Oncoltyic Viruses The Challenge Of Brain Tumors

Brain tumors are generally considered to be amenable to local therapies, such as gene therapy, because in contrast with many other cancers, gliomas rarely metastasize, and their recurrence typically results from the failure of local control. Nevertheless, the promise of many local therapies, including gene therapy, has not been achieved for brain tumors because local therapies have proved incapable of delivering therapeutic agents to the majority of the tumor (25,26). Although malignant gliomas do not meta-stasize outside the central nervous system, they are capable of widespread infiltration throughout the brain, and it is not uncommon for tumor cells to invade the hemisphere opposite the main tumor mass (see Fig. 1) (27). Consequently, for local therapies to be effective they must have the capacity to reach cells distant from the site of initial delivery. In contrast with many other therapies, replication competent adenoviruses have the potential for spreading throughout a brain tumor and for reaching the infiltrating tumor cells because each round of infection-replication-lysis not only kills the infected tumor cells but also produces larger numbers of viral particles that can infect and lyse surrounding contiguous cells. This feature makes replication-competent adenoviruses especially attractive in the treatment of human gliomas (see Fig. 2).

The capacity of viruses to potentially spread throughout the target organ requires them to be selective for tumor cells rather than normal cells. Selective killing is especially critical for brain tumors because the tumor cells that infiltrate far from the solid tumor mass are typically intermingled with normal supportive cells (astrocytes) and

Fig. 1. The histological composition of a GBM. T1-weighted magnetic resonance (MR) image (left) demonstrates a contrast-enhancing tumor mass (white) that when viewed under the microscope (left inset) is composed of abutting tumor cells. T2-weighted MR image (right) shows areas of hyper-intensity (white zone) surrounding the mass; as viewed microscopically (right inset), this zone is composed of infiltrating tumor cells. (Reproduced with permission from ref. 27.)

Fig. 1. The histological composition of a GBM. T1-weighted magnetic resonance (MR) image (left) demonstrates a contrast-enhancing tumor mass (white) that when viewed under the microscope (left inset) is composed of abutting tumor cells. T2-weighted MR image (right) shows areas of hyper-intensity (white zone) surrounding the mass; as viewed microscopically (right inset), this zone is composed of infiltrating tumor cells. (Reproduced with permission from ref. 27.)

functioning neurons, the loss of which results in neurological deficit. Indeed, most therapies for brain tumors fail because of the inability to selectively kill the invading tumor cells without damaging the normal infiltrated brain. Although wild-type adenoviruses were used clinically as early as the 1950s (28,29), concerns about normal tissue injury forestalled this approach, and it was never applied to brain tumors. In the modern era, however, these concerns have been addressed by genetically manipulating viruses to replicate selectively in malignant cells rather than normal cells, while at the same time maintaining their oncolytic potential (virulence). This ability to create tumor-selective viruses has allowed the treatment of brain tumors with adenoviruses.

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