Immunotherapy in Bladder Cancer: A Systematic Review of Clinical Trials and Therapeutic Advances

Immunotherapy in Bladder Cancer: A Systematic Review of Clinical Trials and Therapeutic Advances | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Immunotherapy in Bladder Cancer: A Systematic Review of Clinical Trials and Therapeutic Advances Mohammad Alghafees, Talah Nammor, Turki Alferayan, Abdulaziz Almanie, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6457129/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background: Bladder cancer poses significant morbidity, mortality, and healthcare burdens globally. While non-muscle-invasive bladder cancer (NMIBC) often initially responds to intravesical Bacillus Calmette-Guérin (BCG), many patients become unresponsive to BCG, resulting in recurrence or progression. Emerging immunotherapies, including checkpoint inhibitors (Pembrolizumab, Atezolizumab, Durvalumab), intravesical gene therapies (Nadofaragene Firadenovec, Cretostimogene Grenadenorepvec), and novel cytokine-based therapies (NAI, IL-15 superagonist), present promising alternatives. This systematic review thoroughly synthesizes existing clinical evidence from phase 2 and 3 trials, critically assessing immunotherapeutic options for bladder cancer treatment. Methodology: A comprehensive search was systematically conducted across four databases (PubMed, Cochrane, Web of Science, Scopus), strictly adhering to PRISMA guidelines. Inclusion criteria included only phase 2 and 3 clinical trials evaluating immunotherapies in NMIBC and selected muscle-invasive bladder cancer (MIBC) populations. Two reviewers independently performed study screening, data extraction, and risk-of-bias assessments using the ROB2 tool. Results were synthesized both qualitatively and quantitatively, incorporating detailed comparative analyses and robust statistical descriptions. Results: A total of 778 studies were initially identified; after thorough screening, 10 high-quality clinical trials (phase 2 and 3) met the inclusion criteria. Intravesical Cretostimogene Grenadenorepvec demonstrated the highest complete response [ 1 ] rate (75.2%), with impressive durability (83% maintaining response ≥ 12 months). Intravesical Nadofaragene Firadenovec also exhibited notable efficacy (CR 53.4%, median duration 9.69 months). NAI combined with BCG achieved a robust CR (71%) and a remarkably sustained response (median 26.6 months). Systemic Pembrolizumab showed moderate efficacy (12-month DFS 43.5%) but raised significant toxicity concerns (14% grade ≥ 3 adverse events). Intravesical therapies consistently provided superior cystectomy avoidance (≥ 89% at 12 months) compared to systemic treatments. Safety profiles significantly favored intravesical therapies, which had predominantly mild (grade 1–2) adverse events, while systemic therapies reported notable severe toxicities and treatment-related fatalities. Conclusion: Intravesical immunotherapies, particularly NAI + BCG and Nadofaragene, demonstrate superior efficacy, significant response durability, and favorable safety profiles in treating bladder cancer compared to systemic checkpoint inhibitors, which display moderate efficacy and notable safety concerns. These findings strongly support prioritizing intravesical therapies in NMIBC management, especially for patients who are unresponsive to BCG. Future research should focus on head-to-head randomized controlled trials and biomarker-driven patient selection to optimize clinical outcomes. Bladder Cancer Immunotherapy NMIBC BCG-unresponsive Pembrolizumab Nadofaragene Durvalumab Systematic Review Phase 2/3 Clinical Trials PRISMA Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1.0 Introduction Bladder cancer is among the most prevalent malignancies worldwide, causing significant morbidity, mortality, and healthcare burden [ 2 , 3 ]. Approximately 80% of newly diagnosed cases are classified as non-muscle-invasive bladder cancer (NMIBC), which is characterized by limited invasion of the bladder wall and usually has a favorable prognosis if treated appropriately in the early stages [ 4 , 5 ]. However, recurrence rates of NMIBC remain notably high, ranging from 50–70% after initial treatment, and a considerable proportion (10–30%) progresses to more aggressive muscle-invasive bladder cancer (MIBC), significantly worsening prognosis and patient outcomes [ 6 – 8 ]. The standard care for high-risk NMIBC has historically included transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical instillation of Bacillus Calmette-Guérin (BCG) [ 9 , 10 ]. Although effective, BCG therapy has limitations, including considerable toxicity, recurrence, and a significant proportion of patients eventually becoming unresponsive to treatment, which leaves limited therapeutic options and increases the risk of progression to invasive disease [ 11 , 12 ]. Recently, immunotherapy has revolutionized the treatment landscape for various malignancies, including bladder cancer. Immunotherapeutic approaches, such as immune checkpoint inhibitors (e.g., Pembrolizumab, Atezolizumab, Durvalumab), intravesical gene therapies (e.g., Nadofaragene Firadenovec, Cretostimogene Grenadenorepvec), and novel cytokine-based immunomodulators (e.g., NAI—an IL-15 superagonist), have increasingly shown promising efficacy, particularly in patients who have limited or no response to standard therapies [ 13 , 14 ]. The mechanisms of action of these immunotherapies vary considerably. Checkpoint inhibitors work by reactivating exhausted immune cells within the tumor microenvironment, thereby reinstating the body's natural antitumor responses [ 15 , 16 ]. In contrast, intravesical gene therapies utilize vectors such as adenoviruses to enhance localized immune responses through cytokine gene delivery (interferon alfa-2b or GM-CSF), thereby boosting immune activation within the bladder mucosa. Additionally, cytokine-based immunotherapies, such as NAI, directly enhance natural killer (NK) cell and T-cell proliferation and activation, thus providing durable immune-mediated tumor control [ 17 – 19 ]. Despite rapid advances and promising preliminary results, significant variability in clinical efficacy, response durability, bladder preservation, and treatment safety profiles has emerged in recent trials [ 20 ]. Furthermore, direct comparative data between these novel agents and traditional therapies, or between different classes of immunotherapies, remain sparse [ 21 ]. This lack of comparative evidence complicates clinical decision-making, leaving oncologists uncertain about the optimal sequencing and selection of these novel therapies [ 22 , 23 ]. Therefore, a rigorous and comprehensive synthesis of existing clinical evidence regarding immunotherapeutic options in bladder cancer is critically needed to guide evidence-based clinical decisions and future research directions [ 24 ]. In response to this critical clinical need, we conducted this comprehensive systematic review of immunotherapy in bladder cancer, focusing exclusively on the highest-quality clinical trials (phase 2 and 3), thereby providing robust, actionable evidence to clinicians and stakeholders involved in bladder cancer management. 1.1 Aim The primary aim of this systematic review is to rigorously evaluate and comprehensively synthesize existing high-quality evidence (phase 2 and 3 clinical trials) regarding the efficacy, safety, and clinical applicability of emerging immunotherapeutic strategies for the treatment of bladder cancer (both NMIBC and select MIBC populations), thus providing robust clinical guidance for optimal patient management. 2.0 Methodology This systematic review strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ensuring methodological transparency, reproducibility, and high scientific rigor. 2.1 Search Strategy An extensive and systematic search was conducted in March 2025 across four major electronic databases: Web of Science (WOS), PubMed, Cochrane Library, and Scopus. The comprehensive search was developed using relevant Medical Subject Headings (MeSH terms), keywords, and Boolean operators. The primary search terms included: ("Immunotherapy" OR "Immune checkpoint inhibitors" OR "Pembrolizumab" OR "Atezolizumab" OR "Durvalumab" OR "Nadofaragene Firadenovec" OR "Cretostimogene Grenadenorepvec" OR "BCG" OR "Bacillus Calmette-Guérin") AND ("Bladder cancer" OR "Non-muscle invasive bladder cancer" OR "NMIBC" OR "Muscle-invasive bladder cancer" OR "MIBC") AND ("Clinical trial" OR "Phase 2" OR "Phase 3"). These search strings were carefully customized and optimized for each database to ensure a comprehensive retrieval of relevant studies. 2.2 Inclusion Criteria The review included only randomized controlled trials (RCTs) and prospective single-arm phase 2 and 3 clinical trials. The population of interest comprised adult patients diagnosed with bladder cancer, including both non-muscle-invasive bladder cancer (NMIBC) and selected cases of muscle-invasive bladder cancer (MIBC). Eligible interventions included immunotherapy-based treatments, such as checkpoint inhibitors (Pembrolizumab, Atezolizumab, Durvalumab), intravesical gene therapies (Nadofaragene Firadenovec, Cretostimogene Grenadenorepvec), and immunomodulators like IL-15 agonists (NAI) and Bacillus Calmette-Guérin (BCG). The studies had to report clearly defined clinical outcomes, including complete response rates, disease-free survival (DFS), overall survival (OS), progression rates, cystectomy avoidance, and adverse event profiles. Only full-text articles published in peer-reviewed journals in English were included. No specific publication date limit was imposed to ensure comprehensive retrieval of relevant studies. Exclusion Criteria Studies were excluded if they were retrospective in design, observational studies, review articles, editorials, case reports, commentaries, conference abstracts, or letters. Additionally, studies were excluded if they lacked transparent outcome reporting or presented insufficient data for extraction. Non-English publications or studies without available English translations were also excluded. 2.3 Study Screening and Selection Process Initial search results from all databases were combined, and duplicates were systematically removed using EndNote software. Two independent reviewers then screened all titles and abstracts to identify potentially relevant studies that met the inclusion criteria. Disagreements at this stage were resolved through consensus or arbitration by a third senior reviewer. Following the initial screening, the full texts of potentially relevant articles were thoroughly assessed by the same reviewers to confirm their eligibility. Detailed reasons for exclusion were documented and explicitly reported in the PRISMA flow diagram (Fig. 1 ). 2.4 Data Extraction The data extraction was conducted from the final set of selected studies using a standardized data extraction form specifically developed for this review. The extracted parameters included study characteristics such as the first author, publication year, study design, location, and trial phase. Patient demographics were recorded, including the number of patients, age, gender, and tumor characteristics. Details of the intervention were documented, covering the type of immunotherapy, dosage, route of administration, and treatment regimen. Efficacy outcomes were extracted, including complete response (CR) rates, disease-free survival (DFS) rates at specific time points, overall survival (OS), progression rates, and cystectomy avoidance rates. Safety profiles were captured by noting the incidence, severity, and type of adverse events. The follow-up duration for each study was also recorded. The accuracy and completeness of the extracted data were carefully cross-checked, and any discrepancies were resolved through consensus. 2.5 Quality Assessment of Included Studies (Risk of Bias) The methodological quality and bias risk of the included studies were thoroughly assessed using the revised Cochrane Risk-of-Bias tool (ROB2). Each study was analyzed across five critical domains: the randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selective reporting of results. For each domain, the studies were classified as "low risk," "some concerns," or "high risk." The results of the quality assessment were visually represented using a traffic-light plot, clearly illustrating overall and domain-specific biases for each included study (Fig. 2 ). Disagreements during the quality assessment were addressed through discussion and resolved by consensus or, when necessary, third-party adjudication. 2.6 Synthesis and Reporting of Results Data synthesis involved a comprehensive narrative and statistical analysis approach, clearly describing findings from individual studies. Due to clinical and methodological variability across included trials (differences in patient populations, interventions, and outcome measures), a quantitative meta-analysis was not appropriate. Instead, findings were thoroughly synthesized and critically compared qualitatively, with careful attention to outcome patterns, efficacy measures, durability of responses, safety profiles, and clinical applicability across the various therapies. 3.0 Results Comprehensive database searches (PubMed, Cochrane Library, Web of Science, and Scopus) initially identified 778 studies. After carefully removing duplicates and diligently applying inclusion and exclusion criteria, 10 studies were included in the systematic review. The detailed step-by-step selection and screening process, including reasons for exclusions at each stage, is presented in a PRISMA-compliant flow diagram (Fig. 1 ) and Table 1 . Table 1 Study Characteristics and Outcomes of Immunotherapy in Bladder Cancer Author, Year Design Patient Group Sample Size Intervention & Dosage Primary Outcome(s) Primary Results Duration of Response / Follow-Up Progression & Survival Outcomes Cystectomy Rates Safety & Adverse Events Conclusion & Clinical Implications [ 25 ] Phase 3, single-arm BCG-unresponsive CIS NMIBC 112 Intravesical Cretostimogene Grenadenorepvec weekly ×6 wks, maintenance up to 18 mo Complete Response [ 1 ] CR rate: 75.2% Median CR duration: >9 mo 12-mo cystectomy-free survival: 92.3% Not reported Mostly Grade 1–2 GU AEs Effective and safe intravesical therapy [ 26 ] Phase 3, single-arm BCG-unresponsive CIS/Ta/T1 NMIBC 157 Intravesical Nadofaragene Firadenovec every 3 mo up to 9 mo CR rate (CIS); recurrence-free (Ta/T1) CR (CIS): 53.4% at 3 mo Median CR duration: 9.69 mo Progression to MIBC: 5–6% 12-mo rate: 26% Grade 1–2 local AEs common; 4% ≥Grade 3 Durable responses; safe alternative to cystectomy [ 27 ] Phase 2, single-arm High-risk BCG-failed NMIBC 30 Intravesical Durvalumab 1000 mg every 6 wk High-grade relapse-free survival at 1 yr 1-yr relapse-free: 39% Median NR (~ 13 mo) 1-year bladder-intact survival: 78%; ≥T2 progression: 4 patients Not reported clearly Grade 1 haematuria (17%) Feasible treatment with low toxicity [ 28 ] Phase 2, single-arm BCG-unresponsive NMIBC 172 IV Atezolizumab every 3 wk for 1 yr CR rate at 6 mo (CIS) CR rate (CIS): 27% Median CR duration: 17 mo 18-mo event-free survival (Ta/T1): 49%; 12 patients progressed Not reported clearly 16% Grade 3–5 TRAEs; 3 deaths Modest efficacy; significant AEs; caution in clinical use [ 29 ] Phase 3, randomized controlled Muscle-invasive urothelial carcinoma (MIBC) post-surgery 702 IV Pembrolizumab 200 mg every 3 wk (1 year) vs observation Disease-free survival (DFS) Median DFS: 29.6 mo vs 14.2 mo (HR: 0.73; p = 0.0027) Median follow-up: 44.8 mo 3-yr OS similar (~ 61%) Not applicable Grade ≥ 3 AEs: 50.7%; 5 deaths Significant DFS benefit; no OS benefit yet; careful patient selection required [ 30 ] Phase 2 Muscle-invasive bladder cancer (organ-sparing) NR clearly Gemcitabine + Cisplatin + Nivolumab Pathological response / bladder sparing Pathological CR not detailed clearly in abstract NR clearly Detailed survival data pending Not clearly detailed Toxicities expected from chemotherapy and nivolumab Promising organ-sparing regimen; final conclusions pending [ 31 ] Phase 2 BCG-unresponsive CIS ± Ta/T1 NMIBC 171 Intravesical NAI (IL-15 agonist) ± BCG CR (CIS) & DFS (Ta/T1) CR: 71% CIS cohort; DFS (Ta/T1): 55.4% at 12 mo Median CR duration: 26.6 mo 24-mo DSS: 100%; OS: 94.3% Responders: 9% Mostly Grade 1–2 AEs; no systemic absorption detected Strong efficacy and tolerable safety profile [ 32 ] Phase 2, single-arm High-risk NMIBC, Ta/T1 without CIS 132 IV Pembrolizumab 200 mg every 3 wk up to 35 cycles 12-mo DFS 12-mo DFS: 43.5% Median follow-up: 45.4 mo Survival details NR clearly Not detailed 14% Grade 3–4 AEs; common colitis, diarrhoea; no deaths Pembrolizumab promising but randomized trials needed [ 33 ] Phase 3, randomized controlled Intermediate/high-risk Ta/T1 NMIBC 1355 Intravesical BCG 1/3 vs full dose (FD); 1 vs 3 yr DFS at 5 yrs 1/3D-1 year inferior to FD-3 year; High-risk FD-3 year reduced recurrence (HR 1.61) Median follow-up: 7.1 yr No differences in progression/survival Not clearly detailed No difference in toxicity 1/3D vs FD FD 3-yr beneficial for high-risk only; intermediate-risk patients sufficient with 1 yr [ 34 ] Phase 3, randomized controlled Muscle-invasive urothelial carcinoma (MIBC) adjuvant 702 IV Pembrolizumab 200 mg every 3 wk vs observation DFS, OS DFS significantly improved (HR: 0.73, p = 0.0027); OS no significant improvement yet Median DFS: 29.6 mo 3-year OS ~ 61%; progression details pending Not applicable 50.7% Grade ≥ 3 AEs; 5 treatment-related deaths Clear DFS improvement; OS results pending; safety requires consideration Quality assessment of the included studies, conducted with the ROB2 tool, demonstrated that there is generally a low-to-moderate risk of bias across the included trials. Figure 2 clearly illustrates specific domains of concern, such as randomization methods, deviations from intended interventions, and outcome reporting biases. 3.1 Complete Response [ 1 ] and Disease-Free Survival (DFS) Outcomes Significant variation in efficacy outcomes was evident across studies. Tyson et al. (2024), in the single-arm BOND-003 trial evaluating intravesical Cretostimogene Grenadenorepvec, reported a notably high complete response rate of 75.2% (95% CI: 65–83%) [ 25 ]. Impressively, among responders, 83% maintained their response for at least 12 months, indicating substantial durability. Black et al. (2023) in the single-arm SWOG S1605 trial evaluating the efficacy and safety of intravenous Atezolizumab reported a promising complete response rate of 56% (95% CI: 34–77%) [ 28 ]. Median duration of CR was 17 months with 56% CR rate at 12 months evaluation. In the CIS cohort, 27% CR rate was reported at 6 months evaluation. Further, a 49% (90% CI: 38–60%) 18-month recurrence-free-rate was reported among the 55 patients with Ta/T1 disease. Boorjian et al. (2021) assessed intravesical Nadofaragene Firadenovec in BCG-unresponsive NMIBC patients, reporting an encouraging 53.4% CR rate at the 3-month evaluation in the CIS cohort [ 26 ]. Among initial responders, approximately 45.5% maintained their CR at 12 months, and the median CR duration reached 9.69 months. Furthermore, a promising recurrence-free rate of 43.8% at 12 months was observed among high-grade Ta/T1 patients. Pembrolizumab (Balar et al., 2021), administered intravenously every three weeks, demonstrated a 12-month DFS rate of 43.5% (95% CI: 34.9–51.9%) in high-risk papillary NMIBC without CIS, thereby providing a significant therapeutic alternative for patients who decline radical cystectomy [ 32 ]. Chamie et al. (2022) notably reported a robust 71% CR rate (95% CI: 59.6–80.3%) using intravesical NAI combined with BCG [ 31 ]. This response was remarkably durable, as indicated by a notable median duration of CR at 26.6 months. Figure 3 shows Kaplan-Meier curves for Pembrolizumab, Atezolizumab, Nadofaragene and NAI + BCG agents based on publicly reported event-to-time DFS and OS data. There was no sufficient publicly reported time-to-event DFS and OS data to construct the Cretostimogene Grenadenorepvec survival curves. 3.2 Durability of Response and Bladder Preservation Outcomes Response durability varied significantly among the therapies included. Fragkoulis et al. (2025) investigated intravesical Durvalumab, finding a moderate 39% one-year high-grade relapse-free survival rate (95% CI: 18–59%), yet achieved a strong 78% bladder-intact survival at one year [ 27 ]. This underscored the agent’s utility in bladder preservation strategies despite moderate CR rates. Long-term response rates at ≥ 12 and ≥ 18 months clearly favored intravesical NAI + BCG therapy (61.6% and 51.1%, respectively), closely followed by Nadofaragene. Pembrolizumab exhibited intermediate efficacy, maintaining approximately 43.5% CR at 12 months, which reduced to around 30% at 18 months. These comparative results are clearly illustrated in Fig. 4 . 3.3 Progression and Overall Survival Outcomes Progression rates to muscle-invasive bladder cancer (MIBC) exhibited heterogeneity among therapies. Nadofaragene and NAI + BCG were associated with relatively low progression rates (~ 5–6%). Pembrolizumab and Atezolizumab showed progression rates ranging from 10–15%, indicating a higher risk of progression despite systemic immunotherapy. Notably, the EORTC-GU randomized trial by Oddens et al. (2013) demonstrated that full-dose BCG maintenance for three years significantly reduced recurrence (HR: 1.61, 95% CI: 1.13–2.30, p = 0.009), yet it did not result in statistically significant reductions in progression or mortality [ 33 ]. Overall survival rates across studies remained generally high, consistently exceeding 90% at two years. Boorjian et al. (2022) reported 24-month OS of 91.9% (95% CI: 80.9–96.7%) with at least one dose of Nadofaragene [ 26 ]. Chamie et al. (2022) reported 24-month OS of 91.7% with a dose of NAI + BCG [ 31 ]. 3.4 Adverse Events and Treatment Safety Safety profiles varied significantly between systemic and intravesical therapies. Intravesical therapies generally reported milder, grade 1–2 adverse events. For example, Durvalumab was predominantly associated with grade 1 hematuria (17%). Systemic agents displayed a different toxicity profile, with Pembrolizumab reporting a concerning 14% rate of grade 3–4 adverse events, particularly immune-related colitis and diarrhea. Moreover, systemic atezolizumab therapy was linked to significant treatment-related toxicities, including three deaths. The comprehensive comparative safety and efficacy outcomes are clearly illustrated in Fig. 5 . 3.5 Summary of Treatment Outcomes Overall treatment outcomes, clearly summarized in Fig. 6 , indicate better long-term response maintenance and fewer adverse events with intravesical therapies (notably NAI + BCG and Nadofaragene). Systemic therapies such as Pembrolizumab and Atezolizumab offer moderate efficacy balanced against higher risks of adverse event risks, as shown in Fig. 7 . 4.0 Discussion This systematic review comprehensively analyzed current clinical evidence regarding immunotherapeutic approaches for treating bladder cancer, specifically focusing on non-muscle-invasive bladder cancer (NMIBC) and select muscle-invasive bladder cancer (MIBC) populations. Across the ten included studies, immunotherapies such as intravesical Cretostimogene Grenadenorepvec, Nadofaragene Firadenovec, Durvalumab, and systemic checkpoint inhibitors (Pembrolizumab and Atezolizumab) demonstrated heterogeneous yet promising therapeutic potential. However, clear distinctions in efficacy, durability, safety profiles, and clinical applicability emerged distinctly across the therapeutic modalities. 4.1 Comparative Efficacy and Clinical Implications Intravesical therapies have consistently demonstrated strong clinical efficacy, particularly notable in BCG-unresponsive NMIBC. The highest complete response [ 1 ] rates were reported for intravesical Cretostimogene Grenadenorepvec [ 25 ], achieving a CR of 75.2% with significant durability, as reflected in 83% of responders maintaining their response at one year. This aligns favorably with previous literature suggesting that viral-based immunotherapeutic approaches can generate robust and lasting antitumor responses by enhancing tumor antigen presentation and immune activation pathways [ 28 , 31 ]. Nadofaragene Firadenovec similarly demonstrated significant promise, achieving a CR rate of 53.4% at three months and substantial maintenance of response (45.5% at 12 months) [ 26 ]. The promising efficacy observed with Nadofaragene underscores the potential of adenoviral-mediated interferon gene therapy to effectively stimulate innate and adaptive immune responses, providing durable disease control even in highly refractory patient populations [ 31 ]. In contrast, Durvalumab's intravesical administration presented moderate CR rates (39% one-year relapse-free), yet demonstrated a notably higher bladder preservation rate (78% at one year) [ 27 ]. This highlights the important distinction between achieving absolute CR and clinically meaningful endpoints such as bladder preservation, which significantly impact patient quality of life. However, further comparative analyses through head-to-head randomized trials are required to better clarify Durvalumab's role within existing treatment algorithms. Systemic immunotherapies, particularly checkpoint inhibitors Pembrolizumab and Atezolizumab, demonstrated moderate efficacy in NMIBC and MIBC. Pembrolizumab achieved 43.5% DFS at 12 months in high-risk papillary NMIBC without CIS [ 27 ], thus positioning it as a potential therapeutic option for patients ineligible or unwilling to undergo radical cystectomy. Nonetheless, Pembrolizumab's overall efficacy remained modest compared to intravesical treatments, consistent with findings from KEYNOTE-057 and other checkpoint inhibitor trials, reflecting systemic immune response limitations in superficial bladder tumors [ 28 ]. The findings from this review demonstrate immunotherapy as a viable treatment options for bladder cancer. However, the growing economic burden of immunotherapy cannot be overlooked. Sarfaty et al. (2018) found that it costs more for bladder cancer patients to gain one quality-adjusted life-year with Pembrolizumab compared to chemotherapy in the United States than in UK, Canada and Australia [ 35 ]. Similar findings were reported by Aguiar et al. (2017) indicating high cost-effectiveness of Atezolizumab and reduced quality-adjusted life years [ 36 ]. In other words, a single cycle of treatment with immunotherapy would be more expensive than chemotherapy in countries with high drug prices like the United States. 4.2 Response Durability and Bladder Preservation An important aspect of evaluating immunotherapies in bladder cancer is the durability of therapeutic responses, which critically impacts long-term disease control and patient outcomes. NAI combined with intravesical BCG demonstrated exceptional response durability, achieving a median CR duration of 26.6 months [ 31 ], clearly outperforming other intravesical and systemic therapies. This remarkable durability is likely due to NAI’s robust activation of IL-15 pathways, resulting in sustained immunological memory and prolonged antitumor activity [ 31 ]. Moreover, cystectomy avoidance rates were significantly higher with intravesical agents, particularly Nadofaragene (92.3% at one year) and NAI + BCG (89.2%). This preservation of the bladder is highly desirable for patients, as it directly correlates with improved quality-of-life outcomes, reduced morbidity, and lower healthcare utilization. These findings strongly advocate prioritizing intravesical therapies in clinical decision-making for NMIBC, particularly for patients who highly value bladder preservation [ 25 , 33 ]. 4.3 Progression Rates and Overall Survival While intravesical therapies demonstrated relatively lower progression rates (5–6%) compared to systemic therapies (10–15%), overall survival (OS) rates remained uniformly high across all treatment modalities (> 90% at two years). This indicates that the risk of progression remains manageable within the current therapeutic landscape. The EORTC-GU study (Oddens et al., 2013) notably revealed no significant differences in progression rates across varying BCG dose intensities and maintenance durations, despite clear recurrence advantages with more prolonged therapy [ 33 ]. This finding suggests that while prolonged BCG regimens may effectively suppress recurrences, progression risks might be inherently independent of dosing strategies, possibly driven by biological tumor characteristics rather than by therapeutic intensity alone. The AMBASSADOR trial investigating adjuvant Pembrolizumab following radical cystectomy demonstrated a statistically significant improvement in DFS (HR: 0.73; p = 0.0027), yet no measurable OS benefit was observed at three years. This absence of OS benefit so far underscores the need for careful interpretation and further longitudinal analyses to determine whether DFS advantages ultimately translate into survival improvements, a critical determinant in the adjuvant therapy decision-making process. 4.4 Treatment Safety Profiles and Clinical Decision-Making A notable differentiation emerged in safety profiles between systemic and intravesical therapies. Intravesical therapies such as Durvalumab, Nadofaragene, and NAI + BCG predominantly demonstrated mild (grade 1–2) localized genitourinary adverse events, which are clinically manageable and patient-friendly. Conversely, systemic immunotherapies, particularly checkpoint inhibitors Pembrolizumab and Atezolizumab, were associated with higher incidences of severe grade 3–4 toxicities, including life-threatening immune-mediated colitis and pneumonitis [ 27 , 28 ]. Notably, the SWOG S1605 trial reported concerning safety signals with atezolizumab, including treatment-related fatalities, raising serious considerations regarding its risk-benefit ratio in this patient population. These findings underscore the importance of carefully balancing efficacy with safety considerations. In scenarios where comparable efficacy is attainable with intravesical agents, clinicians should prioritize these safer, better-tolerated therapies to maximize patient safety and minimize adverse events. 4.6 Limitations and Strengths of This Review This review rigorously synthesizes the latest evidence, yet inherent limitations must be acknowledged. One of the limitation was the primarily heterogeneity among studies in patient populations, follow-up durations, and endpoint definitions complicates direct comparative analyses. Another limitation was the potential publication and language bias. Promising agents such as Sasanlimab, TAR-200, and IV Durvalumab were excluded as their findings are not yet peer-reviewed but were presented at scientific meetings. Most included studies were single-arm designs, limiting comparative efficacy conclusions with standard care such as radical cystectomy. The lack of randomized comparisons between immunotherapy and radical cystectomy limits the ability to draw conclusions of their relative benefits. Moreover, current evidence has not demonstrated a significant oncologic advantage for immunotherapy compared to radical cystectomy. This limitation underscores the need for randomized comparisons of the relative benefits of immunotherapy with standard care in treatment of bladder cancer patients. Nonetheless, the review’s strengths lie in its comprehensive methodology, strict adherence to PRISMA guidelines, thorough ROB2 assessments, and the robust statistical detailing of clinical outcomes, providing an authoritative evidence synthesis for clinical practice and future research guidance. 4.7 Recommendations for Future Research and Clinical Practice Future randomized controlled trials should directly compare intravesical and systemic immunotherapies head-to-head to conclusively determine the most clinically beneficial and safest approaches. Also, evaluating biomarkers predictive of response and toxicity could further refine patient selection and therapeutic strategies. Clinically, prioritizing intravesical agents for BCG-unresponsive NMIBC appears justified given the superior efficacy, favorable safety profile, and bladder preservation outcomes demonstrated in this systematic review. 5.0 Conclusion This systematic review provides compelling evidence supporting intravesical immunotherapies especially NAI + BCG and Nadofaragene as highly effective, durable, and safer treatments for bladder cancer. Systemic therapies such as Pembrolizumab and Atezolizumab show moderate efficacy but significantly elevated toxicity concerns. These insights guide clinicians toward personalized, safer, and more effective management strategies, ultimately improving patient outcomes and quality of life in bladder cancer treatment. Declarations Author Contribution Author ContributionsAhmed Alasker (A.A.) – Conceived the study idea, contributed to study design, supervised the overall project, and critically revised the manuscript.Mohammad Alghafees (M.A.) – Conceived and designed the study protocol, performed the literature search, led data extraction and synthesis, and drafted the initial manuscript.Talah Nammor (T.N.) – Participated in literature screening, assisted in data extraction, and contributed to drafting sections of the methodology.Naif Alanazi (N.A.) – Assisted in data extraction and verification, contributed to the risk-of-bias assessment, and provided input for result interpretation.Turki Alferayan (T.A.) – Prepared tables and figures, assisted in data organization, and contributed to editing the results section.Abdulaziz Almanie (A.Alm.) – Participated in literature screening, contributed to PRISMA diagram preparation, and assisted in manuscript formatting.Mohammed Alrashed (M.Alr.) – Assisted in quality assessment of included studies, contributed to data interpretation, and revised the discussion section.Yousef Almarzouq Almarzouq (Y.A.A.) – Verified extracted data, assisted in statistical synthesis, and contributed to the critical revision of the final manuscript.Abdullah Alammari (A.Am.) – Contributed to data analysis and manuscript revisionAll authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.Naif Alanazi (N.A.) – Assisted in data extraction and verification, contributed to the risk-of-bias assessment, and provided input for result interpretation.Turki Alferayan (T.A.) – Prepared tables and figures, assisted in data organization, and contributed to editing the results section.Abdulaziz Almanie (A.Alm.) – Participated in literature screening, contributed to PRISMA diagram preparation, and assisted in manuscript formatting.Mohammed Alrashed (M.Alr.) – Assisted in quality assessment of included studies, contributed to data interpretation, and revised the discussion section.Yousef Almarzouq Almarzouq (Y.A.A.) – Verified extracted data, assisted in statistical synthesis, and contributed to the critical revision of the final manuscript.All authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work. 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N Engl J Med. 2025;392:45–55. Sarfaty M, Hall PS, Chan KK, Virik K, Leshno M, Gordon N, Moore A, Neiman V, Rosenbaum E, Goldstein DA. Cost-effectiveness of pembrolizumab in second-line advanced bladder cancer. Eur Urol. 2018;74(1):57–62. Aguiar PN Jr, Perry LA, Penny-Dimri J, Babiker H, Tadokoro H, De Mello RA, Lopes GL Jr. The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC. Ann Oncol. 2017;28(9):2256–63. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 21 Jan, 2026 Editor assigned by journal 23 Oct, 2025 Reviews received at journal 10 Sep, 2025 Reviews received at journal 29 Aug, 2025 Reviewers agreed at journal 29 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers invited by journal 12 Aug, 2025 Submission checks completed at journal 12 Aug, 2025 First submitted to journal 08 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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1","display":"","copyAsset":false,"role":"figure","size":28905,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePRISMA Flow Diagram\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/48d2e1238cc17595bf13158f.png"},{"id":93063902,"identity":"c6c6d48a-3f79-4ea7-9041-2b95a2ae85fe","added_by":"auto","created_at":"2025-10-08 16:39:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":207918,"visible":true,"origin":"","legend":"\u003cp\u003eDetailed ROB2 Risk-of-Bias Assessment. The traffic-light plot depicts each trial's methodological quality across ROB2 domains (randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, selective reporting). Green indicates low risk, yellow indicates some concerns, and red indicates high risk of bias.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/bebc72d7d014bef90bb09ce4.png"},{"id":93063911,"identity":"611f3d90-68f6-4d21-9a6f-06b625c1e8d8","added_by":"auto","created_at":"2025-10-08 16:39:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":175595,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eKaplan-Meier Analysis of Disease-Free Survival (DFS) and Overall Survival (OS). These survival curves compare DFS and OS probabilities clearly among four major immunotherapeutic agents: Pembrolizumab [32], Atezolizumab [28], Nadofaragene [26], and NAI+BCG [31]. Distinct survival trajectories and median survival estimates highlight comparative efficacy across treatments.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/3045bda5572debdd9f9e4932.png"},{"id":93063891,"identity":"797c1e20-2247-441e-835e-1e75a96cbf41","added_by":"auto","created_at":"2025-10-08 16:39:17","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":116372,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eDurability of Response and Cystectomy Avoidance by Treatment Type. This grouped bar chart explicitly compares the percentage of patients maintaining complete response at ≥12 and ≥18 months and the 12-month cystectomy-free rates across Pembrolizumab [32], Durvalumab [27], Nadofaragene [26], and NAI+BCG [31] treatments.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/e8fba296d988d10da3cd5625.png"},{"id":93064007,"identity":"18438534-da20-41f5-af22-ab1df040e2bd","added_by":"auto","created_at":"2025-10-08 16:39:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":97305,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eClustered Heatmap of Clinical Efficacy and Safety Outcomes. This heatmap provides hierarchical clustering of included studies based on key clinical parameters, such as complete response rates, disease-free survival, cystectomy-free rates, severe adverse events, and progression rates.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/4a11059964e3c6ac4e801260.png"},{"id":93063888,"identity":"0c9ae07b-c52c-44d4-b4a6-69a89916d0d4","added_by":"auto","created_at":"2025-10-08 16:39:17","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":123599,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eDetailed Stacked Bar Plot of Final Patient Outcomes. Explicitly illustrating the proportions of patients achieving maintained CR, experiencing relapse/progression, undergoing cystectomy, and death/ongoing treatment across the four major therapies reviewed. This visualization provides a comprehensive overview of ultimate treatment effectiveness and patient clinical trajectories.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/b67ecbc89cb464c6d957746e.png"},{"id":93063890,"identity":"c6e2b390-7a6d-4a67-8c2d-0b26f6ab9bce","added_by":"auto","created_at":"2025-10-08 16:39:17","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":98558,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eComparative Immunotherapy Outcomes in Bladder Cancer.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/9c98dc278750230d4cef7371.png"},{"id":93067063,"identity":"172de491-eb97-4bc4-958c-204033e29ac6","added_by":"auto","created_at":"2025-10-08 16:55:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1661360,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6457129/v1/fc7f37da-e22f-4b30-ade6-4f3118965c55.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Immunotherapy in Bladder Cancer: A Systematic Review of Clinical Trials and Therapeutic Advances","fulltext":[{"header":"1.0 Introduction","content":"\u003cp\u003eBladder cancer is among the most prevalent malignancies worldwide, causing significant morbidity, mortality, and healthcare burden [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Approximately 80% of newly diagnosed cases are classified as non-muscle-invasive bladder cancer (NMIBC), which is characterized by limited invasion of the bladder wall and usually has a favorable prognosis if treated appropriately in the early stages [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, recurrence rates of NMIBC remain notably high, ranging from 50\u0026ndash;70% after initial treatment, and a considerable proportion (10\u0026ndash;30%) progresses to more aggressive muscle-invasive bladder cancer (MIBC), significantly worsening prognosis and patient outcomes [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The standard care for high-risk NMIBC has historically included transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical instillation of Bacillus Calmette-Gu\u0026eacute;rin (BCG) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although effective, BCG therapy has limitations, including considerable toxicity, recurrence, and a significant proportion of patients eventually becoming unresponsive to treatment, which leaves limited therapeutic options and increases the risk of progression to invasive disease [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecently, immunotherapy has revolutionized the treatment landscape for various malignancies, including bladder cancer. Immunotherapeutic approaches, such as immune checkpoint inhibitors (e.g., Pembrolizumab, Atezolizumab, Durvalumab), intravesical gene therapies (e.g., Nadofaragene Firadenovec, Cretostimogene Grenadenorepvec), and novel cytokine-based immunomodulators (e.g., NAI\u0026mdash;an IL-15 superagonist), have increasingly shown promising efficacy, particularly in patients who have limited or no response to standard therapies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The mechanisms of action of these immunotherapies vary considerably. Checkpoint inhibitors work by reactivating exhausted immune cells within the tumor microenvironment, thereby reinstating the body's natural antitumor responses [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In contrast, intravesical gene therapies utilize vectors such as adenoviruses to enhance localized immune responses through cytokine gene delivery (interferon alfa-2b or GM-CSF), thereby boosting immune activation within the bladder mucosa. Additionally, cytokine-based immunotherapies, such as NAI, directly enhance natural killer (NK) cell and T-cell proliferation and activation, thus providing durable immune-mediated tumor control [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite rapid advances and promising preliminary results, significant variability in clinical efficacy, response durability, bladder preservation, and treatment safety profiles has emerged in recent trials [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Furthermore, direct comparative data between these novel agents and traditional therapies, or between different classes of immunotherapies, remain sparse [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This lack of comparative evidence complicates clinical decision-making, leaving oncologists uncertain about the optimal sequencing and selection of these novel therapies [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Therefore, a rigorous and comprehensive synthesis of existing clinical evidence regarding immunotherapeutic options in bladder cancer is critically needed to guide evidence-based clinical decisions and future research directions [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn response to this critical clinical need, we conducted this comprehensive systematic review of immunotherapy in bladder cancer, focusing exclusively on the highest-quality clinical trials (phase 2 and 3), thereby providing robust, actionable evidence to clinicians and stakeholders involved in bladder cancer management.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003e1.1 Aim\u003c/h2\u003e\u003cp\u003eThe primary aim of this systematic review is to rigorously evaluate and comprehensively synthesize existing high-quality evidence (phase 2 and 3 clinical trials) regarding the efficacy, safety, and clinical applicability of emerging immunotherapeutic strategies for the treatment of bladder cancer (both NMIBC and select MIBC populations), thus providing robust clinical guidance for optimal patient management.\u003c/p\u003e\u003c/div\u003e"},{"header":"2.0 Methodology","content":"\u003cp\u003eThis systematic review strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ensuring methodological transparency, reproducibility, and high scientific rigor.\u003c/p\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Search Strategy\u003c/h2\u003e\u003cp\u003eAn extensive and systematic search was conducted in March 2025 across four major electronic databases: Web of Science (WOS), PubMed, Cochrane Library, and Scopus. The comprehensive search was developed using relevant Medical Subject Headings (MeSH terms), keywords, and Boolean operators. The primary search terms included: (\"Immunotherapy\" OR \"Immune checkpoint inhibitors\" OR \"Pembrolizumab\" OR \"Atezolizumab\" OR \"Durvalumab\" OR \"Nadofaragene Firadenovec\" OR \"Cretostimogene Grenadenorepvec\" OR \"BCG\" OR \"Bacillus Calmette-Gu\u0026eacute;rin\") AND (\"Bladder cancer\" OR \"Non-muscle invasive bladder cancer\" OR \"NMIBC\" OR \"Muscle-invasive bladder cancer\" OR \"MIBC\") AND (\"Clinical trial\" OR \"Phase 2\" OR \"Phase 3\"). These search strings were carefully customized and optimized for each database to ensure a comprehensive retrieval of relevant studies.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Inclusion Criteria\u003c/h2\u003e\u003cp\u003eThe review included only randomized controlled trials (RCTs) and prospective single-arm phase 2 and 3 clinical trials. The population of interest comprised adult patients diagnosed with bladder cancer, including both non-muscle-invasive bladder cancer (NMIBC) and selected cases of muscle-invasive bladder cancer (MIBC). Eligible interventions included immunotherapy-based treatments, such as checkpoint inhibitors (Pembrolizumab, Atezolizumab, Durvalumab), intravesical gene therapies (Nadofaragene Firadenovec, Cretostimogene Grenadenorepvec), and immunomodulators like IL-15 agonists (NAI) and Bacillus Calmette-Gu\u0026eacute;rin (BCG). The studies had to report clearly defined clinical outcomes, including complete response rates, disease-free survival (DFS), overall survival (OS), progression rates, cystectomy avoidance, and adverse event profiles. Only full-text articles published in peer-reviewed journals in English were included. No specific publication date limit was imposed to ensure comprehensive retrieval of relevant studies.\u003c/p\u003e\u003cp\u003eExclusion Criteria Studies were excluded if they were retrospective in design, observational studies, review articles, editorials, case reports, commentaries, conference abstracts, or letters. Additionally, studies were excluded if they lacked transparent outcome reporting or presented insufficient data for extraction. Non-English publications or studies without available English translations were also excluded.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Study Screening and Selection Process\u003c/h2\u003e\u003cp\u003eInitial search results from all databases were combined, and duplicates were systematically removed using EndNote software. Two independent reviewers then screened all titles and abstracts to identify potentially relevant studies that met the inclusion criteria. Disagreements at this stage were resolved through consensus or arbitration by a third senior reviewer. Following the initial screening, the full texts of potentially relevant articles were thoroughly assessed by the same reviewers to confirm their eligibility. Detailed reasons for exclusion were documented and explicitly reported in the PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Data Extraction\u003c/h2\u003e\u003cp\u003eThe data extraction was conducted from the final set of selected studies using a standardized data extraction form specifically developed for this review. The extracted parameters included study characteristics such as the first author, publication year, study design, location, and trial phase. Patient demographics were recorded, including the number of patients, age, gender, and tumor characteristics. Details of the intervention were documented, covering the type of immunotherapy, dosage, route of administration, and treatment regimen. Efficacy outcomes were extracted, including complete response (CR) rates, disease-free survival (DFS) rates at specific time points, overall survival (OS), progression rates, and cystectomy avoidance rates. Safety profiles were captured by noting the incidence, severity, and type of adverse events. The follow-up duration for each study was also recorded. The accuracy and completeness of the extracted data were carefully cross-checked, and any discrepancies were resolved through consensus.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Quality Assessment of Included Studies (Risk of Bias)\u003c/h2\u003e\u003cp\u003eThe methodological quality and bias risk of the included studies were thoroughly assessed using the revised Cochrane Risk-of-Bias tool (ROB2). Each study was analyzed across five critical domains: the randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selective reporting of results. For each domain, the studies were classified as \"low risk,\" \"some concerns,\" or \"high risk.\" The results of the quality assessment were visually represented using a traffic-light plot, clearly illustrating overall and domain-specific biases for each included study (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Disagreements during the quality assessment were addressed through discussion and resolved by consensus or, when necessary, third-party adjudication.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Synthesis and Reporting of Results\u003c/h2\u003e\u003cp\u003eData synthesis involved a comprehensive narrative and statistical analysis approach, clearly describing findings from individual studies. Due to clinical and methodological variability across included trials (differences in patient populations, interventions, and outcome measures), a quantitative meta-analysis was not appropriate. Instead, findings were thoroughly synthesized and critically compared qualitatively, with careful attention to outcome patterns, efficacy measures, durability of responses, safety profiles, and clinical applicability across the various therapies.\u003c/p\u003e\u003c/div\u003e"},{"header":"3.0 Results","content":"\u003cp\u003eComprehensive database searches (PubMed, Cochrane Library, Web of Science, and Scopus) initially identified 778 studies. After carefully removing duplicates and diligently applying inclusion and exclusion criteria, 10 studies were included in the systematic review. The detailed step-by-step selection and screening process, including reasons for exclusions at each stage, is presented in a PRISMA-compliant flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStudy Characteristics and Outcomes of Immunotherapy in Bladder Cancer\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAuthor, Year\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDesign\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatient Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSample Size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntervention \u0026amp; Dosage\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePrimary Outcome(s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePrimary Results\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDuration of Response / Follow-Up\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eProgression \u0026amp; Survival Outcomes\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eCystectomy Rates\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eSafety \u0026amp; Adverse Events\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eConclusion \u0026amp; Clinical Implications\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 3, single-arm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBCG-unresponsive CIS NMIBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e112\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntravesical Cretostimogene Grenadenorepvec weekly \u0026times;6 wks, maintenance up to 18 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComplete Response [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCR rate: 75.2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian CR duration: \u0026gt;9 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e12-mo cystectomy-free survival: 92.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eMostly Grade 1\u0026ndash;2 GU AEs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eEffective and safe intravesical therapy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 3, single-arm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBCG-unresponsive CIS/Ta/T1 NMIBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e157\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntravesical Nadofaragene Firadenovec every 3 mo up to 9 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCR rate (CIS); recurrence-free (Ta/T1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCR (CIS): 53.4% at 3 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian CR duration: 9.69 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eProgression to MIBC: 5\u0026ndash;6%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e12-mo rate: 26%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eGrade 1\u0026ndash;2 local AEs common; 4% \u0026ge;Grade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eDurable responses; safe alternative to cystectomy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 2, single-arm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh-risk BCG-failed NMIBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntravesical Durvalumab 1000 mg every 6 wk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigh-grade relapse-free survival at 1 yr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1-yr relapse-free: 39%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian NR (~\u0026thinsp;13 mo)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1-year bladder-intact survival: 78%; \u0026ge;T2 progression: 4 patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot reported clearly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eGrade 1 haematuria (17%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eFeasible treatment with low toxicity\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 2, single-arm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBCG-unresponsive NMIBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e172\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIV Atezolizumab every 3 wk for 1 yr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCR rate at 6 mo (CIS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCR rate (CIS): 27%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian CR duration: 17 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e18-mo event-free survival (Ta/T1): 49%; 12 patients progressed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot reported clearly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e16% Grade 3\u0026ndash;5 TRAEs; 3 deaths\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eModest efficacy; significant AEs; caution in clinical use\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 3, randomized controlled\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMuscle-invasive urothelial carcinoma (MIBC) post-surgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e702\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIV Pembrolizumab 200 mg every 3 wk (1\u0026nbsp;year) vs observation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDisease-free survival (DFS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMedian DFS: 29.6 mo vs 14.2 mo (HR: 0.73; p\u0026thinsp;=\u0026thinsp;0.0027)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian follow-up: 44.8 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3-yr OS similar (~\u0026thinsp;61%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs: 50.7%; 5 deaths\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eSignificant DFS benefit; no OS benefit yet; careful patient selection required\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMuscle-invasive bladder cancer (organ-sparing)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNR clearly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGemcitabine\u0026thinsp;+\u0026thinsp;Cisplatin\u0026thinsp;+\u0026thinsp;Nivolumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePathological response / bladder sparing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePathological CR not detailed clearly in abstract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNR clearly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eDetailed survival data pending\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot clearly detailed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eToxicities expected from chemotherapy and nivolumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003ePromising organ-sparing regimen; final conclusions pending\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBCG-unresponsive CIS\u0026thinsp;\u0026plusmn;\u0026thinsp;Ta/T1 NMIBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntravesical NAI (IL-15 agonist)\u0026thinsp;\u0026plusmn;\u0026thinsp;BCG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCR (CIS) \u0026amp; DFS (Ta/T1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCR: 71% CIS cohort; DFS (Ta/T1): 55.4% at 12 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian CR duration: 26.6 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e24-mo DSS: 100%; OS: 94.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eResponders: 9%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eMostly Grade 1\u0026ndash;2 AEs; no systemic absorption detected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eStrong efficacy and tolerable safety profile\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 2, single-arm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh-risk NMIBC, Ta/T1 without CIS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e132\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIV Pembrolizumab 200 mg every 3 wk up to 35 cycles\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12-mo DFS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12-mo DFS: 43.5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian follow-up: 45.4 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSurvival details NR clearly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot detailed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e14% Grade 3\u0026ndash;4 AEs; common colitis, diarrhoea; no deaths\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003ePembrolizumab promising but randomized trials needed\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 3, randomized controlled\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIntermediate/high-risk Ta/T1 NMIBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1355\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntravesical BCG 1/3 vs full dose (FD); 1 vs 3 yr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDFS at 5 yrs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1/3D-1\u0026nbsp;year inferior to FD-3\u0026nbsp;year; High-risk FD-3\u0026nbsp;year reduced recurrence (HR 1.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian follow-up: 7.1 yr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNo differences in progression/survival\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot clearly detailed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eNo difference in toxicity 1/3D vs FD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eFD 3-yr beneficial for high-risk only; intermediate-risk patients sufficient with 1 yr\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePhase 3, randomized controlled\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMuscle-invasive urothelial carcinoma (MIBC) adjuvant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e702\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIV Pembrolizumab 200 mg every 3 wk vs observation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDFS, OS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDFS significantly improved (HR: 0.73, p\u0026thinsp;=\u0026thinsp;0.0027); OS no significant improvement yet\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMedian DFS: 29.6 mo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3-year OS\u0026thinsp;~\u0026thinsp;61%; progression details pending\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e50.7% Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs; 5 treatment-related deaths\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eClear DFS improvement; OS results pending; safety requires consideration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eQuality assessment of the included studies, conducted with the ROB2 tool, demonstrated that there is generally a low-to-moderate risk of bias across the included trials. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e clearly illustrates specific domains of concern, such as randomization methods, deviations from intended interventions, and outcome reporting biases.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Complete Response [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and Disease-Free Survival (DFS) Outcomes\u003c/h2\u003e\u003cp\u003eSignificant variation in efficacy outcomes was evident across studies. Tyson et al. (2024), in the single-arm BOND-003 trial evaluating intravesical Cretostimogene Grenadenorepvec, reported a notably high complete response rate of 75.2% (95% CI: 65\u0026ndash;83%) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Impressively, among responders, 83% maintained their response for at least 12 months, indicating substantial durability. Black et al. (2023) in the single-arm SWOG S1605 trial evaluating the efficacy and safety of intravenous Atezolizumab reported a promising complete response rate of 56% (95% CI: 34\u0026ndash;77%) [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Median duration of CR was 17 months with 56% CR rate at 12 months evaluation. In the CIS cohort, 27% CR rate was reported at 6 months evaluation. Further, a 49% (90% CI: 38\u0026ndash;60%) 18-month recurrence-free-rate was reported among the 55 patients with Ta/T1 disease.\u003c/p\u003e\u003cp\u003eBoorjian et al. (2021) assessed intravesical Nadofaragene Firadenovec in BCG-unresponsive NMIBC patients, reporting an encouraging 53.4% CR rate at the 3-month evaluation in the CIS cohort [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Among initial responders, approximately 45.5% maintained their CR at 12 months, and the median CR duration reached 9.69 months. Furthermore, a promising recurrence-free rate of 43.8% at 12 months was observed among high-grade Ta/T1 patients. Pembrolizumab (Balar et al., 2021), administered intravenously every three weeks, demonstrated a 12-month DFS rate of 43.5% (95% CI: 34.9\u0026ndash;51.9%) in high-risk papillary NMIBC without CIS, thereby providing a significant therapeutic alternative for patients who decline radical cystectomy [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eChamie et al. (2022) notably reported a robust 71% CR rate (95% CI: 59.6\u0026ndash;80.3%) using intravesical NAI combined with BCG [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. This response was remarkably durable, as indicated by a notable median duration of CR at 26.6 months. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows Kaplan-Meier curves for Pembrolizumab, Atezolizumab, Nadofaragene and NAI\u0026thinsp;+\u0026thinsp;BCG agents based on publicly reported event-to-time DFS and OS data. There was no sufficient publicly reported time-to-event DFS and OS data to construct the Cretostimogene Grenadenorepvec survival curves.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Durability of Response and Bladder Preservation Outcomes\u003c/h2\u003e\u003cp\u003eResponse durability varied significantly among the therapies included. Fragkoulis et al. (2025) investigated intravesical Durvalumab, finding a moderate 39% one-year high-grade relapse-free survival rate (95% CI: 18\u0026ndash;59%), yet achieved a strong 78% bladder-intact survival at one year [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This underscored the agent\u0026rsquo;s utility in bladder preservation strategies despite moderate CR rates. Long-term response rates at \u0026ge;\u0026thinsp;12 and \u0026ge;\u0026thinsp;18 months clearly favored intravesical NAI\u0026thinsp;+\u0026thinsp;BCG therapy (61.6% and 51.1%, respectively), closely followed by Nadofaragene. Pembrolizumab exhibited intermediate efficacy, maintaining approximately 43.5% CR at 12 months, which reduced to around 30% at 18 months. These comparative results are clearly illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Progression and Overall Survival Outcomes\u003c/h2\u003e\u003cp\u003eProgression rates to muscle-invasive bladder cancer (MIBC) exhibited heterogeneity among therapies. Nadofaragene and NAI\u0026thinsp;+\u0026thinsp;BCG were associated with relatively low progression rates (~\u0026thinsp;5\u0026ndash;6%). Pembrolizumab and Atezolizumab showed progression rates ranging from 10\u0026ndash;15%, indicating a higher risk of progression despite systemic immunotherapy. Notably, the EORTC-GU randomized trial by Oddens et al. (2013) demonstrated that full-dose BCG maintenance for three years significantly reduced recurrence (HR: 1.61, 95% CI: 1.13\u0026ndash;2.30, p\u0026thinsp;=\u0026thinsp;0.009), yet it did not result in statistically significant reductions in progression or mortality [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Overall survival rates across studies remained generally high, consistently exceeding 90% at two years. Boorjian et al. (2022) reported 24-month OS of 91.9% (95% CI: 80.9\u0026ndash;96.7%) with at least one dose of Nadofaragene [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Chamie et al. (2022) reported 24-month OS of 91.7% with a dose of NAI\u0026thinsp;+\u0026thinsp;BCG [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Adverse Events and Treatment Safety\u003c/h2\u003e\u003cp\u003eSafety profiles varied significantly between systemic and intravesical therapies. Intravesical therapies generally reported milder, grade 1\u0026ndash;2 adverse events. For example, Durvalumab was predominantly associated with grade 1 hematuria (17%). Systemic agents displayed a different toxicity profile, with Pembrolizumab reporting a concerning 14% rate of grade 3\u0026ndash;4 adverse events, particularly immune-related colitis and diarrhea. Moreover, systemic atezolizumab therapy was linked to significant treatment-related toxicities, including three deaths. The comprehensive comparative safety and efficacy outcomes are clearly illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Summary of Treatment Outcomes\u003c/h2\u003e\u003cp\u003eOverall treatment outcomes, clearly summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, indicate better long-term response maintenance and fewer adverse events with intravesical therapies (notably NAI\u0026thinsp;+\u0026thinsp;BCG and Nadofaragene). Systemic therapies such as Pembrolizumab and Atezolizumab offer moderate efficacy balanced against higher risks of adverse event risks, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4.0 Discussion","content":"\u003cp\u003eThis systematic review comprehensively analyzed current clinical evidence regarding immunotherapeutic approaches for treating bladder cancer, specifically focusing on non-muscle-invasive bladder cancer (NMIBC) and select muscle-invasive bladder cancer (MIBC) populations. Across the ten included studies, immunotherapies such as intravesical Cretostimogene Grenadenorepvec, Nadofaragene Firadenovec, Durvalumab, and systemic checkpoint inhibitors (Pembrolizumab and Atezolizumab) demonstrated heterogeneous yet promising therapeutic potential. However, clear distinctions in efficacy, durability, safety profiles, and clinical applicability emerged distinctly across the therapeutic modalities.\u003c/p\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Comparative Efficacy and Clinical Implications\u003c/h2\u003e\u003cp\u003eIntravesical therapies have consistently demonstrated strong clinical efficacy, particularly notable in BCG-unresponsive NMIBC. The highest complete response [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] rates were reported for intravesical Cretostimogene Grenadenorepvec [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], achieving a CR of 75.2% with significant durability, as reflected in 83% of responders maintaining their response at one year. This aligns favorably with previous literature suggesting that viral-based immunotherapeutic approaches can generate robust and lasting antitumor responses by enhancing tumor antigen presentation and immune activation pathways [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNadofaragene Firadenovec similarly demonstrated significant promise, achieving a CR rate of 53.4% at three months and substantial maintenance of response (45.5% at 12 months) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The promising efficacy observed with Nadofaragene underscores the potential of adenoviral-mediated interferon gene therapy to effectively stimulate innate and adaptive immune responses, providing durable disease control even in highly refractory patient populations [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn contrast, Durvalumab's intravesical administration presented moderate CR rates (39% one-year relapse-free), yet demonstrated a notably higher bladder preservation rate (78% at one year) [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This highlights the important distinction between achieving absolute CR and clinically meaningful endpoints such as bladder preservation, which significantly impact patient quality of life. However, further comparative analyses through head-to-head randomized trials are required to better clarify Durvalumab's role within existing treatment algorithms. Systemic immunotherapies, particularly checkpoint inhibitors Pembrolizumab and Atezolizumab, demonstrated moderate efficacy in NMIBC and MIBC. Pembrolizumab achieved 43.5% DFS at 12 months in high-risk papillary NMIBC without CIS [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], thus positioning it as a potential therapeutic option for patients ineligible or unwilling to undergo radical cystectomy. Nonetheless, Pembrolizumab's overall efficacy remained modest compared to intravesical treatments, consistent with findings from KEYNOTE-057 and other checkpoint inhibitor trials, reflecting systemic immune response limitations in superficial bladder tumors [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe findings from this review demonstrate immunotherapy as a viable treatment options for bladder cancer. However, the growing economic burden of immunotherapy cannot be overlooked. Sarfaty et al. (2018) found that it costs more for bladder cancer patients to gain one quality-adjusted life-year with Pembrolizumab compared to chemotherapy in the United States than in UK, Canada and Australia [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Similar findings were reported by Aguiar et al. (2017) indicating high cost-effectiveness of Atezolizumab and reduced quality-adjusted life years [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In other words, a single cycle of treatment with immunotherapy would be more expensive than chemotherapy in countries with high drug prices like the United States.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Response Durability and Bladder Preservation\u003c/h2\u003e\u003cp\u003eAn important aspect of evaluating immunotherapies in bladder cancer is the durability of therapeutic responses, which critically impacts long-term disease control and patient outcomes. NAI combined with intravesical BCG demonstrated exceptional response durability, achieving a median CR duration of 26.6 months [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], clearly outperforming other intravesical and systemic therapies. This remarkable durability is likely due to NAI\u0026rsquo;s robust activation of IL-15 pathways, resulting in sustained immunological memory and prolonged antitumor activity [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMoreover, cystectomy avoidance rates were significantly higher with intravesical agents, particularly Nadofaragene (92.3% at one year) and NAI\u0026thinsp;+\u0026thinsp;BCG (89.2%). This preservation of the bladder is highly desirable for patients, as it directly correlates with improved quality-of-life outcomes, reduced morbidity, and lower healthcare utilization. These findings strongly advocate prioritizing intravesical therapies in clinical decision-making for NMIBC, particularly for patients who highly value bladder preservation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Progression Rates and Overall Survival\u003c/h2\u003e\u003cp\u003eWhile intravesical therapies demonstrated relatively lower progression rates (5\u0026ndash;6%) compared to systemic therapies (10\u0026ndash;15%), overall survival (OS) rates remained uniformly high across all treatment modalities (\u0026gt;\u0026thinsp;90% at two years). This indicates that the risk of progression remains manageable within the current therapeutic landscape. The EORTC-GU study (Oddens et al., 2013) notably revealed no significant differences in progression rates across varying BCG dose intensities and maintenance durations, despite clear recurrence advantages with more prolonged therapy [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This finding suggests that while prolonged BCG regimens may effectively suppress recurrences, progression risks might be inherently independent of dosing strategies, possibly driven by biological tumor characteristics rather than by therapeutic intensity alone.\u003c/p\u003e\u003cp\u003eThe AMBASSADOR trial investigating adjuvant Pembrolizumab following radical cystectomy demonstrated a statistically significant improvement in DFS (HR: 0.73; p\u0026thinsp;=\u0026thinsp;0.0027), yet no measurable OS benefit was observed at three years. This absence of OS benefit so far underscores the need for careful interpretation and further longitudinal analyses to determine whether DFS advantages ultimately translate into survival improvements, a critical determinant in the adjuvant therapy decision-making process.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003e4.4 Treatment Safety Profiles and Clinical Decision-Making\u003c/h2\u003e\u003cp\u003eA notable differentiation emerged in safety profiles between systemic and intravesical therapies. Intravesical therapies such as Durvalumab, Nadofaragene, and NAI\u0026thinsp;+\u0026thinsp;BCG predominantly demonstrated mild (grade 1\u0026ndash;2) localized genitourinary adverse events, which are clinically manageable and patient-friendly. Conversely, systemic immunotherapies, particularly checkpoint inhibitors Pembrolizumab and Atezolizumab, were associated with higher incidences of severe grade 3\u0026ndash;4 toxicities, including life-threatening immune-mediated colitis and pneumonitis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Notably, the SWOG S1605 trial reported concerning safety signals with atezolizumab, including treatment-related fatalities, raising serious considerations regarding its risk-benefit ratio in this patient population. These findings underscore the importance of carefully balancing efficacy with safety considerations. In scenarios where comparable efficacy is attainable with intravesical agents, clinicians should prioritize these safer, better-tolerated therapies to maximize patient safety and minimize adverse events.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003e4.6 Limitations and Strengths of This Review\u003c/h2\u003e\u003cp\u003eThis review rigorously synthesizes the latest evidence, yet inherent limitations must be acknowledged. One of the limitation was the primarily heterogeneity among studies in patient populations, follow-up durations, and endpoint definitions complicates direct comparative analyses. Another limitation was the potential publication and language bias. Promising agents such as Sasanlimab, TAR-200, and IV Durvalumab were excluded as their findings are not yet peer-reviewed but were presented at scientific meetings.\u003c/p\u003e\u003cp\u003eMost included studies were single-arm designs, limiting comparative efficacy conclusions with standard care such as radical cystectomy. The lack of randomized comparisons between immunotherapy and radical cystectomy limits the ability to draw conclusions of their relative benefits. Moreover, current evidence has not demonstrated a significant oncologic advantage for immunotherapy compared to radical cystectomy. This limitation underscores the need for randomized comparisons of the relative benefits of immunotherapy with standard care in treatment of bladder cancer patients.\u003c/p\u003e\u003cp\u003eNonetheless, the review\u0026rsquo;s strengths lie in its comprehensive methodology, strict adherence to PRISMA guidelines, thorough ROB2 assessments, and the robust statistical detailing of clinical outcomes, providing an authoritative evidence synthesis for clinical practice and future research guidance.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003e4.7 Recommendations for Future Research and Clinical Practice\u003c/h2\u003e\u003cp\u003eFuture randomized controlled trials should directly compare intravesical and systemic immunotherapies head-to-head to conclusively determine the most clinically beneficial and safest approaches. Also, evaluating biomarkers predictive of response and toxicity could further refine patient selection and therapeutic strategies. Clinically, prioritizing intravesical agents for BCG-unresponsive NMIBC appears justified given the superior efficacy, favorable safety profile, and bladder preservation outcomes demonstrated in this systematic review.\u003c/p\u003e\u003c/div\u003e"},{"header":"5.0 Conclusion","content":"\u003cp\u003eThis systematic review provides compelling evidence supporting intravesical immunotherapies especially NAI\u0026thinsp;+\u0026thinsp;BCG and Nadofaragene as highly effective, durable, and safer treatments for bladder cancer. Systemic therapies such as Pembrolizumab and Atezolizumab show moderate efficacy but significantly elevated toxicity concerns. These insights guide clinicians toward personalized, safer, and more effective management strategies, ultimately improving patient outcomes and quality of life in bladder cancer treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor ContributionsAhmed Alasker (A.A.) \u0026ndash; Conceived the study idea, contributed to study design, supervised the overall project, and critically revised the manuscript.Mohammad Alghafees (M.A.) \u0026ndash; Conceived and designed the study protocol, performed the literature search, led data extraction and synthesis, and drafted the initial manuscript.Talah Nammor (T.N.) \u0026ndash; Participated in literature screening, assisted in data extraction, and contributed to drafting sections of the methodology.Naif Alanazi (N.A.) \u0026ndash; Assisted in data extraction and verification, contributed to the risk-of-bias assessment, and provided input for result interpretation.Turki Alferayan (T.A.) \u0026ndash; Prepared tables and figures, assisted in data organization, and contributed to editing the results section.Abdulaziz Almanie (A.Alm.) \u0026ndash; Participated in literature screening, contributed to PRISMA diagram preparation, and assisted in manuscript formatting.Mohammed Alrashed (M.Alr.) \u0026ndash; Assisted in quality assessment of included studies, contributed to data interpretation, and revised the discussion section.Yousef Almarzouq Almarzouq (Y.A.A.) \u0026ndash; Verified extracted data, assisted in statistical synthesis, and contributed to the critical revision of the final manuscript.Abdullah Alammari (A.Am.) \u0026ndash; Contributed to data analysis and manuscript revisionAll authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.Naif Alanazi (N.A.) \u0026ndash; Assisted in data extraction and verification, contributed to the risk-of-bias assessment, and provided input for result interpretation.Turki Alferayan (T.A.) \u0026ndash; Prepared tables and figures, assisted in data organization, and contributed to editing the results section.Abdulaziz Almanie (A.Alm.) \u0026ndash; Participated in literature screening, contributed to PRISMA diagram preparation, and assisted in manuscript formatting.Mohammed Alrashed (M.Alr.) \u0026ndash; Assisted in quality assessment of included studies, contributed to data interpretation, and revised the discussion section.Yousef Almarzouq Almarzouq (Y.A.A.) \u0026ndash; Verified extracted data, assisted in statistical synthesis, and contributed to the critical revision of the final manuscript.All authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGroup E-ACR. 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Immunotherapy for bladder cancer: latest advances and ongoing clinical trials. Immunol Investig. 2022;51:2226\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRouanne M, Roumigui\u0026eacute; M, Hou\u0026eacute;d\u0026eacute; N, et al. Development of immunotherapy in bladder cancer: present and future on targeting PD (L) 1 and CTLA-4 pathways. World J Urol. 2018;36:1727\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSimons MP, O'Donnell MA, Griffith TS. Role of neutrophils in BCG immunotherapy for bladder cancer. Urologic Oncology: Seminars and Original Investigations. Volume 26. Elsevier; 2008. pp. 341\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGan C, Mostafid H, Khan MS, Lewis DJ. BCG immunotherapy for bladder cancer\u0026mdash;the effects of substrain differences. Nat Reviews Urol. 2013;10:580\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKamat AM, Lamm DL. Immunotherapy for bladder cancer. Curr Urol Rep. 2001;2:62\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBesan\u0026ccedil;on M, Gris T, Joncas F-H, et al. Combining antiandrogens with immunotherapy for bladder cancer treatment. Eur Urol Open Sci. 2022;43:35\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSong D, Powles T, Shi L, Zhang L, Ingersoll MA, Lu YJ. Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches. J Pathol. 2019;249:151\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAskeland EJ, Newton MR, O\u0026rsquo;Donnell MA, Luo Y. Bladder cancer immunotherapy: BCG and beyond. Advances in urology. 2012, 2012:181987.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan Puffelen JH, Keating ST, Oosterwijk E, et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nat Reviews Urol. 2020;17:513\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKamat AM, Bellmunt J, Galsky MD, et al. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. J Immunother Cancer. 2017;5:1\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKawai K, Miyazaki J, Joraku A, Nishiyama H, Akaza H. B acillus C almette\u0026ndash;G uerin (BCG) immunotherapy for bladder cancer: Current understanding and perspectives on engineered BCG vaccine. Cancer Sci. 2013;104:22\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLou K, Feng S, Zhang G, Zou J, Zou X. Prevention and treatment of side effects of immunotherapy for bladder cancer. Front Oncol. 2022;12:879391.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBiot C, Rentsch CA, Gsponer JR, et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci Transl Med. 2012;4:ra137172\u0026ndash;137172.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlexandroff AB, Nicholson S, Patel PM, Jackson AM. Recent advances in bacillus Calmette\u0026ndash;Guerin immunotherapy in bladder cancer. Immunotherapy. 2010;2:551\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJiang S, Redelman-Sidi G. BCG in bladder cancer immunotherapy. Cancers. 2022;14:3073.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTyson MD, Uchio E, Nam J-K, et al. P2-02 pivotal results from BOND-003: A phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for the treatment of high risk, BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ. J Urol. 2024;211:e1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22:107\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFragkoulis C, Bamias A, Gavalas N, et al. Intravesical Administration of Durvalumab for High-risk Non\u0026ndash;muscle-invasive Bladder Cancer: A Phase 2 Study by the Hellenic GU Cancer Group. Eur Urol. 2025;87:281\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBlack PC, Tangen CM, Singh P, et al. Phase 2 trial of Atezolizumab in Bacillus Calmette-Gu\u0026eacute;rin\u0026ndash;unresponsive high-risk non\u0026ndash;muscle-invasive bladder cancer: SWOG S1605. Eur Urol. 2023;84:536\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eApolo AB, Rosenberg JE, Kim WY, et al. Alliance A031501: Phase III randomized adjuvant study of MK-3475 (pembrolizumab) in muscle-invasive and locally advanced urothelial carcinoma (MIBC)(AMBASSADOR) versus observation. American Society of Clinical Oncology; 2019.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGalsky MD, Daneshmand S, Izadmehr S, et al. Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial. Nat Med. 2023;29:2825\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChamie K, Chang SS, Kramolowsky E, et al. IL-15 superagonist NAI in BCG-unresponsive non\u0026ndash;muscle-invasive bladder cancer. NEJM Evid. 2022;2:EVIDoa2200167.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBalar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22:919\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Gu\u0026eacute;rin in intermediate-and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63:462\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eApolo AB, Ballman KV, Sonpavde G, et al. Adjuvant pembrolizumab versus observation in muscle-invasive urothelial carcinoma. N Engl J Med. 2025;392:45\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSarfaty M, Hall PS, Chan KK, Virik K, Leshno M, Gordon N, Moore A, Neiman V, Rosenbaum E, Goldstein DA. Cost-effectiveness of pembrolizumab in second-line advanced bladder cancer. Eur Urol. 2018;74(1):57\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAguiar PN Jr, Perry LA, Penny-Dimri J, Babiker H, Tadokoro H, De Mello RA, Lopes GL Jr. The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC. Ann Oncol. 2017;28(9):2256\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bladder Cancer, Immunotherapy, NMIBC, BCG-unresponsive, Pembrolizumab, Nadofaragene, Durvalumab, Systematic Review, Phase 2/3 Clinical Trials, PRISMA","lastPublishedDoi":"10.21203/rs.3.rs-6457129/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6457129/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eBladder cancer poses significant morbidity, mortality, and healthcare burdens globally. While non-muscle-invasive bladder cancer (NMIBC) often initially responds to intravesical Bacillus Calmette-Gu\u0026eacute;rin (BCG), many patients become unresponsive to BCG, resulting in recurrence or progression. Emerging immunotherapies, including checkpoint inhibitors (Pembrolizumab, Atezolizumab, Durvalumab), intravesical gene therapies (Nadofaragene Firadenovec, Cretostimogene Grenadenorepvec), and novel cytokine-based therapies (NAI, IL-15 superagonist), present promising alternatives. This systematic review thoroughly synthesizes existing clinical evidence from phase 2 and 3 trials, critically assessing immunotherapeutic options for bladder cancer treatment.\u003c/p\u003e\u003ch2\u003eMethodology:\u003c/h2\u003e\u003cp\u003eA comprehensive search was systematically conducted across four databases (PubMed, Cochrane, Web of Science, Scopus), strictly adhering to PRISMA guidelines. Inclusion criteria included only phase 2 and 3 clinical trials evaluating immunotherapies in NMIBC and selected muscle-invasive bladder cancer (MIBC) populations. Two reviewers independently performed study screening, data extraction, and risk-of-bias assessments using the ROB2 tool. Results were synthesized both qualitatively and quantitatively, incorporating detailed comparative analyses and robust statistical descriptions.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eA total of 778 studies were initially identified; after thorough screening, 10 high-quality clinical trials (phase 2 and 3) met the inclusion criteria. Intravesical Cretostimogene Grenadenorepvec demonstrated the highest complete response [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] rate (75.2%), with impressive durability (83% maintaining response\u0026thinsp;\u0026ge;\u0026thinsp;12 months). Intravesical Nadofaragene Firadenovec also exhibited notable efficacy (CR 53.4%, median duration 9.69 months). NAI combined with BCG achieved a robust CR (71%) and a remarkably sustained response (median 26.6 months). Systemic Pembrolizumab showed moderate efficacy (12-month DFS 43.5%) but raised significant toxicity concerns (14% grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events). Intravesical therapies consistently provided superior cystectomy avoidance (\u0026ge;\u0026thinsp;89% at 12 months) compared to systemic treatments. Safety profiles significantly favored intravesical therapies, which had predominantly mild (grade 1\u0026ndash;2) adverse events, while systemic therapies reported notable severe toxicities and treatment-related fatalities.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003eIntravesical immunotherapies, particularly NAI\u0026thinsp;+\u0026thinsp;BCG and Nadofaragene, demonstrate superior efficacy, significant response durability, and favorable safety profiles in treating bladder cancer compared to systemic checkpoint inhibitors, which display moderate efficacy and notable safety concerns. These findings strongly support prioritizing intravesical therapies in NMIBC management, especially for patients who are unresponsive to BCG. Future research should focus on head-to-head randomized controlled trials and biomarker-driven patient selection to optimize clinical outcomes.\u003c/p\u003e","manuscriptTitle":"Immunotherapy in Bladder Cancer: A Systematic Review of Clinical Trials and Therapeutic Advances","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 16:15:16","doi":"10.21203/rs.3.rs-6457129/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-21T16:16:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-23T10:53:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-10T08:51:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-29T11:53:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"318991963212758033029004788644090431272","date":"2025-08-29T11:49:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"135743685750034984848236451244189639245","date":"2025-08-15T08:30:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-12T17:12:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-12T14:23:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Urology","date":"2025-08-09T03:08:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9ecf0012-1f9b-4734-a5ea-be8f83d31821","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-09T18:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-08 16:15:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6457129","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6457129","identity":"rs-6457129","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}