自杀基因疗法结合环磷酰胺肿瘤细胞毒性的提高和抗肿瘤免疫反应的发展

Title:A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity and the Development of an Anti-Tumor Immune Response

Volume: 14 Issue: 3

Author(s): Walid Touati, Thi Tran, Johanne Seguin, Monique Diry, Jean-Pierre Flinois, Claude Baillou, Geraldine Lescaille, Francois Andre, Eric Tartour, Francois M. Lemoine, Philippe Beaune and Isabelle de Waziers

Affiliation:

关键词: 细胞色素P450 2B6，慢病毒，环磷酰胺，肺

摘要: Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6/E7 oncoproteins. In mice bearing tumors composed only of TC1-CYP2B6TM-RED cells, four CPA injections (140 mg/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1-CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8⁺T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans.

Cite this article as:

Touati Walid, Tran Thi, Seguin Johanne, Diry Monique, Flinois Jean-Pierre, Baillou Claude, Lescaille Geraldine, Andre Francois, Tartour Eric, Lemoine M. Francois, Beaune Philippe and de Waziers Isabelle, A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity and the Development of an Anti-Tumor Immune Response, Current Gene Therapy 2014; 14 (3) . https://dx.doi.org/10.2174/1566523214666140424152734