Tice Strain Research Articles

Probing Dermal Immunity to Mycobacteria through a Controlled Human Infection Model.

Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections.

Comparing Clinical Efficacy of Different Bacillus Calmette-Guérin Strains in Patients With T1 High Grade Bladder Cancer.

This study aimed to compare the clinical efficacy of two different Bacillus Calmette-Guérin (BCG) strains, TICE strain (OncoTICE) and Connaught strain (ImmuCyst), as a first line intravesical instillation therapy in patients with T1 high grade bladder cancer. Patients with newly diagnosed T1 high-grade bladder cancer who underwent transurethral resection of bladder tumor (TURBT) followed by intravesical instillation therapy were enrolled. The effects of BCG strain on recurrence, progression, and side effects were analyzed using Kaplan-Meier and Cox proportional hazards models. Among 147 patients, 53 patients received Connaught strain and 94 patients received TICE strain. The completion rate of induction instillation was 92.45% in the Connaught group and 91.49% in the TICE group (p=1.00). The three-year recurrence-free survival rate was 71.7% in the Connaught group and 63.83% in the TICE group (p=0.33), whereas the three-year progression-free survival rate was 96.23% in the Connaught group and 89.36% in the TICE group (p=0.21). On Cox regression test, carcinoma in situ and ≥eight lesions were significant predictors for recurrence. No significant difference was observed in recurrence and progression between the two BCG regimens. The complication rates according to the Cleveland Clinic grading system showed no significant difference between the two groups (p=0.13). Both the Connaught and TICE strains of BCG demonstrated comparable three-year recurrence-free survival rates and three-year progression-free survival rates for T1 high grade bladder cancer, as well as comparable adverse events. Due to the global BCG shortage, further strain comparisons are essential for clinical validation.

A phase II trial of intravesical chemoimmunotherapy with gemcitabine and bacillus Calmette-Guérin (BCG) for patients with BCG-exposed, high-grade, non-muscle–invasive bladder cancer.

TPS579 Background: The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) after exposure to induction only BCG or relapse >12 months after “adequate” BCG is retreatment with BCG. However, ~50% of patients will relapse within 6 months. Thus, there is a critical need to develop novel combination therapies to improve BCG immunotherapy efficacy. Combination BCG with immune checkpoint inhibition is associated with a ~12-18% risk of serious treatment-related adverse events and BCG combined with Mitomycin C (MMC) has unacceptable urinary toxicity. Intravesical Gemcitabine (GEM) is a common treatment for NMIBC, is well tolerated, has better efficacy after BCG than MMC, and, based on preclinical data, may synergistically enhance the efficacy of BCG by augmenting the immune tumor microenvironment. We completed a prospective Phase I trial of chemoimmunotherapy with gemcitabine and BCG in BCG-relapsed/BCG-exposed NMIBC that was well-tolerated (no treatment related grade ≥3 adverse events) with promising early efficacy (95% [19/20] 6-month complete response rate). No dose limiting toxicities were seen. The maximum tolerated dose (MTD) was 2000 mg gemcitabine and 50 mg TICE BCG. Methods: To address the need for more effective and less toxic bladder preserving treatment options by enhancing the effectiveness of BCG, we launched an investigator-initiated phase I/II trial of combination intravesical gemcitabine with BCG in patients with BCG-exposed NMIBC (NCT04179162). The Phase II portion is currently enrolling patients with BCG-exposed carcinoma in-situ (CIS ±Ta/T1) that recurred within 24 months of last BCG (BCG-exposed/BCG-relapsing NMIBC). Patients with BCG-unresponsive disease, contraindication to BCG, or prostatic/ureteral urothelial disease are excluded. Induction intravesical GEM (2000mg, twice weekly) is given weeks 1, 4, 7, and 10 and intravesical BCG (40mg, Tice strain, weekly) is given weeks 2, 3, 5, 6, 8, and 9. Responders receive SWOG maintenance BCG. The primary endpoint is clinical complete response (CR) at 6 months (absence of high-grade disease on cystoscopy/TURBT and negative cytology) using a Simon’s optimal 2-stage design testing the null hypothesis of a true CR of 55% at 6 months (based on historical outcomes of BCG alone) against a 1-sided alternative. In the first stage, the study would stop if ≤ 9/15 patients had a CR. In the second stage, the null hypothesis will be rejected if ≥ 29 CRs are observed in 43 total patients (type I error rate 5% and power of 80% if the true CR rate is 75%). Phase I patients treated at the MTD (14/25) are included in Phase II. Secondary outcomes include recurrence-free, progression-free, and cystectomy-free survival. Correlative studies explore immune and molecular predictors of response and resistance to chemoimmunotherapy in tumor tissue, urine, and blood. Clinical trial information: NCT04179162 .

The comparison of different BCG strains in the intravesical treatment of non-muscle invasive urothelial carcinoma of urinary bladder-A real-world practice.

Bacillus Calmette-Guérin (BCG) has been well recognized as the first-line intravesical therapy for high-risk non-muscle-invasive bladder cancer (NMIBC). Oncotice, the Tice strain of BCG, serves as a viable alternative to the Connaught strain owing to the worldwide shortage of the latter. We retrospectively compared these two strains in terms of efficacy and adverse effects (AE) in patients who underwent at least one maintenance course after induction. In this single-institution, retrospective study, patients diagnosed with NMIBC who were administered either Connaught or Tice intravesical therapy were enrolled. Recurrence was defined as the reappearance of urothelial carcinoma. Progression was defined as stage/grade advance, metastasis, or cancer-related death. The primary outcomes were recurrence-free survival (RFS) and progression-free survival (PFS), and the secondary outcome was AE. A total of 76 and 84 patients receiving Tice and Connaught, respectively were enrolled. The median follow-up periods for the Tice and Connaught groups were 32.0 months (range, 7-69 months) and 81.5 months (range, 9-154 months), respectively. Kaplan-Meier method showed no intergroup difference with regard to 3-year RFS and PFS. On Cox multivariate regression analysis, Tice was a significant predictor for inferior PFS (HR = 5.30; 95% CI, 1.11-25.29; p = 0.036). The AE incidence was 38.3% in the Connaught group and 25.0% in the Tice group (p = 0.079). Tice and Connaught were comparable in terms of RFS, PFS, and AE for patients with NMIBC accepting BCG induction and at least one maintenance course in our real-world practice. However, Tice was a predictor of inferior PFS on multivariate analysis.

The Comparison of Efficacy between the Connaught and Tice Strains of Bacillus Calmette-guérin in Patients with Non-muscle-invasive Bladder Cancer in Taiwan

Purpose: The purpose of the study is to compare the efficacy of Bacillus Calmette-Guérin (BCG) strains, Connaught (ImmuCyst®), and TICE (OncoTICE®) in patients with nonmuscle invasive bladder cancer (nMIBC). Materials and Methods: Patients with nMIBC who underwent transurethral resection between March 1997 and December 2017 were enrolled. TICE was used due to the Connaught strain shortage since 2012; hence, direct comparison of the two strains could not be performed. An intravesical instillation (IVI) regimen of mitomycin-C, doxorubicin, and cisplatin (MDP) was used as the reference for comparison. The MDP group was separated into two cohorts (MDP-1 and MDP-2) that matched the same time period of Connaught and TICE treatment. Patients who did not complete the IVI course before disease recurrence or progression or were not followed up for at least 24 months were excluded. Results: A total of 730 patients were included in the analysis. There were 67 (9.2%), 38 (5.2%), and 625 (85.6%) patients who received the Connaught, TICE, and MDP treatment, respectively. During a median follow-up duration of 59 months, the recurrence rates of the Connaught, MDP-1, TICE, and MDP-2 groups were 10.5%, 22.8%, 28.9%, and 23.0%, respectively. Both BCG groups had higher tumor grades and more instances of carcinoma in situthan their corresponding MDP cohorts. The Connaught and TICE strains had similar effects in preventing tumor recurrence (Connaught vs. MDP, P= 0.876; TICE vs. MDP, P= 0.556). In the multivariable Cox proportional hazard model that included all patients, the Connaught and TICE groups had a similar risk (hazard ratio = 0.784 and 0.850) of recurrence compared to the MDP protocol. Although progression events were more frequently noticed in the Connaught group, the small number of events limited the analysis. Conclusion: The BCG strains, Connaught and TICE, had similar efficacy in reducing bladder tumor recurrence in nMIBC patients. Both strains resulted in similar bladder recurrence-free survival rates to chemotherapeutic agents.

A recombinant selective drug-resistant M. bovis BCG enhances the bactericidal activity of a second-line anti-tuberculosis regimen

Drug-resistant tuberculosis (DR-TB) poses a new threat to global health; to improve the treatment outcome, therapeutic vaccines are considered the best chemotherapy adjuvants. Unfortunately, there is no therapeutic vaccine approved against DR-TB. Our study assessed the therapeutic efficacy of a recombinant drug-resistant BCG (RdrBCG) vaccine in DR-TB. We constructed the RdrBCG overexpressing Ag85B and Rv2628 by selecting drug-resistant BCG strains and transformed them with plasmid pEBCG or pIBCG to create RdrBCG-E and RdrBCG-I respectively. Following successful stability testing, we tested the vaccine’s safety in severe combined immune deficient (SCID) mice that lack both T and B lymphocytes plus immunoglobulins. Finally, we evaluated the RdrBCG’s therapeutic efficacy in BALB/c mice infected with rifampin-resistant M. tuberculosis and treated with a second-line anti-TB regimen. We obtained M. bovis strains which were resistant to several second-line drugs and M. tuberculosis resistant to rifampin. Notably, the exogenously inserted genes were lost in RdrBCG-E but remained stable in the RdrBCG-I both in vitro and in vivo. When administered adjunct to a second-line anti-TB regimen in a murine model of DR-TB, the RdrBCG-I lowered lung M. tuberculosis burden by 1 log10. Furthermore, vaccination with RdrBCG-I adjunct to chemotherapy minimized lung tissue pathology in mice. Most importantly, the RdrBCG-I showed almost the same virulence as its parent BCG Tice strain in SCID mice. Our findings suggested that the RdrBCG-I was stable, safe and effective as a therapeutic vaccine. Hence, the “recombinant” plus “drug-resistant” BCG strategy could be a useful concept for developing therapeutic vaccines against DR-TB.

Assessment of the oncological outcomes of three different bacillus Calmette–Guérin strains in patients with high-grade T1 non-muscle-invasive bladder cancer

ABSTRACT Objective : To determine whether there are significant differences in oncological outcomes between three different bacillus Calmette–Guérin (BCG) strains used for adjuvant intravesical immunotherapy in patients with high-grade T1 (T1HG) non-muscle-invasive bladder cancer (NMIBC). Patients and methods : Data of 590 patients with a diagnosis of primary T1HG NMIBC were retrospectively reviewed. The study included 138 (23.4%) patients who were treated with the Moreau, 272 (46.1%) with the TICE, and 180 (30.5%) with the RIVM strains. All patients included in the analysis received at least five instillations of an induction course and at least two installations of a maintenance course. Due to existing differences in baseline patient characteristics, the association between oncological outcomes and strain groups was investigated by complementary analysis with the implementation of inverse probability weighting (IPW). Results : The 5-year recurrence-free survival (RFS) rate was 70.5%, 66.7% and 55.2% for the Moreau, TICE and RIVM groups, respectively (P = 0.016). The 5-year progression-free survival (PFS) rates were 84.4%, 85% and 77.8% in the Moreau, TICE and RIVM groups, respectively (P = 0.215). The IPW-adjusted Cox proportional hazard regression analysis did not show any differences in RFS between the Moreau and TICE groups (P = 0.69), whereas the RIVM strain was significantly associated with worse RFS compared to the Moreau (hazard ratio [HR] 1.69 for RIVM; P = 0.034) and TICE (HR 1.87 for RIVM; P = 0.002) strains. The IPW-adjusted analysis did not show any significant differences between study groups in terms of PFS. Conclusions : The results of the present study suggest that the Moreau and TICE strains might be superior to the RIVM strain in terms of RFS in patients with T1HG NMIBC. Abbreviations: CIS: carcinoma in situ; IPW: inverse probability weighting; IQR: interquartile range; HR: hazard ratio; HG: high grade; LVI: lymphovascular invasion; MP: muscularis priopria; NMIBC: non-muscle-invasive bladder cancer; PFS: progression-free survival; RCT: randomised controlled trial; RFS: recurrence-free survival; T1HG, high-grade T1; (re-)TURB: (re-staging) transurethral resection of bladder; VH: variant histology

PD47-07 A GENETICALLY MODIFIED BCG THAT OVEREXPRESSES A STING AGONIST SHOWS ENHANCED ANTITUMOR EFFICACY MEDIATED BY AN M1 MACROPHAGE POLARIZATION WITH POTENTIATION OF TRAINED IMMUNITY

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV (PD47)1 Apr 2020PD47-07 A GENETICALLY MODIFIED BCG THAT OVEREXPRESSES A STING AGONIST SHOWS ENHANCED ANTITUMOR EFFICACY MEDIATED BY AN M1 MACROPHAGE POLARIZATION WITH POTENTIATION OF TRAINED IMMUNITY Alok Singh*, Monali Praharaj, Kara Lombardo, Andres Matoso, Gregory Joice, Takahiro Yoshida, Max Kates, David McConkey, William Bishai, and Trinity J. Bivalacqua Alok Singh*Alok Singh* More articles by this author , Monali PraharajMonali Praharaj More articles by this author , Kara LombardoKara Lombardo More articles by this author , Andres MatosoAndres Matoso More articles by this author , Gregory JoiceGregory Joice More articles by this author , Takahiro YoshidaTakahiro Yoshida More articles by this author , Max KatesMax Kates More articles by this author , David McConkeyDavid McConkey More articles by this author , William BishaiWilliam Bishai More articles by this author , and Trinity J. BivalacquaTrinity J. Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000934.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Trained immunity (TI) involving metabolic and epigenetic reprogramming of monocytes/macrophages confers a heightened immune status, and BCG has been shown to be a potent inducer of TI. We hypothesized that a genetically engineered BCG overexpressing a STING agonist may be a stronger inducer of antitumor TI. Using a recombinant BCG strain (BCG-disA-OE) which releases high levels of the STING agonist c-di-AMP, we tested induction of TI phenotypes in NMIBC models in vitro and in vivo. METHODS: WT-BCG (Tice strain) and BCG-disA-OE were compared for their induction of cytokines and phagocytic capacity in primary human and murine macrophages using ELISA, flow-cytometry, and immunofluorescence. We also measured epigenetic changes in the promoter regions of key cytokines using ChIP-PCR in human PBMC-derived monocytes. Antitumor efficacy was tested in the rat MNU-carcinogen model of NMIBC following intravesical BCG instillation weekly x 6 using histochemical tumor grading and qRT-PCR of bladder tissue. RESULTS: Compared with BCG-WT, BCG-disA-OE strains showed increased IFN I, IL-6, TNF-α, MCP-1 and IL-12 levels in primary macrophages and bladder cancer cell lines We observed increased M1 polarization shift and higher phagocytic capacity in primary macrophages after infection with rBCG-disA-OE. The modified BCG also elicited more pronounced epigenetic changes (H3K4Me3) on the TNF-α and IL-6 gene promoters following monocyte training. Intravesical instillations of BCG-disA-OE in MNU-rats resulted into significantly lower tumor involvement index and a more a potent induction of Th1 cytokines compared to BCG-WT. CONCLUSIONS: BCG-disA-OE demonstrated superior antitumor efficacy in the rat NMIBC model. It also elicited greater levels of pro-inflammatory cytokine secretion, M1 macrophage polarization, and epigenetic reprogramming. These observations suggest that BCG-disA-OE elicits more potent trained immunity changes monocytic cell populations in the bladder, and that elevated trained immunity may correlate with treatment outcome. BCG-disA-OE shows promise as a novel intravesical immunotherapy for NMIBC. Source of Funding: Maryland Tedco, Willowcroft Foundation, and Cigarette Restitution Fund © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e928-e928 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alok Singh* More articles by this author Monali Praharaj More articles by this author Kara Lombardo More articles by this author Andres Matoso More articles by this author Gregory Joice More articles by this author Takahiro Yoshida More articles by this author Max Kates More articles by this author David McConkey More articles by this author William Bishai More articles by this author Trinity J. Bivalacqua More articles by this author Expand All Advertisement PDF downloadLoading ...

Does asymptomatic bacteriuria affect the response to intravesical bacillus Calmette-Guérin?

To determine the initial response to intravesical bacillus Calmette-Guérin and the 3-year recurrence rate of high-risk non-muscle-invasive bladder cancer in patients who have asymptomatic bacteriuria. Response and recurrence rates were investigated in 505 patients with high-risk non-muscle-invasive bladder cancer after treatment with induction bacillus Calmette-Guérin (TICE strain) therapy. Initial response was determined after 3months and patients were followed every 3-6months for 3years. Before bacillus Calmette-Guérin and each follow-up cystoscopy, urine cultures were obtained, stratified as no growth, <104, >104 or>105colony-forming unit/mL. Any degree of bacteriuria on culture was classified as asymptomatic bacteriuria. Of the 505 cases, 270 (53%) had asymptomatic bacteriuria. A total of 89% of patients with asymptomatic bacteriuria showed a complete response to bacillus Calmette-Guérin versus 76% of uninfected patients (P=0.001), and 75% of bacteriuric patients survived tumor-free for 3years versus 65% of uninfected patients. Chronic bacteriuria might enhance the response of high-risk non-muscle-invasive bladder cancer to intravesical bacillus Calmette-Guérin and result in longer tumor-free survival than uninfected patients.

Abstract 3253: Next-gen STING-agonist like BCG confers enhanced immunogenicity and antitumor efficacy in vitro and in vivo

Abstract INTRODUCTION: Stimulator of interferon genes (STING), a cytosolic sensor of cyclic dinucleotide (CDN; c-di-AMP and c-di-GMP) activates type I interferons (IFN I) and pro-inflammatory cytokines. Recombinant Bacillus-Calmette Guerin (BCG) overexpressing CDN (STING-agonist) remains unexplored in non-muscle invasive bladder cancer (NMIBC). We hypothesize that intravesical recombinant BCG is more efficacious than BCG for NMIBC. We constructed a novel STING-agonist-like recombinant BCG Pasteur and Tice strains (rBCG-disA-OE) carrying plasmids that harbors di-adenylate cyclase (disA) gene to test this hypothesis. METHODS: WT and rBCG-disA-OE were tested for immunotherapeutic potential in WT and STING-deficient murine macrophages, to ascertain STING-dependent IFN I and pro-inflammatory cytokines activation. Similar experiments were conducted in RT4, J5637, and NBT2 cell lines. Fisher 344 rats intravesically received 4 doses of 1.5 mg/kg N methyl N nitrosurea (MNU) to induce NMIBC. Intravesical instillation of WT- and rBCG-disA-OE was administered weekly x 6. Histologic tumor grade, tumor involvement index, gene expression (q-PCR) as well as systemic immune responses (ELISA) were assessed. Growth and virulence of rBCG-disA-OE in BALB/c and SCID mice were tested using aerosol infection protocol. RESULTS: rBCG-disA-OE Pasteur and TICE strains overexpressing STING-agonist were potent inducers of IFN I in STING-dependent manner in murine macrophages. IFN I induction by rBCG-disA-OE increased TNF-α (P=0.01), IL-6 (P=0.04) and IL-1β (P=0.004) in bladder cancer cells and murine macrophages. Intravesical instillation of rBCG-disA-OE in MNU-rats resulted into significantly (P=0.004) lower tumor involvement index accompanied by a potent induction of IFN I signaling, M1 macrophage associated cytokines (Nos2, P=0.05 &amp; IL-6 P=0.05) and chemokines (CCL2, P=0.048 &amp; MCP-1, P=0.05). rBCG-disA-OE prevented invasive cancer when compared WT-BCG. BALB/c mice infected with rBCG-disA-OE showed significantly less lung bacillary burden (P=0.005) suggesting strain attenuation. SCID-mice infected with rBCG-disA-OE had prolonged survival. CONCLUSION: We demonstrate STING-agonist like rBCG-disA-OE is superior to WT-BCG for induction of macrophage cytotoxicity and activation of IFN I signaling. rBCG-disA-OE demonstrated enhanced antitumor activity and cytokine production in a pre-clinical model of NMIBC suggesting an alternative intravesical agent in BCG unresponsive population. Note: This abstract was not presented at the meeting. Citation Format: Alok K. Singh, Monali Praharaj, Gregory A. Joice, Takahiro Yoshida, Max Kates, David McConkey, William R. Bishai, Trinity J. Bivalacqua. Next-gen STING-agonist like BCG confers enhanced immunogenicity and antitumor efficacy in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3253.

Are There Differences in Toxicity and Efficacy between Various Bacillus Calmette-Guerin Strains in Bladder Cancer Patients? Analysis of 844 Patients

Purpose: To evaluate if there are differences in toxicity and efficacy between different Bacillus Calmette-Guerin (BCG) stains used for intravesical immunotherapy in patients with non-muscle invasive bladder cancer. Methods: We retrospectively analysed a group of 844 patients who received TICE, RIVM and Moreau BCG strains. The allocation of the strain to each patient was random, stemming from differences in supply and distribution. The patients were analysed in terms of toxicity, recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS) and overall survival (OS). Results: In the survival analysis, statistical significance was not reached in any tumour group for any clinical event. TICE caused more local and mild adverse effects and severe complications were mainly associated with RIVM strain. In a group in which the strain was changed during the course of the therapy, significantly more severe complications were observed and, in most of these cases, complications appeared right after the strain change. Conclusions: There were no differences in terms of RFS, PFS, CSS and OS after use of TICE, RIVM and Moreau strains. The complication profile differed statistically between used strains with TICE causing mostly mild complications. Also, strain change during the therapy course was associated with the increased risk of moderate to severe toxicity occurrence.

Safety and efficacy of various strains of bacille Calmette–Guérin in the treatment of bladder tumors in standard clinical practice

BackgroundThe natural progression of bladder tumors (nonmuscle-invasive bladder cancer [NMIBC]) is recurrence with a high rate of progression. Bacille Calmette–Guérin (BCG) has been shown effective in reducing these rates, but there are few comparative studies between strains. Material and methodsAn observational, prospective and multicentre registry studied 433 patients with a 12-month follow-up visit from 961 registered patients, assessing disease-free survival (DFS), progression-free survival (PFS) cancer-specific survival (CSS) and adverse effects. We studied the Tice, Russian, Tokyo, Connaught and RIVM strains. ResultsThe sociodemographic data, NMIBC history, comorbidities, size, number, stage, grade, associated carcinoma in situ and transurethral resection were well balanced. DFSThere were 85 relapses (19.6%). The median DFS time was 20months. When comparing the various strains, we detected no statistically significant differences (log-rank test; p=0.93). LPS: There were 33 cases of progression (7.62%). When comparing the various strains, we detected no statistically significant differences (log-rank test; p=0.69). CSS: Seven patients died (1.68%). When comparing the various strains, we detected no statistically significant differences (log-rank test; p=0.93).In terms of safety, 33.3% of the patients presented some type of adverse effect, mostly lower urinary symptoms (no urinary tract infections) <48h, >48h and haematuria. According to the Common Toxicity Criteria of the European Organisation for Research and Treatment of Cancer, 92.7% of the patients were grade 1. There were no statistically significant differences between the strains. ConclusionsIn this intermediate analysis, the risk of recurrence, progression, specific death and safety were independent of the BCG strain employed.

Eficacia y seguridad de distintas cepas de BCG en el tratamiento del tumor vesical en práctica clínica habitual

BackgroundThe natural progression of bladder tumours (nonmuscle-invasive bladder cancer [NMIBC]) is recurrence with a high rate of progression. Bacille Calmette-Guérin (BCG) has been shown effective in reducing these rates, but there are few comparative studies between strains. Material and methodsAn observational, prospective and multicentre registry studied 433 patients with a 12-month follow-up visit from 961 registered patients, assessing disease-free survival (DFS), progression-free survival (PFS) cancer-specific survival (CSS) and adverse effects. We studied the Tice, Russian, Tokyo, Connaught and RIVM strains. ResultsThe sociodemographic data, NMIBC history, comorbidities, size, number, stage, grade, associated carcinoma in situ and transurethral resection were well balanced.DFS: There were 85 relapses (19.6%). The median DFS time was 20months. When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.93). LPS: There were 33 cases of progression (7.62%). When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.69). CSS: Seven patients died (1.68%). When comparing the various strains, we detected no statistically significant differences (log-rank test; P=.93).In terms of safety, 33.3% of the patients presented some type of adverse effect, mostly lower urinary symptoms (no urinary tract infections) <48h, >48h and haematuria. According to the Common Toxicity Criteria of the European Organisation for Research and Treatment of Cancer, 92.7% of the patients were grade1. There were no statistically significant differences between the strains. ConclusionsIn this intermediate analysis, the risk of recurrence, progression, specific death and safety were independent of the BCG strain employed.

Données comparatives moléculaires, précliniques et cliniques des différentes souches de bacille de Calmette-Guérin (BCG) : revue de la littérature du Comité de cancérologie de l’Association française d’urologie (CCAFU)

To review the differences between the BCG strains used for the treatment of non-muscle invasive bladder cancer (NMIBC) at the molecular level, regarding cytotoxicity, immunogenicity, clinical efficiency, and safety. A systematic review of the literature search was performed from the database MedLine, focused on the following keywords: BCG; bladder; strain; genome; cytotoxicity; immune response; efficiency; safety. Genetic differences between BCG strains have been identified and correlated to their time to differentiation from their initial cultures start, assuming a lower resistance to the host immune defenses of Tice and Danish strains compared to the Connaught strain. Preclinical comparative data showed superior cytotoxic effect and immunogenicity of the Connaught strain compared to Tice and Danish strains. The phaseIII trials have shown superior efficiency of BCG Connaught compared to BCG Tice and BCG Danish compared to BCG Tice regarding recurrence-free survival. Among BCG strains used in France in NMIBC treatment, preclinical and clinical efficiency of Connaught strain was higher than that of the Tice strain. The limits of the currently available studies lie primarily in the lack of use of maintenance therapy.

Systemic BCG-Osis as a Rare Side Effect of Intravesical BCG Treatment for Superficial Bladder Cancer

Intravesical Bacilli Calmette-Guérin (BCG) immunotherapy is a commonly used treatment for superficial bladder cancer. Although the treatment is well tolerated in 95% of cases, life-threatening side effects including BCG sepsis can occur. This report describes the case of an 82-year-old man with a background of lung disease. He developed septic shock and type two respiratory failure after receiving the sixth installation of intravesical BCG (TICE strain) immunotherapy for recurrent bladder Transitional Cell Carcinoma in situ. Despite the early initiation of broad spectrum antibiotics (tazocin and gentamicin), he remained pyrexial. There was a rapid deterioration, and on the second day of his admission, he developed type two respiratory failure secondary to Acute Respiratory Distress Syndrome (ARDS) prompting transfer to Intensive Care for Bilevel Positive Airway Pressure (BiPAP) Ventilation. The blood cultures taken before the induction of antibiotics results were negative. Increasing clinical suspicion of systemic BCG-osis prompted the initiation of antituberculosis therapy (ethambutol, isoniazid rifampicin) and steroids. Following six days of BiPAP and anti-tuberculosis therapy in ITU, his condition started to improve. Following a prolonged hospital stay he was discharged on long term ethambutol therapy. BCG-osis is a well-known though rare side effect of intravesical BCG therapy. We would like to highlight the importance of having a low threshold for starting anti-TB treatment.

Abstract 5390: Anti-IL10-R1 monoclonal antibody with concomitant bacillus calmette-Guérin (BCG) prevents metastatic bladder cancer in an in vivo mouse model

Abstract Introduction: Induction of Th1 immunity is required for effective intravesical BCG immunotherapy of bladder cancer. IL-10 down-regulates the Th1 response and is associated with BCG failure. We previously demonstrated that blocking IL-10 receptor (IL-10R) by systemic administration of anti-IL-10R1 mAb enhanced intravesical BCG (living Pasteur strain) treatment of bladder cancer in an orthotopic mouse model. Here we investigated the effect of anti-IL-10R1 mAb on clinically used BCG (lyophilized TICE strain) for induction of anti-bladder cancer immunity. Methods: Splenocytes were incubated with BCG alone or plus control IgG or ant-IL-10R1 mAb for 24 hours, followed by ELISA analysis of IFN-γ production. Bladder RNA was extracted after 6 treatments (twice weekly) with intravesical (i.b.) BCG plus intraperitoneal (i.p.) control IgG or anti-IL-10R1 mAb, followed by qPCR analysis of IFN-γ mRNA expression. Three groups of 20 mice were inoculated with luciferase-expressing MB49 bladder cancer cells and treated with i.b. PBS plus i.p. PBS (Group 1), i.b. BCG plus i.p. control IgG (Group 2), or i.b. BCG plus i.p. anti-IL-10R1 mAb (Group 3) 2x/wk for 6 total treatments. Mice were monitored weekly using IVIS luminescence and followed for 76 days. A bioluminesence cutoff of 5X104 p/s was used to establish the presence of bladder cancer. At animal death bladders were collected, weighed and processed for histological analysis. In suspected cases of metastatic disease the affected organs were also collected for histological analysis. Results: BCG plus anti-IL-10R1 mAb induced increased IFN-γ production by splenocytes in a dose-dependent manner. BCG plus anti-IL-10R1 mAb substantially increased IFN-γ mRNA. Eleven, 17 and 9 mice from Groups 1, 2 and 3, respectively, developed bladder cancer. One mouse in Group 2 and 2 mice in Group 3 showed cancer regression. 36%, 53% and 0% of Groups 1, 2 and 3 developed metastatic bladder cancer, respectively (p=0.020). While bladder weights for the groups were different, the differences did not reach statistical significance. Conclusions: Anti-IL-10R1 mAb enhances BCG-induced Th1 immune responses both in vitro and in vivo. Intravesical BCG plus anti-IL-10R1 mAb shows statistical significance in preventing metastasis of bladder cancer in an orthotopic bladder tumor mouse model. Anti-IL-10R1 mAb may prove useful in clinical practice for the prevention of metastatic bladder cancer in high-risk patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5390. doi:1538-7445.AM2012-5390

Mycobacterial Infection after Intravesical Bacillus Calmette-Gu?rin Treatment for Bladder Cancer: A Case Report

Bacillus Calmette-Guërin (BCG) has been traditionally used as a vaccine against tuberculosis. Further, intravesical administration of BCG has been shown to be effective in treating bladder cancer. Although BCG contains a live attenuated strain of Mycobacterium bovis, complications such as M. bovis BCG infection caused by BCG administration are extremely rare. Here, we report a case of BCG infection occurring after intravesical BCG therapy. A 67-yr-old man presented with azotemia and weight loss. He had been diagnosed with bladder cancer 4 yr back, and had undergone transurethral resection of the bladder tumor and intravesical BCG (Tice strain) therapy at that time. An acid-fast bacterial strain was isolated from his urine sample. We did not detect Mycobacterium tuberculosis protein 64 (MPT-64) antigen in the isolates obtained from his sample, and multiplex PCR and PCR-reverse blot hybridization assay indicated that the isolate was a member of the M. tuberculosis complex, but was not M. tuberculosis. Finally, sequence analysis of 16S ribosomal RNA and DNA gyrase, subunit B (gyrB) suggested that the organism was M. bovis or M. bovis BCG. Although we could not confirm that M. bovis BCG was the causative agent, the results of the 3 molecular methods and the MPT-64 antigen assay suggest this finding. This is an important finding, especially because M. bovis BCG cannot be identified using common commercial molecular genetics tools.

1658 EFFICACY OF IMMEDIATE POST-TUR MITOMYCIN-C (MMC) INSTILLATION IN HIGH RISK NON-MUSCLE INVASIVE BLADDER CANCER TREATED WITH BACILLUS CALMETTE-GUERIN (BCG)

You have accessJournal of UrologyBladder Cancer: Superficial1 Apr 20111658 EFFICACY OF IMMEDIATE POST-TUR MITOMYCIN-C (MMC) INSTILLATION IN HIGH RISK NON-MUSCLE INVASIVE BLADDER CANCER TREATED WITH BACILLUS CALMETTE-GUERIN (BCG) Moon-Ki Jo, Kanghyon Song, and Jong-Wook Park Moon-Ki JoMoon-Ki Jo Seoul, Korea, Republic of More articles by this author , Kanghyon SongKanghyon Song Seoul, Korea, Republic of More articles by this author , and Jong-Wook ParkJong-Wook Park Seoul, Korea, Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1768AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To evaluate the efficacy of immediate post-TUR MMC instillation in high risk non-muscle invasive bladder cancer treated with BCG. METHODS From January 2000 to December 2007, 162 high risk non-muscle invasive bladder cancer patients underwent TUR and BCG instillation at our institution. Among them 76 patients received additional immediate post-TUR MMC instillation (Group A), and remaining 86 patients underwent TUR and BCG instillation only (Group B). Sixty mg of MMC was mixed with 50ml of normal saline and was instilled in bladder within 4 hours after TUR. Tice strain BCG 12.5mg was used with 6-week induction course followed by 3-week maintenance every 3 months. The recurrence rate, time to recurrence, and stage and grade at recurrence were invstigated. The mean follow-up was 33.4 months. RESULTS There were no significant differences in the characteristics of both groups, including age, sex, stage, and grade. Group A showed significantly lower recurrence rate than Group B (26.3% vs 48.8%, p=0.003). Group A showed somewhat longer time to recurrence but it was not statistically different (24.9 months vs 21.8 months, p=0.293). The change in stage and grade at recurrence were not different between 2 groups. The 5 year recurrence free survival rate was significantly higher in Group A (72% vs 42%, p=0.003). CONCLUSIONS The immediate post-TUR MMC instillation significantly reduced recurrence in high risk non-muscle invasive bladder cancer patients treated by BCG. But it did not influenced the stage and grade at recurrence. Changes in the stage and grade at recurrence MMC + BCG (Group A) BCG (Group B) p-value T stage up 10.0%(2/20) 14.3%(6/42) 0.645 unchanged 55.0%(11/20) 47.6%(20/42) down 35.0%(7/20) 38.1%(16/42) Grade up 15.0%(3/20) 23.8%(10/42) 0.434 unchanged 65.0%(13/20) 61.9%(26/42) down 20.0%(4/20) 14.3%(6/42) © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e666 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Moon-Ki Jo Seoul, Korea, Republic of More articles by this author Kanghyon Song Seoul, Korea, Republic of More articles by this author Jong-Wook Park Seoul, Korea, Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Efficacy of immediate post-TUR mitomycin-C (MMC) instillation in high-risk non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG).

281 Background: To evaluate the efficacy of immediate post-TUR MMC instillation in high risk non-muscle-invasive bladder cancer treated with BCG. Methods: From January 2000 to December 2007, 162 high-risk non-muscle-invasive bladder cancer patients underwent TUR and BCG instillation at our institution. Among them 76 patients received additional immediate post-TUR MMC instillation (Group A), and remaining 86 patients underwent TUR and BCG instillation only (Group B). 60mg of MMC was mixed with 50ml of normal saline and was instilled in bladder within 2 hours after TUR. Tice strain BCG 12.5mg was used with 6-week induction course followed by 3-week maintenance every 3 months. The recurrence rate, time to recurrence, and stage and grade at recurrence were investigated. The mean follow-up was 33.4 months. Results: There were no significant differences in the characteristics of both groups, including age, sex, stage, and grade. Group A showed significantly lower recurrence rate than Group B (26.3% vs 48.8%, p=0.003). Group A showed somewhat longer time to recurrence but it was not statistically different (24.9 months vs 21.8 months, p=0.293). The change in stage and grade at recurrence were not different between 2 groups ( Table ). The 5-year recurrence free survival rate was significantly higher in Group A (72% vs 42%, p=0.003). Conclusions: The immediate post-TUR MMC instillation significantly reduced recurrence in high risk non-muscle-invasive bladder cancer patients treated by BCG. But it did not influenced the stage and grade at recurrence. [Table: see text] No significant financial relationships to disclose.

INTERFERENCE OF MODERN ANTIBACTERIALS WITH BACILLUS CALMETTE-GUERIN VIABILITY

We determine the effects of modern antibacterial chemotherapeutics on bacillus Calmette-Guerin (BCG) viability, particularly those of cycloserine, which has been recommended for treating BCG induced sepsis. The minimal inhibitory concentrations of 31 antibacterial drugs against Connaught BCG strain were determined in vitro by the radiometric BACTEC 460TB method. Minimal inhibitory concentrations were compared with the drug concentrations achievable in blood and urine to estimate systemic or intravesical susceptibility. Susceptibility testing of cycloserine was performed with Connaught, Tice and RIVM BCG strains, using the modified proportion method on Lowenstein-Jensen agar. Connaught BCG was susceptible to quinolones in systemic infections but resistant to beta-lactams, macrolides and some aminoglycosides. It was resistant to pyrazinamide but showed good susceptibility toward the other antituberculosis drugs tested. All 3 BCG strains analyzed were resistant to cycloserine. Most antibacterials may interfere with BCG in the bladder because of high urinary recovery. Antibacterial drug interference with BCG viability should be avoided during intravesical instillation therapy. In cases of severe complications quinolones rather than cycloserine may be given in addition to standard triple antituberculosis drug therapy or if one of these drugs is not tolerated. Our data may contribute toward enhancing the therapeutic safety and efficacy of intravesical BCG immunotherapy by the appropriate use of antibacterial drugs.