Efficacy of BCG Therapy is a Function of Bladder Tumor Immune Microenvironment

卡介苗治疗的疗效是膀胱肿瘤免疫微环境的函数

基本信息

批准号：
8580152
负责人：
JAMES Joseph LEE
金额：
$ 21.66万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580152
关键词：
Aftercare Algorithms Antibodies Attenuated Biological Markers Biopsy Bladder Neoplasm Calmette-Guerin Bacillus Cancer Patient Caring Clinic Cytotoxic T-Lymphocytes Decision Making Development Diagnosis Diagnostic Disease Formalin Goals Histocytochemistry Hypersensitivity Immune Immune response Immunohistochemistry Immunotherapy Individual Infiltration Inflammation Inflammatory Inflammatory Response Intravesical Administration Invasive Lesion Lead Leukocytes Life Link Lymphoid Cell Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Mediating Medical center Metric Modality Outcome Paraffin Embedding Pathologic Pathology Patient Care Patients Population Probability Process Prognostic Marker Relative (related person)Research Design Role Sampling T-Lymphocyte Therapeutic Time Tissues Transitional Cell Carcinoma Translating Treatment outcome base cell killing efficacy testing eosinophil expectation high throughput screening immune activation improved indexing insight novel novel diagnostics novel therapeutics prospective public health relevance response therapeutic target tool tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Transitional cell carcinoma is the most common pathologic subtype of bladder cancer and is observed in over 90% of tumors. The significant majority of initially diagnosed tumors are non-muscle invasive lesions (i.e., Ta, T1, and Tis) with subjects often presenting with combinations of two or more of these tumors. The standard-of-care treatment option for these non-muscle invasive bladder cancers are limited but commonly include intravesical administration of live attenuated Bacillus Calmette-Guerin (BCG). However, there is currently no ability at the time of initial diagnosis to identify which of these patients ill respond to this immune modulating standard-of-care treatment. As a consequence, bladder cancer patients are generally treated using a "one size fits all" approach with only about 60% of treated patients showing no evidence of tumors following BCG immune therapy. Our preliminary immunohistochemical studies using formalin-fixed paraffin embedded initial biopsies (i.e., the only available sample common to all bladder cancer patients from various medical centers/clinics) has provided two insights that suggest the possibility of a novel diagnostic approach to identify BCG therapy-responsive patients. Specifically, the inflammatory/immune responses associated with bladder cancer appear to be Th2-polarized as judged by the preponderance of tumor infiltrating GATA-3+ (Th2) vs. T-bet+ (Th1) T cells and bladder tumors often display evidence of tumor- associated eosinophil infiltration and activation (i.e., degranulation). More importantly, these preliminary insights suggested that assessments of tumor immune responses appear to be positive prognostic indicators of responsiveness to BCG immune therapy. The central hypothesis of this proposal is that the assessments of Th2 immune signature biomarkers in patient biopsies at the time of initial diagnosis will provide needed metrics to identify the 6 out of 10 non-muscle invasive bladder cancer patients responsive to standard-of-care BCG therapy. Our immediate objectives are to translate the immunohistochemical assessments of tumors using antibodies linked with Th2 induced inflammation into an accurate high throughput screen of bladder cancer patients. We will achieve our goals in the short term by completing the following Specific Aim: To demonstrate that the responsiveness of non-muscle invasive bladder cancer to BCG immune therapy correlates with the Th2 character of the tumor immune microenvironment at the time of initial diagnosis (i.e., before the therapeutic decision-making process). In the long term our goal is to translate this validated diagnostic approach into a large prospective patient study designed to test the efficacy of managing bladder cancer patient care with this pathology-based assessment of Th2 biomarkers. Our expectation is that the definition of Th2 immune responses in bladder tumors may also lead to previously untested/novel therapeutic modalities.

描述（由申请人提供）：过渡细胞癌是膀胱癌最常见的病理性亚型，在90％以上的肿瘤中观察到。大多数最初被诊断出的肿瘤的大部分是非肌肉侵入性病变（即TA，T1和TIS）受试者经常出现这些肿瘤的两个或多个组合。这些非肌肉浸润性膀胱癌的护理标准治疗方案受到限制，但通常包括静脉内给药的活体减毒芽孢杆菌 - 塞莱特 - 古素（BCG）。但是，目前在初次诊断时没有能力确定这些患者对这种免疫调节治疗的反应。因此，通常使用“一件尺寸适合所有方法”治疗膀胱癌患者，仅约60％的治疗患者显示出BCG免疫治疗后没有肿瘤的证据。我们使用福尔马林固定的石蜡嵌入的初始活检（即，来自各个医疗中心/诊所的所有膀胱癌患者共有的唯一可用样本）提供了两种见解，这表明了一种新型诊断方法识别BCG治疗治疗疗法应答患者的可能性。具体而言，与膀胱癌相关的炎症/免疫反应似乎是由Th2偏振的，这是通过肿瘤浸润的肿瘤浸润GATA-3+（TH2）与T-bet+（TH1）T细胞和膀胱肿瘤的判断，通常显示出肿瘤 - 肿瘤 - 相关的嗜酸性嗜酸性浸润和激活（I.EE.E.E.E）。更重要的是，这些初步见解表明，对肿瘤免疫反应的评估似乎是对BCG免疫治疗反应的积极预后指标。该提案的中心假设是，在初次诊断时对患者活检中Th2免疫信号生物标志物的评估将提供所需的指标，以识别10个非肌肉入侵性膀胱癌患者中有6例对患者的患者有反应，该患者对患有标准的BCG BCG治疗有反应。我们的直接目的是使用与TH2诱导的炎症相关的抗体对肿瘤进行免疫组织化学评估，为膀胱癌患者的准确高通量筛查。我们将在短期内完成以下具体目标来实现我们的目标：证明非肌肉浸润性膀胱癌对BCG免疫治疗的反应性与初始诊断时肿瘤免疫微环境的Th2特征相关（即在治疗决策过程之前）。从长远来看，我们的目标是将这种经过验证的诊断方法转化为一项大型前瞻性患者研究，旨在测试通过对TH2生物标志物进行这种基于病理的评估来管理膀胱癌患者护理的功效。我们的期望是，膀胱肿瘤中Th2免疫反应的定义也可能导致以前未经测试/新型治疗方式。