Manish Aghi md PhD and E Antonio Chiocca md PhD Introduction

Disappointing results in the treatment of aggressive central nervous system (CNS) neoplasms such as glioblastoma multiforme have fueled a search for novel treatment modalities. New drugs and new radiation modalities have and are being tested. Biological materials have also been explored as potential anticancer agents. Such biological materials include immunotoxins, engineered cells that release diffusible anticancer factors, proteins, stem cells, immune- or vaccine-based modalities, and gene-based and virus-based therapies. The latter type of experimental treatment is the subject of this chapter.

Gene-based therapy indicates the process of introducing into a cancer cell a gene that will reverse or destroy its malignant phenotype. Virus-based therapy is a form of gene therapy, the process of infecting cancer cells with a virus that has been genetically altered so as to destroy that cancer cell and spare normal cells selectively. In fact, several historical reports, dating back from the beginning of the last century until the 1980s, described the administration of attenuated viruses to patients afflicted with incurable cancers, yet this approach was never fully tested and/or widely translated, probably because of its relative lack of appeal compared with the emerging modalities of chemotherapy and radiotherapy (1).

The advent of technologies associated with recombinant DNA in the 1970s and 1980s made it possible to engineer viruses genetically. This allowed the generation of (1) replication-defective viruses (designated as vectors), which cannot grow or produce viral proteins in cells and are used to deliver an anticancer gene (gene therapy); and (2) oncolytic viruses that maintain the ability to grow and replicate in infected tumor but not normal cells (oncolytic viral therapy) (2). Considerable scientific and preclinical excitement has surrounded the application of each of these biologic modalities, although recent events related to the death of a patient treated with gene therapy because he was suffering from an inborn error of metabolism have provided a sobering reminder of the highly experimental nature of these endeavors.

Cancer has become the foremost arena in which gene therapy is applied—a recent summary of 600 published gene therapy clinical trials from 1990 to 2001

From: Minimally Invasive Neurosurgery, edited by: M.R. Proctor and P.M. Black © Humana Press Inc., Totowa, NJ

Fig. 1. Selective replication (i.e., growth) and killing of tumor cells by oncolytic virus. An oncolytic virus (hexagon) will infect and grow into multiple progeny viruses within a tumor cell (upper panel). The cell will die and release such progeny into the extracellular milieu. Progeny oncolytic viruses can then go on and infect additional tumor cells, repeating the entire process. Successive waves of infection and replication set up a spreading infection within the tumor that should lead to regression. However, in normal cells, this does not occur, and replication of the initially infecting oncolytic virus will be aborted.

Fig. 1. Selective replication (i.e., growth) and killing of tumor cells by oncolytic virus. An oncolytic virus (hexagon) will infect and grow into multiple progeny viruses within a tumor cell (upper panel). The cell will die and release such progeny into the extracellular milieu. Progeny oncolytic viruses can then go on and infect additional tumor cells, repeating the entire process. Successive waves of infection and replication set up a spreading infection within the tumor that should lead to regression. However, in normal cells, this does not occur, and replication of the initially infecting oncolytic virus will be aborted.

found that 63% of the trials were in the area of cancer, whereas only 13% were for gene replacement in genetic disorders, the purpose of the first gene therapy clinical trial begun in 1989 (3). Cancer gene therapy involves the administration of a vector (most commonly derived from a virus, but also derived from a chemical lipid construct) to deliver a gene that will impede the survival and growth of tumor cells. If the vector is a virus, it will have been gutted of all its endogenous genes, disabling its ability to grow and directly hurt the cell. Therefore, the entire anticancer effect derives from the delivered anticancer cDNA. Oncolytic viruses, instead, directly lyse tumor cells because they retain almost the entire complement of viral genes that allow for production of viral progeny and lysis of the infected cell, but have been modified so as to allow this process to occur selectively in cancer cells and not normal cells (Fig. 1).

As with conventional therapies, there is a therapeutic window for each gene and viral therapy that defines beneficial anticancer vs toxic side effects. Localized administration of vector to the brain tumor can allow for increased selectivity. Other approaches to increase selectivity consist of using tumor-specific

Fig. 2. Entry of adenovirus into cells via specific binding of a viral ligand to a cell surface receptor. Adenovirus serotype 5 (Ad5), the most common serotype employed in gene transfer, enters cells through the following series of steps: 1, specific binding of virion surface fiber molecules (labeled fiber above) to the coxsackie-adenovirus receptor (CAR); 2, adenovirus internalization is then initiated after the interaction of the penton base protein with cell surface integrins a(v)P3 and a(v)P5; 3, receptor-mediated endocytosis then occurs; 4, virion particles are disassembled in the acidic environment of the endosome. Once tumor-specific receptors are identified, genetic modification of the virion surface molecules that bind cell surface receptors like CAR could create an engineered virus specifically taken up by tumor cells.

Fig. 2. Entry of adenovirus into cells via specific binding of a viral ligand to a cell surface receptor. Adenovirus serotype 5 (Ad5), the most common serotype employed in gene transfer, enters cells through the following series of steps: 1, specific binding of virion surface fiber molecules (labeled fiber above) to the coxsackie-adenovirus receptor (CAR); 2, adenovirus internalization is then initiated after the interaction of the penton base protein with cell surface integrins a(v)P3 and a(v)P5; 3, receptor-mediated endocytosis then occurs; 4, virion particles are disassembled in the acidic environment of the endosome. Once tumor-specific receptors are identified, genetic modification of the virion surface molecules that bind cell surface receptors like CAR could create an engineered virus specifically taken up by tumor cells.

promoters to confer selectivity to the anticancer cDNA or to the replicating oncolytic virus and changing the molecular structure of the surface proteins of the vector or virus in order to target a tumor-specific receptor (Fig. 2).

CNS neoplasms are thought to provide an excellent target for cancer gene therapy because tumor cells are among the few rapidly proliferating cells in the CNS, and most of the gene- or viral-based therapies target cellular division. Proliferation of microglial, endothelial, and glial cells as well as neural stem cells is a much rarer occurrence than that displayed by a glioma cell. Experimentally, viral vectors employed for cancer gene therapy in the brain include those derived from retrovirus, adenovirus, herpes simplex virus-1 (HSV-1), and adeno-associated virus (AAV). Oncolytic viruses employed for brain tumors include HSV-1, adenovirus, reovirus, and poliovirus. Clinically, published gene therapy trials for gliomas have used retroviral and adenoviral vectors to deliver a thymidine kinase cDNA, endowing tumor cells with ganciclovir chemosensi-tivity. Published oncolytic virus trials for gliomas have used HSV-1 and adenoviral mutants (Table 1).

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