Bladder cancer: Predicting response to BCG.

Abstract

287 Background: Our preliminary immunohistochemical studies of bladder cancer patients have shown that 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, as well as by evidence of tumor-associated eosinophil infiltration and activation. The standard-of-care treatment for Tis bladder cancer is intravesical administration of BCG, a Th1-polarizing immunomodulator. The aim of the present study was to assess the Th2/Th1 ratio correlation with response to BCG therapy in patients with Tis bladder cancer. Methods: Two groups of patients were studied. Group A included 20 patients that responded to BCG, and Group B included 20 patients that did not respond to therapy. Response to BCG was determined as presence/absence of disease at 6 months post-BCG therapy. The initial diagnostic biopsies of these patients were subjected to immunohistochemical analysis using commercially available antibodies specific for Th2 (GATA-3+) and Th1 (T-bet+) lymphocytes, and our unique monoclonal antibody specific for eosinophil peroxidase (EPX-mAb). Ten random high powered (400X) fields at the maximum focus of mononuclear infiltration were examined and the number of GATA 3+ and T-bet+ tumor infiltrating T cells were counted to define the G/T ratio for each patient sample. Eosinophils and their degranulation activity were counted in the same fields. Results: Patients with response to BCG therapy had a G/T ratio of ≥ 3 and patients with non-response to BCG therapy had a G/T ratio of ≤ 1.5. Correlation of these scores with subsequent patient outcomes following BCG immune therapy demonstrated that patient responsiveness (i.e., tumor elimination at 6 months) trended with the higher G/T ratio patients. In addition, initial biopsies of BCG responsive patients display a higher number of eosinophils and degranulation relative to BCG non-responsive patients. Conclusions: Evaluations of initial biopsies revealed a strong correlation between Th1 and Th2 immune response with BCG therapy outcomes. The development of specific and novel tools to identify/measure Th2 immune responses in Tis bladder cancer provides a unique opportunity to predict outcomes at the time of diagnosis.