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

• 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
• 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

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）：移行细胞癌是膀胱癌最常见的病理亚型，在超过90%的肿瘤中观察到。绝大多数最初诊断的肿瘤是非肌肉侵入性病变（即，Ta、T1和Tis）， 受试者通常表现为两种或更多种这些肿瘤的组合。这些非肌层浸润性膀胱癌的标准治疗选择有限，但通常包括膀胱内给予减毒活卡介苗（BCG）。然而，目前在初步诊断时没有能力确定这些患者中的哪些对这种免疫调节标准治疗有反应。因此，膀胱癌患者通常使用“一刀切”的方法治疗，只有约60%的治疗患者在BCG免疫治疗后没有显示出肿瘤的证据。我们使用福尔马林固定的石蜡包埋的初始活检（即，唯一可获得的样品是来自不同医疗中心/诊所的所有膀胱癌患者共有的）提供了两种见解，其提示了鉴定BCG治疗反应患者的新诊断方法的可能性。具体地，与膀胱癌相关的炎症/免疫应答似乎是Th 2极化的，如通过肿瘤浸润性加塔-3+（Th 2）相对于T-bet+（Th 1）T细胞的优势所判断的，并且膀胱肿瘤通常显示肿瘤相关的嗜酸性粒细胞浸润和活化的证据（即，脱粒）。更重要的是，这些初步的见解表明，肿瘤免疫反应的评估似乎是对BCG免疫治疗反应性的积极预后指标。该提议的中心假设是，在初始诊断时对患者活检中的Th 2免疫特征生物标志物的评估将提供所需的度量，以鉴定10名非肌肉浸润性膀胱癌患者中的6名对护理标准BCG疗法有反应。我们的近期目标是将使用与Th 2诱导的炎症相关的抗体进行的肿瘤免疫组织化学评估转化为膀胱癌患者的准确高通量筛选。我们将通过完成以下具体目标在短期内实现我们的目标：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Th 2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，旨在测试这种基于病理学的Th 2生物标志物评估管理膀胱癌患者护理的有效性。我们的期望是，膀胱肿瘤中Th 2免疫应答的定义也可能导致以前未经测试/新的治疗方式。