Kim Lohr calls Friday,
Nov. 13, 1998, the blackest day she’s ever known.
As she sat in the driveway of her sons’ after-school
daycare center late that afternoon, an ominous red
light on her dashboard warned that her car had overheated.
With steam puffing from under the hood, Lohr slumped
forward and moaned. What else could go wrong? Already
that morning, she had learned that at 32, she had breast
Lohr, an administrative assistant for the Army Corps
of Engineers in Southern Maryland, was diagnosed with
breast cancer at an uncommonly young age. That made
her chances of recovering more doubtful. Still,
a week later, when her surgeon called to tell her the
results of her lumpectomy, the two women shared hopeful
tears. The tumor had been large—3.5 centimeters—but
all 20 of the examined lymph nodes had been clear.
Maybe she would live to see her children grow up.
For months after that, Lohr went through chemotherapy,
radiation and hormonal treatment with tamoxifen. Then,
for a brief time, she relaxed a little. But in November
2000, she began experiencing nagging back pain, went
for a series of PET scans and discovered the cancer
had spread to her lungs and “my entire spine
was doused with the cancer.” The hormonal treatments
and chemo began again, coupled this time with therapy
to strengthen her increasingly brittle bones.
Finally, late in 2003, Lohr decided to move her care
to Johns Hopkins’ Sidney Kimmel Comprehensive
Cancer Center. There, after studying her case, oncologist
Antonio Wolff met with her to lay out a treatment
plan. Women in her situation, he told her gently, “did
not tend to do well.” When Lohr’s cancer
metastasized to her brain early in 2004, it seemed
to confirm that prediction.
The “war on cancer,” declared 35 years
ago, has turned out to be a long one. And yet, throughout
the 1990s and into the 21st century, death rates from
cancer have continued to decline. With the right treatment
and response, even patients in circumstances as dire
as Kim Lohr’s have begun making it back from
“Simple things we’ve known about for
years are getting applied,” says Martin Abeloff,
director of the Kimmel Cancer Center. “And it’s
not all razzle-dazzle science and technology. Refined
chemotherapy cocktails are yielding better results
with fewer side effects, hormonal therapies have become
a mainstay for breast and prostate cancer; radiation
today is more focused, and aggressive management of
the disease is preventing recurrences.”
But what’s really exciting, Abeloff says, is
that the current data on declining cancer death rates
don’t even reflect the next wave in cancer treatment.
Scientists now know that cancer occurs as a result
of certain genetic mutations. The biology of this disease
actually differs from person to person. That means
a treatment that works for one doesn’t necessarily
work for another. And with this understanding has come
the development of novel, targeted chemotherpies and
Oncologists now are looking at a rapidly widening
array of drugs that attack different parts of the cancer
process. Instead of imperiling cancer cells with the
macro assault of conventional chemotherapy, these cancer
drugs do their work on a micro level. Generally taken
orally with minimal side effects, they take direct
aim at the genetic abnormalities that define the disease.
As a class, they interfere with a specific pathway
in the human body that is responsible for initiating
or maintaining cancer.
Antonio Wolff, who took on Kim Lohr’s treatment
early in 2004, is reluctant to apply war analogies
to the cancer fight. But he uses a military metaphor
to describe what he sees happening: “We are moving
away from carpet bombing to more smart bombing.” It
was the earliest of these smart bombs that he counted
on as he set out to try to help Lohr.
neutralizes one specific protein in the
body. A counter-attacking, laboratory-produced antibody,
it was the first targeted biologic to come to market.
Known commercially as Herceptin, this “monoclonal
antibody” went through national patient studies
all through the 1990s.
“We’d learned by then that breast cancer
is made up of an umbrella of diseases,” Wolff
says. “They can look quite alike under the microscope,
but they have very distinct molecular signatures and
As a key participant in the Herceptin trials, Hopkins
watched with interest as a growing body of results
confirmed that 25 percent of women with breast cancer—those
with an aggressive tumor that proved positive for the
surface protein HER2/neu receptor—lived longer
when they received the drug.
“Today, we know that Herceptin has resulted
in an almost unheard of reduction in the recurrence
of this cancer,” says Ross Donehower, director
of medical oncology here.
Kim Lohr’s breast tumor proved positive for
the HER2/neu receptor early on, so she’d already
been through a course of Herceptin. And yet, even after
neurosurgery and radiation had cleared her of all visible
cancer in her brain, metastases continued to ripple
through her body.
But Wolff was one of the specialists who had begun
viewing Herceptin as the vanguard of a new generation
of cancer treatments, and he thought the drug was worth
another shot in this case.
And so, in the summer of 2004, Lohr walked into a
treatment room at Johns Hopkins, took a deep breath
and headed into her next round of cancer therapy. If
anyone needed a new approach, she did.
In the end, it was Wolff’s belief in Herceptin
that gave Lohr her chance. By the time he took on her
care, her breast cancer had spread to her bones, lungs
and brain, but after he put her back on Herceptin in
2004, the cancer began disappearing.
Today, people who don’t know that Lohr makes
monthly pilgrimages to Hopkins for Herceptin treatments
take her for just one more mom who’s also holding
down a full-time job.
“I got all sorts of medications,” she
says, “but Herceptin was the big kahuna.”
gun control advocate: Her lung cancer had spread by the
time it was discovered. Then, oncologist
David Ettinger put Her on Iressa.
Today, she is cured.
are many who
would also count Elizabeth Jaffee among cancer’s
miracle workers. Jaffee, a Hopkins oncology researcher
who holds an appointment in Cellular and Molecular
Medicine, has spent the better part of a generation
trying to find a workable treatment for the most deadly
of all cancers—pancreatic.
Because pancreas cancer is notoriously chemo- and
radiation-resistant, it has a dismal outlook. No one
even talks about five-year survival rates. Less than
5 percent of patients live that long. In most cases,
because the disease isn’t discovered until it
is well advanced, death occurs within a year.
Jaffee can pinpoint the event in her life that kindled
her interest in this horrible disease. In 1987, when
she was an intern, she received a call from her father
telling her that her 51-year-old uncle had just been
diagnosed with pancreas cancer. “Our families
were very close to each other,” she says. “We
lived just a few miles apart on Long Island, and we
spent every weekend, vacation and holiday together.
My cousins were still in high school when their father,
my uncle, died just three months later. For me, it
Jaffee, who’d been fascinated with immunology
since she was a teenager, began hypothesizing that
she might be able to coax the immune system to mount
a defense to an antigen in a cancer cell, much as it
does to an infection. A fortifying response like that
doesn’t occur naturally in cancer, because many
of the over-expressed or altered proteins in the malignant
cells grow relatively slowly. But Jaffe was convinced
she could challenge the immune system to behave more
aggressively. Her idea was to create a vaccine that
incorporated some of the patient’s own tumor
(inactivated with radiation) and then insert a gene
that would trigger the immune system to respond to
Through painstaking laboratory experiments, over
time the young oncologist began achieving the response
she was after. By 1997, Jaffee believed she had something
in hand that could step up and suppress pancreas cancer
in human patients.
At about that same time, 50-year-old Kathleen Dowell
of Bowie, Md., walked through the doors of Johns Hopkins.
Dowell had just been diagnosed with pancreas cancer
and had come here so John Cameron, then chief of surgery,
could do a Whipple procedure on her. Cameron is the
worldwide master of this complicated operation—known
technically as a pancreaticoduodenectomy—in which
he removes most of the pancreas and parts of adjoining
organs. When Cameron met with Dowell after he operated
on her, his report was as bad as it could be. The cancer
had spread beyond her pancreas, meaning her expected
survival time was less than six months. Dowell prepared
to go home to die, but then something unexpected happened:
Oncologist Donehower stopped by to see her with a question:
Would she consider becoming part of a trial for a new
vaccine for pancreatic cancer?
“What do I have to lose?” Dowell asked
Kathleen Dowell became patient No. 8 in the trial
of GVAX, the first vaccine that Liz Jaffee created
with her clinical partner Daniel Laheru. The protocol
called for her to receive four doses of the vaccine
one to two months apart and a booster shot six months
after the fourth dose. Each dose would be a whopper.
An intradermal injection of 0.3 cubic centimeters is
generally considered the top comfortable volume for
a vaccine, but these patients would receive vaccine
doses of 0.7 cc’s in each shot. To lessen the
effects of the injections, they would be pretreated
with an anesthetic cream called EMLA before each cycle
of shots—one in each arm and one in each upper
thigh. Meanwhile, along with the vaccine, they would
Dowell had her first injection in the spring of 1997.
The shots stung and burned her, but her response to
the chemotherapy was much more distressing. She suffered
seizures and then a stroke that temporarily paralyzed
her right arm and leg. She became so seriously ill
that physicians halted her vaccine injections after
only two doses.
|Liz JaffeE: “With the results we’re getting, We’ll be able to think about making pancreas cancer a chronic disease rather than a death sentence.”
But that isn’t the end of the story. Dowell’s
immune response to two doses of Jaffee’s cancer
vaccine turned out to be stronger than what Jaffee
had expected from the full course of treatment. In
fact, the vaccine prompted Dowell’s immune system
to mount such a powerful T cell response to a tumor-associated
molecule called mesothelin on the vaccine cells that
today, eight years later, she remains cancer-free—a
phenomenon in the world of pancreas cancer. Dowell
is one of three long-term survivors of pancreas cancer
from Jaffee’s first trial. Annual CT scans and
marker tests continue to show that each of these surviving
patients had similarly strong T cell responses.
Since then, Jaffee and Laheru have tested further
renditions of their vaccine. Today, more than two years
after their last trial, 78 percent of the patients
who took part have survived at least two years. In
contrast, statistics on pancreas cancer show that 90
percent of patients whose disease has spread are dead
within a year.
Jaffee is now modulating her vaccine to enhance its
effects and beginning to plan for a large multicenter
trial. “We’re still not hitting home runs,” she
says. “But the results we’re getting make
us think that at some point we’re going to be
able to think about making pancreas cancer a chronic
disease rather than a death sentence.”
oncologist David Ettinger uses almost the
same words as Jaffee when he talks about late-stage
lung cancer. “The goal,” he says, “is
to make this a chronic disease and focus on good quality
of life for the longest period of time. And yes, I
am talking about advanced disease.”
Maybe that’s what’s changed most about
cancer treatment: the fact that today, a top specialist
like Ettinger can hold out hope for anyone with advanced
disease—and mean it. For the doubters, Ettinger
points to patient after patient he’s treated
successfully with the new therapies.
Sarah Brady is one of them. Six years ago, when she
was 58, the national crusader for gun control was living
quietly on the Delaware shore with her husband, Jim (who
took a bullet during the 1981 assassination attempt
on Ronald Reagan) when she was diagnosed with stage
III lung cancer. A lifelong smoker whose father had
died of lung cancer, Brady knew her chances of surviving
for five years were less than 30 percent.
“This is it, then? My life is over?” she
mused. When exploratory surgery found the cancer had
spread to her lymph nodes, death seemed a certainty.
But Brady has practice in beating the odds. She headed
immediately into an intense regimen of radiation and
chemo drugs—taxol, carboplatin, cisplatin and
Navelbene. When she was referred to Hopkins for a PET
scan to evaluate some suspicious shadows, she met Ettinger.
Won over from the start by the oncologist’s brusque
compassion, she asked him, “What do you have
In early 2001, Ettinger put Brady on a trial for
a drug that he thought looked hopeful for lung cancer—Iressa,
one of the new targeted therapies. Brady knew she was
getting Iressa, but she didn’t know how much.
Today, five years later, she’s still on the drug.
But she is cancer-free.
Steve Baylin describes what’s happening in
the world of cancer therapy this way: “To conquer
a disease, we first have to understand it. We have
to know why it occurs, how it develops and how it functions.
And gradually, that’s what we’re doing.”
Baylin, who is chief of cancer biology here, acknowledges
this basic-science detective work has proven especially
daunting with cancer “because these cells are
the most complex things you have ever seen.” But
he himself is an expert in one of the most complex
areas of all: DNA methylation.
Researchers have known for awhile that understanding
the methylation process—in which small carbon
groups from nearby molecules attach to the DNA—would
be vital to understanding cancer. Distorted patterns
of methylation have been found in all types of human
Several years ago, Baylin, along with his longtime
colleague James Herman, set out to analyze how
this distortion is able to occur in a way that disrupts
normal gene functioning. Over time, the two researchers
discovered that as the cancer cells become hypermethylated
at the “start sites” of particular genes,
those genes just stop functioning.
|Steve Baylin: “To
conquer a disease, We have to know
why it occurs.”
“The good news,” Baylin says, “was
that unlike mutations, abnormal methylation is reversible
in the test tube. And we now have drugs like 5-aza-cytidine
that can reduce the number of methyl groups attached
to a patient’s DNA and restore the gene’s
But Baylin and Herman quickly realized that the drug
needs assistance because as the abnormal DNA methylation
occurs, a group of enzymes known as histone deacetylases,
or H-DAC’s, introduces changes in proteins that
collaborate with the methylation to diminish gene function.
And, inhibiting the H-DAC turns out not to be effective
unless 5-aza-cytidine is started first. Once they’d
figured that out, the two researchers realized that
opportunities for novel cancer drugs had suddenly opened
up. By using the two inhibitors in combination, it
would be possible to delay or even reverse the progress
of the disease.
Kepics, the breakthrough couldn’t
have come at a better time. A pharmaceutical representative
from Harrisburg, Pa., Kepics developed leukemia in
2004 when he was 39. Stricken with a variety of debilitating
symptoms, including cellulitis and lung infection,
he was going downhill fast when he met medical oncologist
Steven Gore, who had been studying how Baylin’s
breakthrough could help patients. “He was on
the brink,” Gore says.
Kepics became the first patient in a clinical trial
combining the demethylation agent aza-cytidine with
an H-DAC inhibitor. He began treatment on Nov. 8, 2004,
the day the trial was activated, and received two shots
a day of aza-cytidine for 10 days, followed by the
H-DAC inhibitor. Gore had told him that the new inhibitor
treatment would take three to six months to work, but
as Kepics waited for signs of improvement, he went
through pure hell from the effects of his disease.
An agonizing infection of his esophagus put him in
and out of the hospital and left him unable to eat
As January turned into February, Kepics had lost
50 pounds and felt worse than he’d ever felt
in his life. But he was hanging on. Then, around Valentine’s
Day 2005, he started feeling better and his blood counts
began to come up. By April he was back at work.
Today, Kepics is in full-blown remission from his
disease. He continues to take the drugs, but “I
live a normal life,” he says. “It’s
like I never was sick.”
“Patients have shown dramatic responses,” Baylin
says of the demethylation therapy. “We’ve
had two trials, with some 40 patients on the drugs.
In the first group, we got up to 50 percent response;
in the second, up to 70 percent. In several people,
all symptoms of the disease disappeared. They remain
Donehower sums it all up this way: “There is
no single panacea for cancer, not targeted therapy,
not vaccine, not hormonal treatment, not bone marrow
transplant, not one but all, and each when appropriate
and tailored to the individual patient.”
to this kind of wide-angle perception, physician/ scientists
are achieving successes with once-intractable malignancies.
And sometimes they are even working miracles.