Gene Therapy: Fighting Fire With Fire

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 invaders.

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 fool them.

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 immune response."

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 vaccine.

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 Prize.)

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 specifically."

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 exciting."

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 the disease."

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.)