Stem cells as therapeutic vehicles for the treatment of high-grade gliomas

Abstract

Stem cells have generated great interest in the past decade as potential tools for cell-based treatment of human high-grade gliomas. Thus far, 3 types of stem cells have been tested as vehicles for various therapeutic agents: embryonic, neural, and mesenchymal. The types of therapeutic approaches and/or agents examined in the context of stem cell-based delivery include cytokines, enzyme/prodrug suicide combinations, viral particles, matrix metalloproteinases, and antibodies. Each strategy has specific advantages and disadvantages. Irrespective of the source and/or type of stem cell, there are several areas of concern for their translation to the clinical setting, such as migration in the adult human brain, potential teratogenesis, immune rejection, and regulatory and ethical issues. Nonetheless, a clinical trial is under way using neural stem cell-based delivery of an enzyme/prodrug suicide combination for recurrent high-grade glioma. A proposed future direction could encompass the use of stem cells as vehicles for delivery of agents targeting glioma stem cells, which have been implicated in the resistance of high-grade glioma to treatment. Overall, stem cells are providing an unprecedented opportunity for cell-based approaches in the treatment of high-grade gliomas, which have a persistently dismal prognosis and mandate a continued search for therapeutic options.

Fig. 1.

Schematic presentation of potential concomitant and sequential therapeutic combinations involving a prodifferentiation agent (e.g., BMP) and SC-based delivery of a pro-apoptotic agent (e.g., TRAIL). In the concomitant approach, BMP would be administered to differentiate the GSC, which would then be eliminated by SC-delivered TRAIL. With this approach, it would be optimal for the SC vehicle to be fully differentiated, such as has been shown with ESC-derived astrocytes, to avoid the prodifferentiation effects of BMP (see text). In the sequential approach (in which BMP is administered before the delivery of SC-based TRAIL), the SC-vehicle may be undifferentiated SC (such as NSC or MSC) or alternatively be fully differentiated into a terminal cell, such as an astrocyte. The overall concept depicted in this schematic is to combine the use of SC-based delivery with GSC-directed therapeutics to more effectively eliminate GSC. Abbreviations: SC-Astro, SC-derived astrocytes; SC Astro, SC that can be either differentiated intro astrocytes or remain undifferentiated.