Oncolytic viral anti-cancer therapy: a magic bullet?
_Jane Bradbury_
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The next few years should see major advances in oncolytic viral therapy for
tumours, claims David Kirn (Imperial Cancer Research Fund, London, UK). “The
selective killing of tumour cells caused by viruses replicating within them
but not within normal cells is not a new idea”, he explains. “Back in 1904,
The Lancet published a report of a woman whose leukaemia regressed after a
viral infection. But it's only in the past 20 years that we have been able to
engineer safe viruses for antitumour therapy.”
Oncolytic viral therapy is a very broad area of investigation, continues
Kirn, but at its heart is the development of viruses that kill tumour cells but
leave normal cells unscathed. There are several ways to achieve this, says
Antonio Chiocca (Massachusetts General Hospital, Charlestown, MA, USA), “but
the one that has been most commonly and successfully used experimentally is to
remove genes from the virus or to put new genes in so that viral replication
can occur only in tumour cells”.
About ten different types of virus are being investigated as potential
oncolytic therapies, but adenovirus, herpes simplex virus (HSV), and reovirus are
the clear favourites. Of these, most clinical work has been done with
adenoviruses, in particular with Onyx-015. “To date, we have treated around 250
patients with Onyx-015”, explains Kirn. Wild-type adenovirus will replicate in
normal cells. In Onyx-015 a gene has been deleted which is essential for viral
replication in normal cells but not in tumour cells that have lost p53 tumour
suppressor function. Thus, Onyx-015 replicates preferentially in tumour
cells.
Data from published phase I and II trials show that Onyx-015 is safe, that
it replicates only in tumour tissue, and that although it has minimal
antitumour activity on its own, in combination with chemotherapy its efficacy is much
greater. A phase III trial is now underway in which patients with recurrent
neck and head cancer will be given standard chemotherapy or chemotherapy plus
intratumoral injection of Onyx-015. “This trial started last September”,
says oncologist John Nemuniatis (US Oncology, Dallas, TX, USA), but it will
take some time to accrue all the patients. And, adds Kirn, although the results
with Onyx-015 in patients with head and neck cancer are encouraging, “this
first-generation virus is not a home run. We have now made a more potent virus
with a targeted deletion in another gene needed for viral replication in
normal but not tumour cells. We hope to get viruses such as this into phase I
trials early this year.” Oncolytic viruses based on HSV also look promising.
Indeed, says Kirn, it was work in the early 1990s by Robert Martuza
(Massachusetts General Hospital, Charlestown, MA, USA) that re-ignited interest in
oncolytic virus therapy. The approach taken by Martuza, Chiocca, and others to
achieve selective replication of HSV in tumour cells has been to delete viral
genes needed for nucleotide synthesis. Normal cells do not make sufficient
nucleotides to support viral replication and so HSV carries genes encoding
nucleotide synthesis enzymes. HSV mutants with deletions in these genes cannot
replicate in normal cells but can do so in tumour cells where nucleotide pools are
much higher.
Moira Brown (University of Glasgow, UK), meanwhile, is concentrating on
another aspect of HSV replication. “We found that HSV1716, a mutant in which a
protein called ICP34·5 was deleted, could only grow in rapidly dividing cells”,
she explains. Brown's working hypothesis is that for viral replication to
occur in normal cells, ICP34·5 has to recruit a specific DNA replication
factor. Because tumour cells contain much more of this factor than normal cells,
ICP34·5 is not needed for viral replication in tumour cells. HSV1716 grows in
all the cancer cell types that Brown has tested but she is concentrating on
its effects in glioma cells. “We have completed two phase I trials of direct
viral injection into gliomas and although we cannot say anything definite about
anti-tumour effects, three out of nine patients in our first trial are still
alive, including one who was treated in October, 1997. This is very
encouraging and we plan to start a phase II trial of HSV1716 in patients with glioma
in February.”
Reovirus, the final front runner, differs from adenovirus and HSV in that
replication of wild-type virus is already tumour selective, no engineering is
needed. “Reovirus causes mild respiratory and enteric symptoms”, explains
Patrick Lee (University of Calgary, Alberta, Canada), “and we have discovered
that only cells with an activated ras pathway support reoviral growth. These
cells include the rapidly dividing cells of the respiratory and
gastrointestinal tract that reovirus normally infects and many tumour cells.” Interactions
between the host cell and the virus mean that viral proteins necessary for
replication are produced in only cells with an activated ras pathway.
Consequently, wild-type reovirus will kill tumour cells but not normal cells. “We
started a phase I study last June”, continues Lee, in which we are injecting
reovirus directly into the tumours of patients with head and neck cancer. This
trial should be completed next summer.”
The future, then, looks good for oncolytic therapy but can
replication-competent viruses be safely injected into people? “When the results of all our
trials on Onyx-015 are published, which include intratumoural, intraperitoneal,
intra-arterial, and intravenous administration, I feel sure that people will
realise how safe adenoviruses are”, says Kirn. Nemunaitis concurs, noting
that “we have not found any evidence for Onyx-015 growing in normal cells even
when it was given intravenously”. Lee is also reasonably confident that there
will be no major safety problem with reovirus. “Most of us have been infected
by reovirus as children without even knowing about it”, he comments. Brown,
however, is more cautious. “I would be a fool to say there is absolutely no
possibility of our mutated HSV replicating in normal rapidly dividing cells”,
she comments, “but to date there has been zero toxicity in our trials”.
And what about efficacy? Is oncolytic therapy the elusive, magic anti-cancer
bullet? Unlikely, says Chiocca, “but we are getting indications that
oncolytic virus therapy works well in combination with other therapies. So, maybe
putting this bullet together with other bullets will turn out to be magic.”
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