Virus bahaya digunakan
merawat kanser
Deadly Viruses Being
Used To Combat Incurable Cancers
Zika, polio and adenovirus are hardly the first trio that comes
to mind when considering the 'next big thing' in cancer therapy. Polio alone killed over 3,000 Americans per year in
the 1950s before vaccination programs and continues to ravage the developing
world, while babies with severe brain deformities due to Zika are still being
born in South America.
Despite
this, these killer viruses may well be a surprising source of hope for those
with currently incurable cancers.
The
idea to use viruses as cancer therapy is not new, having been proposed in a
hard-to-pinpoint time in the early 20th century,
with traceable work beginning in earnest in the 1960s. My earliest experience
of a cancer research lab was fifteen years ago in London, UK when I was still
in high school, with a scientist studying viral therapies for pancreatic
cancer. As I progressed through my education, finally becoming a cancer
research scientist, I would sporadically check in on viral treatments,
wondering whether much progress had been made and if anything had been
approved.
For
several years, nothing stood out, but in 2015, I discovered that Amgen’s Imlygic (also known as T-VEC), a
herpesvirus-based therapy for melanoma, was the first viral therapy to be FDA-approved. One of
the more surprising results from initial trials and data gained with more
widespread use since then, has been that infection of tumor cells with the
virus itself, is not the only way in which the therapy affects the cancer.
Phil
Daschner, Program Director of the NCI's Cancer Immunology, Hematology and
Etiology department, said: ‘Imlygic not only treated the primary tumor, but It
triggered the immune system to go after the metastases too.’
This
was somewhat a surprise to the researchers conducting the trial. Imlygic had
not only shown efficacy in treating the tumor which it was targeted to, but had
also somehow triggered the destruction of far-away metastatic tumors, despite
not directly entering those cells.
'Imlygic showed us that the effect of these therapies was not
just virus going into the cells until the tumor cell breaks open and lyses. The
immune system gets involved, increasing the response,' said Daschner.
Imlygic
remains the only viral therapy fully FDA approved to this date, but more are
edging their way through the trial system. Pleasingly, a couple of them are
designed to tackle a devastating type of brain cancer called glioblastoma,
which Senator John McCain was recently diagnosed with,
which only around 10% of patients survive for 3 years or more post
diagnosis and most die within a year.
Zika
would seem to be an odd solution to this problem, producing devastating effects
in infected babies, resulting in abnormally small and deformed brains. But it
is just this propensity to affect developing brain cells that may make it a suitable treatment for glioblastoma,
which originates from similar pools of developing brain cells. Duke University
scientists also won FDA breakthrough therapy status for
their poliovirus-based brain tumor therapy in 2016, so unusually brain cancer
has found itself at the forefront of developing these breakthrough therapies.
Another
researcher leading the development of viruses against hard-to-treat brain
cancer is Juan Fueyo, M.D. at the MD Anderson Cancer Centre, Department of
Neuro-Oncology. He recently led a trial of a new adenovirus-based
therapy for glioma called tasadenoturev, which binds selectively to tumor
cells, with very promising results. Similar to the early results for Imlygic,
the immune system played a huge role in the anti-tumor effect of the adenovirus
therapy.
‘When
we designed oncolytic viruses, we didn’t originally think it was immunotherapy.
It’s the immune system that is actually orchestrating the destruction of the
tumor and our current hypothesis is that this (not the virus itself) is the
main mechanism of treatment,' said Fueyo.
In Fueyo's
most recent study, 37 patients with recurrent brain cancer, including 28 with
glioblastoma were treated with tasadenoturev. Five patients survived more than
3 years after the treatment, with one patient surviving 4.5 years and still
alive at the time of publication of the paper in February of this year.
These may seem like fairly
sobering survival statistics when compared to more treatable cancers, but for
this type of aggressive brain tumor, this is notable progress. In
Fueyo’s trial, those who did respond to the therapy achieved survival times in
excess of the expected and a superior quality of life on treatment, however, almost
all of the patients finally succumbed to their disease.
‘In
this fight between the cancer and the immune system, the cancer won,
eventually,’ said Fueyo.
The current hypothesis as to why
this happens seems to be similar to that for many cancer relapses; that there
is a tiny proportion of cancer cells already existing in the tumor which are
resistant to the therapy. Most of the tumor cells are killed by the therapy,
scans no longer pick up the tumor and patients seem to be in remission, but
months or years later, this small population of cells multiplies into a fully
fledged, therapy-resistant tumor. Researchers aren’t yet sure how this
resistance against viral therapies works and Fueyo stresses that further
clinical trials will try to address this.
Conventional therapies for brain
tumors such as invasive surgeries, radiotherapy and chemotherapies such as
temozolomide, often come with a host of side effects, which can greatly impact
quality of life, perhaps an even more important consideration for those who are
unlikely to achieve cure and where the goal is not just more time, but more
quality time. One of the most interesting revelations of the study was that
patients experienced minimal side-effects from the treatment.
‘Patients
on our trial had an excellent quality of life. They were able to return to
their lives, to work. None of our patients had toxicity,’ said Fueyo.
The
variety of viruses that researchers are modifying to target different types of
cancers is extensive. Polio and Zika for brain tumors, adenoviruses for
multiple tumor types, including pancreatic and even measles virus for ovarian cancer and leukemia, but should a line be drawn where we
conclude that some viruses, for example, Ebola - are just too dangerous to try
to make cancer therapies from?
‘All
of this hype saying all viruses can be modified – I don’t believe that, I think
we will end up using three or four types of virus, ultimately. In some clinical
trials with viruses, patients have died, we need to study this carefully and
figure out which are toxic,’ said Fueyo.
As
Fueyo eludes to, not all patients in trials with viral cancer therapies have
experienced minimal to no side effects like his patients.
‘Viruses
are dangerous, they are dirty bombs which of course we try to control but they
can behave in an unregulated way, we must be careful’ said Fueyo.
So
after decades of research, why have viral therapies just now started to make it
through approvals and into human clinical trials?
‘The
molecular engineering of safety components has become easier with the greater
knowledge of viral genomes and techniques like CRISPR, for example,’ said
Daschner.
‘In
the 90s, no pharma company would invest in oncolytic viruses, it was just too
risky,' said Fueyo.
Today, multiple pharma companies are running
oncolytic viral therapy discovery programs including Pfizer, Celgene and Bristol-Myers Squibb. After Imlygic’s successful FDA-approval and
promising early clinical trial results for glioblastoma viral therapies, can we
expect viral therapies to flood the market now?
'Imlygic set an
important regulatory precedent, I don’t see it as a floodgate opener, more that Imlygic expanded the pipeline for
the development of these viral therapies. Much like immunotherapy and
CAR-T-cells, it’s going to take time for approval of these therapies,' said
Daschner
Both
Fueyo and Daschner are enthusiastic about the potential for viruses in cancer
therapy, particularly in combination with immunotherapy agents that are
designed to unleash the immune system on cancers.
‘The potential for viral vectors
and immunotherapy agents is huge,’ said Daschner.
Soon after Imylgic's first
promising trials on melanoma, researchers published data showing
that combining Imlygic with the PD-1 blocking immunotherapy agent pembrolizumab was more effective than using either alone.
Several
additional combination therapies are indeed snaking their way through the
clinical trial system with trials for liver, colorectal and lung cancers
ongoing in the U.S. and treatment of brain cancers continues to lead the way
with a large U.S. based 13 center clinical trialcombining the adenovirus and
Merck’s PD-1 targeting immunotherapy agent, pembrolizumab with the hope that
the combination will further strengthen the immune system to attack the tumor.
Viruses
are undoubtedly still in the early stages of development, but people with rarer
tumors with low survival rates currently will be relieved that their
cancers are at the forefront of drug development for a change, often being
overlooked for more common cancers.
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