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

Immunotheraphy: Helping the Body Fight Back



Think of any great lopsided battle in history -- like the ill-fated Charge of the Light Brigade during the Crimean War and imagine you could somehow change the odds. What if those valiant Englishmen, the 13th Hussars, had worn bulletproof vests -- or better yet, riot gear and helmets? They would still be outnumbered, but at least they'd have a fighting chance.

Although Simons is not yet certain to what extent the immune system has been amplified, he believes the vaccine has the potential, one day, to stimulate autoimmunity -- to teach the body to recognize prostate cancer as the enemy, and "stomp it out like an infection."


Jonathan Simons, M.D., envisions doing something similar with the body's immune system, by boosting its ability to withstand the siege of prostate cancer, and even increasing its firepower. His secret weapon is GM-CSF, an important immune system gene that's part of the body's normal defenses, but which is one of the earliest casualties in a man's war with prostate cancer. In early trials of a vaccine he and colleagues at Hopkins have developed, the GM-CSF-bearing drug proved not only safe (all drugs must first be tested to see how the body tolerates them, and whether they cause any harmful side effects), but showed promise that the body's immune system could indeed be "cranked up" to help fight cancer.

The early studies have focused on men who underwent a radical prostatectomy, but who still were not cancer-free. These men had micrometastases -- invisible sites of prostate cancer that had spread before surgery ever took place -- as signaled by rising PSA levels within the first year after the operation. So, in battle terms, the enemy has been trounced, but despite the devastating losses a few insurgents -- the micrometastases -- have managed to escape. These rebel bands, for now, are too tiny to cause symptoms, but their potential is deadly. Already, they're working to amass enough soldiers for round two.

Simons believes this is the ideal time to strike -- while the enemy is weakest. He is encouraged by the results of early clinical trials of the vaccine: In 16 of 21 patients, PSA levels rose more slowly, and one man experienced a seven-month partial remission -- a drop in PSA. Thus, at a low dose, there was "preliminary evidence of some anti-tumor activity clinically," says Simons, who presented these results at recent meetings of the American Society of Clinical Oncology and the American Association of Cancer Research. Among other things: The GM-CSF appeared to work as a growth factor for dendritic cells -- crucial cells in the body's arsenal that, in turn, stimulate T cells, diseasefighters that hone in on tumor cells and eliminate them in various ways. The next step is to try, on a national scale, higher doses of the gene therapy vaccine in men with a recurrence of PSA after radical Prostatectomy.

Although Simons is not yet certain to what extent the immune system can be amplified, he believes the vaccine has the potential, one day, to stimulate autoimmunity -- to teach the body to recognize prostate cancer as the enemy, and "stomp it out like an infection." Nobody knows, he adds, just how far the vaccine -- or the body's immune system -- can go. "Are we good enough yet to maximally activate the immune system, and can we catch every prostate cancer cell? The answer is no, we can still do better in how we activate the immune system, and no, we haven't cured anybody yet." At the Brady, scientists hold the word "cured" to the highest standard, meaning that five years after treatment, a man must have an undetectable PSA. "But we are seeing clear-cut evidence that you can start to turn the immune system on against a cancer that no one thought you could ever get the immune system working in. And while we don't have a final answer, we've got a major new avenue of attack."

In the laboratory, the beefed-up immune system promises to attack not only the tumor cells, but the blood vessels around them. This kind of effect is called anti-angiogenesis, and it's one of the most exciting tactics being explored in prostate cancer. (As tumors embark on their path of destruction through the body, they pave the road ahead by laying down new blood vessels -- a process called angiogenesis. Many scientists believe that it might not be necessary to kill every cancer cell, if they can just contain it instead, keep it from going anywhere -- by preventing it from making new roads.) "This has been shown exquisitely in animals with prostate cancer,. says Simons. But in people, it's harder to pinpoint and reach every outpost of cancer, so this approach may not come to fruition as quickly. Nonetheless, Simons hopes that one day gene therapy will create drugs that not only recognize and destroy tumors, but knock out the supporting blood supply, as well.

Simons--who, like all scientists fighting prostate cancer, allows himself to dream of that "someday," which seems closer all the time -- believes that in the future, men with metastatic prostate cancer might not need to take hormones, which have a host of side effects and are not an effective long-term treatment for the disease. "Ultimately, the idea is that if this kind of immunotherapy is successful, men would either never need hormones, or would need only a very brief course, just to get rid of as much disease as possible, and then have the immune system mop up the rest." In the more immediate future, Simons envisions using the vaccine as adjuvant therapy, similar to that now being used successfully in colon cancer, to wipe out the few cancer cells left behind after radical prostatectomy or radiation. "Basically, were taking out a few terrorist cells rather than the entire army. We don't think the immune system can go after large tumors that are the size of a fist, because the cancer cells just outnumber the maximum number of immune cells you could mount. But there are plans for a large national adjuvant therapy study of the vaccine, giving it prior to hormones, with the idea that you could mop up remaining cancer cells with the immune response."

And although immunotherapy will probably not be able to fight advanced prostate cancer, Simons and others believe it still might do some good. "The clinical trial results are compelling enough that there's a multi-institutional trial of the same GM-CSF vaccine in men with hormone-refractory, bone-metastatic prostate cancer. We are concerned that the immune system isn't already taking on more disease than it can handle, but it's worth testing." In this trial, led by Hopkins, scientists will attempt to stimulate the immune system in 40 men with advanced prostate cancer. "The idea would be to slow the disease down, or maybe put a percentage of men into a durable remission. So if a thid of those men got a 12- month improvement in survival, that could be very important -- that would be a clue that we could engineer the immune system even better".

"Induction of Immunity to Prostate Cancer Antigens' results of a Clinical Trial of Vaccination with Irradiated Autologous Prostate Tumor Cells Engineered to Secrete Granulocyte - Macrophage Colony-stimulating Factor Using ex Vivo Gene Transfer. " Jonathan W. Simons, et al.Cancer Research, Vol. 59:5160-5169.



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