Engineered mesenchymal stem cells as vectors in a suicide
gene therapy against preclinical murine models for solid tumors.
Amara I1, Pramil E1, Senamaud-Beaufort C1, Devillers A1, Macedo R2,
Lescaille G2, Seguin J3, Tartour E4, Lemoine FM2, Beaune P1, de Waziers I5.
1. INSERM UMR-S1147, Paris Descartes University, Sorbonne
Paris Cité, 45 rue des Saints Pères, 75006 Paris, France.
2. Sorbonne University, UPMC/Paris 06, UMR-S INSERM U1135,
CNRS ERL 8255, Centre d'Immunologie et Maladies Infectieuses (CIMI-Paris),
Paris, France.
3. 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.
4. INSERM U970, PARCC, Paris Descartes University, Sorbonne
Paris Cité. Faculté de Médecine, 20 rue Leblanc, 75015 Paris, France.
5. INSERM UMR-S1147, Paris Descartes University, Sorbonne
Paris Cité, 45 rue des Saints Pères, 75006 Paris, France. Electronic address:
isabelle.waziers@parisdescartes.fr.
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.
J Control Release. 2016 Oct
10;239:82-91. doi: 10.1016/j.jconrel.2016.08.019. Epub 2016 Aug 23.
Md.
PhD. Rodney Macedo. Past-president del
GII.
