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VOL. 76 (3), 327-342, 2010 ANTITUMORAL ACTIVITY OF ONCOLYTIC VACCINIA VIRUS...

immunity (6, 18). Based on previous observations on the mode of ac-
tion of PKR and our findings here in mice, we suggest that VV-PKR
might exert its antitumour action not by direct virus replication at the
tumour site but through the triggering of innate immune pathways. In
fact, PKR has been shown to activate multiple signalling pathways (6).
By microarray analyses in human tumour cells infected with VV-PKR
we have shown that expression of PKR triggered the induction of 111
genes, of which 97 were upregulated, among those the ATF-3 transcrip-
tion factor involved in stress-induced B-cell apoptosis, which might
also contribute to the antitumor activity of PKR (19). Recently, it has
been shown that induction of the tumour suppressor p53 by DNA-dam-
aging stress results in significant increase in the expression of PKR
and in turn in PKR-associated biological functions like a translation-
al block and apoptosis, thus contributing to tumour suppression (20).
Undoubtedly, induction of PKR in the context of a tumour cell togeth-
er with its activation by the dsRNA provided from the vector VV-PKR
has the advantage that it provides the signals that lead rapidly to in-
nate immune cell activation, like the inflammatory complex, and in
turn to tumour growth control.

The oncolytic VACV vectors that have been developed to date are
either lacking one or several viral genes or expressing exogenous prod-
ucts that improve the killing ability of the virus vector. Among delet-
ed viral genes: TK (thymidine kinase) with produces a nucleotide pool
for replication of the viral genomes, vaccinia growth factor (VGF) that
activates the epidermal growth factor receptor, and a variety of im-
munosuppressive proteins, like B18R which binds and sequester type
I interferons (4). Improvements in the killing activity of the vector are
a variety of molecules, like vectors expressing cytokines, anti-angio-
genic agents, agents that disrupt the extracellular matrix to improve
viral spread, and prodrug-converting enzymes (21-23). Phase I and II
clinical trials are ongoing with some of the oncolytic VACV vectors.
The most advanced vector in the clinic is the one that had inactivat-
ed both TK and VGF and also expresses GM-CSF (21). While all of
the oncolytic VACV vectors developed had full replication capacity,
which makes them more vulnerable to attack by CTLs and antibod-
ies, the vector VV-PKR described here has more restricted replication,
but importantly triggers low antibody response against itself and re-
duces tumour burden.

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