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Translational Medicine 2015: Usage of engineered mesenchymal stem cells in contradiction of cancers - Isabelle De Waziers - Paris Descartes University

Isabelle De Waziers

Gene-Directed Enzyme Pro-Drug Therapy (GDEPT) consists in expression of a suicide gene in tumor cells allowing in place conversion of the pro-drug into cytotoxic metabolites. During a previous work, we demonstrated that the mixture of a mutant CYP2B6 with NADPH Cytochrome P450 reductase (CYP2B6TM-RED), as a suicide gene, and Cyclophosphamide (CPA) might constitute a strong treatment for solid tumors (Touati et al, Curr Gene Ther, 2014). The efficiency of this mix was mainly due to i) an optimized suicide gene ready to metabolize efficiently CPA ii) an efficient bystander effect, iii) the event of an antitumor immune reaction. Major impairments were the directing of the suicide gene exactly to the tumor cells and its low appearance into tumor cells. Indeed, MSCs possess an unprecedented ability to home into tumors due to the inflammatory mediators which are found at the location of a tumor. MSCs are often easily isolated, from tissues like bone marrow (BM-MSCs) and fat (ACS), expanded in culture and efficiently transduced with recombinant viral vectors resulting in important and stable expression of the suicide gene. Once the transduction is performed, the foremost efficient clone for bioactivation of the prodrug are often selected and used for several patients. Indeed, given the minimal expression of the main histocompatibility complex MHC-I and MHC-II, allogeneic expanded Adipose-derived Stem Cells (eASC) delivered locally are well-tolerated and currently in clinical phase III clinical trial clinical trials for the treatment of inflammatory and auto-immune diseases (www.tigenix.com). MSCs expressing luciferase were wont to follow the longer term of MSCs after their intratumoral injections in animal models. Intratumoral injections of CYP2B6TMRED-MSCs and CPA allowed an entire eradication of the tumor in 33% of the mice with none recurrence four months later. Different experiments are now under investigation to enhance the efficiency of this strategy.