Gene therapy and virotherapy: novel therapeutic approaches for brain tumors

Abstract

Glioblastoma multiforme (GBM) is a deadly primary brain tumor in adults, with a median survival of ~12-18 months post-diagnosis. Despite recent advances in conventional therapeutic approaches, only modest improvements in median survival have been achieved; GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are desperately needed. Our group and others are pursuing virotherapy and gene therapy strategies for the treatment of GBM. In this review, we will discuss various virotherapy and gene therapy approaches for GBM currently under pre-clinical and clinical evaluation including direct or conditional cytotoxic, and/or immunostimulatory approaches. We also discuss cutting-edge technologies for drug/gene delivery and targeting brain tumors, including the use of stem cells as delivery platforms, the use of targeted immunotoxins, and the therapeutic potential of using GBM microvesicles to deliver therapeutic siRNAs or virotherapies. Finally, various animal models available to test novel GBM therapies are discussed.

Figure 1

Schematic depiction of the mechanism underlying the induction of a specific anti-GBM immune response using Flt3L/TK gene therapy. First generation adenoviral vectors encoding Flt3L and HSV1-TK are injected into an intracranial brain tumor; ganciclovir is administered systemically. Expression of HSV1-TK in the presence of ganciclovir mediates tumor cell death, releasing endogenous brain tumor antigens and danger signals, including HMGB1. Intratumoral expression of Flt3L recruits dendritic cells (DCs) into the brain tumor milieu where they take up brain tumor antigens released from the dying GBM cells and present them on their MHC complexes. This phenomenon is dependent on the TLR2/RAGE agonist HMGB1, which is released from dying tumor cells. The DCs loaded with brain tumor antigens migrate to the cervical draining lymph nodes where there present brain tumor antigens to naïve T cells, mediating a clonal expansion of brain tumor specific anti-GBM effector T cells. The GBM specific effector T cells then migrate back into the brain and kill residual GBM cells. Therapeutic efficacy of the approach is not diminished when mice are also treated with the chemotherapy temozolomide (TMZ).