Mesenchymal stromal cells retrovirally transduced with prodrug-converting genes are suitable vehicles for cancer gene therapy

Abstract

Summary. -Mesenchymal stem/stromal cells (MSC) possess a set of several fairly unique properties which make them ideally suitable both for cellular therapies and regenerative medicine. These include: relative ease of isolation, the ability to differentiate along mesenchymal and non-mesenchymal lineages in vitro and the ability to be extensively expanded in culture without a loss of differentiative capacity. MSC are not only hypoimmunogenic, but they mediate immunosuppression upon transplantation, and possess pronounced anti-inflammatory properties. They are able to home to damaged tissues, tumors, and metastases following systemic administration. The ability of homing holds big promise for tumor-targeted delivery of therapeutic agents. Viruses are naturally evolved vehicles efficiently transferring their genes into host cells. This ability made them suitable for engineering vector systems for the delivery of genes of interest. MSC can be retrovirally transduced with genes encoding prodrug-converting genes (suicide genes), which are not toxic per se, but catalyze the formation of highly toxic metabolites following the application of a nontoxic prodrug. The homing ability of MSC holds advantages compared to virus vehicles which display many shortcomings in effective delivery of the therapeutic agents. Gene therapies mediated by viruses are limited by their restricted ability to track cancer cells infiltrating into the surrounding tissue, and by their low migratory capacity towards tumor. Thus combination of cellular therapy and gene delivery is an attractive option -it protects the vector from immune surveillance, and supports targeted delivery of a therapeutic gene/protein to the tumor site.Keywords: mesenchymal stromal cells; retroviral vectors; cancer gene therapy; prodrug-converting genes * Corresponding author: E-mail: miroslava.matuskova@savba.sk; phone: +421-2-593-27418. Abbreviations: 5-FC = 5-fluorocytosine; 5-FU = 5-fluorouracil; AT-MSC = adipose tissue-derived mesenchymal stromal/stem cells; CD = cytosine deaminase; CD::UPRT-MSC = MSC expressing cytosine deaminase::uracil phosphoribosyl transferase; GCV = ganciclovir; GCV-TP = ganciclovir triphosphate; GDEPT = gene directed enzyme prodrug therapy; HSVtk = Herpes simplex virus thymidine kinase; MLV = murine leukemia virus; MSC = mesenchymal stromal cells/mesenchymal stem cells; PNP = purine nucleoside phosphorylase; RCRV = replication competent retroviral vector; UPRT = uracil phosphoribosyl transferase

Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model

“…1 Mesenchymal stromal cells (MSC) were proven to be suitable cellular vehicles for GDEPT approaches. [2][3][4] MSC represent a population with high proliferation capacity 5,6 and the genetic engineering does not compromise their key properties; therefore they can serve for the cell-directed enzyme/prodrug therapy (CDEPT) in the antitumor treatment. 7 Moreover, several studies demonstrated the inherent chemoresistant properties of the MSC that enable them to withstand the suicide effect and thus prolong the bystander toxicity exerted on the neighboring tumor cells.…”

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

“…In recent years, MSCs have been studied as vehicles to deliver anti-cancer treatments because there is evidence that MSCs home to tumour sites. They can be induced to express anti-cancer proteins [e.g., interleukin (IL) 2], to produce pro-drug activating enzymes, which ensures that the active drug will only be localized in the tumour, or to deliver oncolytic viruses [20][21][22][23] . For these applications, the homing and persistence of MSCs in the target tissue are desirable [24] .…”

Gene therapy strategies using engineered stem cells for treating gynecologic and breast cancer patients (Review)

“…The mechanisms operating in various GEPT are different and therefore the biological properties of given cell types are important to be evaluated. Most GEPT employs viral vector mediated gene transfer protocols, which are usually limited by the restricted ability of the virus to track cancer cells infiltrating into the surrounding tissue and its low migratory capacity towards the tumor, implying that combination of cellular therapy and gene delivery is an attractive option (72). For GESTECs expressing prodrug-converting genes, the response of tumor cells associated with gap-junctional intercellular communication (GJIC) and expression of enzymes involved in drug metabolism and ABC transporters should be taken into consideration for the selection of the most efficient treatment strategy (73).…”