Therapy For Bladder Cancer Research Articles

Abstract 609: The predictive power of tertiary lymphoid structures in assessing response to trimodal therapy in muscle invasive bladder cancer

Abstract Introduction: Radical cystectomy is the standard of care for muscle invasive bladder cancer (MIBC). Radiotherapy (RT) is a bladder preserving option that offers patients comparable survival rates. However, up to 30% of patients require salvage cystectomy. Emerging evidence points to an important yet poorly understood link between response to RT and the tumor microenvironment (TME). Notably, tertiary lymphoid structures (TLS) are being investigated as a potential local hub for mounting an immune response. These lymph-node-like structures are highly organized with a B cell zone surrounded by T cells. Mature TLS also have an active germinal center (GC) with follicular dendritic cells. A number of studies correlated TLS with improved outcomes in several types of solid cancers. Here, we explore the use of TLS and its associated immune TME as a predictive biomarker for response to RT in MIBC. Methods: Hematoxylin and Eosin (H&E) stained formalin-fixed-paraffin-embedded sections of pre-RT biopsy from 147 MIBC patients were examined to identify TLS presence with confirmation from a pathologist. Subsequent multiplex immunohistochemistry (mIHC) staining with CD21 and CD23 characterized TLS maturity. To investigate the interaction between TLS and TME, tissue microarrays (TMAs) were constructed, and gene expression profiles were obtained for 106 patients using NanoString’s Digital Spatial technology. Moreover, the TMAs were stained with CD20, Neutrophil Elastase, CD68, CD8, CD4, and FoxP3 by mIHC. Image analysis was performed on the Halo platform. TLS gene signature was correlated to the immune infiltration and the patient outcomes. Results: H&E revealed that 19.7% of patients (n=68) had TLS with a GC, 17.0% (n=25) had TLS without a GC, and 12.9% (n=19) had no TLS. In the remaining 50.3% of cases (n=74), confirmation of TLS presence required staining with CD3 and CD20. Gene expression of TLS marker CXCL13 was higher among complete responders to RT (p-value=0.0440). This trend was weakened when we examined a previously described 12-chemokine TLS signature (p= 0.1506). When segregating patients into TLS high/TLS low groups based on the gene signature, we observed significantly higher infiltration of CD8+ T cells (p<0.0001), neutrophils (p=0.005), regulatory T cells (p=0.0278), and B cells (p=0.0247) among the TLS high group. No difference in macrophage infiltration was observed between the two groups.Conclusion: Our results point to a nuanced role of TLS in the context of response to RT and in relation to the TME. Further histological analysis of TLS characteristics is necessary to paint a picture of the different immune profiles we observe in our cohort and their association with the outcomes of RT. Overall, our study could identify an immune signature that could serve as a selection criterion for patients who would benefit the most from bladder-sparing therapies. Citation Format: Nour Hassan, José Joao Mansure, Mina Farag, Ronald Kool, Eva Michaud, Mohanned Alessa, Luis Souhami, Fabio Cury, Fadi Brimo, Wassim Kassouf. The predictive power of tertiary lymphoid structures in assessing response to trimodal therapy in muscle invasive bladder cancer [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 609.

Long‐Term Retention Microbubbles with Three‐Layer Structure for Floating Intravesical Instillation Delivery (Small 14/2023)

Bladder Cancer Therapy In article number 2205630, Jianhua Zhou and co-workers develop a three-layer microbubble as a floating drug delivery system for intravesical instillation therapy. The microbubbles can not only display excellent long-term retention in the bladder but also deliver a mass of drugs to enable drugs to maintain an effective concentration in the bladder, which exhibits high antitumor efficacy on bladder cancers.

LBA03-10 ROLE OF INTRAVESICAL BACILLE CALMETTE GUERIN(BCG) IN ERADICATING ASYMPTOMATIC BACTERIURIA IN BLADDER CANCER PATIENTS-A PROSPECTIVE STUDY

You have accessJournal of UrologyCME1 Apr 2023LBA03-10 ROLE OF INTRAVESICAL BACILLE CALMETTE GUERIN(BCG) IN ERADICATING ASYMPTOMATIC BACTERIURIA IN BLADDER CANCER PATIENTS-A PROSPECTIVE STUDY Ganesh Prasad Sankarapandian Ganesh Prasad SankarapandianGanesh Prasad Sankarapandian More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003426.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although intravesical Bacille Calmette Guerin therapy for high grade superficial bladder cancer is not specifically contra indicated in people with asymptomatic bacteriuria, generally urologist are reluctant in administering this to such patients because of a possible risk of bacterial sepsis or BCG sepsis.On the other hand, anti bacterial treatment of asymptomatic bacteriuria leads to treatment delay and promotes tumour progresssion. This study is done to investigate whether intravesical BCG therapy alone can eradicate bacterial infection in asymptomatic bactreriuric patients on intravesical BCG therapy for bladder tumour. METHODS: A Single institutional prospective cohort study of bacteriuric adults with non muscle invasive bladder cancer who underwent outpatient based BCG intravesical therapy from November 2020 to November 2021 were followed up for one year till November 2022. 25 High grade non muscle invasive bladder cancer patients who underwent intravesical BCG therapy were compared with 25 low grade non muscle invasive bladder cancer patients. All patients had asymptomatic bacteriuria,none recieved antibiotic therapy before ,during or after cystoscopy procedure .Urine culture were repeated after 3,6 and 12 months after completion of one year post TURBT. All patients were followed up for a minimum of one year. The end point was number of patients who became bacteria free at 3,6,12 months. RESULTS: None of BCG treated patients, but three control patients developed febrile urinary tract infections and were removed from the study. Of the study group out of 25 patients who recieved intravesical BCG 20 were continuously bacteria free at the end of one year compared with 8 out of 22 patients in the control group. CONCLUSIONS: Intravesical BCG is associated with clearance of Uropathogens in bladder cancer patients possibly due to an augmented innate host immunity. Source of Funding: Self (Author) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1196 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ganesh Prasad Sankarapandian More articles by this author Expand All Advertisement PDF downloadLoading ...

A systematic review of the efficacy of intravesical electromotive drug administration therapy for non-muscle invasive bladder cancer.

Non-muscle invasive bladder cancer (NMIBC) is characterized by a high rate of recurrence and progression, despite surgery and adjuvant therapies. To analyze the published results on the effectiveness of mitomycin C (MMC) applied with an electromotive drug administration device (EMDA) in the treatment of patients with non-muscle invasive bladder tumors. A systematic review was conducted using the PubMed and Google Scholar search platforms. We selected the studies that included the recurrence and/or progression rates or complete response rate in patients diagnosed with NMIBC according to their treatment and included MMC applied with EMDA. The last search was performed in November 2021. The search yielded 64 articles; 11 articles met the selection criteria. In two of the 11 selected articles, mitomycin C was applied with an EMDA device (MMC-EMDA) as an ablative treatment, avoiding surgery in 50% of the patients. In 1 of the 11 studies, the application of MMC-EMDA was used as an induction treatment using a single preoperative instillation with promising results. In the remaining 8 studies, adjuvant MMC was applied with the EMDA device; in 3 of these 8 cases, treatment with MMC-EMDA alone was applied initially. In another3 cases the same treatment was applied after nonresponse to bacillus Calmette Guerin (BCG), and in the last 2 studies, MMC-EMDA was applied in combination with the classic therapy (BCG). All the studies selected supported the efficacy and safety of MMC-EMDA in patients with intermediate and high- risk bladder cancer. In 3 studies, adjuvant therapy with MMC-EMDA was performed in nonresponders to BCG, finding that adjuvant therapy with MMC-EMDA applied to BCG nonresponders without CIS avoided or delayed surgery. The application of EMDA-enhanced MMC has been studied at different times of disease and with different administration protocols. It appears to delay bladder tumor recurrence and progression in certain populations. However, the methodological limitations of the published studies prevent definitive conclusions about its efficacy.

MP48-06 PATIENT-REPORTED TREATMENT BURDEN OF INTRAVESICAL THERAPY FOR BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP48-06 PATIENT-REPORTED TREATMENT BURDEN OF INTRAVESICAL THERAPY FOR BLADDER CANCER Amanda Myers, Benjamin Ristau, Matthew Mossanen, Deborah Kaye, Mark Tyson, Stephanie Chisolm, Frank Sloan, Colleen Ball, Angela Smith, and Timothy Lyon Amanda MyersAmanda Myers More articles by this author , Benjamin RistauBenjamin Ristau More articles by this author , Matthew MossanenMatthew Mossanen More articles by this author , Deborah KayeDeborah Kaye More articles by this author , Mark TysonMark Tyson More articles by this author , Stephanie ChisolmStephanie Chisolm More articles by this author , Frank SloanFrank Sloan More articles by this author , Colleen BallColleen Ball More articles by this author , Angela SmithAngela Smith More articles by this author , and Timothy LyonTimothy Lyon More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003294.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intravesical therapy is the mainstay of treatment for non-muscle invasive bladder cancer (NMIBC). However, patients with NMIBC can face time, travel, and financial barriers to access intravesical therapy which may impact patient adherence to treatment. Therefore, we sought to quantify patient-reported treatment burden while receiving intravesical therapy for bladder cancer. METHODS: We conducted a cross-sectional survey of bladder cancer patients in the Bladder Cancer Advocacy Network (BCAN) Patient Survey Network to investigate patient-reported burden of intravesical therapy. Multiple choice survey questions were developed by investigators, then iteratively revised and improved by review from clinician and patient advocate stakeholders during the 2021 BCAN annual meeting. Eligible participants received at least one dose of intravesical therapy, including BCG and/or chemotherapy, delivered in an ambulatory setting. Survey was administered in November 2021 and was available for 1 month to respondents. RESULTS: A total of 233 patients responded to the survey (18% response rate), with a median age of 70 years (range 33-88). Respondents were 36% female and 97% white. A travel time >30 minutes to an intravesical treatment facility was reported by 55% (126/231) of patients, and 33% (77/231) reported personal out-of-pocket costs greater than $25 associated with each trip. Fifty-six percent (129/232) brought caregivers to their appointments. More than half of patients (56%, 129/232) reported spending more than 2 hours on each intravesical instillation, with 18% (42/232) spending more than 4 hours. Missing work for intravesical installations was reported by 36% (82/230) of patients, and of those who did, the majority (70%, 57/81) missed at least half a day of work (4 or more hours). Sixty-one respondents (26%) felt the process of receiving bladder instillations adversely affected their ability to perform regular daily activities. BCG shortages increased travel or wait time for intravesical therapy for 9% (20/229) of respondents. CONCLUSIONS: Bladder cancer patients reported considerable travel distances, time requirements, out-of-pocket costs, and need for caregiver support in the process of receiving intravesical therapy. Innovative intravesical care delivery processes are needed to reduce the burden of care for our bladder cancer patients. Source of Funding: n/a © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e657 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Amanda Myers More articles by this author Benjamin Ristau More articles by this author Matthew Mossanen More articles by this author Deborah Kaye More articles by this author Mark Tyson More articles by this author Stephanie Chisolm More articles by this author Frank Sloan More articles by this author Colleen Ball More articles by this author Angela Smith More articles by this author Timothy Lyon More articles by this author Expand All Advertisement PDF downloadLoading ...

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers

BackgroundRadiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). ObjectiveTo analyze predictors of complete response (CR) and survival after RT for MIBC. Design, setting, and participantsThis was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. Outcome measurements and statistical analysisRegression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). Results and limitationsThe median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3–4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29–0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034–0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46–2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25–3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79–3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46–0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51–0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01–1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34–2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17–1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49–0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51–0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12–1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. ConclusionsRT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. Patient summaryWe investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

Patient and Caregiver Perceptions of Advanced Bladder Cancer Systemic Treatments: Infodemiology Study Based on Social Media Data.

In 2022, it was estimated that more than 80,000 new cases of bladder cancer (BC) were diagnosed in the United States, 12% of which were locally advanced or metastatic BC (advanced BC). These forms of cancer are aggressive and have a poor prognosis, with a 5-year survival rate of 7.7% for metastatic BC. Despite recent therapeutic advances for advanced BC, little is known about patient and caregiver perceptions of different systemic treatments. To further explore this topic, social media can be used to collect the perceptions of patients and caregivers when they discuss their experiences on forums and online communities. The aim of this study was to assess patient and caregiver perceptions of chemotherapy and immunotherapy for treating advanced BC from social media-posted data. Public posts on social media in the United States between January 2015 and April 2021 from patients with advanced BC and their caregivers were collected. The posts included in this analysis were geolocalized to the United States; collected from publicly available domains and sites, including social media sites such as Twitter and forums such as patient association forums; and were written in English. Posts mentioning any line of chemotherapy or immunotherapy were qualitatively analyzed by two researchers to classify perceptions of treatments (positive, negative, mixed, or without perception). A total of 80 posts by 69 patients and 142 posts by 127 caregivers mentioning chemotherapy, and 42 posts by 31 patients and 35 posts by 32 caregivers mentioning immunotherapy were included for analysis. These posts were retrieved from 39 public social media sites. Among patients with advanced BC and their caregivers, treatment perceptions of chemotherapy were more negative (36%) than positive (7%). Most of the patients' posts (71%) mentioned chemotherapy factually without expressing a perception of the treatment. The caregivers' perceptions of treatment were negative in 44%, mixed in 8%, and positive in 7% of posts. In combined patient and caregiver posts, immunotherapy was perceived positively in 47% of posts and negatively in 22% of posts. Caregivers also posted more negative perceptions (37%) of immunotherapy than patients (9%). Negative perceptions of both chemotherapy and immunotherapy were mainly due to side effects and perceived lack of effectiveness. Despite chemotherapy being standard first-line therapy for advanced BC, negative perceptions were identified on social media, particularly among caregivers. Addressing these negative perceptions of treatment may improve treatment adoption. Strengthening support for patients receiving chemotherapy and their caregivers to help them manage side effects and understand the role of chemotherapy in the treatment of advanced BC would potentially enable a more positive experience.

METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS.

The present study aimed to explore the potential roles of the methyltransferase‑like 3 (METTL3)‑mediated methylation of RAS related (RRAS) mRNA in the tumorigenesis and development of bladder cancer (BCa). For this purpose, the relative expression levels of METTL3 in BCa specimens and cell lines were measured using reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. The association between the METTL3 expression level and the clinical characteristics of patients with BCa was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis databases. Cellular experiments were performed to confirm the effects of METTL3 on the proliferative, migratory and invasive capacities of BCa cells. RT‑qPCR, western blot analysis, methylated RNA immunoprecipitation (MeRIP)‑qPCR and dual‑luciferase report assays were utilized to verify the METTL3/RRAS/YTH N6‑methyladenosine (m6A) RNA binding protein 2 (YTHDF2) regulatory axis in BCa. The results revealed that METTL3 expression was markedly increased in BCa specimens and cell lines, and was associated with poor clinical characteristics of patients with BCa. Invitro and invivo assays demonstrated that the silencing of METTL3 markedly suppressed the proliferative, migratory and invasive capacities of BCa cells. MeRIP‑PCR and dual‑luciferase report assays indicated that METTL3 could bind to the m6A sites of RRAS mRNA and suppress the transcriptional activity of RRAS. YTHDF2 could recognize the m6A sites of RRAS and mediate RRAS degradation. On the whole, the findings of the present study reveal the pivotal role of METTL3‑catalyzed m6A modification in BCa tumorigenesis and development. The change could facilitate BCa tumor growth and metastasis by suppressing RRAS expression in an m6A YTHDF2‑dependent manner. Targeting the METTL3/RRAS/YTHDF2 regulatory axis may thus prove to be a promising strategy for the diagnosis and therapy of BCa.

Synergistic ferroptosis-starvation therapy for bladder cancer based on hyaluronic acid modified metal-organic frameworks.

Bladder cancer (BCa) is one of the most common malignancies of the urinary tract. Metastasis and recurrence of BCa are the leading causes of poor prognosis, and only a few patients can benefit from current first-line treatments such as chemotherapy and immunotherapy. It is urgent to develop more effective therapeutic method with low side effects. Here, a cascade nanoreactor, ZIF-8/PdCuAu/GOx@HA (ZPG@H), is proposed for starvation therapy and ferroptosis of BCa. The ZPG@H nanoreactor was constructed by co-encapsulation of PdCuAu nanoparticles and glucose oxidase into zeolitic imidazolate framework-8 (ZIF-8) modified by hyaluronic acid. The vitro results indicated that ZPG@H enhanced intracellular reactive oxygen species levels and reduced mitochondrial depolarization in the tumor microenvironment. Therefore, the integrated advantages of starvation therapy and chemodynamic therapy endow ZPG@H with a perfect ferroptosis inducing ability. This effectiveness, combined with its excellent biocompatibility and biosafety, means that ZPG@H could make a critical contribution to the development of novel BCa treatments.

Mutations in genes encoding innate immune molecules identified in bladder cancer samples as potential biomarkers for immunotherapy with BCG and agonists

Bacillus Calmette–Guérin (BCG) immunotherapy for the treatment of bladder cancer (BC) depends on the recognition of bacteria by extracellular toll-like receptors (TLRs) or the detection of mycobacterial DNA by endosomal TLRs or the cGAS-STING pathway. Agonists related to these innate immune pathways have been developed as adjuvants to potentiate the effects of immunotherapy. As innate immune pathways are important for the action of BCG and other agonists proposed for BC therapy, we decided to investigate the presence of mutations in the main receptors of these pathways. The Cancer Genome Atlas (TCGA) database was screened to identify BC-related mutations (apart from oncogenes), targeting, in particular, TLRs, the adaptor molecule MyD88, and the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) immune pathway. Among 1,724 BC entries, 103 mutations were identified in 80 affected cases in the cohort. TLR9 and TLR10 ranked among the most frequent mutated genes observed in the affected cases in our search (13 mutations each). Through all analyzed data, the search for MYD88 gene recovered only 1 mutation input in the database. Mutations in the STING and cGAS genes were found in one and four cases, respectively. We also evaluated clinical data, including the pathologic stage of BC, and gene expression from 103 mutations entries. This article attempts to highlight the relevance of mutations in genes coding for innate immune molecules in BC samples as potential biomarkers to predict individual disease outcome, and specifically to help find the appropriate treatment for each person in the future.

Health care resource utilization, quality metrics, and costs of bladder cancer within the Oncology Care Model.

New and emerging therapies have significantly changed the bladder cancer (BC) treatment landscape and can potentially affect spending and patient care in CMS' Oncology Care Model (OCM), a service delivery and payment model for voluntarily participating practices. The objectives of this analysis were to estimate health care resource utilization (HCRU) and benchmark spending per OCM episode of BC, and to model spending drivers and quality metrics. Retrospective cohort study. A retrospective cohort study was conducted of OCM episodes triggered by receipt of anticancer therapy among Medicare beneficiaries from 2016 to 2018. Based on this, an average performance estimation was conducted to assess the impact of hypothetical changes in novel therapy use by OCM practices. BC accounted for approximately 3% (n = 60,099) of identified OCM episodes. Relative to low-risk episodes, high-risk episodes were associated with greater HCRU and worse OCM quality metrics. Mean spending per high-risk episode was $37,857 (low-risk episode: $9204), with $11,051 spent on systemic therapies and $7158 on inpatient services. In the estimation, high- and low-risk BC exceeded the spending target by 1.7% and 9.4%, respectively. This did not affect payments to practices and no retrospective payments were necessary. As 3% of OCM episodes were attributed to BC, with only one-third classified as high-risk, controlling expenditure on novel therapies for advanced BC is unlikely to affect overall practice performance. The average performance estimation further emphasized the minimal impact that novel therapy spending in high-risk BC has on OCM payments to practices.

Bioengineered bacterial outer membrane vesicles encapsulated Polybia-mastoparan I fusion peptide as a promising nanoplatform for bladder cancer immune-modulatory chemotherapy.

Nanosized bacterial outer membrane vesicles (OMVs) secreted by Gram-negative bacteria have emerged as a novel antitumor nanomedicine reagent due to their immunostimulatory properties. The encapsulated bacterial composition in OMVs can be edited via manipulating bioengineering technology on paternal bacteria, allowing us to design an ingenious antitumor platform by loading the Polybia-mastoparan I (MPI) fusion peptide into OMVs. OMVs containing the MPI fusion peptide were obtained from bioengineered Escherichia coli transformed with recombinant plasmid. The antitumor efficacy of bioengineered OMVs in vitro was verified by performing cell viability and wound-healing and apoptosis assays using MB49 and UMUC3 cells, respectively. Subcutaneous MB49 tumor-bearing mice were involved to investigate the tumor inhibition ability of bioengineered OMVs. Moreover, the activated immune response in tumor and the biosafety were also evaluated in detail. The resulting OMVs had the successful encapsulation of MPI fusion peptides and were subjected to physical characterization for morphology, size, and zeta potential. Cell viabilities of bladder cancer cells including MB49 and UMUC3 rather than a non-carcinomatous cell line (bEnd.3) were decreased when incubated with bioengineered OMVs. In addition, bioengineered OMVs restrained migration and induced apoptosis of bladder cancer cells. With intratumor injection of bioengineered OMVs, growths of subcutaneous MB49 tumors were significantly restricted. The inherent immunostimulation of OMVs was demonstrated to trigger maturation of dendritic cells (DCs), recruitment of macrophages, and infiltration of cytotoxic T lymphocytes (CTLs), resulting in the increased secretion of pro-inflammatory cytokines (IL-6, TNF-α, and IFN-γ). Meanwhile, several lines of evidence also indicated that bioengineered OMVs had satisfactory biosafety. Bioengineered OMVs fabricated in the present study were characterized by strong bladder cancer suppression and great biocompatibility, providing a new avenue for clinical bladder cancer therapy.

Current Status of Perioperative Therapy in Muscle-Invasive Bladder Cancer and Future Directions.

Cisplatin-based combination chemotherapy has been a standard of care in the perioperative management of muscle-invasive bladder cancer for years, but several novel therapies are under active investigation. This review aims to provide an update on recent relevant literature and a forward look at the future landscape of adjuvant and neoadjuvant therapy in muscle-invasive bladder cancer patients who opt for radical cystectomy. The recent approval of nivolumab as adjuvant therapy established a new treatment option for high-risk patients with muscle-invasive bladder cancer after radical cystectomy. Several phase II studies of chemo-immunotherapy combinations and immunotherapy alone have reported pathological complete responses in the 26-46% range, including studies in cisplatin-ineligible patients. Randomized studies of perioperative chemo-immunotherapy, immunotherapy alone, and enfortumab vedotin are ongoing. Muscle-invasive bladder cancer remains a challenging disease associated with significant morbidity and mortality; however, increasing options in systemic therapy and an increasingly personalized approach to cancer treatment suggest continued future improvements in patient care.

In Brief: Adstiladrin – A Gene Therapy for Bladder Cancer

Nadofaragene firadenovec-vncg (Adstiladrin – Ferring), an adenoviral vector-based gene therapy, has been approved by the FDA for treatment of adults with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors. It is the first adenoviral vector-based gene therapy to be approved in the US for this indication. The immune checkpoint inhibitor pembrolizumab (Keytruda) was approved for the same indication in 2021.

Nadofaragene Firadenovec: First Approval.

Nadofaragene firadenovec (nadofaragene firadenovec-vncg; Adstiladrin®) is a non-replicating adenoviral vector-based gene therapy developed by Ferring Pharmaceuticals for the treatment of high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). Nadofaragene firadenovec constitutes vector DNA that encodes for interferon (IFN)-α2b and is the first approved gene therapy in bladder cancer. The production of IFN-α2b by transfected urothelial cells is associated with anticancer activity, including immunostimulatory, antiangiogenic and apoptotic effects. In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.

Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer.

Intravesical gemcitabine and docetaxel (Gem/Doce) has been established as a safe and efficacious salvage treatment for recurrent NMIBC since 2015. Despite widespread adoption of this regimen, long-term outcomes have not been described. We report our experience with intravesical Gem/Doce following BCG failure in a large cohort of patients with extended follow-up. We retrospectively identified 97 patients at our institution treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Monthly maintenance for 2 years was initiated if disease free at first follow-up. Outcomes included recurrence-free survival (RFS), high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS). Survival probabilities were estimated using the Kaplan-Meier method. Median follow-up was 49 months. Median age was 73 years, and 71% of the cohort had CIS containing disease. Thirty five percent of the cohort had BCG-unresponsive disease. Complete response at 3-month surveillance was 74% and median duration of response was 25 months. At 1, 2, and 5 years, HG-RFS was 60%, 50%, and 30%, respectively. HG-RFS was similar among BCG-unresponsive patients and the overall cohort. During follow-up, 20 patients underwent cystectomy and 15 patients experienced disease progression. Five-year PFS, CFS, CSS, and OS were 82%, 75%, 91%, and 64%, respectively. In this long-term analysis, intravesical Gem/Doce for high-risk NMIBC after BCG failure yielded a 75% 5-year bladder preservation rate and a 91% 5-year cancer-specific survival rate. Further prospective trials are warranted.

Adenoviral gene therapy for bladder cancer.

Enhanced by polyamide surfactant Syn3, intravesical administration of rAd-IFNα2b results in transduction of the virus into the bladder epithelium, resulting in the synthesis and expression of local IFNα2b cytokine. Upon secretion, IFNα2b binds to the IFNα receptor on bladder cancer and other cells, resulting in signaling via the JAK-STAT pathway. A plethora of induced IFN-stimulated genes containing IFN-sensitive response elements that contribute to activation of pathways restrict cancer growth.

The efficacy of radiotherapy based combined therapy for unresectable locally invasive bladder cancer and its associated factors analysis

Objective: Retrospective analysis of the efficacy and influencing factors of bladder preservation integrated therapy for unresectable invasive bladder cancer confined to the pelvis was done, also including the bladder function preservation and adverse effects analysis. Methods: Sixty-nine patients with unresectable locally invasive bladder cancer who received radiotherapy-based combination therapy from March 1999 to December 2021 at our hospital were selected. Among them, 42 patients received concurrent chemoradiotherapy, 32 underwent neoadjuvant chemotherapyand 43 with transurethral resection of bladder tumors (TURBT) prior to radiotherapy. The late adverse effect of radiotherapy, preservation of bladder function, replase and metastasis and survival were followed-up. Cox proportional hazards models were applied for the multifactorial analysis. Results: The median age was 69 years. There were 63 cases (91.3%) of uroepithelial carcinoma, 64 of stage Ⅲ and 4 of stage Ⅳ. The median duration of follow-up was 76 months. There were 7 grade 2 late genito urinary toxicities, 2 grade 2 gastrointestinal toxicities, no grade 3 or higher adverse events occurred. All patients maintained normal bladder function, except for 8 cases who lost bladder function due to uncontrolled tumor in the bladder. Seventeen cases recurred locally. There were 11 cases in the concurrent chemoradiotherapy group with a local recurrence rate of 26.2% (11/42) and 6 cases in the non-concurrent chemoradiotherapy group with a local recurrence rate of 22.2% (6/27), and the difference in local recurrence rate between the two groups was not statistically significant (P=0.709). There were 23 cases of distant metastasis (including 2 cases of local recurrence with distant metastasis), including 10 cases in the concurrent chemoradiotherapy group with a distant metastasis rate of 23.8% (10/42) and 13 cases in the non-concurrent chemoradiotherapy group with a distant metastasis rate of 48.1% (13/27), and the distant metastasis rate in the non-concurrent chemoradiotherapy group was higher than that in the concurrent chemoradiotherapy group (P=0.036). The median 5-year overall survival (OS) time was 59 months and the OS rate was 47.8%. The 5-year progression-free survival (PFS) time was 20 months and the PFS rate was 34.4%. The 5-year OS rates of concurrent and non-concurrent chemoradiotherapy group were 62.9% and 27.6% (P<0.001), and 5-year PFS rates were 45.4% and 20.0%, respectively (P=0.022). The 5-year OS rates of with or without neoadjuvant chemotherapy were 78.4% and 30.1% (P=0.002), and the 5-year PFS rates were 49.1% and 25.1% (P=0.087), respectively. The 5-year OS rates with or without TURBT before radiotherapy were 45.5% and 51.9% (P=0.233) and the 5-year PFS rates were 30.8% and 39.9% (P=0.198), respectively. Multivariate Cox regression analysis results showed that the clinical stage (HR=0.422, 95% CI: 0.205-0.869) was independent prognostic factor for PFS of invasive bladder cancer. The multivariate analysis showed that clinical stages (HR=0.278, 95% CI: 0.114-0.678), concurrent chemoradiotherapy (HR=0.391, 95% CI: 0.165-0.930), neoadjuvant chemotherapy (HR=0.188, 95% CI: 0.058-0.611), and recurrences (HR=10.855, 95% CI: 3.655-32.638) were independent prognostic factors for OS of invasive bladder cancer. Conclusion: Unresectable localized invasive bladder cancer can achieve satisfactory long-term outcomes with bladder-preserving combination therapy based on radiotherapy, most patients can retain normal bladder function with acceptable late adverse effects and improved survival particularly evident in patients with early, concurrent chemoradiotherapy and neoadjuvant chemotherapy.

Neoadjuvant chemotherapy plus radical cystectomy (NAC-RC) versus trimodality therapy (TMT) in early-stage small cell bladder cancer: Comparison of outcomes.

476 Background: Small cell bladder cancer is a rare and aggressive histological variant with a paucity of data to guide the optimal management strategy in non-metastatic disease. NAC-RC and TMT (maximal transurethral resection of bladder tumor + chemoradiation) have been variably employed based on institutional preferences, and we aim to compare outcomes between these two approaches. Methods: We queried the National Cancer Database for adult patients with small cell bladder cancer diagnosed during the years 2004 to 2018. Patients with small cell histology and early-stage clinically node-negative bladder cancer (cT1-4N0M0) were included and divided into two groups based on the treatment strategy employed – NAC-RC or TMT. Patients who did not receive any definitive local therapy and those who received chemotherapy or radiation in the adjuvant setting were excluded. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 1262 patients were identified – 629 (49.8%) underwent NAC-RC while 633 (50.2%) received TMT. Patients in the NAC-RC group were younger (median 67 vs. 74 years, P &lt;0.001) and more frequently Males (81% vs 76%, p = 0.02). Clinical T stage was comparable between the groups (P = 0.38). Patients with private insurance (P &lt; 0.001) and higher income tiers (P = 0.04) were more likely to receive NAC-RC in lieu of TMT. Overall survival in the NAC-RC group was significantly longer than the TMT group (median of 41.3 vs. 25.4 months, log-rank P &lt; 0.001). On multivariable analysis, only the type of treatment modality employed was independently predictive of overall survival (Hazard Ratio of 1.22 for TMT, with 95% CI 1.05-1.43, P = 0.01). Conclusions: In early-stage clinically node-negative small cell bladder cancer, NAC-RC was associated with significantly longer overall survival compared to TMT.

Gene signatures for predicting the response to immune checkpoint inhibitor by integrating bulk and single-cell sequence data in patients with bladder cancer.

535 Background: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in bladder cancer (BC) therapy, only a limited fraction of patients benefit from it. Thus, we aim to establish gene signature (iGS) and develop a model that predicts the response of ICI for the patients with BC. Methods: We collected bulk RNA expression data from BC cohort (GSE176307) receiving ICI and single-cell sequencing data from patients with BC (GSE135337). Single-sample gene set enrichment (ssGSEA) analysis was used to develop predictive iGS. Clinical benefit of ICI was defined as a complete or partial response or stable disease at week 24. The gene ontology (GO) and pathway enrichment analysis were established through DAVID database. Logistic regression model was constructed with iGS and clinical factors. The final model was validated by the K-fold cross validation technique. Results: We integrated bulk RNA expression data and single-cell sequencing data, and identified subset of cells (N= 157) that were associated with the overall survival (OS) of patients receiving ICI. These cells were compared with all other cells, and 85 up-regulated differentially expressed genes (DEGs) were identified. DEGs were mainly enriched in 'antigen processing and presentation of exogenous peptide antigen via MHC class II', 'peptide antigen assembly with MHC class II protein complex' and 'immune response' in the biological process enrichment analysis. High iGS score, that was derived from ssGSEA, was significantly associated with longer OS in multivariate Cox regression analysis (Hazard ratio: 0.40, P = 0.02) Final prediction model for clinical benefit included iGS score [odds ratio (OR) = 3.89], tumor mutation burden (OR = 9.8) and age (OR = 0.93) with accuracy of 0.80 and an area under the receiver operator characteristic curve (AUROC) of 0.77. Conclusions: We showed the potential of iGS from bulk and single cell RNA sequencing for predicting clinical benefit of ICI in BC.