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.

A systematic review and meta‐analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

“…In the complete dataset, intracranial delivery (rather than intralesional) and multiple dosing (particularly four or more doses) were most effective. In contrast to the difficulties of transfecting tumours in humans with glioma, we were surprised that, taken together, systemic therapies were as efficacious as those delivered intracranially 42, 43. Over 90% of the thymidine kinase studies administered gene therapy intracranially with a single dose—analogous to clinical practice 16, 44, 45, 46…”

“…This contrasts with human therapy where transfection rates are low; the blood–brain barrier is obstructive in glioma therapeutics, preventing the use of systemic vector delivery,43, 61 even when vectors are delivered distal to the ophthalmic artery (Dr Robin Grant, personal communication), as tumour penetration is poor and side effects high. When implanted locally, distribution throughout the tumour is difficult to achieve 43. This may be attributable to differences in the central nervous system anatomy and the host immune system 43…”

Advances in Diagnostic and Treatment Modalities for Intracranial Tumors

“…Common therapeutic strategies include suicide gene therapy, oncolytic treatment, immunomodultion, gene replacement, proapoptotic treatment, and antiangiogenesis 175, 203. Successful delivery or efficacy of gene therapy approaches using viral vectors and plasmid DNA has been shown experimentally in canine brain tumor cells and brain using adenoviral,204, 205, 206, 207, 208, 209 retroviral201, 202, 210 herpes,211 and adeno‐associated viral212, 213, 214 delivery.…”

“…Several approaches are being explored including gene therapy delivery of immunostimulatory genes such as IL‐2, 4, 12, TNF alpha, interferon alpha, beta, and gamma and dendritic cell growth factors such as Flt3L. Several “vaccine”‐based approaches have been developed including vaccination with patient dendritic cells “primed” with tumor antigen, tumor peptides, heat shock proteins, and autologous and allogenic tumor cell preparations 203, 230, 231, 232, 233. Limited information is available defining immune cell activity in canine brain tumors, but preliminary studies defining immune cell infiltration in canine meningiomas,234 and the ability of Flt3L to stimulate canine dendritic cells,235 suggest that there will be many similarities to human tumors.…”

Medulloblastoma Treatment using Gene Therapy

“…Suicide gene therapy has been proposed with mechanism that viral vectors or cell carriers are genetically modified to express an enzyme that is able to convert an inactive prodrug into toxic metabolites at the tumor sites, resulting in tumor cell killing specifically [23]. Herpes simplex virus thymidine kinase (HSV-tk) with ganciclovir (GCV) is the most extensively applied system in which the inactive prodrug ganciclovir (GCV) is converted into a toxic metabolite called GCVtriphosphate by HSV-tk [24].…”