Safety of an antitumor drug based on the recombinant vaccinia virus strain VV-GMCSF-Lact (preclinical studies)

Introduction. Virotherapy is one of the most promising and rapidly developing approaches in antitumor therapy. An antitumor drug based on the recombinant vaccinia virus strain VV-GMCSF-Lact, developed by a team of researchers of the Institute of Chemical Biology and Fundamental Medicine SB RAS and the State Research Center of Virology and Biotechnology "Vector", has demonstrated high antitumor efficacy against human and animal tumors. For further pharmaceutical development of VV-GMCSF-Lact evaluation of its systemic toxicity and pharmacological safety in preclinical studies is required.

Aim. Evaluation of the general toxicity and pharmacological safety of an antitumor drug based on the recombinant strain of vaccinia virus VV-GMCSF-Lact.

Materials and methods. A non-toxic dose level study in females of ICR mice, Wistar rats, and California rabbits after intravenous (iv) administration at the maximum possible doses for each animal species was conducted. Acute toxicity of the drug was evaluated in ICR mice and SD rats with a single iv or subcutaneous (sc) administration of the drug at two doses: 1 × 10⁷ PFU (human equipotent therapeutic dose) and the maximal dose for each animal species. Subchronic toxicity was studied in SD rats and New Zealand White rabbits with multiple sc administration (4 injections at 1-week intervals) of the drug at doses of 1 × 10⁷ PFU and 5 × 10⁷ PFU. The pharmacological safety of the drug was assessed in SD rats as part of subchronic toxicity studies.

Results and discussion. When determining the non-toxic dose level of the oncolytic virus VV-GMCSF-Lact with proven antitumor activity, doses exceeding the single human therapeutic dose (1 × 10⁷ PFU) by 7.5 times (mice), 30 times (rats), and 150 times (rabbits) were achieved. The observed clinical signs indicated that the achieved doses were close to the maximum tolerated. Acute toxicity studies showed that subcutaneous administration of the drug was safe at doses equivalent to the human therapeutic dose, as well as at 5-fold (mice) and 20-fold (rats) the human therapeutic dose. Intravenous administration at the indicated doses could induce a response from the organs of the immune system. Subchronic toxicity study showed that the drug was safe at doses of 1 × 10⁷ PFU and 5 × 10⁷ PFU and did not exert toxic effects on motor activity, the cardiovascular system, or the respiratory system.

Conclusion. Preclinical studies of the general toxicity and pharmacological safety of a drug with proven antitumor activity, developed on the basis of the recombinant VV-GMCSF-Lact strain of the vaccinia virus, showed that the drug is safe at the doses used and can be recommended for clinical trials.

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