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Engineered mesenchymal stem cells as vectors in a suicide gene therapy against preclinical murine models for solid tumors

Abstract : Gene-directed enzyme pro-drug therapy (GDEPT) consists of expressing, in tumor cells, a suicide gene which converts a pro-drug into cytotoxic metabolites, in situ. In a previous work, we demonstrated that the combination of the suicide gene CYP2B6TM-RED (a fusion of a triple mutant of CYP2B6 with NADPH cytochrome P450 reductase) and cyclophosphamide (CPA) constituted a powerful treatment for solid tumors. In this work, we investigated the use of mesenchymal stem cells (MSCs) as cellular vehicles for the delivery of our suicide gene. MSCs were genetically engineered ex-vivo to stably express CYP2B6TM-RED. Ex vivo and in vivo investigations showed that MSCs expressing CYP2B6TM-RED were able 1) to bioactivate CPA and produce local cytotoxic metabolites in tumor sites and 2) to destroy neighboring tumor cells through a bystander effect. Intratumoral injections of CYP2B6TM-RED-MSCs and CPA completely eradicated tumors in 33% of mice without recurrence after 6 months. Rechallenge experiments demonstrated an efficient immune response. These data suggest that MSCs expressing CYP2B6TM-RED with CPA could represent a promising treatment for solid tumors to test in future clinical trials. (C) 2016 Elsevier B.V. All rights reserved.
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https://hal-cnrs.archives-ouvertes.fr/hal-03290596
Contributor : Colette Orange <>
Submitted on : Monday, July 19, 2021 - 1:42:08 PM
Last modification on : Saturday, July 24, 2021 - 3:30:02 AM

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Ikrame Amara, Elodie Pramil, Catherine Senamaud-Beaufort, Audrey Devillers, Rodney Macedo, et al.. Engineered mesenchymal stem cells as vectors in a suicide gene therapy against preclinical murine models for solid tumors. Journal of Controlled Release, Elsevier, 2016, 239, pp.82-91. ⟨10.1016/j.jconrel.2016.08.019⟩. ⟨hal-03290596⟩

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