The use of viruses to treat cancer depends upon the ability of these agents to specifically infect and lyse cancer cells while not harming normal cells. These properties are made possible by a variety of tumor-specific abnormalities, including preferential production of certain proteins on the tumor cell surface that can serve as viral entry receptors; the enhanced activity of specific promoters and enhancers to drive expression of viral genes governing reproduction; the use of tumor-specific micro-RNAs to make viral gene expression cell specific; and the increased immunogenicity of tumor-specific antigens caused by the immune response to virus infection and the expression of immunostimulatory genes delivered by the vector.
Viruses from nine different families (Adenoviridae, Picornaviridae, Herpesviridae, Paramyxoviridae, Parvoviridae, Reoviridae, Poxviridae, Retroviridae, and Rhabdoviridae) are currently in clinical trials to test their safety and anticancer properties. The genomes of many viruses have been modified to confer greater efficacy and specificity for tumor cells. Oncolytic virotherapy has not been free of serious toxicities (see Volume II, Box 5.15), but in general, the treatments have been welltolerated after local or systemic injection.
A challenge to the development of oncolytic viruses is the host antiviral immune response, which can blunt therapeutic efficacy. Several approaches have been used to address this problem, including the substitution of structural proteins from different human or animal serotypes and the production of novel serotypes by chemical modification of virus particles. Different serotypes can be used when the patient is immune to the original vector, due to either previous infection or treatment. Viral structural proteins may also be modified to bind proteins that are specific to the target cells, conferring greater specificity for tumor lysis. Such targeting may also involve postentry steps. For example, many tumor genes are expressed at aberrantly high levels; the promoters and enhancers responsible for such high expression have been identified and used to drive synthesis of viral genes encoding proteins that mediate in cell killing. Another approach to conferring specificity for tumor cells is to insert in the viral genome targets of micro-RNAs that are produced in nontumor cells.
vector that makes the cell more susceptible to destruction by drugs or immune therapies. An example is the insertion of the herpes simplex virus thymidine kinase gene, which converts prodrugs such as ganciclovir to a nucleoside analog that halts DNA synthesis. Insertion of the human sodium-iodide symporter gene into measles virus allows tumor cells to concentrate lethal beta-emitting isotopes. Oncolytic viruses have also been produced that carry the gene encoding granulocyte-macrophage colony-stimulating factor (GM-CSF). The synthesis of this protein stimulates proliferation of the eponymous cells that turn the adaptive immune system against the tumor cells. From the first use of a vaccine strain of rabies virus to treat melanomatosis in the 1950s, our progress in understanding the biology of cancer, combined with the ability to genetically modify viruses by manipulation of infectious DNA clones, has led to the development of many rationally designed oncolytic viruses with greater clinical safety and efficacy