Therapeutic Modulation of COX-2-induced Immunosuppression in Metastatic RCC

COX-2 诱导的转移性肾细胞癌免疫抑制的治疗调节

• 批准号: 7407464
• 负责人: BRIAN I RINI
• 金额: $ 29.36万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-16 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407464
• 关键词: Antineoplastic Agents; Biology; Blood; Cell Count; Cells; Clinical; Clinical Trials; Control Groups; Coxibs; Dendritic Cells; Eligibility Determination; Evaluation; Goals; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Infiltration; Interferon-alpha; Label; Lead; Lymphocyte Subset; Malignant Neoplasms; Malignant neoplasm of kidney; Mediating; Metastatic Renal Cell Cancer; Numbers; Outcome; Patients; Phase II Clinical Trials; Phenotype; Population; Primary Neoplasm; Production; Prostaglandin-Endoperoxide Synthase; Protein Overexpression; Proteins; Rate; Renal Cell Carcinoma; Renal carcinoma; Staining method; Stains; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Tissues; Tumor Tissue; Upper arm; Week; celecoxib; clinical effect; clinically relevant; cyclooxygenase 1; cyclooxygenase 2; cytokine; immunoregulation; insight; interferon alpha5; peripheral blood; response; tumor

DESCRIPTION (provided by applicant): A previous clinical trial in metastatic renal cell carcinoma (RCC) of interferon alpha (IFNA) combined with a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, demonstrated clinical responses only in patients with tumors expressing high levels of COX-2. Thus, a hypothesis was generated that COX-2 inhibition may alter the biology of high COX-2-expressing RCC and enhance the clinical effect of IFNA. This project proposes to prospectively test this hypothesis through a clinical trial of this combination limited to patients with 3+ COX-2 expression and further to explore the mechanisms that drive the anti-tumor effect of IFNA and celecoxib in metastatic RCC. Given that RCC patients with 3+ COX-2 expression represent a significant fraction (20-30%) of the total RCC population, this translational project has clinical relevance. The central hypothesis and long-term goal is to inhibit COX-2 in RCC tumors with high levels of COX-2 expression to overcome immunosuppression and enhance clinical benefit with IFNA. The specific aims are: 1) To estimate the objective response rate of interferon alpha plus celecoxib in metastatic RCC patients with 3+ COX-2 tumor immunostaining. 2) To compare immune parameters in metastatic RCC patients with 3+ COX-2 tumor immunostaining to patients with < 1+ tumor immunostaining and 3) To evaluate the effect of celecoxib and interferon alpha on immune parameters in metastatic RCC patients with 3+ COX-2 tumor immunostaining. An open-label, single-arm phase II trial will be conducted in 34 metastatic RCC patients with 3+ COX-2 tumor immunostaining. Screened metastatic RCC patients with < 1+ COX-2 staining will serve as a control group for evaluation of immune parameters. Patients meeting eligibility criteria will receive IFNA 5 MU s.c. 5x/week and celecoxib 400 mg p.o. BID continuously. Baseline tumor tissue will be stained for COX-2 and infiltrating T cells. Baseline and post- treatment peripheral blood will be analyzed for T regulatory cell number, dendritic cell number and activation status and T cell phenotype (Th1/Th2). This original approach seeks to capitalize on a clinical observation and further explore the cellular immune mechanism of COX-2- mediated immunosuppression. Successful completion of the above aims will lead to a significant therapy advance in metastatic RCC and insight into COX-2 biology. This project seeks to determine how a protein, cyclooxygenase-2 (COX-2), impacts the inherent immune response to kidney cancer and if COX-2 inhibition can enhance the clinical effect of an anti-cancer drug, interferon alpha, in kidney cancer. This project will have broad implications for the immunoregulation of cancer and how expression and modulation of COX-2 expression influences the immune response to cancer.

描述（由申请人提供）：先前在干扰素α（IFNA）转移性肾细胞癌（RCC）的临床试验中，结合了环氧酶-2（COX-2）抑制剂Celecoxib，仅在表达高水平COX-2的肿瘤患者中才显示出临床反应。因此，假设COX-2抑制可能会改变表达高COX-2的RCC的生物学，并增强IFNA的临床作用。该项目提议通过该组合的临床试验前瞻性地检验该假设，仅限于3+ COX-2表达患者，并进一步探索了驱动转移性RCC中IFNA和Celecoxib的抗肿瘤效应的机制。鉴于3+ COX-2表达的RCC患者占RCC总人群的显着部分（20-30％），因此该转化项目具有临床相关性。中心假设和长期目标是抑制高水平COX-2表达的RCC肿瘤中的COX-2，以克服免疫抑制并提高IFNA的临床益处。具体目的是：1）估计3+ COX-COX-COX-2肿瘤免疫染色的转移性RCC患者中干扰素α和塞来氧化的客观反应率。 2) To compare immune parameters in metastatic RCC patients with 3+ COX-2 tumor immunostaining to patients with < 1+ tumor immunostaining and 3) To evaluate the effect of celecoxib and interferon alpha on immune parameters in metastatic RCC patients with 3+ COX-2 tumor immunostaining.将在34例34例COX-COX-COX-2肿瘤免疫染色的转移性RCC患者中进行开​​放标签的单臂II期试验。筛分的转移性RCC <1+ COX-2染色患者将作为评估免疫参数的对照组。符合资格标准的患者将获得IFNA 5 MU S.C. 5倍/周和塞来昔布400毫克P.O.连续出价。基线肿瘤组织将用于COX-2和浸润T细胞染色。将分析基线和治疗后血液的血液调节细胞数，树突状细胞数和激活状态以及T细胞表型（TH1/TH2）。这种原始方法旨在利用临床观察，并进一步探索COX-2介导的免疫抑制的细胞免疫机制。上述目标的成功完成将导致转移性RCC的重大疗法和对COX-2生物学的见解。该项目旨在确定蛋白质环氧酶-2（COX-2）如何影响对肾癌的固有免疫反应，以及COX-2抑制是否可以增强抗癌药物Interferon Alpha，In肾癌的临床作用。该项目将对癌症的免疫调节以及COX-2表达的表达和调节对癌症的免疫反应有广泛的影响。