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.
Immune responses directed toward many cancers are characterized by targeted cell-killing activities mediated by cytotoxic T cells (a.k.a. Th1 responses). However, certain tumors such as bladder cancer instead appear to elicit immune responses that are traditionally linked with allergies (a.k.a. Th2 responses). These immune responses also include the tissue recruitment of rare white blood cells known as eosinophils. Although the specific roles for these Th2 responses in bladder cancer are yet to be defined, evidence has nonetheless accumulated to suggest that these responses are predicative of patient outcomes following the standard-of-care treatment typically used against these tumors. Our development of specific and novel tools (i.e., biomarkers) to identify Th2 immune responses thus provides a unique opportunity to stratify bladder cancer patients prior to therapy decisions. In turn, this novel diagnostic ability will enhance bladder cancer management strategies and ultimately improve patient care as well as increase survival.
|Nunez-Nateras, Rafael; Castle, Erik P; Protheroe, Cheryl A et al. (2014) Predicting response to bacillus Calmette-Guerin (BCG) in patients with carcinoma in situ of the bladder. Urol Oncol 32:45.e23-30|