Gene therapy trials for the treatment of high-grade gliomas

Abstract

High-grade gliomas remain relatively resistant to current therapy. Local recurrence is a common feature and the majority of patients progress despite conventional therapy. One modality-gene therapy-has shown a lot of promise in early preclinical and clinical studies aimed at advancing the treatment of this disease. In this review, we provide a comprehensive overview of clinical trials involving gene therapy in the field of neuro-oncology. The use of different delivery vehicles, including liposomes, cells, and viruses, as well genes, especially cytokines and suicide genes, are explored in detail. The unique features and advantages/disadvantages of the different vectors employed are compared based on results of human studies. We discuss both the limitations and successes encountered in these clinical trials, with an emphasis on the lessons learned and potential ways of improving current gene therapy protocols.

Figure 1

Median survival in clinical gene therapy trials for malignant glioma. Trials involving less than nine patients and/or trials where full survival data is not available were excluded. Filled bars represent VPCs-mediated RV-HSV-tk gene therapy; open bars randomized controlled group. (●) Adenovirus-mediated HSV-tk gene therapy; (○) ONYX-015 therapy; (▽) adenovirus-mediated p53 gene therapy; (◇) Herpes simplex type 1 mutant therapy Reproduced from Pulkkanen and Yla-Herttuala 2005 with kind permission from Macmillan Publishers Ltd: [Molecular Therapy].

Figure 2

Kaplan-Mayer survival graphs of patients with RV HSV-tk and GCV treatment vs. standard treatment from a phase III clinical trial with patients with GBM (Rainov, 2000). (A) Graph showing time to death (overall survival time). (B) Graph showing time to death (overall survival time) for all patients in whom GBM was confirmed by central pathology review. Differences between groups are not significant. Reproduced from Rainov, 2000 with kind permission from Human Gene Therapy.

Figure 3

VPC-mediated RV-HSV-tk gene therapy was compared to Ad-HSV-tk gene therapy (Sandmair et al, 2000). MRI follow-up 3 months after treatment. (A–C) MRI of patient 10 shows a right temporal GBM, (A) before, (B) day 1 and (C) 3 months after VPC mediated RV-HSV-tk treatment. Shown is a subtotal surgical resection and fast regrowth of the tumor despite the gene therapy. (D–F) MRI of patient 19 shows a left recurring frontal anaplastic astrocytoma before (D), 1 day (E) and 3 months (F) after the operation, radiation and adenovirus-mediated gene therapy. Shown is a total tumor resection and no signs of tumor regrowth 3 months after the treatment. (J–L) MRI of patient 21 shows a left recurring frontoparietal GBM before (J), 1 day (K) and 3 months (L) after reoperation and adenovirus mediated gene therapy. Shown is a subtotal tumor resection and no signs of tumor regrowth 3 months after treatment. Reproduced from Sandmair et al, 2000 with kind permission from Human Gene Therapy.

Figure 4

Kaplan-Mayer survival graph of patients after Ad or VPC-RV-mediated or HSV-tk gene therapy for GBM. The difference in outcome between the patients with adenovirus-mediated gene therapy (n=7) and VPC-RV-mediated gene therapy (n=7) was statistically significant (p < 0.012, Fisher exact test). Patients who received β-galactosidase marker gene (n=7) served as controls. X, Means survival time for each group. Reproduced from Sandmair et al, 2000 with kind permission from Human Gene Therapy.

Figure 5

Kaplan-Mayer survival graphs for patients treated with Ad-HSV-tk gene therapy and randomized controls bearing malignant gliomas. (A) All patients. (B) Patients with GBM. Log-rank regression analysis was performed. Reproduced from Immonen et al, 20045 with kind permission from Macmillan Publishers Ltd: [Molecular Therapy].