Gene therapy for brain tumors: basic developments and clinical implementation

Abstract

Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM.

Figure 1. Diagram illustrating the effects of adenoviral mediated TK/Flt3L gene therapy

Intra-tumoral injections of adenovirus expressing TK in combination with adenovirus expressing Flt3L into a brain tumor induce tumor cell death, release of intracellular inflammatory molecules, such as HMGB1 and tumor antigen. Flt3L recruits DCs to the tumor site, where they phagocytose tumor cell remnants and migrate to the dLN followed by priming of a T cell mediated cytotoxic anti-tumor immune response. Abbreviations: Tu-Tumor; NK- natural killer cell; dLN- draining lymph node; TLR- toll like receptor; GCV- Ganciclovir; TK- thymidine kinase; Flt3L- fms-like tyrosine kinase 3 ligand. HMGB1- high-mobility group box-1.