Humane stamcellen gemodificeerd m.b.v. lentivirale vectoren voor de expressie van suicide- en imaging reportergenen als therapie voor orale plaveiselcelcarcinoma’s

Doelstelling :

This project aims to develop a new therapy for head and neck cancer, of which 75% is caused by alcohol and tobacco use (1). The treatment of OSCC is still inadequate which highlights the urgent need for novel therapies with total tumor elimination and limited loss of non-cancerous tissue (2).

This study focuses on the use of human dental pulp stem cells (DPSC), a subtype of mesenchymal stem cells (MSC) (3). Our group has extensively explored their in vitro and in vivo characteristics (4-6). DPSC are isolated from the dental pulp of third molars removed for orthodontic reasons, have a high proliferation rate and home specifically to several tumor types in vitro.

In my project, DPSC are genetically modified into vehicles for suicide gene therapy which serve as a novel treatment approach for OSCC. Hence, DPSC are transduced with a lentiviral vector encoding a so-called “suicide gene”, the herpes simplex virus type 1 thymidine kinase (HSV1-tk), and firefly luciferase (Fluc).

Suicide gene therapy relies on the expression of a prodrug-activating enzyme encoded by the suicide gene HSV1-tk. The enzyme converts a nontoxic prodrug into a cytotoxic metabolite and the subsequent therapeutic effect results in cell death (7, 8). In stem cell-mediated suicide gene therapy, stem cells express the suicide gene. Therapeutic effects are based on the bystander effect, in which stem cells pass on their cytotoxic content to surrounding tumor cells via gap junctions (7, 8) (Figure 1).
This mechanism is known to be highly successful and relies on the administration of its specific prodrug ganciclovir (GCV) (9, 10). This not only leads to tumor cell death but also eliminates DPSC that have been genetically adapted, making this a safe system to use in patients.

So far, the delivery of GCV is empirical and not based on real-time monitoring of the cells. To overcome this limitation, we use state-of-the-art non-invasive imaging methods to monitor the tumor size as well as the therapeutic cells over time by means of magnetic resonance imaging (MRI), bioluminescence imaging (BLI) and positron emission tomography (PET).