Gene Therapy for Brain Tumors

Abstract

Gene therapy has opened new doors for treatment of neoplastic diseases. This new approach seems very attractive, especially for glioblastomas, since treatment of these brain tumors has failed using conventional therapy regimens. Many different modes of gene therapy for brain tumors have been tested in culture and in vivo. Many of these approaches are based on previously established anti-neoplastic principles, like prodrug activating enzymes, inhibition of tumor neovascularization, and enhancement of the normally weak anti-tumor immune response. Delivery of genes to tumor cells has been mediated by a number of viral and synthetic vectors. The most widely used paradigm is based on the activation of ganciclovir to a cytotoxic compound by a viral enzyme, thymidine kinase, which is expressed by tumor cells, after the gene has been introduced by a retroviral vector. This paradigm has proven to be a potent therapy with minimal side effects in several rodent brain tumor models, and has proceeded to phase 1 clinical trials. In this review, current gene therapy strategies and vector systems for treatment of brain tumors will be described and discussed in light of further developments needed to make this new treatment modality clinically efficacious.

Quantitation of HSV mass distribution in a rodent brain tumor model

“…Although the amount of virus delivered to tumor is low, selective propagation in tumor (but not elsewhere) by a replication conditional vector, such as hrR3, will serve to expand the therapeutic index in vivo, as even a single infective virion could give rise to a 'chain reaction' of cell lysis within the tumor. 16 The major advantage of using a replication-conditional oncolytic vector, such as hrR3, is that it can potentially treat invasive tumor beyond the normal reach of the traditional therapies of surgery and radiation therapy. Most gliomas recur within 3 cm of the neurosurgical resection margin, even after administration of radiation therapy.…”

“…Intra-arterial delivery has the major potential advantage of being able to treat invasive tumor cells and satellite lesions beyond the primary site of tumor. The large size, complex geometry, multifocality and diffusely infiltrating margins of human gliomas 16 indicates the need for both diffuse and focal therapies. Intra-arterial delivery appears most suited for the diffuse treatment of the tumor margin, because of its propensity to localize to this area.…”

Pre-existing herpes simplex virus 1 (HSV-1) immunity decreases, but does not abolish, gene transfer to experimental brain tumors by a HSV-1 vector

“…[1][2][3] The advantages of HSV-1 include: (1) the ability to infect a broad range of cells in both mitotic and non-mitotic phases; (2) the physical stability of the virus, allowing for on site application of high titers of virus; (3) the means for extensive genetic manipulation of the genome, so that at least 30 kb of the total 152 kb genome can be replaced by transgenes in some mutants; and (4) the capacity for selective replication in dividing cells. Replication-conditional HSV-1 mutants have been evaluated extensively in rodent models of CNS glioma.…”

Gene therapy in the CNS

“…The following are given by way of example out of a rich literature (for review see Kramm et al; 203 Weyerbrock and Oldfield 204 ). One of the first therapeutic transgenes to be used was the HSV-thymidine kinase gene, as this enzyme can convert ganciclovir to a toxic nucleotide analogue which disrupts DNA synthesis leading to cell death.…”