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International Clinical Trials
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Chemotherapy – as any cancer patient will tell you – is not for the
faint of heart, but it can kill many forms of cancer. A form of
chemotherapy, originally discovered as a cancer treatment almost 70
years ago, is still routinely prescribed for most types of the disease.
The treatment works by targeting fast-growing cells, such as those
typically found in rapidly growing tumours. But while chemotherapy can
shrink tumours, they often grow back and become resistant or refractory
to the treatment.
To combat this resistance, chemotherapy is now often used in
combination with other treatments that have different mechanisms for
attacking and killing cancer cells. Doctors must be cautious when
combining treatments to ensure that the regimen does not become too
toxic for patients to tolerate. The goal is to introduce drugs that can
be used synergistically with chemotherapy to not only extend life, but
to improve quality of life while undergoing treatment.
THE POTENTIAL OF ONCOLYTIC VIRUSES
One approach that has proven quite promising is known as oncolytic
virotherapeutics. Here, viruses are harnessed to infect, multiply
within and subsequently lyse cancer cells. The drug targets the tumour
and protects normal tissue.
Several types of oncolytic viruses have been developed to date. These
include the adenovirus, which is a nonenveloped virus with a
double-stranded, linear DNA genome that forms particles that are 70 to
90 nm in size. There are multiple engineered versions of this virus in
clinical trials, including Onyx-015 and H101. The latter has been
approved in China and is sold by Shanghai Sunway Biotech.
A second form of oncolytic virus is Newcastle-disease virus (NDV). This
is an enveloped virus with a singlestranded, negative-sense RNA genome
that forms pleiomorphic particles ranging from 150 to 300 nm. Naturally
attenuated versions, such as PV701, are in clinical development.
Although still in Phase 1 testing, slow virus infusion rather than
injection seem to mitigate side effects. Maryland-based Wellstat
Biologics reported positive Phase 1 open-label data for PV701, but
Phase 2 data are not yet available.
Poxviruses are a family of enveloped viruses that contain a
double-stranded, linear DNA genome and form particles that are 200 nm
in diameter and 300 nm in length. Myxoma and vaccinia are family
members that are under therapeutic development. Among several
candidates, the most advanced poxvirus is Jennerex’s JX-594, for which
positive Phase 2 liver cancer data were reported last year and a larger
randomised Phase 2 liver cancer study is planned for 2011.
It may come as a surprise to some that the herpes simplex virus is also
under consideration as an oncolytic virus. This is an enveloped virus
with a double-stranded, linear DNA genome that forms particles that are
150 to 200 nm in diameter. Many engineered versions are in clinical
trials for the treatment of multiple cancer forms, the most advanced of
which is probably BioVex’s (now part of Amgen) OncoVEX, a modified
herpes simplex virus containing genes encoding GM-CSF, which is
currently undergoing Phase 3 testing in both melanoma, and head and
neck cancer. Other earlier-stage oncolytic viruses include
Germany-based Medigene’s G207 (targeted brain cancer in Phase 2
testing), and NV1020 (targeted liver metastasis from colorectal cancer
in Phase 2 testing) though neither agent is active in Medigene’s
pipeline, and UK-based Crusade Laboratories’ HSV-1716 (Seprehvir) has
undergone Phase 1 oral cancer testing and a clinician-sponsored Phase 1
CNS solid tumour study is underway.
Picornaviruses are a family of non-enveloped viruses with
single-stranded, positive-sense RNA genomes that form particles that
range from 18 to 30 nm. Members of this family that are being tested as
oncolytic therapeutics include coxsackieviruses and engineered versions
of poliovirus. The latter is in development at a few locations,
including research institutes at Duke University and Stony Brook
University, and has shown some preclinical efficacy against
glioblastoma multiforme and neuroblastoma. Viralytics is developing the
coxsackievirus A21 (CAVATAK) in a Phase 2 advanced melanoma study and
smaller Phase 1 trials are also active.
Vesicular stomatitis virus (VSV) is an enveloped virus with a
single-stranded, negative-sense RNA that forms 65 to 185 nm
bullet-shaped particles. This virus is still in the research stage; two
constructs have recently been tested at the Mount Sinai School of
Medicine in New York.
REOVIRUSES: THE MOST PROMISING OPTION?
Finally, we come to what some consider the most promising form of
oncolytic virus: the reovirus. This is a non-enveloped virus with a
double-stranded, segmented RNA genome that forms particles that are 60
to 90 nm. The reovirus preferentially replicates in cancer cells that
feature a common mutation known as an ‘activated Ras pathway’, while
sparing normal cells. This makes it intrinsically tumour selective
without the need for any genetic manipulation.
Reovirus is a virus with no known associated disease. It replicates in
the cytoplasm and therefore does not integrate into the cell’s DNA.
Reovirus is found everywhere in nature and has been isolated from
untreated sewage, river and stagnant waters. Exposure to reovirus is
common in humans, with half of all children by the age of 12 having
been exposed and up to 100 per cent testing positive by adulthood.
Tumours bearing an activated Ras pathway can’t activate the anti-viral
response mediated by the host cellular protein, PKR. Studies have shown
that reovirus actively replicates in transformed cell lines with an
active Ras signalling pathway, eventually killing the host cell and
freeing the viral progeny that go on to infect and kill more tumour
cells. When normal cells are infected with reovirus, the immune system
can neutralise the virus. Approximately one-third of human cancers have
activating mutations in the Ras gene itself, and it is possible that
more than two-thirds of cancer cells have an activated Ras signalling
pathway because of activating mutations in genes upstream or downstream
of Ras.
HOW REOVIRUSES MIGHT HELP
While it has been demonstrated in animal studies that reovirus is
capable of treating metastatic cancer in immunocompetent mice, it has
also been shown that reovirus, used in conjunction with
immunosuppressive drugs, can effectively prolong animal survival.
Combining IV reovirus therapy with Cyclosporine A, an immune
suppressant, significantly inhibited tumour regrowth. In a model of
disseminated LLC metastatic lung cancer in C57BL mice, treatment with
reovirus and either Cyclosporine A or T cell depleting antibodies
(anti-CD4 and anti-CD8 Ab) led to an increase in survival compared to
treatment with reovirus alone.
These results supported the development of clinical protocols in which
immune suppressive drugs could be combined with a systemically
administered reovirus in the treatment of cancer. The combination of
reovirus with various chemotherapies in human colorectal cancer cell
lines demonstrated synergistic cytotoxic activity. In addition to
modulating the immune response, the use of chemotherapies along with
reovirus treatment may enhance intratumoral spread of the virus.
One drug that has been developed from the naturally occurring reovirus
is Reolysin from Oncolytics Biotech Inc. The drug has demonstrated
impressive results in clinical trials on its own, but particularly in
combination with certain chemotherapeutics. In preclinical studies in a
wide variety of cancer cell lines, investigators found that when used
together, reovirus and chemotherapy resulted in more efficient and
synergistic anti-cancer activity than when each agent was used on its
own.
These combinations are showing extremely good results in human trials,
particularly in refractory head and neck cancer patients. Many head and
neck cancer patients treated with a combination of Reolysin and
chemotherapy to date have experienced dramatic and prolonged tumour
shrinkage, without increasing adverse side effects. Non-small cell lung
cancer (NSCLC) is another potential target for this treatment
combination. The Cancer Therapy & Research Center at the University
of Texas Health Science Center – a big proponent of oncolytic viruses –
has committed to funding up to five Phase 2 clinical trials using
Reolysin in combination with chemotherapy against a variety of advanced
cancers.
CONCLUSION
It is difficult to provide a crystal-clear economic forecast for
oncolytic viruses as a whole, but an indicator of their potential
future sales earnings can be derived from examining two oncolytic
brands already on the market. The first of these is Tarceva, which was
introduced in 2004. An oral oncolytic that is prescribed for patients
with advanced-stage non-small cell lung cancer, it earned $20 million
in 2004, $387 million in 2005, and $813 million in 2006. Sales reached
$1.215 billion in 2008. The second, Thalomid, which was sold at the
beginning of 2003 for use in treating multiple myeloma, enjoyed sales
of $224 million that first year and had reached $505 million by 2008.
The year-on-year, steadily increasing demand for these two oncolytic
drugs potentially translates into a similar growth market for the
entire sector.
As we have seen above, there are a number of oncolytic viruses that
have shown potential use in cancer treatment. Future research studies
will give us an even clearer perspective on which, if any, of these
viruses offer the most effective route toward a reliable and
commercially viable complement to chemotherapy for oncologists and
their patients.
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