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Treatment of non-muscle invasive bladder cancer with Bacillus Calmette-Guerin (BCG): Biological markers and simulation studies.

ABSTRACT: Intravesical Bacillus Calmette-Guerin (BCG) vaccine is the preferred first line treatment for non-muscle invasive bladder carcinoma (NMIBC) in order to prevent recurrence and progression of cancer. There is ongoing need for the rational selection of i) BCG dose, ii) frequency of BCG administration along with iii) synergistic adjuvant therapy and iv) a reliable set of biochemical markers relevant to tumor response. In this review we evaluate cellular and molecular markers pertinent to the immunological response triggered by the BCG instillation and respective mathematical models of the treatment. Specific examples of markers include diverse immune cells, genetic polymorphisms, miRNAs, epigenetics, immunohistochemistry and molecular biology 'beacons' as exemplified by cell surface proteins, cytokines, signaling proteins and enzymes. We identified tumor associated macrophages (TAMs), human leukocyte antigen (HLA) class I, a combination of Ki-67/CK20, IL-2, IL-8 and IL-6/IL-10 ratio as the most promising markers for both pre-BCG and post-BCG treatment suitable for the simulation studies. The intricate and patient-specific nature of these data warrants the use of powerful multi-parametral mathematical methods in combination with molecular/cellular biology insight and clinical input.

SUBMITTER: Kiselyov A

PROVIDER: S-EPMC4661599 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Treatment of non-muscle invasive bladder cancer with Bacillus Calmette-Guerin (BCG): Biological markers and simulation studies.

Kiselyov Alex A Bunimovich-Mendrazitsky Svetlana S Startsev Vladimir V

BBA clinical 20150610

Intravesical Bacillus Calmette-Guerin (BCG) vaccine is the preferred first line treatment for non-muscle invasive bladder carcinoma (NMIBC) in order to prevent recurrence and progression of cancer. There is ongoing need for the rational selection of i) BCG dose, ii) frequency of BCG administration along with iii) synergistic adjuvant therapy and iv) a reliable set of biochemical markers relevant to tumor response. In this review we evaluate cellular and molecular markers pertinent to the immunol ...[more]

PMID: 26673853

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Project description:ObjectivesThe treatments for high-grade non-muscle invasive bladder cancer (NMIBC) vary between bladder preserving intravesical approaches and radical cystectomy. The impact of these treatments on health-related quality of life may vary widely. The purpose of this study was to elicit the general public's perspective on quality of life, measured as utility scores associated with treatment for Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC and disease progression, for supporting economic evaluation of newly developed treatments for NMIBC.Materials and methodsPart I involved the development and testing of health states describing NMIBC, which was informed by a rapid review, expert input and a patient advisor. Part II involved elicitation of societal utility values for the different health states. Time trade-off (TTO) interviews were conducted with members of the UK general public. Five health states described different NMIBC scenarios including disease recurrence and progression. Participants ranked each health state, followed by the TTO valuation exercise. Descriptors included NMIBC symptom severity, impact and treatment characteristics.ResultsIn total, 202 members of the general public participated. The mean age was 46 (standard deviation [SD] 14.6) years. Sample mean (SD) EQ-5D-5L visual analogue scale (VAS) and index scores were 83.2 (12.3) and 0.89 (0.18), respectively. Mean utilities were 0.781 for No High-Grade Recurrence, 0.586 for High-Grade Recurrence, 0.572 for > 1-Year Post-cystectomy and 0.283 for metastatic disease. The First Year Post-cystectomy path health state had a mean utility of 0.288. Pairwise comparisons found statistically significant differences between utilities (p < 0.001), except between High-Grade Recurrence and > 1-Year Post-cystectomy (p = 0.524). There were significant differences in utility scores by age and employment status.ConclusionThis study provides utility scores for health states describing living with NMIBC, which is associated with a significant health-related quality-of-life burden. These values address an existing gap in available data and have the potential to be used in models evaluating the cost-effectiveness of both current and newly developed treatments for bladder cancer.

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 Bacillus Calmette-Guerin (BCG) vaccine has been in use for 99 years, and is regarded as one of the oldest human vaccines known today. It is recommended primarily due to its effect in preventing the most severe forms of tuberculosis, including disseminated tuberculosis and meningeal tuberculosis in children; however, its efficacy in preventing pulmonary tuberculosis and TB reactivation in adults has been questioned. Several studies however have found that asides from its role in tuberculosis prevention, the BCG vaccine also has protective effects against a host of other viral infections in humans, an effect which has been termed: heterologous, non-specific or off-target.ObjectivesAs we approach 100 years since the discovery of the BCG vaccine, we review the evidence of the non-specific protection offered by the vaccine against viral infections, discuss the possible mechanisms of action of these effects, highlight the implications these effects could have on vaccinology and summarize the recent epidemiological correlation between the vaccine and the on-going COVID-19 pandemic.ResultsSeveral epidemiological studies have established that BCG does reduce all-cause mortality in infants, and also the time of vaccination influences this effect significantly. This effect has been attributed to the protective effect of the vaccine in preventing unrelated viral infections during the neonatal period. Some of such viral infections that have been investigated include: herpes simplex virus (HSV), human Papilloma virus (HPV), yellow fever virus (YFV), respiratory syncytial virus (RSV) and influenza virus type A (H1N1). These effects are thought to be mediated via induction of innate immune memory as well as heterologous lymphocytic activation. While epidemiological studies have suggested a correlation, the potential protection of the BCG vaccine against COVID-19 transmission and mortality rates is currently unclear. Ongoing clinical trials and further research may shed more light on the subject in the future.ConclusionBCG is a multifaceted vaccine, with many numerous potential applications to vaccination strategies being employed for current and future viral infections. There however is a need for further studies into the immunologic mechanisms behind these non-specific effects, for these potentials to become reality, as we usher in the beginning of the second century since the vaccine's discovery.

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Treatment of non-muscle invasive bladder cancer with Bacillus Calmette-Guerin (BCG): Biological markers and simulation studies.

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Treatment of non-muscle invasive bladder cancer with Bacillus Calmette-Guerin (BCG): Biological markers and simulation studies.

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