A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity and the Development of an Anti-Tumor Immune Response - Archive ouverte HAL Access content directly
Journal Articles Current Gene Therapy Year : 2014

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

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Walid Touati
  • Function : Author
Thi Tran
  • Function : Author
Monique Diry
  • Function : Author
Jean-Pierre Flinois
  • Function : Author
Claude Baillou
  • Function : Author
Geraldine Lescaille
  • Function : Author
Francois Andre
  • Function : Author
Eric Tartour
Francois M. Lemoine
  • Function : Author
Philippe Beaune
  • Function : Author
Isabelle de Waziers
  • Function : Author

Abstract

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.
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hal-03291078 , version 1 (19-07-2021)

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Walid Touati, Thi Tran, Johanne Seguin, Monique Diry, Jean-Pierre Flinois, et al.. 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), pp.236-246. ⟨10.2174/1566523214666140424152734⟩. ⟨hal-03291078⟩
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