The art of gene therapy for glioma: a review of the challenging road to the bedside

Abstract

Glioblastoma multiforme (GBM) is a highly invasive brain tumour that is unvaryingly fatal in humans despite even aggressive therapeutic approaches such as surgical resection followed by chemotherapy and radiotherapy. Unconventional treatment options such as gene therapy provide an intriguing option for curbing glioma related deaths. To date, gene therapy has yielded encouraging results in preclinical animal models as well as promising safety profiles in phase I clinical trials, but has failed to demonstrate significant therapeutic efficacy in phase III clinical trials. The most widely studied antiglioma gene therapy strategies are suicide gene therapy, genetic immunotherapy and oncolytic virotherapy, and we have attributed the challenging transition of these modalities into the clinic to four major roadblocks: (1) anatomical features of the central nervous system, (2) the host immune system, (3) heterogeneity and invasiveness of GBM and (4) limitations in current GBM animal models. In this review, we discuss possible ways to jump these hurdles and develop new gene therapies that may be used alone or in synergy with other modalities to provide a powerful treatment option for patients with GBM.

Figure 1

Highlights the advantages and limitations of the most commonly studied antiglioma gene therapies. (A) Suicide gene therapy inhibits cell division by blocking DNA replication. In this system, tumour cells are transfected by a gene that encodes for an enzyme that converts a systemically administered prodrug into an active drug toxic to glioma cells. (B) Oncolytic viral therapy takes advantage of viral infection and selective replication of virus in tumour cells through various genetic alterations of the virus genome thereby rendering the virus tumour specific and oncolytic. (C) Immunomodulatory gene therapy induces a host immune response to counteract the immune privileged central nervous system and immunosuppressive tumour microenvironment through various strategies. (D) Synthetic vectors such as nanoparticles are unique in their ability to be delivered systemically and cross the blood–brain barrier. This approach has been employed to deliver genetic material such as DNA plasmid, proteins, RNA interference (RNAi) and small interfering RNA (siRNA) that silence genes and provide the opportunity for the development of drugs against specific glioma targets.

Figure 2

An up-to-date overview of results obtained from glioma clinical trials that used virus. (A) Replication incompetent viruses or non-replicating viruses bearing suicide transgenes have been extensively studied and applied in clinical trials. Retro-mediated and adenoviral-mediated herpes simplex type 1 thymidine kinase (HSV-tk) gene therapies are the most commonly studied in clinical trials. Retrovirus: Prados et al, Rainov, Shand et al, Palu et al, Klatzmann et al, Izquierdo et al and Ram et al. Adenovirus: Trask et al, Sandmair et al, Smitt et al, Germano et al, Immonen et al and Lang et al. (B) Replication competent oncolytic virus such as conditionally replicating adenoviruses, herpes simplex virus (HSV) mutant vectors, Newcastle disease virus (NDV), and reovirus have all been tested in the clinical setting for treatment of glioma. HSV-1 (G207): Markert et al and Markert et al. HSV-1 (1716): Papanastassiou et al, Kesari et al and Rampling et al. NDV (MTH-68/H): Wagner et al, Csatary and Bakacs, and Csatary et al. NDV (NDV-HUJ): Freeman et al. Reovirus: Forsyth et al. AdV (ONYX-015): Chiocca et al.