Live Viruses in Cancer Treatment

Live Viruses in Cancer Treatment

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.

Potential Advantages

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 tumors—unlike leukemias and lymphomas—is not a
problem for current strategies in the clinical development of viral

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]


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