Efficacy Of Bacillus Calmette-Guerin Research Articles

Abstract PR005: Final results from a Phase I trial of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin (BCG) for patients with BCG-exposed high-grade non-muscle invasive bladder cancer

Abstract Background: Although retreatment with BCG is considered standard of care for patients with BCG-exposed high-grade (HG) non-muscle invasive bladder cancer (NMIBC), less than 50% of patients are expected to respond. As such, the ability to augment the efficacy of BCG in this population remains a critical unmet need. Preclinical studies suggest that intravesical gemcitabine (Gem) may demonstrate synergistic efficacy with BCG by favorably altering the tumor microenvironment. We therefore sought to evaluate the safety, tolerability, and preliminary clinical efficacy of GemBCG in patients with BCG-exposed HG NMIBC through an IRB-approved Phase I/II clinical trial. Methods: Patients with BCG-exposed papillary HG NMIBC (Ta/T1) with or without carcinoma in situ (CIS) that recurred within 24 months of BCG therapy were eligible for this trial. Exclusion criteria included BCG-unresponsive disease, contraindication to BCG therapy, or ureteral/urethral urothelial disease. Consenting patients underwent complete transurethral resection of bladder tumors followed by intravesical Gem twice weekly (weeks 1, 4, 7, 10) for a total of 8 doses. Dose escalation of Gem was performed from 50-2000 mg using a Bayesian modified continual reassessment method. Intravesical Gem instillations alternated with weekly intravesical TICE BCG therapy (weeks 2, 3, 5, 6, 8, 9) for a total of 6 doses fixed at 50 mg followed by maintenance BCG in responders. Complete response (CR) rates and progression to muscle-invasive bladder cancer (MIBC) or cystectomy were evaluated at 12 months of follow up in the Phase I cohort. Results: A total of 25 patients was enrolled (median age 70 years [IQR 64-75]), all of which have at least 12 months of follow up. Of these, 88% (22/25) were male. Median duration of bladder cancer treatment prior to enrollment was 385 days (IQR 173-634), and 28% (7/25) previously received either maintenance therapy (3/25) or >1 induction courses of BCG (4/25). Based on centralized pathology review, a total of 68% had CIS ± papillary disease (8 HGTa, 5 HGT1, and 4 Tis), while 32% had papillary-only disease (4 HGTa and 4 HGT1). No dose limiting toxicities were observed, and 14/25 patients were treated at the maximum tolerated dose. The treatment was well tolerated with no patient experiencing treatment-related Grade 3-5 toxicity. CR rates at 6 months and 12 months were 96% (24/25) and 92% (23/25), respectively. No progression to MIBC or radical cystectomy was observed. Conclusion: Combination GemBCG in BCG-exposed HG NMIBC is well tolerated and appears to provide excellent cancer control. Based on these encouraging findings and the ongoing phase II portion (NCT04179162), a prospective randomized controlled trial comparing GemBCG to BCG alone for BCG-exposed NMIBC is planned through the National Clinical Trial Network (Alliance A032303). Citation Format: Syed M. Alam, Christopher D. Gaffney, Jessica Lavery, Merve Basar, Neeta D'Souza, Christian Hernandez, Melissa McCarter, Patricia Moran, Kristen Stasi, Kara Worth, Daniel Sjoberg, Guido Dalbagni, Timothy Donahue, Sherri Donat, Dean Bajorin, Bernard H. Bochner, Alvin Goh, Judy Sarungbam, Hikmat Al-Ahmadie, Eugene J. Pietzak. Final results from a Phase I trial of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin (BCG) for patients with BCG-exposed high-grade non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR005.

Efficacy of Bacillus Calmette-Guérin in Cancer Prevention and Its Putative Mechanisms.

Bacillus Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis. Although it was developed as a prophylactic vaccine against tuberculosis (TB), researchers have also evaluated it for preventing cancer development or progression. These studies were inspired by the available data regarding the protective effects of microbial infection against cancers and an inverse relationship between TB and cancer mortality. Initial studies demonstrated the efficacy of BCG in preventing leukemia, melanoma and a few other cancers. However, mixed results were observed in later studies. Importantly, these studies have led to the successful use of BCG in the tertiary prevention of non-muscle invasive bladder cancer, wherein BCG therapy has been found to be more effective than chemotherapy. Moreover, in a recently published 60-year follow-up study, childhood BCG vaccination has been found to significantly prevent lung cancer development. In the present manuscript, we reviewed the studies evaluating the efficacy of BCG in cancer prevention and discussed its putative mechanisms. Also, we sought to explain the mixed results of BCG efficacy in preventing different cancers.

BCG vaccination reduces bovine tuberculosis transmission, improving prospects for elimination.

Bacillus Calmette-Guérin (BCG) is a routinely used vaccine for protecting children against Mycobacterium tuberculosis that comprises attenuated Mycobacterium bovis. BCG can also be used to protect livestock against M. bovis; however, its effectiveness has not been quantified for this use. We performed a natural transmission experiment to directly estimate the rate of transmission to and from vaccinated and unvaccinated calves over a 1-year exposure period. The results show a higher indirect efficacy of BCG to reduce transmission from vaccinated animals that subsequently become infected [74%; 95% credible interval (CrI): 46 to 98%] compared with direct protection against infection (58%; 95% CrI: 34 to 73%) and an estimated total efficacy of 89% (95% CrI: 74 to 96%). A mechanistic transmission model of bovine tuberculosis (bTB) spread within the Ethiopian dairy sector was developed and showed how the prospects for elimination may be enabled by routine BCG vaccination of cattle.

Management of T1G3 Transitional Cell Carcinoma of Urinary Bladder with Intravesical Bacillus Calmette-Guerin (BCG): Our Experience

Aim: To determine efficacy of BCG in T1G3 urinary bladder tumors at department of urology Chandka Medical College Larkana. Patients and Methods: This is retrospective study, patient were selected from hospital record from July 2016 to June 2022. Around 80 included in our study group who were treated in our department for management of high grade non-muscle invasive bladder tumor. After following inclusion and exclusion criteria TURBT were performed and BCG was installed intravesically for induction and maintenance purpose. Patients were followed for 5 years and data was collected on study specific proforma. Results: 80 patients were included in our study with mean age 35year +5.5 SD. Transurethral resection of urinary bladder tumor was performed in all patients with bladder growth. Induction and maintenance instillation of bacillus Calmette-Guerin (BCG) therapy was given to all. The recurrence was noted in 5 patients (6.25%) and the progression was also seen in these 5 patients (6.25%). Disease-specific survival is 93.75% at the follow-up of 5 years. As prevalence of ca bladder is increasing day by day and bladder is sole organ for storing urine so nowadays strategies of treatment is bladder saving surgery. So patient will feel comfortable with natural bladder and on other hand it will minimize complication related to artificially generated urinary bladder. Conclusion: Maintenance BCG therapy for T1G3 bladder tumors is an effective treatment, with satisfactory results and bladder preservation. Keywords: Ca bladder, intravesival chemotherapy, BCG, T1G3 and management.

Chronic social defeat stress-induced depression reduces BCG efficacy by promoting regulatory T-cell levels in mice

Despite the initial successes of the Bacillus Calmette-Guerin (BCG) vaccine in children, its efficacy against tuberculosis is highly variable. There is a lack of understanding about how mental conditions influence BCG vaccination. Here, we used the chronic social defeat stress (CSDS) model to explore the effects of depression on BCG vaccination efficacy. We observed higher lung and spleen bacterial loads and a lower organ index in depressed compared to BCG mice. Meanwhile, a relatively lower T cell protective efficacy was observed in both compared to control and BCG mice via a mycobacterium growth inhibition assay (MGIA). Cytokine expression of IL-12p40, IL-1β, IL-17, TNF-α and IFN-γ was reduced, whereas the expression of IL-10 and IL-5 was increased in the spleen of both compared to BCG mice. Moreover, the proportions of CD4+IFN-γ+, CD8+IFN-γ+ T lymphocytes and CD4+ effector/central memory T cells were reduced in the splenocytes of the depressed BCG mice. Depression promotes CD4+ regulatory T cells (Treg) and myeloid-derived suppressor cell (MDSC) generation in depressed mice, contributing to the reduced pro-inflammatory immune response upon BCG vaccination. This study provides insight into the decreased protective immunity by BCG vaccination attributable to depression in mice.

The bladder microbiota is not significantly altered by intravesical BCG therapy

IntroductionBladder microbiota dysbiosis has been associated with several urological disorders. However, dysbiosis markers in bladder cancer have not been identified and little is known about the effect of Bacillus Calmette-Guérin (BCG) intravesical therapy on the bladder microbiota. In this study, we compared the bladder microbiota of patients with non-muscle-invasive bladder cancer (NMIBC) undergoing BCG therapy to nononcological controls. We also longitudinally analyzed the impact of BCG therapy on the bladder microbiota of NMIBC patients and addressed whether bladder microbiota is associated with BCG efficacy. MethodsWe collected catheterized urine samples from males with intermediate/high-risk NMIBC (cancer group, n = 32) or benign prostatic hyperplasia (control group, n = 41). The cancer group also provided urine samples during and after BCG induction. We used 16S rRNA gene sequencing to characterize the bladder microbiota. Bladder microbiota parameters, such as diversity and taxonomic composition, were compared between groups and associated with clinicopathological data and BCG efficacy. ResultsWe observed no significant differences between the bladder microbiota of NMIBC patients and controls. BCG intravesical instillations did not significantly alter the bladder microbiota of NMIBC patients, and BCG was rarely detected in the bladder during and after BCG therapy. Microbiota diversity and overall composition before BCG induction did not influence disease persistence at 3 months. However, higher abundance of Lactobacillus, Streptococcus, and Cutibacterium in the pre-BCG bladder microbiota was associated with BCG effectiveness. ConclusionWe were unable to identify markers of bladder microbiota dysbiosis among male NMIBC patients. Moreover, we demonstrated for the first time using longitudinally collected samples that BCG cannot persist in the bladder microbiota nor significantly alter its diversity and composition. The associations found between bladder microbes and BCG efficacy highlight the potential of microbial-based therapeutic and risk-stratification strategies in the intermediate/high-risk NMIBC setting.

Proteome and immunogenicity differences in BCG Pasteur ATCC 35734 and its derivative, the vaccine candidate BCGΔBCG1419c during planktonic growth in 7H9 and Proskauer Beck media

Bacillus Calmette–Guèrin (BCG) remains as the only vaccine employed to prevent tuberculosis (TB) during childhood. Among factors likely contributing to the variable efficacy of BCG is the modification in its antigenic repertoire that may arise from in vitro growth conditions. Our vaccine candidate, BCGΔBCG1419c, improved protection against TB in mice and guinea pigs with bacteria grown in either 7H9 OADC Tween 80 or in Proskauer Beck Tween 80 media in independent studies. Here, we compared the proteomes of planktonic cultures of BCG and BCGΔBCG1419c, grown in both media. Further to this, we compared systemic immunogenicity ex vivo elicited by both types of BCG strains and cultures when used to vaccinate BALB/c mice. Both the parental strain BCG Pasteur ATCC 35734, and its isogenic mutant BCGΔBCG1419c, had several medium-dependent changes. Moreover, ex vivo immune responses to a multiantigenic (PPD) or a single antigenic (Ag85A) stimulus were also medium-dependent. Then, not only the presence or absence of the BCG1419c gene in our strains under study affected the proteome produced in vitro but also that this was affected by culture medium, potentially leading to changes in the capacity to induce ex vivo immune responses.

Bacillus Calmette-Guerin (BCG) therapy is safe and effective in non-muscle invasive bladder cancer (NMIBC) patients with immunomodulating conditions

IntroductionBacillus Calmette-Guerin (BCG) is the most effective therapy available to treat high-risk nonmuscle invasive bladder cancer (NMIBC) patients. However, for patients with immunomodulating conditions BCG is a relative contraindication due to efficacy and safety concerns. To our knowledge, no population-level study evaluating the efficacy and safety profile of BCG for immunomodulated patients exists. MethodsNMIBC patients aged 66 years or older were identified in the Surveillance, Epidemiology, and End Results (SEER) – Medicare database from 1975–2013. All patients completed adequate BCG (at least 5 plus 2 treatments completed within 12 months of diagnosis). Two groups were defined: an immunomodulated population identified by immunomodulating conditions such as solid-organ transplantation, HIV, and autoimmune conditions, and an immunocompetent group. The primary endpoint was 5-year progression-free survival defined as progression to systemic chemotherapy, checkpoint inhibitors, radical or partial cystectomy, metastasis, or cancer-specific death. A safety analysis was performed as a secondary outcome. ResultsIn a total of 4,277 patients with NMIBC who completed adequate BCG, 606 (14.2%) were immunomodulated. The immunomodulated group was older at diagnosis (P < 0.001), more likely to be female (P < 0.001), more likely to live in a metropolitan area (P < 0.001), and had higher Charlson comorbidity scores (P < 0.001). There were no differences in progression to chemotherapy (P = 0.17), checkpoint inhibitors (P > 0.99), radical cystectomy (P = 0.40), partial cystectomy (P = 0.93), metastasis (P = 0.19), cancer-specific death (P = 0.18) or 5-year total bladder cancer progression (P = 0.30) between the groups. For the safety analysis, rates of disseminated BCG were similar between immunomodulated and immunocompetent patients (0.7% vs. <1.8%, P = 0.51). On multivariable analysis 5-year total bladder cancer progression (HR 1.07 [CI 0.88–1.30]) was similar between the groups. ConclusionRates of bladder cancer progression and disseminated BCG complications 5-years after BCG therapy were similar regardless of immunomodulation status. These findings suggest that BCG intravesical therapy can be offered to immunomodulated patients with high-risk NMIBC although theoretical infectious complication risks remain.

Prognostic Significance of HER2 Expression in Patients with Bacillus Calmette-Guérin–exposed Non–muscle-invasive Bladder Cancer

BackgroundGuidelines recommend intravesical instillation of bacillus Calmette-Guérin (BCG) as the first-choice treatment for intermediate- and high-risk non–muscle-invasive bladder cancer (NMIBC). However, there is no therapeutic biomarker for predicting BCG efficacy, especially in high-risk cases with high failure rates. HER2 expression is considered a prognostic factor for bladder cancer. ObjectiveTo elucidate the predictive value and significance of HER2 expression in patients with BCG-exposed NMIBC. Design, setting, and participantsA total of 454 patients with NMIBC were included. All patients started BCG intravesical instillation (1.2 × 108 CFU, strain D2PB302) 2–6 wk after transurethral resection of bladder tumor and received 19 treatments over a period of 1 yr. HER2 immunohistochemistry (IHC) results available for 314 patients. Outcome measurements and statistical analysisThe outcomes investigated were recurrence-free survival (RFS) and progression-free survival (PFS). Outcome relationships were explored using multivariable Cox regression and log-rank analysis. Results and limitationsIn the IHC population, 35.7% of patients had HER2 overexpression (IHC score 2/3+). This group had a poor 5-yr RFS rate of 16.5%, in comparison to 68.0% in the group with low HER2 expression (p < 0.001). Patients with high-risk NMIBC and HER2 overexpression had the highest risk of BCG treatment failure, with 5-yr RFS and PFS rates of 19.0% and 58.2%, respectively. Conversely, HER2-negative (IHC score 0) patients with high-risk NMIBC experienced a long-term BCG benefit, with 5-yr RFS and PFS rates of 80.8% and 92.1%, respectively. Limitations include the retrospective study design and the limited details regarding BCG use. ConclusionsHER2 was an independent predictor of poor BCG efficacy in NMIBC. Patients with high-risk NMIBC and HER2 overexpression had the highest risk of disease recurrence and progression after exposure to BCG. Anti-HER2 targeted therapies could be considered for these patients. Patient summaryMeasurement of blood levels of the protein HER2 can be used to predict outcomes after BCG (bacillus Calmette-Guérin) bladder therapy for patients with intermediate- or high-risk non–muscle-invasive bladder cancer. Measurement results for HER2 may help in guiding personalized treatment for these patients.

Diminished Short-Term Efficacy of Reduced-Dose Induction BCG in the Treatment of Non-Muscle Invasive Bladder Cancer.

The ongoing Bacillus Calmette-Guérin (BCG) shortage has created challenges for the treatment of non-muscle invasive bladder cancer (NMIBCa). Our objective was to evaluate the efficacy of reduced-dose induction BCG (RD-iBCG) compared to full-dose induction BCG (FD-iBCG) regarding recurrence rates. We hypothesized that patients receiving RD-iBCG may recur at a higher rate compared to those who received FD-iBCG therapy. A retrospective review of all patients with NMIBCa treated with intravesical therapy at our institution between 2015-2020 was conducted. Inclusion criteria consisted of having a diagnosis of AUA intermediate or high-risk NMIBCa with an indication for a six-week induction course of FD or RD-BCG with at least 1 year of documented follow up. The data were censored at one year. Propensity score matching for age, sex, tumor pathology, and initial vs. recurrent disease was performed. The primary endpoint was bladder cancer recurrence, reported as recurrence-free survival. A total of 254 patients were reviewed for this study. Our final cohort was 139 patients after exclusion. Thirty-nine percent of patients had HGT1 disease. 38.6% of patients receiving RD-BCG developed a recurrence of bladder cancer within a one-year follow-up as compared to 33.7% of patients receiving FD therapy. After propensity matching, this value remained statistically significant (p = 0.03). In conclusion, RD-iBCG for NMIBCa is associated with a significantly greater risk of recurrence than full-dose induction therapy, suggesting that RD-iBCG may not be equivalent or non-inferior to full-dose administration in the short term.

Abstract 2127: TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation

Abstract Introduction: Bacillus Calmette-Guérin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC) following transurethral resection. However, patients often have heterogeneous responses. Even among those who initially respond well to BCG, 10-20% relapse. Identification of reliable biomarkers predicting the efficacy of BCG remains an unmet need. En bloc resection is a novel technique representing a substantial advancement in the surgical management of NMIBC. We sought to investigate genomic and tumor microenvironmental (TME) profiles in NMIBC and explore potential predictive markers for BCG treatment following en-block resection. Methods: A total of 40 patients with high-risk NMIBC (cTis-T1N0M0) were retrospectively enrolled who underwent en bloc resection followed by BCG instillation. Surgical samples were subjected to NGS sequencing using a 520-gene panel (Burning Rock Biotech, Guangzhou) and multiplex immunofluorescence (mIF) assay. Results: The cohort had a median age of 63 years, and 80% were male. After a median follow-up of 21.8 months, 19/40 patients relapsed with a one-year relapse-free survival (RFS) rate of 57.5%. All tumors were microsatellite stable and showed a median TMB of 7.98muts/Mb. Genomic profiling revealed a high prevalence of alterations in TERT (55%), KDM6A (32.5%), KMT2D (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%), KMT2C (25%), and ARID1A (20%). TME analysis showed higher proportions of M1 macrophages and CD56 dim NK cells in the tumoral compartment and more intense infiltration of CD8+ T cells, exhausted CD8+T, CD56 bright NK cells, and M2 macrophages in the stromal compartment. Multivariate analysis identified TERT C228T mutation (HR=3.28 [95%CI:1.225-8.79], p=0.0181) and alteration in KDM6A (HR=2.94 [95%CI:1.040-8.29], p=0.042) as two independent factors associated with inferior RFS. Patients with concomitant TERT C228T and KDM6A alteration had the shortest RFS (median RFS:5.83months) compared with those who were free of (median RFS: NR) or harbored either one of the two alterations (median RFS:9.13months) (p=0.0022). We also found that tumoral infiltration of CD8+T cells was positively associated with RFS (HR=0.29 [95%CI:0.097-0.885], p=0.0208). Conclusion: The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment. Our findings may facilitate the stratification of patients and better guide the clinical decision-making on the management of NMIBC. Citation Format: Qi-Dong Xia, Yao-Bing Chen, Jian-Xuan Sun, Chen-Qian Liu, Jin-Zhou Xu, Zhi-Peng Yao, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Lin Shao, Si-Qi Li, Zheng Liu, Shao-Gang Wang. TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2127.

MP63-13 TRIALS IN PROGRESS: A PHASE I/II TRIAL OF INTRAVESICAL CHEMOIMMUNOTHERAPY WITH GEMCITABINE AND BACILLUS CALMETTE-GUÉRIN (BCG) FOR PATIENTS WITH BCG-EXPOSED HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

You have accessJournal of UrologyCME1 Apr 2023MP63-13 TRIALS IN PROGRESS: A PHASE I/II TRIAL OF INTRAVESICAL CHEMOIMMUNOTHERAPY WITH GEMCITABINE AND BACILLUS CALMETTE-GUÉRIN (BCG) FOR PATIENTS WITH BCG-EXPOSED HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) Christopher Gaffney, NEETA D'Souza, Christian Hernandez, Melissa McCarter, Patricia Moran, Kristen Staci, Kara Worth, Guido Dalbagni, Timothy Donahue, Sherri Donat, Bernard Bochner, Judy Sarungbam, Dean Bajorin, Hikmat AL-Ahmadie, Daniel Sjoberg, Alvin Goh, and Eugene Pietzak Christopher GaffneyChristopher Gaffney More articles by this author , NEETA D'SouzaNEETA D'Souza More articles by this author , Christian HernandezChristian Hernandez More articles by this author , Melissa McCarterMelissa McCarter More articles by this author , Patricia MoranPatricia Moran More articles by this author , Kristen StaciKristen Staci More articles by this author , Kara WorthKara Worth More articles by this author , Guido DalbagniGuido Dalbagni More articles by this author , Timothy DonahueTimothy Donahue More articles by this author , Sherri DonatSherri Donat More articles by this author , Bernard BochnerBernard Bochner More articles by this author , Judy SarungbamJudy Sarungbam More articles by this author , Dean BajorinDean Bajorin More articles by this author , Hikmat AL-AhmadieHikmat AL-Ahmadie More articles by this author , Daniel SjobergDaniel Sjoberg More articles by this author , Alvin GohAlvin Goh More articles by this author , and Eugene PietzakEugene Pietzak More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003321.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The standard of care for high-risk NMIBC after exposure to induction only BCG or relapse >12 months after “adequate” BCG is retreatment with BCG. However, ∼50% will relapse within 6 months. Intravesical Gemcitabine (GEM) is a well-tolerated, common treatment for NMIBC with better efficacy after BCG than mitomycin C which may synergistically enhance the efficacy of BCG by augmenting the immune tumor microenvironment. We are evaluating gemcitabine and BCG (GemBCG) intravesical chemoimmunotherapy to address the need for more effective and less toxic bladder preserving treatments by enhancing BCG efficacy. METHODS: This is an investigator-initiated Phase I/II trial of GemBCG for BCG-exposed NMIBC enrolling patients with BCG-exposed carcinoma in-situ (CIS±Ta/T1) that recurred within 24 months of last BCG (BCG-exposed/BCG-relapsing NMIBC, Figure 1). Patients with BCG-unresponsive disease, contraindication to BCG, or prostatic/ureteral urothelial disease are excluded. The primary endpoint for Phase I was safety and dose tolerability. The primary endpoint for Phase II 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) we plan to enroll 19 and 24 patients in the first and second stage, respectively. Phase I patients treated at the maximum tolerated dose (MTD) are included in phase II. Secondary outcomes include recurrence progression, and cystectomy-free survival. Correlative studies explore immune and molecular predictors of response and resistance to chemoimmunotherapy in tumor tissue, urine, and blood. RESULTS: Of the 25 patients who completed Phase I, 14/25 were treated at the MTD and processed to Phase II. Treatment was well-tolerated (no treatment related grade ≥3 adverse events) and demonstrated promising early efficacy (95% [19/20] CR at 6-months). CONCLUSIONS: A combination of intravesical GEM and BCG appears safe and well tolerated in patients with BCG-relapsed/BCG-exposed NMIBC. Promising early efficacy data requires completion of Phase II for confirmation (NCT04179162). Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e876 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Gaffney More articles by this author NEETA D'Souza More articles by this author Christian Hernandez More articles by this author Melissa McCarter More articles by this author Patricia Moran More articles by this author Kristen Staci More articles by this author Kara Worth More articles by this author Guido Dalbagni More articles by this author Timothy Donahue More articles by this author Sherri Donat More articles by this author Bernard Bochner More articles by this author Judy Sarungbam More articles by this author Dean Bajorin More articles by this author Hikmat AL-Ahmadie More articles by this author Daniel Sjoberg More articles by this author Alvin Goh More articles by this author Eugene Pietzak More articles by this author Expand All Advertisement PDF downloadLoading ...

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 .

A century of BCG vaccination: Immune mechanisms, animal models, non-traditional routes and implications for COVID-19

Bacillus Calmette-Guerin (BCG) has been used as a vaccine against tuberculosis since 1921 and remains the only currently approved vaccine for this infection. The recent discovery that BCG protects against initial infection, and not just against progression from latent to active disease, has significant implications for ongoing research into the immune mechanisms that are relevant to generate a solid host defense against Mycobacterium tuberculosis (Mtb). In this review, we first explore the different components of immunity that are augmented after BCG vaccination. Next, we summarize current efforts to improve the efficacy of BCG through the development of recombinant strains, heterologous prime-boost approaches and the deployment of non-traditional routes. These efforts have included the development of new recombinant BCG strains, and various strategies for expression of important antigens such as those deleted during the M. bovis attenuation process or antigens that are present only in Mtb. BCG is typically administered via the intradermal route, raising questions about whether this could account for its apparent failure to generate long-lasting immunological memory in the lungs and the inconsistent level of protection against pulmonary tuberculosis in adults. Recent years have seen a resurgence of interest in the mucosal and intravenous delivery routes as they have been shown to induce a better immune response both in the systemic and mucosal compartments. Finally, we discuss the potential benefits of the ability of BCG to confer trained immunity in a non-specific manner by broadly stimulating a host immunity resulting in a generalized survival benefit in neonates and the elderly, while potentially offering benefits for the control of new and emerging infectious diseases such as COVID-19. Given that BCG will likely continue to be widely used well into the future, it remains of critical importance to better understand the immune responses driven by it and how to leverage these for the design of improved vaccination strategies against tuberculosis.

FACTORS PREDICTING THE OUTCOME OF BCG (BACILLUS CALMETTE-GUERIN) THERAPY

Background: Bacillus Calmette-Guerin is currently con­sidered to be the gold standard in conservative treatment for intermediate and high risk non-muscle invasive blad­der cancer (NMIBC). However, up to 40% of the patients, treated with adjuvant BCG therapy, experience failure. As the new methods of treatment after BCG failure ap­pear, there is a need to assess efficacy of this therapy in order to improve appropriate treatment during or before BCG therapy. Aim: To review the latest studies on factors, predicting BCG efficacy, and provide summarized information re­garding treatment outcomes in current practice. Methodology: The search was conducted in MEDLINE (Pubmed) and ScienceDirect databases using predeter­mined keywords: Bacillus Calmette-Guerin (BCG), fai­lure, intravesical therapy, outcome, response, predicting factors, immunological markers, efficacy. 10 articles pu­blished since 2017 were included in this literature review. Results: Prognostic factors such as the use of antibiotics prior to the therapy, body mass index (BMI), lympho­vascular invasion (LVI), endothelin-1 (ET-1), tumor substaging, CD4/CD8, GATA3/T-bet, CD163/CD68, neu­trophil-to-lymphocyte (NLR) ratios are promising factors for estimating the possible response of BCG therapy be­fore undergoing treatment. Blood eosinophil count and percentage, FISH test following 3 months after first BCG instillation and a Cytokine Panel for Response to Intrave­sical Therapy (CyPRIT) nomogram showed huge poten­tial for predicting BCG outcome during BCG treatment. Conclusion: There are quite many possible clinicopatho­logic, immunological, immunohistochemical and anam­nestical factors that could predict the success of BCG therapy. However, in order to include prognostic fac­tors in treatment guidelines, further studies should be performed to determine which of these factors have the greatest clinical value.

Abstract 1282: Elevated T cell exhaustion and immune cell infiltration is associated with BCG failure in patients with non-muscle invasive bladder cancer

Abstract Introduction: Gold standard treatment in patients with high-risk non-muscle invasive bladder cancer (NMIBC) includes Bacillus Calmette-Guérin (BCG), which activates the immune cells to kill remaining cancerous cells after surgical removal of the tumors. However, 40% of patients do not have a clinical benefit of BCG. The presence of immune cells, their functional state, as well as genomic alterations in the tumor and the normal appearing urothelial tissue, defined as field effect, may have significant impact on therapeutic outcome. Materials and methods: To investigate this, we analyzed samples from 156 patients diagnosed with NMIBC, including 237 tumors, 569 urine samples, and 305 biopsies of adjacent normal appearing urothelium. Patients had a median follow-up time of 8 years. 70 patients (45%) progressed to muscle-invasive bladder cancer or experienced early high grade recurrence within two years after ended BCG treatment, defined as BCG failure. Urinary levels of 92 immune-oncology related proteins were measured in pre- and post-treatment samples using the Olink proteomics platform. Total RNA- and whole exome sequencing (WES) data was generated from tumors before and after BCG. Clonal patient-specific mutations were selected for deep-targeted sequencing of the adjacent normal appearing biopsies. The level of field effect was defined as the mean of the variant allele frequency for mutations observed in normal biopsies. Results: We found that treatment with BCG activated the immune system regardless of clinical outcome. However, patients differed in urinary protein profile after BCG depending on their clinical response. Transcriptomic analysis of tumors showed that UROMOL2021 subtypes were significantly associated with outcome and clinical response (p=0.018). Paired tumors showed a shift in subtype to an immune infiltrated subtype (class 2b) after treatment in 36% of cases. Patients with BCG failure showed signs of immune exhaustion after treatment indicated by higher expression of the T cell exhaustion marker genes CTLA4 (p=0.0067), LAG3 (p=0.00012), TIM-3 (p=0.022), KLRG1 (p=0.028), and PD-1 (p=0.047), and higher immune cell infiltration (p=0.011). Genomic features such as mutational signatures and mutational load were not predictive of clinical response. Interestingly, BCG-responsive patients had a high level of field effect before BCG (p=0.0026), suggesting that field effect could lead to increased BCG efficacy. Conclusion: BCG treatment was associated with immune system activation reflected in both urine and tissue samples. In patients with BCG failure, we observed an immune exhausted phenotype after treatment, and we observed a high level of field effect before treatment in responsive patients. Collectively, this could indicate that increased immunogenicity and prolonged immune activation are key factors in BCG treatment responsiveness. Citation Format: Trine Strandgaard, Iver Nordentoft, Emil Christensen, Sia Lindskrog, Philippe Lamy, Karin Birkenkamp-Demtröder, Torben Steiniche, Jørgen Bjerggaard Jensen, Lars Dyrskjøt. Elevated T cell exhaustion and immune cell infiltration is associated with BCG failure in patients with non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1282.

CFP10-loaded PLGA nanoparticles as a booster vaccine confer protective immunity against Mycobacterium bovis.

Introduction: The limited efficacy of BCG (bacillus Calmette-Guérin) urgently requires new effective vaccination approaches for the control of tuberculosis. Poly lactic-co-glycolic acid (PLGA) is a prevalent drug delivery system. However, the effect of PLGA-based nanoparticles (NPs) against tuberculosis for the induction of mucosal immune response is no fully elucidated. In this study, we hypothesized that intranasal immunization with culture filtrate protein-10 (CFP10)-loaded PLGA NPs (CFP10-NPs) could boost the protective immunity of BCG against Mycobacterium bovis in mice. Methods: The recombinant protein CFP10 was encapsulated with PLGA NPs to prepare CFP10-NPs by the classical water-oil-water solvent-evaporation method. Then, the immunoregulatory effects of CFP10-NPs on macrophages in vitro and on BCG-immunized mice in vivo were investigated. Results: We used spherical CFP10-NPs with a negatively charged surface (zeta-potential -28.5 ± 1.7 mV) having a particle size of 281.7 ± 28.5 nm in diameter. Notably, CFP10-NPs significantly enhanced the secretion of tumor necrosis factor α (TNF-α) and interleukin (IL)-1β in J774A.1 macrophages. Moreover, mucosal immunization with CFP10-NPs significantly increased TNF-α and IL-1β production in serum, and immunoglobulin A (IgA) secretion in bronchoalveolar lavage fluid (BALF), and promoted the secretion of CFP10-specific interferon-γ (IFN-γ) in splenocytes of mice. Furthermore, CFP10-NPs immunization significantly reduced the inflammatory area and bacterial load in lung tissues at 3-week post-M. bovis challenge. Conclusion: CFP10-NPs markedly improve the immunogenicity and protective efficacy of BCG. Our findings explore the potential of the airway mucosal vaccine based on PLGA NPs as a vehicle for targeted lung delivery.

Recombinant BCG to Enhance Its Immunomodulatory Activities.

The bacillus Calmette–Guérin (BCG) is an attenuated Mycobacterium bovis derivative that has been widely used as a live vaccine against tuberculosis for a century. In addition to its use as a tuberculosis vaccine, BCG has also been found to have utility in the prevention or treatment of unrelated diseases, including cancer. However, the protective and therapeutic efficacy of BCG against tuberculosis and other diseases is not perfect. For three decades, it has been possible to genetically modify BCG in an attempt to improve its efficacy. Various immune-modulatory molecules have been produced in recombinant BCG strains and tested for protection against tuberculosis or treatment of several cancers or inflammatory diseases. These molecules include cytokines, bacterial toxins or toxin fragments, as well as other protein and non-protein immune-modulatory molecules. The deletion of genes responsible for the immune-suppressive properties of BCG has also been explored for their effect on BCG-induced innate and adaptive immune responses. Most studies limited their investigations to the description of T cell immune responses that were modified by the genetic modifications of BCG. Some studies also reported improved protection by recombinant BCG against tuberculosis or enhanced therapeutic efficacy against various cancer forms or allergies. However, so far, these investigations have been limited to mouse models, and the prophylactic or therapeutic potential of recombinant BCG strains has not yet been illustrated in other species, including humans, with the exception of a genetically modified BCG strain that is now in late-stage clinical development as a vaccine against tuberculosis. In this review, we provide an overview of the different molecular engineering strategies adopted over the last three decades in order to enhance the immune-modulatory potential of BCG.

BCG efficacy in nonmuscle-invasive bladder cancer after prior radiation treatment for prostate cancer.

482 Background: Prostate radiotherapy is associated with worse oncologic outcomes in patients with bladder cancer. This is thought to be secondary to microvascular damage resulting in propagation of inflammation. There is sparse data on the effect of prior radiotherapy on the efficacy of intravesical Bacillus Calmette-Guerin (BCG) in patients with non-muscle invasive bladder cancer (NMIBC). We sought to evaluate BCG response and outcomes in NMIBC patients who have previously undergone prostate radiotherapy compared to patients with no prior history of pelvic radiotherapy. Methods: This is a retrospective cohort study that includes patients who received intravesical BCG for NMIBC at our institution from 2001 to 2019. Data were collected on patient and pathologic characteristics. Patients were stratified into three cohorts: prior radiotherapy (RT), radical prostatectomy (RP), and no prostate cancer (No PCa). Wilcoxon rank sum test and Chi-squared test were used for comparison between groups. The primary endpoints included recurrence at one-year, progression to MIBC and progression to metastatic disease. Results: In 199 total patients who underwent BCG for NMIBC, 23 had a prior history of radiotherapy treatment for prostate cancer, while 17 underwent prior radical prostatectomy. Overall, 41.2% of patients had recurrence at one year. There was no difference in recurrence at one year between the cohorts: 42.8% No PCa, 29.4% RP and 39.1% RT; p = 0.56. There was also no difference in progression to MIBC (6.9% No PCA, 0% RP, and 8.7% RT) or progression to metastatic disease (6.9% No PCA, 5.9% RP and 4.3% RT) with p = 0.50 and 0.89 respectively. Conclusions: The efficacy of intravesical BCG does not appear to be modified by prior radiation treatment for prostate cancer in patients with NMIBC.[Table: see text]

Role of oral pentosan polysulfate in Bacillus Calmette-Guérin therapy in patients with non-muscle-invasive bladder cancer.

PurposeIntravesical Bacillus Calmette–Guérin (BCG) instillation, although an important treatment for non-muscle-invasive bladder cancer, exerts local and systemic adverse effects. Pentosan polysulfate (PPS) is a bladder mucosal protective drug that acts by replacing mucus in the glycosaminoglycan layer of the damaged urothelium. We hypothesized that co-administration of oral PPS with BCG instillation would relieve BCG-related adverse effects without affecting its efficacy.Materials and MethodsA total of 217 patients receiving BCG instillation were enrolled. They were placed in two groups and analyzed retrospectively: group A (n=122) received BCG instillation only and group B (n=95) received 100 mg of PPS thrice daily during the BCG treatment.ResultsAfter BCG instillation, the rate of BCG-treatment discontinuation owing to adverse effects was 15.6% in group A and 6.3% in group B (p=0.034). The proportion of patients with bacteriuria after BCG was higher in group B; however, no statistical difference was observed (28.7% vs. 41.1%; p=0.057). The proportion of patients with pyuria was significantly higher in group B (81.1% vs. 91.6%; p=0.029). The proportion of patients using antibiotics was significantly higher in group A (73.8% vs. 43.2%; p=0.001). The recurrence rate within 1 year was 29 (23.8%) in group A vs. 19 (20.0%) in group B (p=0.507). Univariate and multivariate analyses showed that antibiotic use had a statistically significant effect on BCG discontinuation.ConclusionsOral PPS effectively decreased the discontinuation rate and antibiotic use without affecting the BCG efficacy.