Abstract 26P
Background
Stimotimagene copolymerplasmid (SC) is a non-viral anti-tumor gene therapy drug comprising supercoiled plasmid DNA (pDNA) encapsulated in a polycationic envelope (PPT: PEI-PEG-TAT peptide). The plasmid encodes two therapeutic genes: herpes simplex virus thymidine kinase (HSVtk) and human granulocyte-macrophage colony-stimulating factor (hGM-CSF). HSVtk converts the prodrug ganciclovir to a toxin in cells that have been transfected by the SC. GM-CSF stimulates proliferation and differentiation of antigen-presenting cells. SC therapy consists of two steps: (1) triple intratumoral injection of SC, (2) intravenous administration of ganciclovir.
Methods
A total of 13 patients with melanoma, sarcoma, breast carcinoma, and perianal squamous cell carcinoma were consecutively randomized into 4 cohorts in a multicenter, open-label, phase I clinical trial («3+3» design). Patients received intratumoral administration of SC at a dose of 20-40 μg pDNA/cm3 administered once, twice, or three times at 5-day intervals, depending on the planned dosing regimen within the cohort, against a background of intravenous 15-day administration of ganciclovir. The drug biodistribution was assessed with real-time PCR by quantifying the plasmid DNA levels in peripheral blood, urine, and tumor tissue biopsy of patients.
Results
SC demonstrated a favorable safety profile, with no serious adverse events (SAEs) related to the drug administration reported, the treatment tolerability was rated as satisfactory/good, and no dose-limiting toxicity was achieved (CTCAE 5.0). The drug is characterized by a maximum DNA level detected in tumor tissue, with a linear increase in serum DNA level reaching its maximum 4-8 hours following administration with a subsequent elimination to undetectable levels by Day 90 in most patients.
Conclusions
The safety profile of SC was favorable. Based on the results of the study, the optimal therapeutic dose was determined to be as 40 μg per cm3 of tumor focus, administered in a threefold regimen with an interval of 5 days.
Clinical trial identification
NCT05578820.
Editorial acknowledgement
Legal entity responsible for the study
Gene Surgery LLC.
Funding
National Technology Initiative.
Disclosure
All authors have declared no conflicts of interest.