Introduction & Objectives: Intravesical administration of live attenuated Bacillus Calmette-Guerin (BCG) is the main therapy for intermediate/high risk non-muscle invasive bladder cancer (NMIBC). However, the response rate is only 60%. In addition, for those patients (pts) with tumors staged as T1 or Cis (carcinoma in situ) that do not respond to BCG, the risk of progression to muscle invasive disease could reach 50%. Intravesical BCG acts as a local immunomodulator, inducing a massive response of inflammatory cells (Th1 polarization) and ultimately the generation of a cytotoxic response that eliminates the tumor. Our hypothesis is that pts with a pre-existing tumor microenvironment of Th2 polarized lymphocytes and eosinophils would be susceptible to polarization towards Th1 after administration of BCG and respond to therapy; instead, pts that already have a Th1 polarized tumor microenvironment, would not respond to BCG, probably because the tumor has already developed escape mechanisms to the Th1 response. Our goal is search for a biomarker score to predict BCG response, in pre-treatment biopsies (pre-BCG) of high risk NMIBC pts.
Material and Methods: We evaluated retrospectively high risk NMIBC patients (n=32) treated with a 6-week induction plus a 3-week maintenance (6+3) intravesical instillations of BCG 120 mg, Danish strain SSI, (follow up > 2 years). Responders were defined as those without evidence of disease and non-responders as any recurrence after an adequate BCG treatment (at least 5+2). In pre-treatment RTU biopsies, we evaluated by immunohistochemistry the polarization of the tumor microenvironment, quantifying T-bet+ (Th1) and GATA-3+(Th2) lymphocytes ratio and the density and degranulation of eosinophils (at the maximal eosinophils focus). A Th2 Score was defined combining lymphocyte polarization GATA3+/Tbet+ (G/T) plus (eosinophils density x eosinophils degranulation). The goal was correlate our biomarker score with BCG response.
Results: Response rate was 59.4% in the study population. We observed a G/T ratio (top quartile >38) clearly associated to BCG response, although near statistical significance (p=0.063). We also evidenced higher number of eosinophils and granules among responders. But combining every single variable into a Th2 score, we demonstrated that higher scores are found in the responders (no-recurrence, p=0.053).
Conclusions: Even when these preliminary results are encouraging, given the retrospective characteristics of this study and the biases that could occur, we are initiating a prospective study to evaluate the score as a predictive biomarker of clinical response to BCG for NMIBC pts adding evaluation of peripheral blood and urine biomarkers.
