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

描述(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%的肿瘤中可观察到。大多数最初诊断的肿瘤是非肌肉侵袭性病变(即Ta、T1和Tis)， 受试者通常表现为两种或两种以上这种肿瘤的组合。这些非肌肉浸润性膀胱癌的标准治疗选择是有限的，但通常包括膀胱内注射减毒卡介苗(BCG)。然而，目前还没有能力在初步诊断时确定这些患者中哪些对这种免疫调节护理标准治疗有反应。因此，膀胱癌患者通常采用“一刀切”的方法进行治疗，只有大约60%的接受治疗的患者在接受卡介苗免疫治疗后没有发现肿瘤的证据。我们的初步免疫组织化学研究使用福尔马林固定的石蜡包埋的初始活检(即来自不同医疗中心/诊所的所有膀胱癌患者共同的唯一可用样本)提供了两个见解，表明一种新的诊断方法的可能性，以识别卡介苗治疗敏感的患者。具体地说，与膀胱癌相关的炎症/免疫反应似乎是Th2极化的，根据肿瘤浸润性GATA-3+(Th2)与T-bet+(Th1)T细胞的优势来判断，膀胱癌经常表现出与肿瘤相关的嗜酸性粒细胞浸润和激活(即脱颗粒)的证据。更重要的是，这些初步的见解表明，对肿瘤免疫反应的评估似乎是对卡介苗免疫治疗反应的积极预后指标。这项建议的中心假设是，在初始诊断时对患者活检组织中Th2免疫标志物的评估将提供必要的衡量标准，以确定10名非肌肉浸润性膀胱癌患者中有6名对标准护理卡介苗治疗有反应。我们的近期目标是将使用与Th2诱导的炎症相关的抗体对肿瘤的免疫组织化学评估转化为对膀胱癌患者的准确高通量筛查。我们将在短期内通过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卡介苗免疫治疗的反应性与最初诊断时(即治疗决策过程之前)肿瘤免疫微环境的Th2特征相关。从长远来看，我们的目标是将这种有效的诊断方法转化为一项大型的前瞻性患者研究，旨在通过这种基于病理学的Th2生物标记物评估来测试管理膀胱癌患者护理的有效性。我们的期望是，在膀胱肿瘤中Th2免疫反应的定义也可能导致以前未经测试的/新的治疗方式。

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.