Mechanism of action and translation to the clinic of detalimogene voraplasmid (EG-70): A novel, investigational, non-viral immunotherapy for non-muscle-invasive bladder cancer (NMIBC).
Authors: Vikram M. Narayan, Yair Lotan, Marie-Line Goulet, Shauna Dauphinee, Daniel Veilleux, Kristine S Louis, David Lazure, Sarah Stevenson, Darius Bilimoria, Fazmina Zamzameer, Ximin Chen, Sébastien Sublemontier, Sahar Amirkhani, Carlos Fleet, Raj Pruthi, Anthony Cheung, James C. Sullivan, Vignesh T. Packiam, Ashish M. Kamat
Journal: Journal of Clinical Oncology (2025)

826 Background: Detalimogene voraplasmid (EG-70) is a novel, investigational, non-integrating, non-viral gene therapy designed to elicit local stimulation of anti-tumor immune response in the bladder while mitigating the risk of systemic toxicities from immune stimulation. It is administered by intravesical instillation (IVI) to eligible patients with NMIBC to drive bladder-localized expression of innate (RIG-I agonists) and adaptive (IL-12) immune regulators and remodel the tumor microenvironment. LEGEND is an ongoing Phase 1/2 study (NCT04752722) investigating the safety and efficacy of detalimogene voraplasmid in bacillus Calmette Guerin (BCG)-unresponsive NMIBC. We present preclinical data supporting the mechanism of action of detalimogene voraplasmid, which involves immune cell recruitment, tumor microenvironment remodeling and immune training on neoantigens and tumor clearance. Methods: Preclinical evaluation of detalimogene voraplasmid was conducted in vitro in relevant cell lines and in vivo in an orthotopic syngeneic model of bladder cancer in immunocompetent C57BL/6 mice. Luciferase-expressing MB49 cells were instilled in the bladder on Day 1; following confirmation of tumor engraftment by in vivo bioluminescence imaging on Day 9, mice received two weekly IVIs of mEG-70 (a murine surrogate of EG-70) on Days 10&amp;17. Efficacy of mEG-70 was assessed post-dosing by flow cytometry, MSD immunoassays, immunohistochemistry, bioluminescence in vivo imaging, and overall survival. Animal experimentation was approved by the Institutional Animal Care Committee (IACC) and conducted in accordance with Canadian Council on Animal Care (CCAC) guidelines. The Phase 1 component of the LEGEND study evaluated detalimogene voraplasmid in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS). Results: Immune profiling revealed remodeling of the tumor microenvironment from an immunosuppressive phenotype to a pro-inflammatory milieu supportive of tumor clearance. Accordingly, administration of mEG-70 was associated with marked reduction in tumor burden and improvement in survival in mice. As demonstrated by either bladder or flank tumor cell rechallenge, the anti-tumor immune response in surviving tumor-free mice resulted in durable protection against subsequent tumor re-challenge, and systemic immune memory. In the Phase 1 part of the LEGEND study, detalimogene voraplasmid was generally well tolerated, with an overall complete response rate of 73% in patients with NMIBC with CIS. Conclusions: These preclinical findings demonstrate that detalimogene voraplasmid delivers genetically encoded immunostimulatory payloads locally to the bladder. The mechanism of action described preclinically has been translated into the clinic in the Phase 1 part of the LEGEND study.