title: 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 6months. 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.
authors: INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
authors: Ikrame
authors: I
authors: Amara
authors: INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
authors: Elodie
authors: E
authors: Pramil
authors: INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
authors: Catherine
authors: C
authors: Senamaud-Beaufort
authors: INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
authors: Audrey
authors: A
authors: Devillers
authors: Sorbonne University, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France.
authors: Rodney
authors: R
authors: Macedo
authors: Sorbonne University, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France.
authors: Géraldine
authors: G
authors: Lescaille
authors: INSERM U1022, CNRS UMR8151, Paris Descartes University, Faculty of Pharmacy, Chimie ParisTech, Sorbonne Paris Cité, Chemical, Genetic and Imaging Pharmacology Laboratory, 4 avenue de l'observatoire, 75006 Paris, France.
authors: Johanne
authors: J
authors: Seguin
authors: INSERM U970, PARCC, Paris Descartes University, Sorbonne Paris Cité. Faculté de Médecine, 20 rue Leblanc, 75015 Paris, France.
authors: Eric
authors: E
authors: Tartour
authors: Sorbonne University, UPMC/Paris 06, UMR-S INSERM U1135, CNRS ERL 8255, Centre d'Immunologie et Maladies Infectieuses (CIMI-Paris), Paris, France.
authors: François M
authors: FM
authors: Lemoine
authors: INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
authors: Philippe
authors: P
authors: Beaune
authors: INSERM UMR-S1147, Paris Descartes University, Sorbonne Paris Cité, 45 rue des Saints Pères, 75006 Paris, France. Electronic address: isabelle.waziers@parisdescartes.fr.
authors: Isabelle
authors: I
authors: de Waziers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D005818:Genetic Engineering / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy
keywords: Cyclophosphamide; Cytochrome P450 2B6 (CYP2B6); Immune response; Preclinical models; Therapeutic stem cells