Virus Polio Rawat kanser otak
Poliovirus
To Treat Brain Cancer
Certain things have a natural order. Breakfast before lunch.
Infancy before adolescence. Autumn before winter.
So I was surprised to read an article last week in Science
Translational Medicine about experiments at Duke University
treating cancer in human cells and in mice with an engineered poliovirus, when
the television news show 60
Minutes had reported on four patients receiving the treatment
for brain tumors back in 2015. Doesn’t preclinical work – cells and animal
models – come first?
I decided to investigate.
IMMUNOLOGY 101
The idea to redirect an immune response against a pathogen to fight
cancer goes
back to the late nineteenth century, when Manhattan physician
William Coley became intrigued by a man’s neck tumor that melted away after he
contracted a nasty Streptococcus skin
infection. After he found a few more cases, Dr. Coley began to experiment by
rubbing bacteria-oozing goop into skin breaks in a few cancer patients. Every
so often, tumors shrank. The approach, ignored for many decades, became known
as “Coley’s toxins.”
The immune system attacks other pathogens including viruses, as
well as cancer cells and transplanted cells, with two lines of defense—an
immediate “innate” response that’s general, and a more specific, slower
“adaptive” response.
First, a pathogen encounters “sentinel” (aka
“antigen-presenting”) cells, the macrophages and dendritic cells. They’re
festooned with proteins, called Toll-like receptors, which bind like Velcro to
molecules on broad classes of pathogens. The binding sends out cascades of
biochemical signals that launch the innate immune response: cells pour out
anti-viral biochemicals (complement, collectins, and interferons) and trigger
the adaptive response, causing T cells to secrete more interferons and activate
B cells, which produce antibodies. (Bear with me, this is important.)
Nervous tissue consists of nerve cells (neurons) as well as the
much more abundant glia. Immunotherapy against brain cancer targets the glia,
specifically the star-shaped astrocytes. Once thought to merely fill spaces and
support neurons, a little like the view of housewives in the 1950s, glia
are actually a vital part of the signaling that keeps the nervous system going.
Neurons normally don’t divide and so their DNA doesn’t have the
opportunity to mutate into cancer. But glia do proliferate. And cancerous glia
– gliomas – divide explosively.
DEPLOYING POLIOVIRUS
Matthias
Gromeier, MD, had the idea to use poliovirus to combat recurrent glioma in
the mid 1990s, while at Stony Brook. He described what’s now called PVSRIPO in
a paper in
2000. It stands for Polio Virus Sabin-Rhinovirus Poliovirus.
PVSRIPO, a retooled Sabin live poliovirus vaccine, can’t enter
neurons and has a bit of human (cold-causing) rhinovirus. In those early
experiments, it vanquished induced brain tumors in mice and entered glioma
cells growing in culture from patients undergoing surgery.
Wild poliovirus infects motor neurons in the brainstem and
spinal cord of primates only, causing “flaccid paralysis” in 1-2% of people.
(See Vaccine
Memories: From Polio to Autism). The virus also infects glia,
by latching onto a protein, CD155, on their surfaces. Glioma cells are
especially dense with CD155. Normally, when CD155 isn’t serving as a poliovirus
receptor, it links lining (epithelial) cells into sheets. Perhaps poliovirus
originated as a borrowed bit of a human genome that encodes a protein that
fits, like a puzzle piece, into CD155.
The modified poliovirus doesn’t cause polio, but is a vaccine.
It unleashes an army of white blood cells that attack or attract the immune
defense to the cancer – neutrophils, dendritic cells, and T cells.
A MONSTROUS TUMOR
The worst of the worst, glioblastoma multiforme originates in astrocytes.
Eric Holland, MD, PhD, today at the Fred Hutchinson Cancer Research Center,
called it “the terminator” in an editorial accompanying
Dr. Gromeier’s 2000 report.
“Multiforme” refers to the myriad ways that this tumor takes
over a human brain. It produces areas of decay or bleeding, while
microscopically unfurling tiny tentacles everywhere, perhaps recapitulating the
fast growth of an embryo’s brain. Surgery can “debulk” the tumor, and radiation
and the oral chemo drug temozolomide can help, but almost always some
tentacles persist. Tumor cells’ genomes are riddled with mutations. Changed,
extra, and missing DNA bases sabotage the signaling that regulates the cell
division cycle.
In 2000, Dr. Gromeier and colleagues hypothesized that their
viral invention could coax an immune response against glioma cells. They
thought it would do so by bursting, or lysing, the cells. And so was born the
“oncolytic poliovirus for human tumors” that finally received a patent on
August 3, 2017. I’ll call it OncPo because I can’t remember PVSRIPO. It
would turn out to do much more than the investigators imagined in 2000.
CLINICAL TRIALS
The journey from compelling idea to animal/cell experiments to
clinical trial typically takes a decade or longer, and OncPo’s saga is no
exception.
The phase 1 clinical trial that Scott Pelley reported on
for 60
Minutes in 2015 and updated a
year later was filed at ClinicalTrials.gov in late 2011, and the
first patient treated on May 11, 2012. The trial was to enroll 61 patients, and
the TV show followed four of them. All had grade IV malignant glioma and
received the viruses through catheters snaked into their tumors under MRI
guidance.
The team formed Istari Oncology to sponsor the trial. Now in phase
2, it has added the chemo drug lomustine, which helped earlier patients. A
separate clinical
trial will test safety and preliminary efficacy in kids, in whom
gliomas are rare.
Results were so promising that in May 2016, FDA assigned OncPo
“breakthrough therapy” status, which presumably speeds evaluation. A “natural
history” study reported in that month’s Journal of Clinical Oncology provided
the data backing the designation. It found that median survival for 15 treated
patients was 12.6 months compared to 10.5 months for 124 untreated “historical
controls.” By 24 months, 23.3% of the treated patients were alive compared to
13.7% of the controls. Higher doses, the investigators suggested, should
improve efficacy even more.
60 Minutes updated their story with the
breakthrough status. But let’s rewind the tape.
60 MINUTES
The TV show followed the clinical trial at Duke for 10
months. The first episode that catalyzed nearly everyone I know to
immediately alert me sent my hype detector into overdrive:
“In just a moment, polio will be dripped into the brain of
58-year-old Nancy Justice. Her glioblastoma tumor was discovered in 2012.
Surgery, chemotherapy and radiation bought her two and a half years. But the
tumor came roaring back. Now, the virus in this syringe, which mankind has
fought to eradicate from the earth, is the last chance she has in the world.”
Duke’s Chief of Neurosurgery Dr. John Sampson, used 3D MRIs to
guide the delivery of the viruses into Nancy’s brain as she smiled and chatted
away.
Pelley credited Dr. Gromeier, calling the idea his “obsession,”
and then with a winning entry into the annals of science oversimplification
asked the good doctor, “When you went to your colleagues and said, ‘I’ve got it. We’ll use the
polio virus
to kill cancer,’ what did they say?”
Cringeworthy quotes from Dr. Henry Friedman, deputy director of
Duke’s Brain Tumor Center, followed, continuing the aw-shucks view of how
biomedical science works:
“We thought the polio virus might help her. We had no idea what it
would do in the long haul. It was a crapshoot. It’s roll the dice and hope that
you’re gonna get an answer that is coming up sevens and not coming up snake
eyes.”
Try putting that into a submission to the FDA.
Pelley went on to call OncPo “a Frankenstein virus” that “releases toxins that poison
the cell.” I’d hardly call the body’s own
unleashed interferon a toxin, so perhaps Pelley had heard of
Coley’s toxins after all. He then went on to confuse FDA approval of testing the
virus with approval of the treatment –
a sure recipe for fueling false hope.
Still, despite the hyperbole, OncPo is a success in the world of
new cancer treatments, which can mean just a few months of disease-free
survival. But the experimental protocol is far too sensitive and complex to be
premature primetime fodder, IMHO. Indeed, after those first few patients did
well on a low dose, it was upped. But the higher dose caused extreme
inflammation in one patient’s brain, paralyzing and then killing her.
All told, out of 21 patients treated in the phase 1 trial, 8 had
died by May 2016 – but survival had increased by 6 months. That’s certainly
something.
One success is Stephanie Lipscomb, a young nursing student when
treated in 2012. According to Facebookshe
appears to be alive and well, a nurse now and a mother. News reports of course
called her “cancer-free,” but that’s a term, as a geneticist who has had
cancer, that I never use, because nevertheless, micrometastases persist. Nancy
Justice, the first patient profiled who smiled as OncPo dripped into her brain,
died April 6, 2016, from a recurrence. The cancer can return from the few
glioma cells that don’t bear the poliovirus receptor.
REVELATIONS IN THE RECENT PAPER
Four patients do not a breakthrough make. Meanwhile, Dr.
Gromeier, with co-senior author Smita Nair, PhD, an immunologist at Duke, and
others, continued to pursue precisely how OncPo highlights glioma cells to the
immune system.
The new experiments track the effect on human cancer cell
types growing in culture. OncPo bursts the cells, as expected, but they leave
behind a clue: double-stranded RNA molecules. The RNAs come from an
intermediate stage of the virus that binds to the Toll-like receptors, and that
indicates an unexpected activation of the innate immune response, which
unleashes inflammation.
Remember the bit of rhinovirus stitched into OncPo? It may get
the ball rolling, activating dendritic cells, which release interferon and
activate the T cells that zero in on the antigens that dot the tumor cell
surfaces, as neutrophils rush to the scene. That’s how it happens. The new study also
engineered mice that make human CD155, and those mice had an innate immune
response to infection with OncPo too.
The overall result: the immune system “sees” the cancer cells.
What the new slew of experiments reveals is that poliovirus
doesn’t just burst cancer cells, it also elicits a broader immune response. And
that may suggest new ways to treat glioblastoma and other cancers.
“Knowing the steps to generate an immune response will enable us
to rationally decide whether and what other therapies make sense in combination
with poliovirus to improve patient survival,” summed up Dr. Gromeier. Added Dr.
Nair, “Not only is poliovirus killing tumor cells, it is also infecting the
antigen-presenting cells, which allows them to function in such a way that they
can now raise a T-cell response that can recognize and infiltrate a tumor.”
But a powerful broader lesson emerges: a linear
scientific method that leads to a conclusion (or treatment) isn’t the way
research works. As I’ve written in dozens of textbook editions, science is a
cycle of inquiry. Questioning and learning never cease, even for something as
accepted as climate change or how vaccines work. And it’s why continued
preclinical experiments are informing the next round of clinical trials to
evaluate the promising, if century-old, idea to detour an immune response
to infection to fight cancer.
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