EG-70 (detalimogene voraplasmid), an investigational non-viral gene therapy, is showing promise in patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS). Presented at the 2024 International Bladder Cancer Network (IBCN) Annual Meeting, preclinical and phase 1 clinical study results suggest that EG-70 elicits a local anti-tumor immune response in the bladder, potentially leading to durable efficacy while mitigating systemic toxicities.
Mechanism of Action
EG-70's mechanism involves two key components:
- Innate immune system activation: Dual RIG-I agonists stimulate NK cells and attenuate suppressor cells, promoting tumor killing and T-cell recruitment.
- Adaptive immune system activation: Secreted IL-12 promotes a T-cell-dependent cytokine response, enhancing tumor killing and establishing immune memory. Bladder-restricted production aims to maximize therapeutic effect while minimizing systemic adverse events.
Preclinical Efficacy
Preclinical studies using a murine surrogate formulation of EG-70 (mEG-70) administered intravesically in C57BL/6 mice demonstrated significant anti-tumor activity. In an orthotopic bladder cancer model (MB49), mEG-70 remodeled the tumor microenvironment from immunosuppressive to pro-inflammatory, decreasing myeloid cells and IL-4 levels while increasing NK cells, T cells, and pro-inflammatory cytokines. Administration of mEG-70 was associated with a marked reduction in tumor burden and significant improvement in survival in murine xenografts. The anti-tumor response was largely immune-mediated, with durable clearance of tumors and protection against subsequent tumorigenic re-challenge, both locally and distally.
Phase 1/2 Clinical Trial Results
In the phase 1/2 LEGEND study (NCT04752722), EG-70 was assessed in 24 patients with high-risk BCG-unresponsive NMIBC with CIS. Patients received 2 or 4 doses of EG-70 every 12-week cycle, using a 3+3 dose escalation design. The primary endpoint was safety, and the secondary endpoint was efficacy at 3 months. Intravesical instillations of EG-70 were well-tolerated across all dose levels, with an overall complete response rate of 73%. Any grade treatment-related adverse events occurred in 54.2% of patients, with no grade 4/5 events. The most common treatment-related adverse events included hematuria, urinary tract infection, and micturition urgency. At the dose selected for phase 2, complete response rates were 70% at 3 months and 60% at 6 months.
Implications and Future Directions
These findings suggest that EG-70 represents a promising new approach for patients with BCG-unresponsive NMIBC. The dual mechanism of action, involving both innate and adaptive immune stimulation, may overcome resistance to existing therapies. Further studies are warranted to confirm these findings and to evaluate the long-term efficacy and safety of EG-70 in this patient population. Dr. James Sullivan, Chief Scientific Officer of enGene Inc., presented these findings at IBCN 2024.
