A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions


Giving Prostate Cancer a Killer Cold

Ron Rodriguez: "A few years ago, we figured out how to make the bomb. Now we've learned how to control it, so it's more specific."

Most of us just want to get rid of the common cold. It takes vision to look at the common cold virus and think: Aha, opportunity! But that's exactly what radiation oncologist Ted DeWeese, M.D., and urologist Ron Rodriguez, M.D., Ph.D., have done, and their vision is paying off in exciting new therapeutic approaches for killing prostate cancer.

The common cold in question is a genetically revved-up adenovirus, called CG706, programmed by Rodriguez to detonate only in cells where it finds PSA. Its potency was tested in the first gene therapy trial for this type of virus, in 20 men who had a local recurrence of prostate cancer (detected when their PSA levels started going up) after radiation treatment.

In this trial, recently completed, DeWeese administered droplets of the virus using a system he designed several years ago, similar to the system used to administer brachytherapy seeds-a highly precise computer program that places tiny doses of virus at exact intervals within the prostate, guided by transrectal ultrasound and CTimaging.

"Giving external radiation to these cells, and then adding the virus, killed about seven times more effectively than either the virus alone or the radiation alone. The radiation makes the virus replicate even better."

DeWeese, who is also on the faculty of the Kimmel Cancer Center, is a master in "dosimetry"-the scientific way of knowing exactly how much ground each tiny bit of virus will cover. He has plotted these doses in minute detail, using CT scanning and laser microscopy techniques, and has found that each drop of virus spreads in a sphere, about 10 millimeters in diameter, the size of a small grape.

The trial was a Phase I study, designed to make sure a drug is safe for patients to take, and the researchers found-just as they had expected-that side effects were minimal. "It was quite easily tolerated, which we and the FDA were happy about," DeWeese reports. "However, what we were really interested in was what happened to the prostate." Would the virus kill cancer cells? Would it do what cold viruses normally do-replicate, and cause a lot of trouble to the cells in its target-or would the body's immune system recognize the invader as an old adversary, and fight it off? "We've all had colds before," says DeWeese.

"We all walk around with antibodies to these common cold viruses. About half of us have a special kind of antibody, called a neutralizing antibody, that is ready to attack. When we started our first study, about half the patients had neutralizing antibodies to the adenovirus, and over the subsequent months, all the patients developed these antibodies. But here's the good news: The presence of those antibodies didn't seem to correlate with how well they responded to the virus treatment."

DeWeese, Rodriguez, and colleagues tracked the virus's progress through biopsies and changes in the PSA level in the blood, and found that the virus was doing its job beautifully-it killed prostate cancer cells. "We could see that on the biopsies," says DeWeese. And the patients who received the highest doses of virus had the best response. "At the top two dose levels, half of the patients had their PSAs drop by more than 50 percent. We gave the highest dose that we could make, and we probably could give even more, because the virus is so well controlled, and because it only kills prostate cancer cells." The limiting factor is a technical one; at this moment, it's scientifically impossible for the researchers to pack a more concentrated viral punch into CG706.

Rodriguez, who is studying even more potent viruses, including one laced with diphtheria (read "Looking for the Ultimate Search-and-Destroy Cancer Weapons), is amazed by how far the team's research has come in a very short time. "A few years ago, we figured out how to make the bomb, but we didn't know how to control it. Now we've learned how to control it, to make it more active, and we've learned how to aim it better, so it's more specific. It's really come along very nicely."

What DeWeese calls the "Achilles heel" of any adenovirus-based treatment is the idea that the body's immune system will cut off the virus at the knees, and stop it from taking hold and killing the cancer. He and Rodriguez have a different take on this idea, which they hope to prove one day soon: "We believe that this is part of the reason why it works-that we induce an immune response to the virus. The virus is replicating and killing cells, but also your own body is trying to get rid of that virus-and that, in and of itself, will also be anti-cancer."

Next: Combining the Virus with Radiation
What could the scientists do to make the virus even more effective? DeWeese has a couple of ideas: One, it might have more "oomph" if given even earlier, in men with less cancer-ideally, in men with what DeWeese calls "intermediate risk" prostate cancer, "patients with T2b cancer, that you can feel on both sides of the prostate, or men with a Gleason 7, or men with a PSA between 10 and 20." But these men are also candidates for radiation therapy, or for surgery. "Because we know that radiation alone or surgery could be standard therapy for this group of patients, and we believe that radiation alone could be improved upon for that group, that's why we're going to target these men."

DeWeese and Rodriguez tracked the virus's progress through biopsies and changes in the PSA level in the blood, and found that the virus was doing its job beautifully-it killed prostate cancer cells.

DeWeese believes the combination will be synergistic: "In classic science terms, you can mathematically prove that when you give the two together, they kill far more than either individually." He has proven this theory in the laboratory, in culture dish experiments, and then in animals with prostate cancer. "We were able to show that giving external radiation to these cells, and then adding the virus, killed about seven times more effectively than either the virus alone or the radiation alone. The radiation makes the virus replicate even better. We haven't figured out exactly why that's happening. But when we took the tumors out of these animals, it was very clear that the combination treatment caused considerably more widespread cell death than either one individually. And the animals actually were gaining weight during the treatment-so they didn't seem to have any toxicity from this more effective cancer-killing combination."

Looking for the Ultimate Search-and-Destroy Cancer Weapons

What's worse than the common cold? Diphtheria. Ron Rodriguez, M.D., Ph.D., who genetically harnessed the adenovirus and taught it to kill prostate cells, has not put all his viral cancer-killing eggs in one basket. Instead, he's working with a handful of serious weapons, trying to determine which will prove most lethal to-and thus, most likely to cure-prostate cancer.

These cancer-killing viruses, called oncolytic viruses, have achieved spectacular results in his laboratory experiments. One of them, a virus that contains the bacterial toxin diphtheria, for example, has proven even more effective than the adenovirus at killing prostate cancer tumors in animals. "Eighty percent of our animals with prostate cancer have been completely cured when we treat them with a single injection, over a year after treatment. The cancer has never come back. We've never had that happen with any of our other vectors," says Rodriguez. "That's pretty impressive, and we're very excited."

But diphtheria is not, as they say in Hollywood, quite ready for prime time yet. Rodriguez and colleagues are working to fine-tune the virus that packages it-to keep its potency, but limit its toxicity to other cells. Dealing with diphtheria is like holding the proverbial hot potato, and this has proved a great challenge to Rodriguez. The toxin is so deadly that even the cells that make up its delivery system-if diphtheria were a letter, these cells would be the mailbox-have proven susceptible to it. "We've gotten around that problem by designing new packaging cell lines"-cast-iron vessels that remain impervious to the toxin.

Diphtheria's other big challenge has been its risk of what military strategists call collateral damage-harm to the innocent bystanders, cells that have nothing to do with prostate cancer, but happen to be situated next to PSA-containing cells. "If we use the hand-grenade analogy," explains Rodriguez, "right now, we throw the bomb into a lot of cells, and prostate cells will pull the pin very easily.

Other cells will not, but there are still some nonprostate cells that are pulling the pin, and they die." Rodriguez has worked out this problem by making the diphtheria-containing virus still more specific, so the other cells can't "pull the pin" and activate the toxin.

Based on this work, and on other viruses he's investigating, Rodriguez is already planning the next generation of cancer vaccines, which he believes will be more cancer-specific, more powerful, more stimulating to the body's immune system- which means the body's own weapons will be more adept at fighting the cancer, too-and even able to target and kill metastatic disease. "We've come a long way," he says. "When we first started this work, we achieved a proof of concept; we could get some stimulation of the immune system, so the body would recognize prostate cancer cells and start to work against them, but not in any significant way.

Then we got a response in a few patients-we're talking single-digit responses. Then, in our most recent trial, one-fourth of the patients had a partial response, meaning more than a 50-percent drop in the PSA that's sustained. We've done that in about a five-year period. The way I see it, this is growing exponentially. We're getting better at this very quickly."

An added bonus: It may even be that because of the virus's effectiveness, the doctors can lower the dose of radiation needed, and minimize some of that treatment's side effects, such as rectal or urethral injury.

The FDA has approved another Phase I study-again, designed to make sure the combined treatment is safe-for DeWeese and Rodriguez, to try the virus and radiation together in patients. After the initial treatment, the patients will undergo follow- up PSA tests every three months, and a prostate biopsy after 18 months. If the treatment, as DeWeese and Rodriguez expect, proves safe, the next step will be to study the combined treatment in a larger, multicenter study.


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