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The use of intravesical BCG in urothelial carcinoma of the bladder.

ABSTRACT: The high recurrence and progression rates of non-muscle invasive bladder cancer (NMIBC) have led investigators to study the use of intravesical therapy in order to prevent them. Bacillus Calmette-Guérin (BCG) has been successfully used for this indication to treat NMIBC for more than four decades. BCG is the only intravesical agent shown to reduce the risk of progression of NMIBC to muscle-invasive disease. Despite over 40 years of clinical use, the precise mechanism of action for what has often been considered the most successful cancer immunotherapy in humans remains largely unknown. Unfortunately, BCG therapy is not a universal panacea and it still fails in up to 40% of patients. Many of these patients, especially in the high-risk category (T1 high-grade disease, carcinoma in situ) will require aggressive therapy like cystectomy or in selected cases, bladder-sparing options like chemo-radiation. Indeed, there is no gold standard intravesical treatment after BCG failure.

SUBMITTER: Alhunaidi O

PROVIDER: S-EPMC6411413 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The use of intravesical BCG in urothelial carcinoma of the bladder.

Alhunaidi Omar O Zlotta Alexandre R AR

Ecancermedicalscience 20190226

The high recurrence and progression rates of non-muscle invasive bladder cancer (NMIBC) have led investigators to study the use of intravesical therapy in order to prevent them. Bacillus Calmette-Guérin (BCG) has been successfully used for this indication to treat NMIBC for more than four decades. BCG is the only intravesical agent shown to reduce the risk of progression of NMIBC to muscle-invasive disease. Despite over 40 years of clinical use, the precise mechanism of action for what has often ...[more]

PMID: 30915163

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Project description:BackgroundIntravesical Bacillus Calmette-Guerin (BCG) is an effective treatment for bladder superficial carcinoma and it is being tested in interstitial cystitis patients, but its precise mechanism of action remains poorly understood. It is not clear whether BCG induces the release of a unique set of cytokines apart from its pro-inflammatory effects. Therefore, we quantified bladder inflammatory responses and alterations in urinary cytokine protein induced by intravesical BCG and compared the results to non-specific pro-inflammatory stimuli (LPS and TNF-alpha). We went further to determine whether BCG treatment alters cytokine gene expression in the urinary bladder.MethodsC57BL/6 female mice received four weekly instillations of BCG, LPS, or TNF-alpha. Morphometric analyses were conducted in bladders isolated from all groups and urine was collected for multiplex analysis of 18 cytokines. In addition, chromatin immune precipitation combined with real-time polymerase chain reaction assay (CHIP/Q-PCR) was used to test whether intravesical BCG would alter bladder cytokine gene expression.ResultsAcute BCG instillation induced edema which was progressively replaced by an inflammatory infiltrate, composed primarily of neutrophils, in response to weekly administrations. Our morphological analysis suggests that these polymorphonuclear neutrophils are of prime importance for the bladder responses to BCG. Overall, the inflammation induced by BCG was higher than LPS or TNF-alpha treatment but the major difference observed was the unique granuloma formation in response to BCG. Among the cytokines measured, this study highlighted the importance of IL-1beta, IL-2, IL-3, IL-4, IL-6, IL-10, IL-17, GM-CSF, KC, and Rantes as discriminators between generalized inflammation and BCG-specific inflammatory responses. CHIP/Q-PCR indicates that acute BCG instillation induced an up-regulation of IL-17A, IL-17B, and IL-17RA, whereas chronic BCG induced IL-17B, IL-17RA, and IL-17RB.ConclusionTo the best of our knowledge, the present work is the first to report that BCG induces an increase in the IL-17 family genes. In addition, BCG induces a unique type of persisting bladder inflammation different from TNF-alpha, LPS, and, most likely, other classical pro-inflammatory stimuli.

Project description:BackgroundThe systemic immune-inflammation index (SII) has emerged as a promising marker predicting the prognosis of some cancers, while its role in urothelial carcinoma (UC) remains uncertain, especially in upper urinary tract urothelial carcinoma (UTUC). This meta-analysis aimed to investigate the association of SII with the prognosis of UC and the response to intravesical Bacillus Calmette-Guerin (BCG) therapy of non-muscle invasive bladder cancer (NMIBC).MethodsA systematic search in PubMed, Embase, Web of Science, and the Cochrane Library was performed to identify relevant studies. The extracted hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate the association between SII and overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) of patients with UC. Additionally, we pooled odds ratios (ORs) and 95% CIs to assess the relationship between SII and BCG response in patients with NMIBC. Subgroup and sensitivity analyses were performed to explore potential sources of heterogeneity.ResultsTwenty studies comprising a total of 12,645 patients were eligible. This meta-analysis revealed that high SII levels independently increased the risk of OS (HR 1.55, 95%CI 1.25-1.92), CSS (HR 1.82, 95%CI 1.36-2.45), and RFS (HR 1.26, 95% CI 1.18-1.35) in patients with UC, including those with upper tract urothelial carcinoma. Additionally, elevated SII levels could predict a lower response to intravesical BCG treatment (OR 0.18, 95%CI 0.07-0.45) and higher disease recurrence (HR 1.61, 95%CI 1.31-1.98) in patients with NMIBC. Furthermore, elevated SII levels were positively associated with advanced age, lymphovascular invasion, hydronephrosis, and high tumor grade and stage (pT ≥ 3).ConclusionsElevated preoperative SII levels are associated with poor survival outcomes in patients with UC, as well as worse response to BCG treatment in patients with NMIBC. Therefore, SII can serve not only as an independent prognostic predictor of patients with UC but also as a guide for BCG therapy in NMIBC.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023409077, identifier CRD42023409077.

Project description:PurposeNonmuscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with bacillus Calmette-Guérin or chemotherapy. For bacillus Calmette-Guérin-refractory disease, systemic anti-PD-1 (programmed cell death protein 1) immune checkpoint inhibition is a treatment. Our aim is to test whether intravesical instillment with anti-PD-1 inhibitor treats localized bladder cancer as effectively as systemic administration.Materials and methodsWe investigated an orthotopic mouse model of urothelial bladder cancer using MBT2 cells instilled into the bladders of syngeneic, wild-type C3H mice. Groups of 10 mice received each treatment for comparison of intravesical anti-PD-1, intraperitoneal anti-PD1, and intravesical chemotherapy. The primary outcome was overall survival and secondary outcomes included long-term immunity and toxicity.ResultsAnti-PD-1 administered by bladder instillment (intravesical route) successfully treats localized bladder cancer and has similar overall survival to anti-PD-1 by systemic route. Anti-PD-1 by either route provides a significant survival advantage over control antibody. Anti-PD-1 increases CD8+ cell infiltration in tumors, particularly when administered intravesically. Antibody treatment avoids toxicity observed for intravesical chemotherapy. Mice who cleared their tumors after initial treatment were rechallenged with tumor engraftment 3-9 months later without any additional treatment. Initial anti-PD-1-treated mice did not grow tumors when rechallenged, which suggests long-term immunity exists, but initial mitomycin-treated mice readily grew tumors indicating no immunity occurred by chemotherapy treatment.ConclusionsIntravesical administration of anti-PD-1 is a promising treatment route for localized bladder cancer, with comparable overall survival to systemic anti-PD-1 in this mouse model. Intravesical anti-PD-1 increases CD8+ T cells in treated tumors and long-term immunity was seen to tumor rechallenge.

Project description:Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG's antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC. A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires. Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1-2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: -26% (-51% to 24%) for placebo, 9.6% (-59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (-31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02). Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.

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The use of intravesical BCG in urothelial carcinoma of the bladder.

Publications

The use of intravesical BCG in urothelial carcinoma of the bladder.

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