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

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.