Urinary Cytokine Profile to Predict Response to Intravesical BCG with or without HS-410 Therapy in Patients with Non–muscle-invasive Bladder Cancer

Abstract

Background: Despite extensive research to identify biomarkers of response in patients with non-muscle-invasive bladder cancer (NMIBC), there is no biomarker to date that can serve this purpose. Herein, we report how we leveraged serial urine samples to query a panel of cytokines at varying time points in an attempt to identify predictive biomarkers of response in NMIBC. Methods: Serial urine samples were collected from 50 patients with intermediate-or high-risk NMIBC enrolled in a phase II study, evaluating intravesical BCG AE intradermal HS-410 therapy. Samples were collected at baseline, week 7, week 13, week 28, and at end of treatment. A total of 105 cytokines were analyzed in each sample. To predict outcome of time-to-event (recurrence or progression), univariate and multivariable Cox analyses were performed. Results: Fifteen patients developed recurrence and 4 patients progressed during the follow-up period. Among clin-icopathologic variables, ever-smoker versus nonsmoker status was associated with an improved response rate (HR 0.38; 95% confidence interval (CI), 0.14-0.99; P ¼ 0.04). In the most clinically relevant model, the percent change (for 100 units) of IL18-binding protein-a (HR 1.995; 95% CI, 1.16-3.44; P ¼ 0.01), IL23 (HR 1.12; 95% CI, 1.01-1.23; P ¼ 0.03), IL8 (HR 0.27; 95% CI, 0.07-1.08; P ¼ 0.06), and IFNg-induced protein-10 (HR 0.95; 95% CI, 0.91-0.99; P ¼ 0.04) at week 13 from baseline best predicted time to event. Conclusions: Urinary cytokines provided additional value to clinicopathologic features to predict response to immunemodulating agents in patients with NMIBC. Impact: This study serves as a hypothesis-generating report for future studies to evaluate the role of urine cytokines as a predictive biomarker of response to immune treatments.

Establishment of a novel risk score model by comprehensively analyzing the immunogen database of bladder cancer to indicate clinical significance and predict prognosis

“…Beginning with the favorable response of bacillus Calmette-Guérin (BCG) intravesical instillation for BCa reported in 1976, the door of immunotherapy for BCa was gradually opened [8]. To date, BCG, together with pirarubicin and other chemotherapeutics, has been regarded as the standard adjuvant treatment for nonmuscle invasive bladder cancer (NMIBC), which accounts for approximately 70% of BCa [9,10]. Although the therapeutic effect of BCG in NMIBC is significant and the tumor-specific immunity induced by BCG has been extensively studied, the mechanisms remain unclear owing to the multiple biological processes involved, including congenital immunity and acquired immunity.…”

Assessing treatment response after intravesical bacillus Calmette–Guerin induction cycle: are routine bladder biopsies necessary?

“…Efforts to predict response to BCG treatment also include the use of urinary and tissue molecular markers [24][25][26][27]. Unfortunately, none of them has yet entered routine clinical practice.…”

Investigating the STING Pathway to Explain Mechanisms of BCG Failures in Non-Muscle Invasive Bladder Cancer: Prognostic and Therapeutic Implications

“…Several previous studies have reported the urinary cytokine profiles soon after BCG instillation. The most consistent of these surrogate chemokines of IFN activation are CXCL10, IFN␥, IL-1, IL-6, IL-10, IL-2, TNF␣ and IL-12 [18,19]. Urinary levels of these chemokines constitute the primary indicators of the magnitude of IFN activation and/or immune cell recruitment.…”