Bacillus Calmette-Guérin Immunotherapy Research Articles

Systemic versus localized Bacillus Calmette Guérin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: Novel role of trained immunity.

Treatment for higher-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti-tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time-to-recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG-induced trained immunity modulates anti-tumor immune responses. Compared with intravesical BCG, which led to a tumor-promoting immune microenvironment, intravenous BCG resulted in an anti-tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid-derived suppressor cells. Polarization toward anti-tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre-treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre-treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co-instillation of BCG-trained macrophages with ovalbumin-expressing bladder tumor cells increased the proportion of tumor-specific CTLs. Furthermore, BCG-trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti-tumor responses, and that BCG-induced trained immunity is important in driving anti-tumor adaptive immunity.

BCG immunotherapy promotes tumor-derived T-cell activation through the FLT3/FLT3LG pathway in bladder cancer.

Bladder instillation therapy is a common treatment for superficial or nonmuscle invasive bladder cancer. After surgery or reresection, chemotherapy drugs (epirubicin) or medications such as Bacillus Calmette-Guérin (BCG) are used for bladder instillation therapy, which can reduce the risk of bladder cancer recurrence and progression. However, the specific mechanism by which BCG stimulates the antitumor response has not been thoroughly elucidated. Additionally, although BCG immunotherapy is effective, it is difficult to predict which patients will have a positive response. In this study, we explored the BCG-induced immune response and found that high levels of Fms-related receptor tyrosine kinase 3 ligand (FLT3LG) were expressed after BCG treatment. This FLT3LG can directly act on CD8+ T cells and promote their proliferation and activation. The use of FLT3 inhibitors can neutralize the antitumor effects of BCG. In vitro experiments showed that FLT3LG can synergize with T-cell receptor activators to promote the activation of tumor-derived T cells. This study partially elucidates the mechanism of CD8+ T-cell activation in BCG immunotherapy and provides a theoretical basis for optimizing BCG instillation therapy in bladder cancer.

Abstract B051: GSTT2 modulates the bladder tumor environment and response to BCG Immunotherapy

Abstract The purpose of this study was to elucidate the impact of Glutathione -S-transferase Theta 2 (GSTT2) loss on the response of bladder tumors to Mycobacterium Bovis, Bacillus Calmette Guerin (BCG) immunotherapy. GSTT2 gene expression is controlled by a promoter deletion that occurs frequently in 25-29% of Asians and 41% of Caucasians. The GSTT2 promoter deletion correlated with better response to BCG therapy in a retrospective analysis of patients who received less BCG therapy. To understand this response, we generated GSTT2 knockout mice to elucidate the role of GSTT2 in BCG immunotherapy. Female C57BL/6J mice from GSTT2 wildtype (WT) and KO backgrounds were orthotopically implanted with MB49-PSA cells (murine MB49 cells secreting human PSA). To view the impact of GSTT2 loss on BCG immunotherapy, mice were treated with only 4 instillations of BCG Tokyo. This therapeutic schedule would not result in a high cure rate and but was chosen as we expected it to provide insights into the anti-tumor response. Mice were treated weekly with intravesical BCG Tokyo instillations and tumor growth was monitored by urinary PSA secretion. Final tumor presence was confirmed by real-time PCR analysis of PSA gene expression. One day after the last instillation the bladders (n=7) were harvested for single cell RNA sequencing (Parse Biosciences). Cell clusters were identified by their gene expression profiles. The response to BCG in terms of the cure rate was similar in KO and WT mice (cure rate of 18-20%) but several genes were differentially expressed. Genes with a Log2FC value of +1.5 in KO mice (Peak1, Rpph1, Gphn and Gm19551) and -1.5 in KO (Rora, Tshz2, Sh3gl2, Ankfn1, Rbms3, Naaladl2, Prkn, Mecom, Fmo5, Saa3, Tmprss2, C3, Gm10800 and Gm10801) relative to WT mice were examined. Based on the literature, these genes either block tumor progression (Rora, Tshz2, Sh3gl2 and Gphn); promote tumor progression (Ankfn1, Rbms3, Naaladl2, Prkn, Mecom, Fmo5, Tmprss2, Saa3, C3, Peak1, Rpph1) or modulate immune cells (C3, Saa3 and Rpph1). The majority of these genes were not previously associated with bladder cancer. Interrogation of the TCGA database showed that high expression of Gphn, Peak1 and GSTT2 correlated with poorer outcomes in bladder cancer patients in terms of disease-free survival (HR=1.9 log rank p=0.00038). While expression of the genes downregulated in KO mice and GSTT2 resulted in better outcomes with lower expression of all the genes (HR=1.4, log rank p=0.042). This data indicates that the loss of GSTT2 expression impacts the response of tumors to BCG immunotherapy, primarily by modulating the expression of genes associated with cancer progression and the expression of genes in multiple cell types. Given the common loss of GSTT2 expression in man this gene may be a parameter that should be evaluated in further detail in patients receiving BCG immunotherapy. Citation Format: Ratha Mahendran, Mugdha Vijay Patwardhan, Qin Kane Toh, Edmund Chiong. GSTT2 modulates the bladder tumor environment and response to BCG Immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B051.

Engineered Macrophages Tune Intratumoral Cytokines through Precisely Controlled Self-Pyroptosis to Enhance Bladder Cancer Immunotherapy.

Engineered macrophages are a promising tool for drug delivery and immunotherapy in cancer treatment. However, simultaneous targeted enrichment and controllable immunological activation of these macrophages at the tumor site remains challenging. As a solution, macrophages loaded with an advanced nanoparticle encapsulating CpG-conjugated magnetic nanoclusters (MNC) with indocyanine green (ICG) and nigericin (NIG) (MNC-ICG-NIG@SiO2 (MINS)), utilizing Se─Se bond-modified SiO2, are designed and applied in bladder cancer, which is typically managed surgically, followed by Bacillus Calmette-Guerin (BCG) adjuvant instillation therapy. Upon intravenous administration, BCG-mediated tumor-localized inflammation leads to targeted accumulation of MINS@MΦ. MINS@MΦ accumulates within the tumor tissue and is immunologically activated through laser irradiation, leading to ICG-mediated generation of reactive oxygen species, Se─Se bond cleavage, and subsequent NIG release to induce self-pyroptosis. Consequently, MINS@MΦ releases Fe2+ ions and CpG, thus promoting the M1 polarization of tumor-associated macrophages and secretion of appropriate antitumor cytokines. However, without intervention, MINS@MΦ undergoes apoptosis in the bloodstream after 48h without eliciting any immune response. Therefore, this innovative approach optimizes and enhances the efficacy of BCG immunotherapy by precisely modulating the cytokines for effective bladder cancer treatment without inducing a systemic inflammatory response.

Prognosis of patients with T1 low-grade urothelial bladder cancer treated with bacillus Calmette-Guérin immunotherapy.

The existence and prognosis of T1LG (T1 low-grade) bladder cancer is controversial. Also, because of data paucity, it remains unclear what is the clinical history of bacillus Calmette-Guérin (BCG) treated T1LG tumors and if it differs from other NMIBC (non-muscle-invasive bladder cancer) representatives. The aim of this study was to analyse recurrence-free survival (RFS) and progression-free survival (PFS) in patients with T1LG bladder cancers treated with BCG immunotherapy. A multi-institutional and retrospective study of 2510 patients with Ta/T1 NMIBC with or without carcinoma in situ (CIS) treated with BCG (205 T1LG patients) was performed. Kaplan-Meier estimates and log-rank test for RFS and PFS to compare the survival between TaLG, TaHG, T1LG, and T1HG NMIBC were used. Also, T1LG tumors were categorized into EAU2021 risk groups and PFS analysis was performed, and Cox multivariate model for both RFS and PFS were constructed. The median follow-up was 52 months. For the T1LG cohort, the estimated RFS and PFS rates at 5-year were 59.3% and 89.2%, respectively. While there were no differences in RFS between NMIBC subpopulations, a slightly better PFS was found in T1LG NMIBC compared to T1HG (5-year PFS; T1LG vs. T1HG: 82% vs. 89%; P<0.001). A heterogeneous classification of patients with T1LG NMIBC was observed when EAU 2021 prognostic model was applied, finding a statistically significant worse PFS in patients classified as high-risk T1LG (5-year PFS; 81.8%) compared to those in intermediate (5-year PFS; 93,4%), and low-risk T1LG tumors (5-year PFS; 98,1%). The RFS of T1LG was comparable to other NMIBC subpopulations. The PFS of T1LG tumors was significantly better than of T1HG NMIBC. The EAU2021 scoring model heterogeneously categorized the risk of progression in T1LG tumors and the high-risk T1LG had the worst PFS.

Systemic Bacillus Calmette-Guérin (BCG) Infection and Accompanying Warm Autoimmune Haemolytic Anaemia Following Intravesical BCG Immunotherapy.

Systemic bacillus Calmette-Guérin (BCG) infection following intravesical BCG instillation is a rare but serious consequence. A high level of suspicion and scrutiny of history is of paramount importance for diagnosis.Autoimmune haemolytic anaemia secondary to systemic BCG infection is even rarer.Autoimmune haemolytic anaemia resolution was in parallel with improvement in systemic BCG infection.

Intratumoral PD1+CD38+Tim3+ CD8+ T Cells in Pre-BCG Tumor Tissues Are Associated with Poor Responsiveness to BCG Immunotherapy in Patients with Non-Muscle Invasive Bladder Cancer.

Intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) is a standard of care therapy for non-muscle invasive bladder cancer (NMIBC), which accounts for about 75% of newly diagnosed urothelial cancer. However, given the frequent recurrence and progression, identification of a pre-treatment biomarker capable of predicting responsiveness to BCG in NMIBC is of utmost importance. Herein, using multiparametric flow cytometry, we characterized CD8+ T cells from peripheral blood and tumor tissues collected from 27 pre-BCG patients bearing NMIBC to obtain immune correlates of bladder cancer prognosis and responsiveness to BCG therapy. We observed that intratumoral CD8+ T cell subsets were highly heterogenous in terms of their differentiation state and exist at different proportions in tumor tissues. Remarkably, among the different CD8+ T cell subsets present in the tumor tissues, the frequency of the terminally exhausted-like CD8+ T cell subset, marked as PD1+CD38+Tim3+ CD8+ T cells, was inversely correlated with a favorable outcome for patients and a responsiveness to BCG therapy. Moreover, we also noted that the intratumoral abundance of the progenitor exhausted-like PD1+CD8+ T cell subset in pre-BCG NMIBC tumor tissues was indicative of better recurrence-free survival after BCG. Collectively, our study led to the identification of biomarkers that can predict the therapeutic responsiveness of BCG in NMIBC.

Mathematical model for BCG-based treatment of type 1 diabetes

This work introduces the first model of immunotherapy treatment, namely the Bacillus Calmette-Guerin (BCG) vaccine, for Type 1 Diabetes (T1D). The model takes into consideration the interaction network between multiple immune cell types and compartments. A set of ordinary differential equations (ODEs) is introduced to capture the connectivity between these variables and the clinical presentation of the disease. Four subsets of the T1D mice and healthy controls that exhibit normal and high-level glucose consumption are evaluated using the proposed model. Numerical results obtained for mice suggest that BCG treatment of the T1D patients that follow healthy eating habits normalizes glucose to levels observed in non-diabetic controls. Furthermore, glucose consumption profoundly influences disease progression. This outcome suggests that immunotherapy may modulate molecular and cellular manifestations of the disease but it does not eliminate T1D. Of note, our data, obtained from numerical simulations, indicate that the BCG immunotherapy treatment may benefit healthy controls on a high-glucose diet and can be used as a tool for further clinical investigation of BCG usage to control T1D.

Association of Histone H3 Trimethylation in Circulating Monocytes with Lack of Early Recurrence in Patients with Bladder Cancer following BCG Induction Therapy

BACKGROUND: The mode of action of Bacillus Calmette-Guérin (BCG) in the treatment of patients with non-muscle invasive bladder cancer (NMIBC) is incompletely understood, but recent studies support an association between BCG-induced trained immunity in circulating monocytes and disease-free survival. OBJECTIVE: We compared epigenetic profiles in monocytes from NMIBC patients with early disease recurrence with those from recurrence-free patients. METHODS: We conducted chromatin immunoprecipitation and DNA sequencing (ChIP-seq) on monocytes from seven patients treated with BCG (four with early recurrences and three recurrence-free after one year) to determine genome-wide distribution and abundance of histone 3 lysine 4 trimethylation (H3K4me3) prior to and after five weeks of induction therapy. RESULTS: Genome-wide H3K4me3 profiles before or after BCG induction distinguished patients with early recurrences from those remaining recurrence-free. Furthermore, H3K4me3 levels at genes involved in specific pathways were increased in the recurrence-free group. Independent quantification showed increased H3K4me3 levels in elements of the Wnt and AMPK signaling pathways in the recurrence-free group before BCG initiation, while elements of the MAPK showed increased levels after five weeks of induction in the same group. Validation of these genes on an independent cohort of four additional patients that remained recurrence-free after one year and three with early recurrences revealed consistent increases in H3K4me3 levels associated with MAPK pathway genes after five weeks of BCG treatment in the recurrence-free group. CONCLUSIONS: Recurrence-free survival following BCG immunotherapy for NMIBC is associated with the accumulation of H3K4me3 at specific gene loci, and could lead to identification of prognostic biomarkers.

Topical instillation of BCG immunotherapy for biopsy-proven primary upper urinary tract carcinoma in situ: A single institution series and systematic review.

Primary upper tract carcinoma in situ (UTcis) is a rare disease whose diagnosis and natural history are poorly understood. Radical nephroureterectomy is the standard of care but in imperatives or selected cases, topical instillations of Bacillus Calmette-Guérin (BCG) may represent a good alternative. The aim of this study was to report the histologic response to BCG instillations for the treatment of biopsy-proven UTcis and to systematically assess the current evidence on topical BCG instillation for the treatment of UTcis. This is a retrospective analysis of patients with biopsy-proven UTcis treated with BCG instillation between 1995 and 2020 in an expert center. The initial diagnosis was performed by a standardized random biopsy scheme during ureterorenoscopy (URS) in patients with positive cytology but negative CT and bladder biopsies. BCG course consisted of 6 weekly instillation of 81 mg Immucyst (Sanofi Pasteur MSD AG, Baar, Switzerland). Administration techniques were single-J, double-J and nephrostomy tube. The primary outcome was the rate of complete histological response at the 3-month 2nd-look-URS. Kaplan-Meier analysis curves assessed recurrence- and progression-free survival. A total of 22 patients (23 renal units) were included. Twenty-one (91.3%) patients completed the planned 6-week instillation cycle. Only one major complication was recorded (renal tuberculosis). Twenty patients had a 3-month 2nd-look-URS, with a complete histological response achieved in 17/20 cases (85%). After a median time of follow-up of 40 months (30-62), 8/20 patients harbored disease recurrence, including 5 cases of disease progression (≥pT2). The main limitations are the retrospective and non-comparative design of the study. Our systematic review (CRD42022324876) identified 15 studies (289 renal units). UTcis suffers from the lack of a standardized definition, and considerable heterogeneity has been found in making the diagnosis and assessing the response to treatment. Our study is the first to propose a histological diagnosis of UTcis as well as a histological re-evaluation of the response to treatment. Topical instillations of BCG appear to be a promising alternative, avoiding radical treatment in the majority of cases.

HER2/neu expression status of post BCG recurrent non-muscle-invasive bladder urothelial carcinomas in relation to their primary ones.

Transurethral resection (TUR) followed by adjuvant therapy is still the treatment of choice of Non-Muscle-Invasive Bladder Urothelial Carcinoma (NMIBUC). However, recurrence is one of the most troublesome features of these lesions. Early second resection and adjuvant BCG therapy has been shown to improve the outcome. To evaluate the prognostic value of C-erbB-2 (HER2/neu) expression status in Non-Muscle-Invasive Bladder Urothelial Carcinoma cases, before and after intravesical Bacillus Calmette Guerin (BCG immunotherapy). HER2/neu expression was studied in 120 (Ta-T1) Non-Muscle-Invasive Urothelial Carcinoma cases. The expression was evaluated and compared to the expression after Bacillus Calmette Guerin (BCG) immunotherapy. HER2/neu expression in low and high grade of the Non- Muscle-Invasive Urothelial Carcinoma was (38%) and (83%) respectively. The difference of the expression rates by tumor grade was statistically significant. In recurring lesions post BCG therapy, C-erbB-2 expression was markedly decreased (31.6%) when compared to its expression before therapy (65%). The HER2/neu expression increased as the tumor grade rose. The reduction in expression following BCG treatment in Non-Invasive transitional cell carcinoma cases could reflect a reduction of the potential malignancy of the tumor.

Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

Emerging trends of BCG immunotherapy for bladder cancer in last decade: a bibliometric and visualization analysis.

One of the milestones in bacterial-mediated therapy for cancer, Bacillus Calmette-Guerin (BCG) has been used to treat bladder cancer (BC) for more than 30 years. BCG immunotherapy is now the standard of care for high-grade non-muscle invasive bladder cancer (NMIBC) following transurethral resection. We searched the Web of Science core collection (WoSCC) database and used bibliometric methods through CiteSpace (version 5.1.R6), VOSviewer (version 1.6.18) and R-Bibliometrix (version R 4.2.1) to analyze and discuss the current status and trends of BCG therapy of BC from 2012 to 2021 in terms of co-occurrence, co-polymerization and visualization. A total of 2476 publications were found, with the majority coming from the United States and China. Over the last decade, overall yearly outputs have increased fivefold, from 117 papers in 2012 to 534 records in 2021. Most publications were produced by the University of Texas System. The authors, Ashish M. Kamat of the University of Texas-MD Anderson Cancer Center in the United States, and Shahrokh F. Shariat of Weill Cornell Medical College, were pioneers in this field with the most publications. The journals, Urologic Oncology Seminars and Original Investigations, Cancers and Frontiers in Oncology, have published a dramatic increase in the number of articles, and tumor and urology nephrology research directions have received the most attention from journals. Furthermore, recent research has concentrated on muscle-invasive bladder cancer (MIBC). BCG therapy mechanism, BCG dose and strains, targeted therapy and immune checkpoint inhibitors (ICIs) for BC were attractive research contents, with ICIs (PD-1, PD-L1) being the most popular study point in recent years. With more research on tumor immunology, screening for more reliable biomarkers for precision treatment, and the development of combination regimens of ICIs, targeted treatment of BC stem cells, and personalized BC therapies may be promising areas of immunotherapy research in the coming years. The results of this bibliometric study can provide the current status and research trends of BCG therapy for BC in the last decade, and also further complements the research content of bacterial-mediated cancer therapy.

LBA02-04 OUTCOMES AND GENOMIC CHARACTERISTICS OF NEWLY DIAGNOSED HIGH GRADE TA PAPILLARY UROTHELIAL CARCINOMA TREATED WITH INTRAVESICAL CHEMOTHERAPY VS BACILLUS CALMETTE GUERIN (BCG): A COMPARATIVE STUDY DURING THE BCG SHORTAGE

You have accessJournal of UrologyCME1 Apr 2023LBA02-04 OUTCOMES AND GENOMIC CHARACTERISTICS OF NEWLY DIAGNOSED HIGH GRADE TA PAPILLARY UROTHELIAL CARCINOMA TREATED WITH INTRAVESICAL CHEMOTHERAPY VS BACILLUS CALMETTE GUERIN (BCG): A COMPARATIVE STUDY DURING THE BCG SHORTAGE Song Jiang, Manuel de Jesus E, Peter A. Reisz, Karissa Whiting, Carissa Chu, Wesley Yip, Andrew T. Lenis, Nicole Benfante, Eugene Cha, Timothy F. Donahue, Irina Ostrovnaya, Alvin Goh, Guido Dalbagni, Bernard H. Bochner, and Eugene J. Pietzak Song JiangSong Jiang More articles by this author , Manuel de Jesus EManuel de Jesus E More articles by this author , Peter A. ReiszPeter A. Reisz More articles by this author , Karissa WhitingKarissa Whiting More articles by this author , Carissa ChuCarissa Chu More articles by this author , Wesley YipWesley Yip More articles by this author , Andrew T. LenisAndrew T. Lenis More articles by this author , Nicole BenfanteNicole Benfante More articles by this author , Eugene ChaEugene Cha More articles by this author , Timothy F. DonahueTimothy F. Donahue More articles by this author , Irina OstrovnayaIrina Ostrovnaya More articles by this author , Alvin GohAlvin Goh More articles by this author , Guido DalbagniGuido Dalbagni More articles by this author , Bernard H. BochnerBernard H. Bochner More articles by this author , and Eugene J. PietzakEugene J. Pietzak More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003361.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Appropriate risk stratification of non-muscle invasive bladder cancer remains a central component of deciding treatment. Current criteria used to determine risk of disease recurrence and progression are based largely on historic cohorts before standardization of adjuvant intravesical treatments. The ongoing BCG shortage emphasizes the need for accurate contemporary data to best allocate BCG when supplies are limited. During periods of BCG shortage, our institution restricted BCG utilization to only those with HGT1 or carcinoma in situ (CIS), thus patients with HGTa without CIS were “naturally randomized” to receive either BCG or intravesical chemotherapy based on the time period of their initial diagnosis. METHODS: Retrospective review of an institutional database identified patients with newly diagnosed HGTa without CIS treated at MSKCC from 2017-2021. BCG restrictions were in effect between 01/19 and 04/20. Progression was defined as ≥T1 disease or radical cystectomy. The association of clinicopathologic variables and recurrence was performed with univariable Cox regression. Kaplan-Meier curves were used to visualize time to recurrence and progression. RESULTS: We identified 307 patients with papillary HGTa without CIS, 236 who were treated with BCG, and 71 with intravesical chemotherapy (N=60 mitomycin C, N=11 gemcitabine). Median follow up was 24 months for the BCG treated group, and 18 months from the chemotherapy treated group. There were no significant differences between the two groups regarding age, gender, tumor size, or tumor multiplicity. Targeted exon sequencing of pre-treatment tumors in 59 patients was performed and demonstrated no significant differences between treatment groups. Cumulative risk of high-grade recurrences was similar between the chemotherapy and BCG groups, with 86% vs 90% and 78% vs 82% recurrence-free survival at 6 and 12 months, respectively. Similarly, progression free survival was 89% at 12 months for both groups, but further follow up is needed. CONCLUSIONS: In this “naturally randomized” study, we report comparable clinical efficacy between chemotherapy and BCG immunotherapy, suggesting that intravesical chemotherapy is a reasonable alternative during the BCG shortage for patients with newly diagnosed HGTa without CIS. While our data is encouraging, there remains a critical need for better alternatives to BCG, especially for patients with higher risk non-muscle invasive bladder cancer. Source of Funding: NCI © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1187 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Song Jiang More articles by this author Manuel de Jesus E More articles by this author Peter A. Reisz More articles by this author Karissa Whiting More articles by this author Carissa Chu More articles by this author Wesley Yip More articles by this author Andrew T. Lenis More articles by this author Nicole Benfante More articles by this author Eugene Cha More articles by this author Timothy F. Donahue More articles by this author Irina Ostrovnaya More articles by this author Alvin Goh More articles by this author Guido Dalbagni More articles by this author Bernard H. Bochner More articles by this author Eugene J. Pietzak More articles by this author Expand All Advertisement PDF downloadLoading ...

MP08-17 BACILLUS CALMETTE–GUÉRIN STRAINS DON’T MATTER: RESULTS FROM A TERRITORY-WIDE RETROSPECTIVE COHORT STUDY

You have accessJournal of UrologyCME1 Apr 2023MP08-17 BACILLUS CALMETTE–GUÉRIN STRAINS DON’T MATTER: RESULTS FROM A TERRITORY-WIDE RETROSPECTIVE COHORT STUDY Kang Liu, Hongda Zhao, Xuan Chen, Peter Ka-Fung Chiu, Chi-Fai Ng, and Jeremy Yuen-Chun Teoh Kang LiuKang Liu More articles by this author , Hongda ZhaoHongda Zhao More articles by this author , Xuan ChenXuan Chen More articles by this author , Peter Ka-Fung ChiuPeter Ka-Fung Chiu More articles by this author , Chi-Fai NgChi-Fai Ng More articles by this author , and Jeremy Yuen-Chun TeohJeremy Yuen-Chun Teoh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Adjuvant intravesical Bacillus Calmette–Guérin (BCG) immunotherapy is recommended for non-muscle-invasive bladder cancer (NMIBC), except those low-risk patients. However, whether different strains of BCG have different efficacy on survival outcomes in the long term remains controversial. The current study tries to provide further evidence with a territory-wide retrospective cohort. METHODS: We retrospectively included 2,602 NMIBC patients with adjuvant intravesical BCG immunotherapy around Hong Kong from 2001 to 2020. Kaplan–Meier plotter with the log-rank test was used to explore overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression-free survival (PFS). Multivariable Cox regression analysis was used to balance clinical characteristics and to estimate hazard ratios (HRs) with a 95% confidence interval (CI). Adequate BCG treatment subgroup analysis was performed. RESULTS: Of 2,602 patients, 1291 (49.6%) received Connaught strain 81mg, 199 (7.6%) received Connaught strain 27mg, 1014 (49.2%) received Tokyo strain, and 98 (3.8%) received Danish strain. Although the Connaught strain 27mg group were inferior to the Connaught strain 81mg group in OS (HRs: 1.256, 95% CI: 1.047-1.507), CSS (HRs: 1.693, 95% CI: 1.079-2.657) and PFS (HRs: 1.857, 95% CI: 1.198-2.876) in the whole cohort, the differences were eliminated upon subgroup analysis focusing on patients who received adequate BCG treatment (Table 1, Figure 1). The other two strains, i.e. Tokyo and Danish strains, had similar survival outcomes with the Connaught strain 81mg group in both the whole cohort and the adequate BCG treatment subgroup. CONCLUSIONS: In this large BCG cohort, no significant differences in survival outcomes were observed between Connaught, Tokyo, and Danish strains as soon as adequate BCG treatment was given. Source of Funding: UGC Research Matching Fund 8601521 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e101 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kang Liu More articles by this author Hongda Zhao More articles by this author Xuan Chen More articles by this author Peter Ka-Fung Chiu More articles by this author Chi-Fai Ng More articles by this author Jeremy Yuen-Chun Teoh More articles by this author Expand All Advertisement PDF downloadLoading ...

Bladder tumor Resection Weight as a Prognostic Factor for Recurrence and Progression in Patients With High-Risk Non-Muscle Invasive Bladder Treated With BCG.

Predicting outcomes of patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is critical. Here, we evaluate whether bladder tumor resection weight might serve as a prognostic factor for recurrence and progression of HR-NMIBC patients treated with Bacillus Calmette-Guérin (BCG). In this retrospective, single-centre study in the UK, we analysed a consecutive cohort of HR-NMIBC patients who have received adequate intravesical BCG immunotherapy between 2009 and 2019. Univariable and multivariable Cox proportional hazards models were used to assess the association of resection weight and established predictors with recurrence and progression. A total of 187 HR-NMIBC patients were analysed. The median resection weight was 1.4g (range: 0.2-28.5g). Within a median follow-up of 41 months, 58 (31%) tumors recurred and 19 (10%) progressed. Fifty-four patients (29%) died from any cause and 16 (9%) died from bladder cancer. Both the risk of recurrence (P=.007) and progression (P=.019) increased with rising resection weight. On the multivariable analysis, a resection weight of ≥ 2g and ≥ 3g conferred a 4.35-fold and a 9.03-fold increased risk of bladder cancer recurrence (P < .001) and progression (P < .001), respectively. The addition of resection weight improved the C index of multivariable standard prognostic models to a clinically significant extent (+ 3.8% for recurrence,+4.3% for progression). In our HR-NMIBC patient cohort treated with BCG, bladder tumor resection weight was associated with disease recurrence and progression. Its addition improves discrimination of standard prognostic factors. Measurement may therefore be considered for routine clinical practice.

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 &gt;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 .

Adjuvant Intravesical Chemotherapy Versus Immunotherapy for All Risk Groups of Patients With Non-muscle Invasive Bladder Cancer.

The treatment strategy for non-muscle invasive bladder cancer (NMIBC) has not changed significantly over the past 30 years. Chemotherapeutic agents (mitomycin-C, epirubicin, etc.) and BCG (Bacillus Calmette-Guerin) immunotherapy are used as adjuvant intravesical therapy. To compare the difference between adjuvant chemotherapy and adjuvant immunotherapy in their efficacy of reducing the number of tumor recurrences. In this prospective clinical study, which included 99 patients with NMIBC from March 2018.-March 2023., we publish the results for all risk groups of patients treated with intravesical chemotherapy Epirubicin or with BCG immunotherapy, after TURBT (Trans urethral resection of bladder tumor) within 1 year. Patients were stratified into 2 groups. The first group was treated with Epirubicin (1 dose within 24 hours of surgery, then 6 weekly instillations and 3 maintenance doses), and the second group was treated with BCG (2-3 weeks after TURBT 6 weekly instillations, and 3 maintenance doses). The monitoring period was 24 months. In patients treated with intravesical chemotherapy, recurrence occurred in 9 patients (17.64%), and in patients treated with BCG, recurrence occurred in 7 patients (14.58%). A similar incidence of disease recurrence was observed in both groups (p=0.787). The results of our study show a similar therapeutic response by risk groups of patients treated with chemotherapy and immunotherapy. Since BCG production will cease in the future, the task of urologists is to introduce intravesical chemotherapy into wider use and to modernize it as a safe and effective method of adjuvant treatment for non-muscle-invasive bladder cancer.

Preoperative systemic inflammation response index is an independent prognostic marker for BCG immunotherapy in patients with non-muscle-invasive bladder cancer.

The Systemic Inflammatory Response Index (SIRI) is a novel prognostic biomarker based on peripheral blood counts of neutrophils, monocytes, and lymphocytes. Recent evidence suggests that it is associated with poor prognosis in various cancers. However, the predictive value of the SIRI in non-muscle-invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) immunotherapy remains elusive. Therefore, this study aimed to evaluate the potential of SIRI as a prognostic factor in these patients. A total of 540 patients with NMIBC who underwent BCG immunotherapy following transurethral resection of bladder tumor (TURBT) were enrolled in this study. Using receiver operating characteristic (ROC) curves and the Youden index, patients were divided into high and low SIRI groups based on the cutoff values. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of BCG non-response. Thereafter, propensity score matching (PSM) was used to eliminate bias due to confounding factors between the low and high SIRI groups. Finally, the Kaplan-Meier method was used to compare recurrence-free survival (RFS) and progression-free survival (PFS) between the two groups. Multivariable logistic regression analysis revealed that high SIRI (p=0.001), high MLR (p=0.015), and high tumor pathological T stage (p=0.015) were significantly correlated with non-response to BCG therapy. In addition, both RFS and PFS were shorter in the high SIRI group than in the other group before and after PSM (both p < 0.05). Collectively, our results indicate that the combination of tumor pathological T staging and the SIRI can enhance the predictive power of BCG response. Pretreatment peripheral blood SIRI can be employed to predict the response to BCG immunotherapy and the prognosis of NMIBC patients. Taken together, the combination of T stage and SIRI demonstrated robust performance in predicting the response to BCG immunotherapy in NMIBC patients.

Preoperative sarcopenia and systemic immune-inflammation index can predict response to intravesical Bacillus Calmette-Guerin instillation in patients with non-muscle invasive bladder cancer.

BackgroundTo explore the prognostic significance of sarcopenia and systemic immune-inflammation index (SII) for response to intravesical Bacillus Calmette-Guerin (BCG) in patients with intermediate-, and high-risk non-muscle invasive bladder cancer (NMIBC).MethodsWe retrospectively analyzed 183 consecutive patients treated in Qilu hospital of Shandong University for a first diagnosis of intermediate and high risk NMIBC. Using computed tomography scans at the third lumbar vertebra level, we calculated skeletal muscle index (SMI). Sarcopenia was defined as SMI <43 cm2/m2 for males with BMI < 25 kg/m2, <53 cm2/m2 for males with BMI ≥ 25 kg/m2, and <41 cm2/m2 for females. The response to intravesical BCG immunotherapy and relapse-free survival (RFS) were analyzed.ResultsCompared with BCG responders, BCG non-responders were associated with sarcopenia (P < 0.001), carcinoma in situ (P < 0.001), T1 stage (P < 0.001), multiple tumor (P < 0.001), tumor diameter >=3cm (P < 0.001), and have a significant increase of neutrophil-to-lymphocyte ratio (NLR) (P < 0.001), platelet to lymphocyte ratio (PLR) (P = 0.004), SII (P < 0.001). The area under the ROC curve (AUC) of the BMI, NLR, PLR, and SII for response to intravesical BCG immunotherapy were 0.425, 0.693, 0.631, and 0.702 respectively. Logistic regression analysis demonstrated that sarcopenia and SII were predictors of response to intravesical BCG immunotherapy. The Kaplan-Meier survival analysis showed that the RFS of patients with BCG response, lower SII and no sarcopenia was significantly increased compared with that of patients with BCG non-response, higher SII and sarcopenia, respectively. Subgroup analysis demonstrated that the RFS of patients with high SII and sarcopenia was significantly decreased compared with those with low SII and no sarcopenia in Ta stage subgroup, T1 stage subgroup, non-Cis subgroup, multiple tumor subgroup, single tumor subgroup, tumor diameter≥3cm subgroup and tumor diameter<3cm subgroup, respectively (P < 0.05). However, there was no significant difference in RFS for patients in CIS subgroup (P > 0.05). Multivariate Cox analysis shown that sarcopenia (p=0.005) and high SII (p = 0.003) were significantly associated with poor RFS.ConclusionsBoth sarcopenia and high SII are useful predictors of response to intravesical BCG in intermediate- and high-risk NMIBC patients. Patients with intermediate- and high-risk NMIBC that had sarcopenia or high SII at diagnosis were associated with poor RFS, and the combination of sarcopenia and SII may be a better predictor of RFS.