Gene therapy of glioblastoma

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Originally released December 16, 1997; last updated August 13, 2018; expires August 13, 2021

Overview

There is no satisfactory method for treating glioblastoma. Gene therapy is one of the promising innovative approaches. This article describes several methods of gene therapy applicable to brain tumors. Most of the initial clinical trials were with herpes simplex virus–thymidine kinase gene therapy, but it did not eliminate the tumor, which is a requirement for cure. Among the newer approaches, oncolysis by genetically modified bacteria appears to be the most promising approach.

Key points

 

• Several gene therapy approaches for brain tumors have been investigated in preclinical studies.

 

• Clinical trials have shown that gene therapy can be carried out safely but did not increase survival of the patients with glioblastoma.

 

• Some gene therapy strategies such as RNA interference may enhance the effect of concomitant chemotherapy.

 

• Innovative strategies for glioblastoma that are promising include targeted gene therapy delivered by nanoparticles.

Historical note and terminology

Historical aspects, nomenclature, and biology of glioblastoma are described in malignant astrocytomas. There was no remarkable development in the treatment of glioblastoma for nearly half a century, until the first clinical trial of the herpes simplex virus, thymidine kinase, and ganciclovir gene therapy system in glioblastoma (Oldfield and Ram 1993). At the end of 1998, after completion of phase 3 clinical trials, this gene therapy approach was discontinued from further development because it failed to show efficacy. Various innovations employed to treat this condition are listed in Table 1 and some of these are linked to gene therapy. The number of current research projects to find a cure for glioblastoma exceeds 100, but thus far, none of these has succeeded in curing this disease. This article includes recent advances in gene therapy, as well as antisense therapy, considered to be a form of gene therapy.

Table 1. Innovative Therapies for Glioblastoma Multiforme

New chemotherapeutic agents

 

Innovations for the delivery of anticancer drugs

 

• Intraoperative polymer implants in residual tumor bed containing anticancer drugs
• Magnetic cationic microsphere delivery system
• Chemotherapeutic agents incorporating biodegradable polymer wafers
• Stereotactic implantation of microspheres containing anticancer drugs
• Lipid-coated microbubbles as a delivery vehicle

Strategies to overcome the blood-tumor barrier for delivery of chemotherapy

 

• Intra-arterial chemotherapy
• Nanotechnology-based controlled delivery through blood-brain barrier

Chemotherapy sensitization

 

• Hyperbaric oxygen
• Photodynamic therapy for chemosensitization

Innovations of radiotherapy

 

• Boron neutron capture therapy
• Brachytherapy: implantation of interstitial radiation-emitting seeds into the tumor
• Enhancing effect of radiotherapy by hyperbaric oxygen
• Radiosurgery: enhancing effects of ionizing radiation

Inhibition of tumor growth

 

• Receptor tyrosine kinases as a signal blocker to hinder the growth of gliomas
• Telomerase inhibition
• Antiangiogenesis therapy
• Polyinosinic-polycytidylic acid given intramuscularly
• Thalidomide, systemic administration
• Targeting epidermal growth factor receptor-mediated metabolic pathway

 

Local destruction of tumor

 

• Genetical modified bacteria for tumor-specific lysis
• Hyperthermia
• Interleukin-4 fusion toxin injection
• Intraoperative photodynamic therapy
• Oncolysis by genetically modified viruses
• Tumor treating fields

Immune therapy

 

• Recombinant interleukin-2 and lymphokine activated killer cells
• Monoclonal antibodies
• Radiolabeled antibodies injected directly into the tumor
• Recombinant immunotoxins specific for epidermal growth factor receptor
• Biodegradable polymer implants containing immunotoxins
• Brain tumor vaccines

Cell therapy

• Encapsulated cells engineered to produce therapeutic molecules
• Grafting of stem cells producing therapeutic molecules, such as IL-4 gene

Gene therapy

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