Association of the commensal urinary microbiome with response to Bacillus Calmette-Guérin (BCG) immunotherapy in nonmuscle invasive bladder cancer.

Abstract

423 Background: Standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC) is intravesical BCG. Despite its established efficacy, up to 50% of patients may recur. The development of predictive biomarkers for BCG immunotherapy would enhance treatment algorithms and potentially uncover mechanisms of resistance. Recent data have characterized the presence of a commensal urine microbiome, but its role in BCG-treated NMIBC patients remains unexplored. We assessed the composition of the urine microbiome in NMIBC patients and evaluated associations with response to therapy. Methods: Patients with a newly diagnosed bladder tumor were enrolled prior to TURBT on an institutional review board-approved study at a single institution. Adjuvant BCG instillation was administrated to high-risk patients according to the surgical histology. Urine samples for microbiome assessment were collected by catheterization to eliminate urethral contamination before the TURBT and up to 8 additional timepoints. 16S sequencing and analysis was performed on baseline specimens prior to BCG. Results: Among 31 patients enrolled, 10 (32%) recurred and 21 (68%) had no recurrence with a median follow up of 6 months. Median age was 69 years (range 46-87), and 9 (29%) patients were female and 22 patients (71%) were male. The most abundant phyla observed were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes. Together these accounted for > 99% of the phyla detected in the cohort. Global analysis of distances by operational taxonomic units (OTUs) indicated a significant difference between patients with and without recurrence (Bonferroni-corrected P = 0.017). The abundance of Proteobacteria was higher in patients with recurrence (P = 0.035), with stronger differences observed for specific classes such as Gammaproteobacteria (P = 0.0025). Firmicutes such as Lactobacillales were more abundant in patients without recurrence (P = 0.049). Conclusions: In this study we detected variation in the composition of the urine microbiome in NMIBC patients, which may predict response to BCG immunotherapy. Further studies to confirm these results are ongoing.

Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers

“…Recent prospective analysis of RCC patients treated with ICI revealed association between gut microbial diversity and benefit to treatment [210]. In non-muscle invasive bladder cancer, composition of the urinary microbiome was associated with response to BCG immunotherapy [211]. Manipulation of the microbiome through fecal microbiota transplant can influence efficacy of ICI and this is being evaluated in clinical trials [212,213].…”

The Urinary Microbiome: Role in Bladder Cancer and Treatment

“…This study implies that Corynebacterium could be used as a positive marker because it shares taxonomic similarities with M. bovis [ 171 ]. Sweis et al reported that BCG-treated patients with enriched Firmicutes , such as Lactobacillus , did not experience recurrence [ 172 ]. However, Proteobacteria levels were significantly higher among patients with recurrences following BCG therapy [ 172 ].…”

“…Sweis et al reported that BCG-treated patients with enriched Firmicutes , such as Lactobacillus , did not experience recurrence [ 172 ]. However, Proteobacteria levels were significantly higher among patients with recurrences following BCG therapy [ 172 ]. As numerous types of bacteria including BCG can adhere to the extracellular matrix of the bladder mucosa, it is conceivable for urinary microbiota to saturate the BCG-binding sites [ 5 ].…”

The Urinary Microbiome and Bladder Cancer: Susceptibility and Immune Responsiveness

“…may provide some beneficial role in treatment and prevention of bladder cancer. Our group has recently reported data from a study in which we characterized the role of the urine microbiome in 31 patients with high-risk NMIBC undergoing BCG treatment [56]. DNA was extracted and 16S sequencing data were generated using Illumina paired-end sequencing.…”