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Live Viruses in Cancer Treatment

Live Viruses in Cancer Treatment

The use of live viruses for the treatment of cancer has been
extensively studied in several preclinical and clinical models, as discussed in
Nemunaitis’ thorough historical review of the subject.

The initial evaluation of any new agent meant to treat a disease process must
prove first and foremost that it is safe to humans. Accordingly, the use of
live, replication-competent viruses has, in general, proven to be safe with low
toxicity profiles when administered to humans. This has been documented with the
widespread use of rabies, polio, influenza, and smallpox vaccine viruses. The
enhanced infective and binding properties coupled with the lower innate
pathogenicity of several of these viral strains also make them attractive to
researchers in the field of cancer immunology.

Mechanisms of Action

The exact mechanisms of virus-mediated antitumor responses have not been
fully elucidated, but they undoubtedly involve the killing of tumor cells and
complex interactions between virus-infected tumor cells and reactive immune
pathways. Some examples include the up-regulation of major histocompatiblity
complex (MHC) expression, stimulation of T-cell-mediated immunity, and virally
induced changes in tumor antigen expression.[1]

In fact, virus-augmented antitumor immunity has historically been attributed
to the "helper antigen" effect, as first described by Lindenmann and
Klein.[2] This is similar to the concept of "haptenization" in that
the immune response against autologous tumor may be enhanced if strong viral
antigens are recognized in association with weak tumor immunogens.[3] During
cellular infection, viral antigens incorporate into the entire plasma membrane
juxtaposing these strong and weak immunogens. Indeed, these observations led to
clinical trials utilizing virally induced tumor lysates as adjuvants in the
treatment of human cancers.[4-6]

The ability of oncolytic viruses to selectively target and lyse tumor cells
without damaging normal tissues results in tumor cell destruction and the spread
of progeny virions to adjacent tumor cells. Recent advances in molecular and
recombinant DNA technology have enabled investigators to modify these viruses,
allowing for increased target specificity and oncolytic activity.

Dr. Neumunaitis provides an excellent example of this with the genetically
modified adenovirus ONYX-015. This virus has been altered such that it
selectively targets cells that have a mutated or nonfunctioning p53 tumor
suppressor gene product. Another example of this is provided by work performed
by Lee and colleagues [7]. These researchers showed that the human reovirus is
selectively restricted to cells with an activated Ras pathway, a mutation found
in several cancer types. This virus was effective as an oncolytic agent in a
human glioblastoma xenograft and murine breast carcinoma model.

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