Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.

Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.

Immunotherapeutic prospects and progress in bladder cancer.

Bladder cancer is one of the most common malignant tumours of the urogenital system, with high morbidity and mortality. In most cases, surgery is considered the first choice of treatment, followed by adjuvant chemotherapy. However, the 5-year recurrence rate is still as high as 65% in patients with non-invasive or in situ tumours and up to 73% in patients with slightly more advanced disease at initial diagnosis. Various treatment methods for bladder cancer have been developed, and hundreds of new immunotherapies are being tested. To date, only a small percentage of people have had success with new treatments, though studies have suggested that the combination of immunotherapy with other therapies improves treatment efficiency and positive outcomes for individuals, with great hopes for the future. In this article, we summarize the origins, therapeutic mechanisms and current status of research on immunotherapeutic agents for bladder cancer.

Early life vaccination reprograms the metabolism and function of myeloid cells in neonates.

Vaccination after birth provides protection against pathogen infection and immune related disorders in healthy children. The detailed effects of vaccination on neonatal immunity, however, remain largely unknown. Here, we reported that vaccination using Bacillus Calmette-Guérin (BCG) diminished the immunosuppressive function of myeloid-derived suppressor cells in neonatal mice, an immature myeloid population. A combination of single-cell transcriptome, metabolite profiling, and functional analysis demonstrated that upregulation of mTOR/HIF1a signalling and the enhanced glycolysis explained the effects of BCG on neonatal myeloid cells. Pharmalogical inhibition of glycolysis or mTOR signalling efficiently rescued the effects of BCG on neonatal myeloid cells. These observations suggest that BCG facilitates the maturation of myeloid cells in early life, which may contribute to its beneficial effects against immune disorders later in life.

Determining reference ranges for lymphocyte proliferation responses to phytohemagglutinin and Bacillus Calmette-Guérin in Iranian children.

PURPOSE: To establish reference ranges (RRs) for stimulation index of T cell proliferation triggered by phytohemagglutinin (PHA-SI) and Bacillus Calmette-Guérin (BCG-SI). METHODS: This study investigated data from 359 healthy children and 35 patients with cellular immunodeficiency as positive controls (2010-2021). We applied a colorimetric-based method (BrdU) to measure proliferation and determine the RRs at the 2.5th and 97.5th percentiles (95% confidence intervals). A cross-validation approach was performed. RESULTS: In healthy controls, the RRs for PHA-SI and BCG-SI ranged between 3 and 5.2 and 2.52 to 5.2, respectively. PHA-SI and BCG-SI were in Severe Combined Immunodeficiency (SCID) patients from 1.2 to 2.5 and 0 to 2, while in Mendelian susceptibility to mycobacterial diseases (MSMD) patients, 2.53 to 4.5 and 0.74 to 2.2, respectively. The thresholds' accuracy was checked for testing reference intervals with diagnostic effects. CONCLUSION: This study establishes PHA-SI and BCG-SI reference ranges to aid in diagnosing and treating congenital immunodeficiency diseases.

Mycobacterium bovis BCG Given at Birth Followed by Inactivated Respiratory Syncytial Virus Vaccine Prevents Vaccine-Enhanced Disease by Promoting Trained Macrophages and Resident Memory T Cells.

Respiratory syncytial virus (RSV) infects more than 60% of infants in their first year of life. Since an experimental formalin-inactivated (FI) RSV vaccine tested in the 1960s caused enhanced respiratory disease (ERD), few attempts have been made to vaccinate infants. ERD is characterized by Th2-biased responses, lung inflammation, and poor protective immune memory. Innate immune memory displays an increased nonspecific effector function upon restimulation, a process called trained immunity, or a repressed effector function upon restimulation, a process called tolerance, which participates in host defense and inflammatory disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) given at birth can induce trained immunity as well as heterologous Th1 responses. We speculate that BCG given at birth followed by FI-RSV may alleviate ERD and enhance protection through promoting trained immunity and balanced Th immune memory. Neonatal mice were given BCG at birth and then vaccinated with FI-RSV+Al(OH)3. BCG/FI-RSV+Al(OH)3 induced trained macrophages, tissue-resident memory T cells (TRM), and specific cytotoxic T lymphocytes (CTL) in lungs and inhibited Th2 and Th17 cell immune memory, all of which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented the innate tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. Therefore, BCG given at birth to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants. IMPORTANCE RSV is the leading cause of severe lower respiratory tract infection of infants. ERD, characterized by Th2-biased responses, inflammation, and poor immune memory, has been an obstacle to the development of safe and effective killed RSV vaccines. Innate immune memory participates in host defense and inflammatory disease. BCG given at birth can induce trained immunity as well as heterologous Th1 responses. Our results showed that BCG/FI-RSV+Al(OH)3 induced trained macrophages, TRM, specific CTL, and balanced Th cell immune memory, which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. BCG at birth as an adjuvant to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants.

The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

PURPOSE: Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. MATERIALS AND METHODS: Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. RESULTS: Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. CONCLUSIONS: For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Grade Heterogeneity in High-Grade Urothelial Carcinomas: Does It Have an Impact on the Survival of Patients With Intermediate/High-Risk Nonmuscle-Invasive Bladder Cancer Who Received Adequate Adjuvant Bacillus Calmette-Guérin Therapy?

PURPOSE: We aimed to compare recurrence-free survival (RFS) and progression-free survival (PFS) of the patients with pure high-grade (HG) vs mixed-grade (MG) nonmuscle-invasive bladder cancer who received adequate bacillus Calmette-Guérin therapy. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using data from an institutional database. The study included patients diagnosed with HG nonmuscle-invasive bladder cancer at the initial transurethral resection specimen between 2010 and 2020. The initial transurethral resection specimens of all patients were reevaluated by a dedicated uropathologist. The percentage of low-grade tumor areas accompanying HG areas was determined for each case. Time-to-event analysis was performed using the Kaplan-Meier method. RFS and PFS rates were compared between groups. RESULTS: Of the 203 patients enrolled in the study, 69 (34%) had MG tumors. Recurrence was observed in 41 out of 134 patients (30.6%) in the HG group and in 19 out of 69 patients (27.5%) in the MG group. The 36-month RFS rates were 69% (CI: 62-77) and 72% (CI: 62-83) for the HG-urothelial carcinoma (UC) and MG-UC groups, respectively. The RFS rates were similar between groups (log-rank, P = .58). Progression was observed in 22 out of 134 patients (16.4%) in the HG group and in 4 out of 69 patients (5.8%) in the MG group. The 36-month PFS rates were 84% (CI: 77-90) and 94% (CI: 89-100) for the HG-UC and MG-UC groups, respectively. The pure HG-UC group had a worse PFS than the MG-UC group (log-rank, P = .042). Multivariate analysis demonstrated that age and tumor grade were significant risk factors for the development of progression. CONCLUSIONS: The indication of MG-UC category separately from pure HG carcinomas in the pathology report seems to be an important issue that can guide patient management. In this way, both more accurate risk classification and more accurate patient counseling can be performed. More importantly, the treatment plan can be made more accurately. For more precise conclusions, our results should be supported by prospective studies with larger sample size.

Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.

BACKGROUND: Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated. RESULTS: In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1ß) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed. CONCLUSIONS: We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

Comparative transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium tuberculosis and Mycobacterium bovis BCG.

Mycobacterium tuberculosis (MTB) and Mycobacterium bovis (M. bovis) are closely related pathogenic mycobacteria known to cause chronic pulmonary infections in both humans and animals. Despite sharing nearly identical genomes and virulence factors, these two bacteria display variations in host tropism, epidemiology, and clinical presentations. M. bovis Bacillus Calmette-Guérin (BCG) is an attenuated strain of M. bovis commonly utilized as a vaccine for tuberculosis (TB). Nevertheless, the molecular underpinnings of these distinctions and the intricacies of host-pathogen interactions remain areas of ongoing research. In this study, a comparative transcriptomic analysis was conducted on human leukemia macrophages (THP-1) infected with either MTB H37Rv or M. bovis BCG (Tokyo strain) to elucidate common and strain-specific responses at the transcriptional level. RNA sequencing was utilized to characterize the transcriptomes of human primary macrophages infected with MTB or BCG at 6 and 24 h post-infection. The findings indicate that both MTB and BCG induce substantial and dynamic alterations in the transcriptomes of THP-1, with a notable overlap in the quantity and extent of differentially expressed genes (DEGs). Moreover, gene ontology (GO) enrichment analysis unveiled shared pathways related to immune response, cytokine signaling, and apoptosis. The immune response of macrophages to bacterial infections at 6 h exhibited significantly greater intensity compared to that at 24 h. Furthermore, distinct gene sets displaying notable variances between MTB and BCG infections were identified. The profound impact of MTB infection on macrophage gene expression, particularly within the initial 6 h, was evident. Additionally, downregulation of pathways such as Focal adhesion, Rap1 signaling pathway, and Regulation of actin cytoskeleton was observed. The pathways associated with inflammation reactions and cell apoptosis exhibited significant differences, with BCG triggering macrophage apoptosis and MTB enhancing the survival of intracellular bacteria. Our findings reveal that MTB and BCG provoke similar yet distinct transcriptional responses in human macrophages, indicating variations in their pathogenesis and ability to adapt to host environments. These results offer novel insights into the molecular mechanisms governing host-pathogen interactions and may contribute to a deeper understanding of TB pathogenesis.

Systemic neutrophils are triggered by respiratory Bacillus Calmette- Guérin and mediate pulmonary mycobacterial clearance in synergy with the triggering receptor expressed on myeloid cells 1.

Tuberculosis remains a threat to public health. The only approved vaccine, Bacillus Calmette-Guérin (BCG), is administered intradermally and provides limited protection, and its effect on innate immunity via the respiratory route has not been fully elucidated. A mouse model with genetically depleted TREM1 and seven-color flow cytometry staining were used to characterize the comprehensive immune response induced by respiratory BCG, through evaluating organ bacterial loads, lung histopathology, and lung immunohistochemistry. During respiratory BCG infection, the murine lungs displayed effective bacterial clearance. Notably, marked differences in neutrophils were observed between thymus and bone marrow cells, characterized by a significant increase in the expression of the triggering receptor expressed on myeloid cells 1 (TREM1). Subsequently, upon depletion of TREM1, a reduction in pulmonary neutrophils was observed, which further exacerbated bacterial loads and resulted in worsened pathology following respiratory BCG infection. In summary, up-regulated expression of TREM1 in rapidly increasing circulating neutrophil by pulmonary BCG is required for an efficient host response to BCG infection, and suggests the important role of TREM1 in neutrophil-related pulmonary bacteria clearance and pathology.

BCG vaccination and multiple sclerosis risk: A Norwegian cohort study.

INTRODUCTION: Bacillus Calmette-Guérin (BCG) vaccination induces long-lasting effects on the adaptive and innate immune systems and prevents development of experimental autoimmune encephalomyelitis and possibly also inflammatory disease activity in multiple sclerosis (MS). OBJECTIVE: The objective is to examine if BCG given in early adulthood decreases MS risk. METHODS: From 791,369 (52% females) Norwegians participating in a national tuberculosis screening program from 1963 to 1975, we collected information on BCG vaccination and tuberculosis disease status. Later, MS disease was ascertained through both the Norwegian MS Registry and Biobank and the Norwegian Death Registry. We used logistic regression models to assess the relationship between BCG vaccination and MS risk. RESULTS: In those BCG vaccinated, mean age at vaccination was 15.6 (standard deviation (SD) = 5.5) years. A total of 2862 (65% females) MS cases were retrieved. Overall, we found no association between MS risk and BCG vaccination. Compared to non-BCG-vaccinated individuals with no signs of tuberculosis infection, odds ratio (OR) for MS was 1.00 (95% confidence interval (CI) = 0.80-1.25) in the BCG-vaccinated group. In those not BCG vaccinated because of latent tuberculosis infection, the corresponding OR was 0.86 (95% CI = 0.66-1.13). CONCLUSION: We found no evidence of BCG vaccination or latent tuberculosis infection in young adulthood being linked to MS risk.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Association between Bacillus Calmette-Guérin (BCG) vaccination and inflammatory bowel disease: A two-stage sampling design within the Quebec Birth Cohort on Immunity and Health (CO·MMUNITY).

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccination, primarily administered to prevent tuberculosis, exhibits nonspecific immune effects and could play a role in inflammatory bowel disease prevention. We investigated the associations of BCG with Crohn's disease and ulcerative colitis, and assessed sex-differences. METHODS: This two-stage study included 365,206 Canadians from the Quebec Birth Cohort on Immunity and Health (1970-2014; stage 1). Vaccination status was registry-based and inflammatory bowel disease cases were identified from health services with validated algorithms. We documented additional factors among 2644 participants in a nested case-control study in, 2021 (stage 2). A two-stage logistic regression analysis was applied to estimate the odds ratios (OR), corrected for sampling fractions and adjusted for confounding factors. We used interaction terms to assess sex-differences on the multiplicative scale. RESULTS: In the stage 1 sample, 2419 cases of Crohn's disease and 1079 of ulcerative colitis were included. Forty-six percent of non-cases received the BCG vaccine as compared to 47% for Crohn's disease and 49% for ulcerative colitis. Associations differed by sex. BCG vaccination was not associated with Crohn's disease among men (OR = 0.91; 95% CI: 0.79-1.04) but was related to an increased risk among women (OR = 1.13; 95% CI: 1.00-1.28, P interaction: 0.001). For ulcerative colitis, there was a tendency toward a slightly elevated risk among men (OR = 1.09; 95%CI: 0.90-1.32), whereas the risk was more substantial for women (OR = 1.17; 95% CI:0.99-1.39, P interaction: <0.001). CONCLUSION: BCG vaccination does not play a preventive role in inflammatory bowel disease. Our results point to distinct associations between men and women.

N-803 Plus BCG Treatment for BCG-Naïve or -Unresponsive Non-Muscle Invasive Bladder Cancer: A Plain Language Review.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC).One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive). WHAT HAPPENED IN THE STUDIES?: In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 µg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 µg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 µg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row. WHAT WERE THE KEY TAKEAWAYS?: N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease.Clinical Trial Registration: NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).

Addition of the IL-15 superagonist N-803 to BCG therapy produces a high rate of success in eliminating non-muscle invasive bladder cancer in both BCG-naive and BCG-unresponsive patients, with long-lasting effects that allow patients to avoid surgical removal of the bladder.

CREST: phase III study of sasanlimab and Bacillus Calmette-Guérin for patients with Bacillus Calmette-Guérin-naïve high-risk non-muscle-invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG in combination with programmed cell death-1 (PD-1) inhibitors may yield greater anti-tumor activity compared with either agent alone. CREST is a phase III study evaluating the efficacy and safety of the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG for patients with BCG-naive high-risk NMIBC. Eligible participants are randomized to receive sasanlimab plus BCG (induction ± maintenance) or BCG alone for up to 25 cycles within 12 weeks of TURBT. The primary outcome is event-free survival. Secondary outcomes include additional efficacy end points and safety. The target sample size is around 1000 participants.

Non-muscle-invasive bladder cancer (NMIBC) is the most common type of bladder cancer. Most people have surgery to remove the cancer cells while leaving the rest of the bladder intact. This is called transurethral resection of a bladder tumor (TURBT). For people with high-risk NMIBC, a medicine called Bacillus Calmette-Guérin (BCG) is placed directly inside the bladder after TURBT. A 'high risk' classification means that the cancer is more likely to spread or come back after treatment. Some people's cancer does not respond to BCG or returns after BCG treatment. Researchers are currently looking at whether BCG combined with other immunotherapies may prevent cancer growth more than BCG on its own. Immunotherapy helps the immune system recognize and kill cancer cells. Sasanlimab is an immunotherapy medicine that is not yet approved to treat people with NMIBC. It is given as an injection under the skin. In this CREST study, researchers are looking at how safe and effective sasanlimab plus BCG is for people with high-risk NMIBC. Around 1000 people are taking part in CREST. They must have had TURBT 12 weeks or less before joining the study. Researchers want to know how long people live without certain events occurring, such as bladder cancer cells returning. A plain language summary of this article can be found as Supplementary Material. Clinical Trial Registration: NCT04165317; 2019-003375-19 (EudraCT) (ClinicalTrials.gov).

The impact of second transurethral resection on survival outcomes in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin therapy.

OBJECTIVE: Several guidelines recommended that second transurethral resection should be performed in patients with diagnosis of high-risk non-muscle-invasive bladder cancer. However, therapeutic benefits of second transurethral resection before bacillus Calmette-Guérin intravesical instillation were conflicting amongst previous studies. We investigated the prognostic impact of second transurethral resection before bacillus Calmette-Guérin instillation in high-risk non-muscle-invasive bladder cancer patients. METHODS: This retrospective study included 3104 non-muscle-invasive bladder cancer patients who received bacillus Calmette-Guérin instillations between 2000 and 2019 at 31 collaborative institutions. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors of intravesical recurrence, disease progression, cancer-specific mortality and overall mortality. RESULTS: In the entire population, patients undergoing second transurethral resection (33%, 1026/3104) had a lower risk of intravesical recurrence on univariate analysis (hazard ratio 0.85, 95% confidence interval 0.73-0.98, P = 0.027), although it did not remain significant on multivariate analysis (hazard ratio 0.90, 95% confidence interval 0.76-1.07, P = 0.24). Subgroup analysis revealed that, in pT1 patients (n = 1487), second transurethral resection was significantly correlated with a lower risk of intravesical recurrence on multivariate analysis (hazard ratio 0.80, 95% confidence interval 0.64-1.00, P = 0.048), but lower risks of disease progression (hazard ratio 0.75, 95% confidence interval 0.56-1.00, P = 0.049), cancer-specific mortality (hazard ratio 0.54, 95% confidence interval 0.35-0.85, P = 0.007) and overall mortality (hazard ratio 0.73, 95% confidence interval 0.55-0.97, P = 0.027) on univariate analysis. CONCLUSIONS: Second transurethral resection confers accurate pathological staging and could be used to safely select good candidates for intravesical bacillus Calmette-Guérin instillation. We further confirm that second transurethral resection could confer an oncological benefit in pT1 bladder cancer patients treated by bacillus Calmette-Guérin instillation, and so strongly recommend second transurethral resection in this patient population.

A new neonatal BCG vaccination pathway in England: a mixed methods evaluation of its implementation.

INTRODUCTION: The introduction of a national evaluation of newborn screening for Severe Combined Immunodeficiency (SCID) in England triggered a change to the selective Bacillus Calmette-Guerin (BCG) vaccination programme delivery pathway, as this live attenuated vaccine is contraindicated in infants with SCID. The neonatal BCG vaccination programme is a targeted programme for infants at increased risk of tuberculosis and used to be offered shortly after birth. Since September 2021 the BCG vaccine is given to eligible infants within 28 days of birth, when the SCID screening outcome is available. We explore the experiences of those implementing the new pathway, and how they made sense of, engaged with, and appraised the change. METHODS: A mixed-methods evaluation was conducted between October 2022 and February 2023. This involved national online surveys with BCG commissioners and providers and qualitative semi-structured interviews with commissioners, providers, and Child Health Information System stakeholders in two urban areas. Survey data was analysed using descriptive statistics and interview data was analysed thematically. The data was triangulated using Normalization Process Theory as a guiding framework. RESULTS: Survey respondents (n = 65) and qualitative interviewees (n = 16) revealed that making sense of the new pathway was an iterative process. Some expressed a desire for more direction on how to implement the new pathway. The perceived value of the change varied from positive, ambivalent, to concerned. Some felt well-prepared and that improvements to data capture, eligibility screening, and accountably brought by the change were valuable. Others were concerned about the feasibility of the 28-day target, reductions in vaccination coverage, increased resource burden, and the outcome of the SCID evaluation. New collaborations and communities of practice were required to facilitate the change. Three main challenges in implementing the pathway and meeting the 28-day vaccination target were identified: appointment non-attendance; appointment and data systems; and staffing and resourcing. Feedback mechanisms were informal and took place in tandem with implementation. CONCLUSION: The new NHS neonatal BCG service specification has created an effective structure for monitoring and managing the BCG vaccination programme, but further work is required to support delivery of the 28-day vaccination target and improve uptake rates.

Assessing the impact of COVID-19 on routine immunization in Sierra Leone.

BACKGROUND: The COVID-19 pandemic had a profound impact on healthcare systems and services, including routine immunization (RI). To date, there is limited information on the effects of the COVID-19 pandemic on RI in West African countries such as Sierra Leone, which had already experienced public health emergencies that disrupted its healthcare system. Here, we describe the impact of the COVID-19 pandemic on the RI of key antigens in Sierra Leone. METHODS: We used vaccination data from the District Health Information System for BCG, measles-rubella 1 and 2, and pentavalent 1 and 3 antigens. We compared 2019, 2020, 2021, and 2022 annual coverage rates for the selected antigens at the national and district levels. We used the Pearson chi-square test to assess the difference between annual coverage rates between 2019 and 2020, 2020-2021, and 2021-2022. RESULTS: National coverage rates for all antigens declined in 2019-2020, notably measles-rubella 1 and pentavalent 3 (-5.4% and - 4.9%). Between 2020 and 2021, there was an overall increase in coverage (+ 0.2% to + 2.5%), except for measles-rubella 2 (-1.8%). Measles-rubella antigens rebounded in 2021-2022, while others decreased between - 0.5 and - 1.9% in coverage. Overall, all district-level coverage rates in 2022 were lower than those in 2019. Most districts decreased between 2019 and 2022, though a few had a continuous increase; some had an increase/recovery between 2020 and 2021; some districts had recovered 2019 levels by 2022. CONCLUSION: The COVID-19 pandemic impacted Sierra Leone's national BCG, measles-rubella, and pentavalent antigen immunization, which were not fully restored in 2022. Most districts experienced notable coverage declines during the pandemic, though a few reached or surpassed 2019 rates in 2022. Examining pandemic impact can benefit from a focus beyond the national level to identify vulnerable regions. Sierra Leone's post-pandemic RI reestablishment needs targeted strategies and continual investments for equitable access and coverage, as well as to prevent vaccine-preventable diseases.

A Safer Method for Disinfection of Bacillus Calmette-Guerin-Containing Urine: A Prospective, Randomized Study.

INTRODUCTION: The aim of the study was to examine whether disinfection of bacillus Calmette-Guerin-containing urine with etaprocohol® (ethanol 76.9-81.4 vol % and isopropanol as an additive) is safer than disinfection with sodium hypochlorite. METHOD: In prospective research, safety and efficacy was analyzed in 5 patients in the etaprocohol® disinfection group and 5 patients in the sodium hypochlorite disinfection group. The primary endpoint was the temperature change after disinfection and the secondary endpoint was the unpleasantness of the odor caused by disinfection. Additionally, concentration of gas produced was also examined. Sensory tests were taken from staff who performed urine disinfection and the odor generated by disinfection was evaluated. As a safety protocol, post-BCG-treated urine is cultured to verify the negativity for mycobacteria. RESULTS: Mycobacteria were disinfected in all cases. The temperature rise following disinfection was significantly higher in the sodium hypochlorite group. The sensory test outcomes were significantly worse in the group disinfected with sodium hypochlorite. The concentration of gas generated immediately after disinfection in both groups reached the maximum value and declined quickly. CONCLUSIONS: Disinfection of bacillus Calmette-Guerin-containing urine with etaprocohol® was safer than disinfection with sodium hypochlorite, and an equivalent disinfection effect was achieved.