Background. Chimeric Antigen Receptor T-cell (CAR-T) therapy demonstrates significant potential in oncology; however, its application in solid tumors, particularly ovarian cancer, is subject to several limitations. The development of novel T-lymphocyte vectors specific to tumor antigens necessitates a comprehensive preclinical assessment, including the study of the pharmacokinetic profile. Objective. To establish the key pharmacokinetic parameters of the developed CAR-T cell product (GM-TLP) designed for the therapy of CA125-expressing tumors. Materials and methods. The study was conducted on outbred mice and Chinchilla rabbits. The animals received a single intravenous injection of genetically modified T-lymphocytes, transfected with the CA125-specific plasmid, at a dose of $10^6$ cells per injection. Pharmacokinetic parameters were assessed by the quantitative determination of plasmid DNA in the mononuclear cell fraction of the blood and homogenates of internal organs using real-time PCR (qPCR) over a period of 30 days post-administration. Results. It was found that the maximum concentration of plasmid DNA in the blood of animals is reached 30 minutes after injection. A rapid decrease in concentration was shown during the first day, followed by reaching a plateau (11.2 – 13 % of cmax in the period from 3 to 12 days. By the 30th day, the concentration was approaching the background values. Rapid distribution of GM-TLP into parenchymal organs was noted: maximum concentrations in the spleen (44.8 ± 8.98 pg/ml), liver (25.4 ± 4.56 pg/ml), lungs (18.9 ± 3.87 pg/ml) and thymus (12.3 ± 2.54 pg/ml) were also recorded after 30 minutes. The modified lymphocytes and plasmid DNA persisted in the studied tissues during the entire follow-up period (30 days). Conclusion. The obtained pharmacokinetic data confirm the ability of the developed CAR-T cell product for rapid distribution and sustained persistence in the body of experimental animals. This prolonged persistence is a critically important factor for ensuring a sustained antitumor effect. The established pharmacokinetic parameters provide a solid basis for the further development and optimization of the therapeutic strategy.
Rajesh Ranjit – Postgraduate Student and Assistant, Department of Oncology and Roentgenoradiology named after V.P. Kharchenko, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN University), Moscow, Russia.
Tatiana M. Kulinich – Cand. Sci. (Med.), Head of the Laboratory of Immunology, Oncocytology and Cell Technologies, Research Department of Molecular Biology and Experimental Tumor Therapy, Russian Scientific Center of Roentgenoradiology (RSCRR), Ministry of Health of Russia, Moscow, Russia.
Olga I. Goncharova – Research Laboratory Assistant, Laboratory of Cell and Gene Therapy, Russian Scientific Center of Roentgenoradiology (RSCRR), Ministry of Health of Russia, Moscow, Russia.
Elena I. Parfenyuk – Junior Researcher, Laboratory of Immunology and Oncocytology, Research Department of Molecular Biology and Experimental Tumor Therapy, Russian Scientific Center of Roentgenoradiology (RSCRR), Ministry of Health of Russia, Moscow, Russia.
Vladimir K. Bozhenko – Dr. Sci. (Med.), Professor, Head of the Department of Molecular Biology and Experimental Tumor Therapy, Russian Scientific Center of Roentgenoradiology (RSCRR), Ministry of Health of Russia, Moscow, Russia.
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