Gene Therapy: Fighting Fire With Fire
Hopkins researchers have been learning about prostate
cancer cells, cracking their secret code, and developing
ingenious ways to change and even fool them.
Prostate cancer cells are cunning: One of their first official functions
of advancement is to cloak themselves -- in effect, by knocking out
the enemy's radar screen -- so the body won't spot them as foreign
All warfare is based on deception, wrote the great Chinese general
Sun Tzu 2,500 years ago in The Art of War: "if you know the
enemy . . . you need not fear the result of a hundred battles."
Over the last few years, Johns Hopkins researchers have taken this
concept to heart -- learning about prostate cancer cells, cracking
their secret codes, and devising ingenious ways to change and even
Imagine being able to program the body's DNA like a computer chip,
sending it on a selective search-and-destroy mission targeted only
at prostate cancer cells. This is what oncologist Jonathan Simons,
M.D., and urology resident Ron Rodriguez, M.D., Ph.D., have figured
out how to do in the laboratory.
Their goal is gene therapy -- using the body's own tools, DNA
molecules, to treat cancer that can't be cured by surgery or
radiation -- and they're coming at it from two angles: Genetically
engineered "vaccines" made from a man's own cancer cells, and
doctored viruses that can act as Trojan horses, slipping into the
body, attaching themselves to prostate cancer cells and
exterminating them before they even suspect anything's amiss.
A cancer "vaccine"
Several years ago, Simons began looking for a way to crank up the
body's immune system, and so strengthen its ability to fight off
cancer. The sophisticated recipe for his ex-vivo (Latin for
"out of the body") work involves culturing a man's own prostate
tissue removed during radical prostatectomy, irradiating the cells so
they can no longer grow (this is similar to the "dead" vaccines used
to treat such diseases as polio and measles), adding a key
ingredient -- a gene called GM-CSF, which activates the immune system
in unprecedented ways -- and then putting this concoction back into
the body as a vaccine.
GM-CSF is a cytokine, in effect an "upper" for the immune system.
"We're very enamored of it," says Simons, who, with Fray F. Marshall,
M.D., Schwartz Distinguished Professor of Urology, conducted the
first gene therapy trials at Hopkins, and was the first to show that
it works in kidney cancer. "GM-CSF is the most powerful signal
to the immune system known; it says 'Start to recognize me. I am
a foreign invader.' So we can teach a patient's immune system to
recognize the cancer cells that escaped before the prostate was
removed." (Radical prostatectomy can't cure cancer if there are
micrometastases -- tiny, invisible bits of cancer that have somehow
escaped the prostate and set up shop elsewhere. These are the seeds
of lethal cancer, and these are the unseen enemies gene therapy is
designed to find and kill.) "In concept, it's a form of adjuvant
therapy, with part of the drug being the patient's own cancer."
Why is this needed? Why does the immune system need help to recognize
something that's been growing right under its nose? Because prostate
cancer cells make it their business to disable GM-CSF as soon as possible.
"They don't want to be recognized," Simons says. "Cancers don't make
GM; if they did, we probably wouldn't have cancer. They make sure
that it gets turned off," one of a series of sneaky maneuvers in a
"stealth apparatus" that Simons has identified.
The trick, Simons continues, "is to get a high-enough dose, and have the
best ratio of lowest amount of cancer to the maximum amount of
Although there's some "very exciting early evidence" in the handful of
patients participating in early tests of this gene therapy, "it's still
very much in its infancy," Simons cautions. "We've gone beyond the
Wright brothers -- in the sense that we're sure that it looks
interesting, we can fly the thing up and down the coast, but we're not
up to Lindburgh yet."
Ron Rodriguez, M.D. (left) and Jonathan Simons, M.D., Ph.D.
One challenge is simply making enough of the drug per patient -- and for
now, this depends entirely on who much the tumor scientists are able to
extract from the prostate specimen. "Many patients have less than a gram"
-- about a thumbnail's worth of tumor. "It's lethal as anything, but
that's not a lot, as it turns out," in terms of having enough
vaccine-making material to work with. To solve this problem,
Simons is working to make a more generic, less patient-specific
A "Magic Bullet?"
Which brings us to the in-vivo (for "in the body") work. Ron
Rodriguez, who's leading this effort, envisions a "shot" for cancer
that would work even in advanced disease. "What can you do now for
a man with advanced disease? Well, you can give him hormones, but the
effect doesn't always last long enough," he says. (For more on this,
click here.) "So this is a strategy to try to help
those patients who are going to die of their disease, because today
there's not cure for it when it's at that stage."
Enter the adenovirus, an upper respiratory virus -- at least, that's what
it looks like on the outside. On the inside, it's a souped-up,
cancer-killing machine, genetically engineered to deliver its special
surprise package only to cells that make PSA (in other words,
prostate cancer cells). "What we've done," says Rodriguez, "is to
make the virus so that it only replicates in prostate cells, and when
it replicates, it lyses (destroys) cells."
In the laboratory, Rodriguez and Simons (using viruses provided by a
company called Calydon) remodeled the virus so that it's controlled
by the PSA promoter, a small stretch of DNA near the PSA gene in the
body. (The PSA promoter acts as a chemical switch that governs how
PSA is produced.)
So, unlike chemotherapy, which often tends to have a "buckshot" approach --
killing everything, good and bad, in range, with limited effect in prostate
cancer -- the virus acts like a high-powered rifle with only one target
in its sights -- PSA-making cells. In other cells, it can't be turned on;
with no point of entry, it just brushes past, looking for the next
PSA-making cell. "And the effect, at least in animal models so far, is
that we've been able to completely cure tumors that are quite large
with a single injection," says Rodriguez. "A one-centimeter tumor is a
huge amount of tumor, grossly out of proportion to body size for a
little mouse, and that's how much we're able to cure." (For this work,
Rodriguez won the American Urological Association's 1997 Research Essay
Unlike the vaccine, the virus is not patient-specific; theoretically,
it will work in any man with PSA-making cells. The elegance of
this approach is that it simply doesn't matter whether a cancer cell
responds to hormones or is hormone-resistant (to read related stories,
click here or click here). "The
only thing that matters is whether the tumor cells are capable of
producing PSA." Even though, as cancer progresses, some cells become
streamlined and lose their ability to make PSA (to read related article,
click here), "the good news for us is, we're pretty
convinced that they don't get stripped-down so low that they don't make
any," says Simons. ("But they definitely make less," he adds --
and this is another "stealth" technique.)
A virus -- any virus -- works like a terrorist in the body: Like the
Trojan horse, it invades an unsuspecting cell, overpowers its defenses,
and co-opts its machinery to do the virus's bidding. When it's consumed
all the cell's resources -- stripping it clean, like a locust in a wheat
field -- and has no more use for the cell, it destroys it and moves on.
Normally, when the body realizes that a virus is on the loose, it sends
its own powerful home guard -- warrior cells in the immune system -- to
fend off the intruder. The body almost always wins (except for a few
stark, lethal exceptions, such as HIV, the AIDS virus). So one bonus with
engineered adenovirus is that, once the body discovers its presence,
"you've activated the immune system to come in and clear the virus, and
you may be able to get autoimmunization against your tumor." Although
it's still theoretical, the idea here is also to enlist the immune
system -- perhaps through techniques learned from the vaccine work
described above -- to help the virus on its mission.
Rodriguez envisions the virus as a "one-shot" treatment: "Once you give
a single injection and it makes its way to prostate cells and starts
replicating, you won't have to give any more, because it continues to
propagate itself until it's done the job." In animals, tumors start
shrinking (as measured by calipers) in about two weeks; after about
six weeks, the tumors are completely gone.
"The fact that we can kill any cell that makes PSA selectively sounds, all
of a sudden, a lot like a 'magic bullet' type of approach. And the fact
that we can cure laboratory animals of cancers that a lot of patients have
-- huge tumors -- is very exciting," says Simons. Even more so is the
further promise of DNA-altering technology: "The DNA molecule is a lot
like a computer disk," Simons continues, "you can program it, you can
manipulate DNA as a drug. Now, we can turn on signals that say, 'Die,
you PSA-positive cell.' But what we're trying to do right now is
make it even better. If you know the letters of the alphabet and are
creative and do experiments, you can literally write in the code of the
DNA a kind of special prescription for killing prostate cancer cells
Cracking the DNA code is, to the world of prostate cancer research, the
equivalent of discovering the Rosetta stone -- the key that unlocked
Egyptian hieroglyphics. "For the first time, we're really starting to
understand the enemy we're trying to kill," says Simons, "and that's very
It's also rather unique in a field where, often, doctors may know a
particular medicine works but not why it does, adds Simons,
whose father was one of the first patients to be cure of Hodgkin's
disease with a then-experimental form of chemotherapy. "I cannot tell
you how that was done; we still don't know how chemotherapy works. But
the interesting thing is, I can tell you exactly at the molecular
level how this in-vivo gene therapy works."
Simons credits the progress of this work at Hopkins to Patrick Walsh, M.D.,
urologist-in-chief and Donald S. Coffey, Ph.D., director of research.
"Years ago, they saw the future as a molecular medicine -- that you
would write prescriptions based on a real molecular understanding of
Even though this virus work is still experimental, and it hasn't been tested
in humans yet, Rodriguez believes the potential in this technology is
"unbelievable. For all sorts of tumors, and even for benign disease. I
think someday, it may be possible that people with BPH can get a single
injection and be cured."
With this work and research in other forms of treatment for advanced
disease, particularly angiogenesis inhibitors (see related article by
clicking here), "there's a lot of promise
now that we're really going to chance survival favorably," says Simons.
"And hopefully, really start to cure people. It all comes from a new
understanding of the disease."
Simons dreams of prostate cancer, one day, being "sort of a freak thing
that occasionally you might see, and you could treat, like
tuberculosis today, compared to the way it was in the 1920s -- as this
profound epidemic that has been completely controlled by medical and
surgical therapy. TB was just as incurable back then."
Would a virus or vaccine ever replace surgery as the definitive treatment?
"No, they would all work together. TB was cured by public health
prevention; there was a role for surgery always, and then it required
four different kinds of drugs to really eradicate it. I think it
will be surgery and radiation combined with whole new ways of
systematic treatment -- and, of course, prevention -- that's going to do
it. Ultimately, the answer will be to try to change our diets, and
reduce the predisposing factors. I think it's all of the above." (For
more on diet and prevention, click here.)