Dr. Nemunaitis gives a scholarly and informative historical review of antineoplastic viral therapy using recombinant DNA biotechnologies. The field predates the polymerase chain reaction and restriction enzymes; it has its roots in observations by Jenner and experiments that are over 100 years old.
The fundamental assumption underlying the use of viruses to treat cancer is that the genes they employ in their own life cycle can be redirected toward killing cancer cells. Viruses have evolved in our biosphere to be highly effective at killing host cells. Viruses express the genes involved in that process in a robust and precise way, making them powerful immunologic costimulatory molecules as antigens. Our species’ only countermeasure has been to develop vigorous immune responses upon infection. Thus, using viral genes as "associated antigens" for presenting human tumor-associated antigens to the immune system is a pharmacologic exploitation of the power that attenuated viruses possess in vaccination.
Nemunaitis reviews two overall therapeutic approaches: (1) the use of viruses as platforms for inducing immune responses against infected cells (often live virus vaccines containing tumor associate antigens), and (2) the use of oncolytic viruses that infect and kill cancer cells with a selective cytoxicity favoring the killing of tumor cells rather than adjacent normal cells.
The attraction of viral therapy for experimental therapeutics derives from two properties of viruses that are seen regardless of whether they are directly infecting and killing tumor cells or generating T cells and antibodies against the tumor after a vaccination approach.
The first rationale comes from the fact that either strategy can kill tumor cells independent of where they are in the cell cycle. Unlike the majority of Food and Drug Administration (FDA)-approved antineoplastic drugs currently used by clinicians, viruses can kill tumor cells anywhere in the cell cycle. Many cancers have developed genetic mechanisms to escape apoptosis but have a low percentage of cells at any given time in DNA replication. The "kinetic resistance" of solid tumorsunlike leukemias and lymphomasis not a problem for current strategies in the clinical development of viral therapies.
The second rationale derives from multiple laboratory observations (cited by Nemunaitis) that historically chemotherapy-refractory tumor types are sensitive to the cell-killing effects of certain classes of viruses. For example, selective "oncolytic" herpesviruses can kill chemotherapy-refractory brain tumor cells, and "oncolytic" adenoviral vectors can replicate and kill chemotherapy-resistant head and neck tumor cells and hormone-refractory prostate cancer cells.[1-5] Importantly, the permutations of genetic-engineering possibilities for viruses that confer highly selective replication in tumor cells but not normal cells continues to expand. For example, the unique expression of the prostate-specific antigen (PSA) gene and its upstream regulatory DNA sequences have permitted the construction of adenoviral vectors that selectively replicate and kill PSA-expressing cells.[3,4]