Doctors Said Immunotherapy
Would Not Cure Her Cancer.
They Were Wrong
No one
expected the four young women to live much longer. They had an extremely rare,
aggressive and fatal form of ovarian cancer. There was no standard treatment.
The women,
strangers to one another living in different countries, asked their doctors to
try new immunotherapy drugs that had revolutionized treatment of cancer. At
first, they were told the drugs were out of the question — they would not work
against ovarian cancer.
Now it
looks as if the doctors were wrong. The women managed to get immunotherapy, and
their cancers went into remission. They returned to work; their lives returned
to normalcy.
The tale
has befuddled scientists, who are struggling to understand why the drugs worked
when they should not have. If researchers can figure out what happened here,
they may open the door to new treatments for a wide variety of other cancers
thought not to respond to immunotherapy.
“What we
are seeing here is that we have not yet learned the whole story of what it
takes for tumors to be recognized by the immune system,” said Dr. Jedd Wolchok,
chief of the melanoma and immunotherapeutics service at Memorial Sloan
Kettering Cancer Center in New York.
“We need
to study the people who have a biology that goes against the conventional
generalizations.”
Four women
hardly constitutes a clinical trial. Still, “it is the exceptions that give you
the best insights,” said Dr. Drew Pardoll, who directs the Bloomberg-Kimmel
Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.
The cancer
that struck the young women was hypercalcemic small cell ovarian cancer, which
typically occurs in a woman’s teens or 20s. It is so rare that most oncologists
never see a single patient with it.
But Dr.
Douglas Levine, director of gynecologic oncology at New York University Langone
Medical Center, specialized in this disease. A few years ago, he discovered
that the cancer was driven by a single gene mutation. The finding was of little
use to patients — there was no drug on the horizon that could help.
Women with
this form of ovarian cancer were sharing news and tips online in a closed Yahoo
group. Dr. Levine asked to become part of the group and began joining the
discussions. There he discovered patients who had persuaded doctors to give
them an immunotherapy drug, even though there was no reason to think it would
work.
The idea
behind immunotherapy is to dismantle a molecular shield that some tumors use to
avoid an attack by the body’s white blood cells.
The immune
system sees these tumors as foreign — they are fueled by hundreds of genetic
mutations, which drive their growth and are recognized by the body. But when
white blood cells swarm in to attack the cancer cells, they bounce back, rebuffed.
Immunotherapy
drugs pierce that protective shield, allowing the immune system to recognize
and demolish tumor cells. But the new drugs do not work against many common
cancers.
Those
cancers are supported by fewer genetic mutations, and experts believe that the
tumor cells just do not look threatening enough to the body to spur a response.
So the immune system leaves them alone.
Lung
cancer, a genetic type of colorectal cancer and melanoma have huge numbers of
mutations, and immunotherapy drugs often are successful in treating them.
Cancers of the prostate, pancreas, breast, ovaries — and most other tumors —
carry few mutations.
“These are
the cancers that rarely respond,” Dr. Pardoll said.
The idea
that the drugs might work against something like hypercalcemic ovarian cancer,
which is fueled by just one genetic mutation, just made no sense.
“For the
vast majority of cancers, there is
an amazingly clean correlation between response to therapy and mean mutational
load,” Dr. Pardoll said.
But there
were a few oddball exceptions. An unusual skin cancer called Merkel cell
carcinoma responded to immunotherapy, scientists found. It is caused by a
virus, and researchers suggested the infection itself draws the attention of
the immune system.
Mesothelioma
also responded, perhaps because the asbestos that caused it also inflames the
immune system. And some kidney cancers responded to immunotherapy treatment; no
one knows why.
And then
came a handful of women with a rare ovarian cancer. Oriana Sousa, 28, a
psychologist in Marinha Grande, Portugal, was one of them.
She found
out she had cancer in December 2011. She knew something was wrong — for several
months she had been feeling tired, constipated and endlessly thirsty. She began
vomiting and had abdominal cramps. But her doctors told her she was fine and
not to worry.
Finally,
her aunt, a nurse, suggested she see a different doctor, who performed a CT
scan of her abdomen. It revealed a huge mass. The doctor operated to find out
what it was. Two days later, he gave her the bad news: Cancer, and a really
terrible form of it.
For the
next four years, Ms. Sousa’s doctors tried to control the cancer, giving her
rounds of chemotherapy, radiotherapy and surgery. But every time, new tumors
emerged.
“I
suffered a lot, and I felt I had no life,” she said.
Things are
different now. In 2015, she finally persuaded a doctor to give her an
immunotherapy drug, nivolumab. Immediately, her tumors shrank and continued
shrinking as she continued with the drug — so much that her doctors now say she
has no evidence of disease. Life has returned to normal.
“Generally
after work, I go to the gym and do classes and work out,” she said. “People who
don’t know what I have been through, they can’t imagine I am an oncology
patient.”
What saved
her? Dr. Eliezer M. Van Allen, a cancer researcher at Dana-Farber Cancer
Institute, has come across one clue.
He found
that a gene mutated in kidney cancer was sort of a master regulator of other
genes, controlling which were turned on and when. But the regulated genes were
normal and did not produce proteins that the immune system might recognize as
abnormal.
Nonetheless,
patients responding to immunotherapy were the ones with the master gene
mutation. “We saw this result and weren’t sure what to make of it,” he said.
Dr. Levine
and his colleagues found the same phenomenon in patients with hypercalcemic
ovarian cancers. One explanation, he and Dr. Van Allen said, is that the immune
system may recognize that cells in which genes are erratically turning on and
off are dangerous and should be destroyed.
“That is
strictly hypothesis,” Dr. Levine cautioned.
One thing
is clear, though: When pathologists examine these tumors, they find white blood
cells in them — as if the immune system were trying to attack. And that finding
has led both Dr. Pardoll and Dr. Padmanee Sharma of M.D. Anderson Cancer Center
in Houston to plan new clinical trials.
They know
that immunotherapy fails most patients, even those with cancers that are most
likely to respond. So they have set out to create a test to determine who might
respond to immunotherapy and then treat those patients — regardless of their
cancer type.
Dr.
Sharma’s study, funded by the Parker Institute, is getting ready to enroll
patients. The researchers will look at pathology slides of patients’ tumors to
see if white blood cells are worming their way into the cancers. If so, the
patients will get an immunotherapy drug to help activate their white blood cells
to attack the tumor.
If there
are few white blood cells in the tumor tissue, patients will get a combination
of two immunotherapy drugs to help move more white blood cells into the tumor
and help them attack.
“The trial
is written for all comers,” Dr. Sharma said. “If we have learned anything, it
is that it is not the tumor type we are treating — it is the immune system.”
At Johns
Hopkins, Dr. Pardoll and his colleagues are planning a similar trial. They will
be looking for tumors — it does not matter what type — that have a protein,
PD-L1, on the surface that repels the immune system. Any patient whose tumor
fits that description will get an immunotherapy drug.
It’s a
shot in the dark. But sometimes such a shot finds the mark, as Ms. Sousa will
tell you.
“Incredible
things happen, and against all the odds,” she said.
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