Details

Autor(en) / Beteiligte

• Barbey, Odile
• Lulka, Hubert
• Hanoun, Naima
• Belhadj-Tahar, Hafid
• Vernejoul, Fabienne
• Cambois, Gilles
• Tiraby, Michèle
• Buscail, Louis
• Gross, Fabian
• Cordelier, Pierre

Titel

Preclinical development of non-viral gene therapy for patients with advanced pancreatic cancer

Ist Teil von

• Molecular therapy. Methods & clinical development, 2023-06, Vol.29, p.162-172

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Pancreatic cancer remains one of the greatest challenges in oncology for which therapeutic intervention is urgently needed. We previously demonstrated that the intra-tumoral gene transfer of somatostatin receptor 2, to combat tumor aggressiveness, or of deoxycytidine kinase and uridylate monophosphate kinase, to sensitize to gemcitabine chemotherapy, has anti-tumoral potential in experimental models of cancer. Here, we describe the development of the CYL-02 non-viral gene therapy product that comprises a DNA-plasmid encoding for the three aforementioned genes, which expression is targeted to tumor cells, and complexed with polyethyleneimine non-viral vector. We performed pre-clinical toxicology, bio-distribution, and therapeutic activity studies of CYL-02 in two rodent models of pancreatic cancer. We found that CYL-02 is safe, does not increase gemcitabine toxicity, is rapidly cleared from blood following intravenous administration, and sequestered in tumors following intra-tumoral injection. CYL-02 drives the expression of therapeutic genes in cancer cells and strongly sensitizes tumor cells to gemcitabine, both in vitro and in vivo, with significant inhibition of tumor cells dissemination. This study was instrumental for the later use of CYL-02 in patients with advanced pancreatic cancer, demonstrating that rigorous and thorough preclinical investigations are informative for the clinical transfer of gene therapies against this disease. [Display omitted] Cordelier et al. describe the preclinical development of a non-viral gene therapy product for patients with pancreatic cancer that encodes genes that inhibit tumor growth and sensitize to chemotherapy, from biodistribution to toxicity and therapeutic efficacy. This work stemmed for first-in-man clinical trials.