四常见的恶性肿瘤， 2019年约有80，500例新病例和17，500例死亡。尽管它是治疗成本最高的癌症， 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 占这些死亡的大多数，因为转移性疾病患者的5年生存率仅为 百分之十五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 或免疫检查点抑制。新型免疫检查点（IC）抑制剂， 包括抗PD 1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。 在临床局限性肌层浸润性膀胱癌（MIBC）患者中， 支持使用基于顺铂的新辅助化疗的证据。两种广泛接受的方案， 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联合 化疗和免疫治疗，合理地联合收割机这两种治疗方式，必须准确地 了解MVAC和GC如何影响免疫微环境，以及如何最好地排序化疗， 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。腔内肿瘤 具有低基线免疫浸润亚型具有免疫基因标记的显著增加 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 而不是GC处理。相比之下，GC显著增加了已知促进对大肠杆菌抗性的基因特征， 膀胱癌的IC治疗（成纤维细胞TGFB反应特征[FTBRS]和EMT_Stroma）。这些结果 总体上表明，在腔膀胱癌中，MVAC促进发炎肿瘤免疫 微环境允许IC抑制，而GC增加基质扩张，已知与 免疫治疗抵抗。总的来说，我们的初步数据表明，MVAC应更好地结合联合收割机与 IC治疗优于GC。成功完成本提案将在前瞻性队列中验证这些发现 在随机临床试验（SWOG 1314）背景下收集的配对MVAC或GC前后样本， 确定哪些特异性抗肿瘤药物改变免疫微环境并提高对 免疫治疗，以及概述如何最好地排序抗肿瘤剂和免疫检查点 阻断尿路上皮膀胱癌。