This study evaluated the safety and pathological response rate of local oncolytic virus CG0070 combined with systemic PD-1 inhibitor nivolumab in cisplatin-intolerant patients with muscle-invasive bladder cancer, providing a potential strategy for neoadjuvant therapy.
Literature Overview
This paper titled 'Oncolytic immunotherapy with nivolumab in muscle-invasive bladder cancer: a phase 1b trial', published in Nature medicine, reviews and summarizes the safety and preliminary efficacy of oncolytic virus CG0070 combined with PD-1 inhibitor nivolumab in cisplatin-intolerant patients with muscle-invasive bladder cancer (MIBC). The study included 21 patients and observed no dose-limiting toxicity, with a pathological complete response rate (pCR) of 42.1% and a 1-year recurrence-free survival rate of 70.4%. The study further revealed that pCR correlated with baseline E2F activity and tumor mutation burden (TMB), while the formation of tertiary lymphoid structures (TLS) was associated with complete response, highlighting the potential of oncolytic virus combined with PD-1 inhibitors in MIBC neoadjuvant therapy.
Background Knowledge
Treatment of muscle-invasive bladder cancer (MIBC) has long relied on cisplatin-based neoadjuvant chemotherapy, but approximately 50% of patients cannot tolerate this regimen due to comorbidities. Recent trials of immune checkpoint inhibitors (ICIs) as monotherapy in the neoadjuvant setting for MIBC have shown pCR rates ranging from 7% to 46%, with nivolumab monotherapy yielding a pCR rate of only 7-17%. CG0070, an oncolytic virus, is a conditionally replicating adenovirus whose E1A gene is controlled by the E2F1 promoter, enabling replication specifically in tumor cells with dysregulated Rb pathways and expressing GM-CSF to enhance local and systemic anti-tumor immunity. This study aims to explore the safety and anti-tumor activity of CG0070 combined with nivolumab, as well as to analyze associations between biomarkers and immune response mechanisms.
Research Methods and Experiments
This was a single-arm, phase 1b open-label clinical trial that enrolled cisplatin-intolerant patients with clinical stage cT2-4aN0-1M0 MIBC. Patients received weekly intravesical instillations of CG0070 (1×10^12 viral particles) and intravenous nivolumab (480 mg) in weeks 2 and 6. The primary endpoint was safety assessment (according to NCI CTCAE v5.0 criteria), while secondary endpoints included pathological complete response rate and 1-year recurrence-free survival. The study also assessed immune-related biomarkers, including E2F activity, TMB, PD-L1 expression in tumor tissues, changes in urinary GM-CSF concentration, T-cell infiltration, and TLS formation.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides a safe and effective novel neoadjuvant treatment strategy for cisplatin-intolerant MIBC patients. Future research should further validate the role of TLS formation and humoral immunity in treatment response and explore the long-term efficacy of combination therapy.
Conclusion
This study demonstrates that the combination of oncolytic virus CG0070 and PD-1 inhibitor nivolumab is safe and exhibits significant anti-tumor activity in cisplatin-intolerant patients with muscle-invasive bladder cancer. It reveals a positive correlation between pathological complete response and baseline E2F activity and tumor mutation burden, and highlights the notable formation and maturation of tertiary lymphoid structures in patients achieving complete response, suggesting a synergistic role of humoral and cellular immunity. This study provides a theoretical and clinical basis for future development of more effective neoadjuvant immunotherapy regimens.
