Cancer has been growing inside Peter Alfke's prostate for 13 years. For several years, the best available treatment worked. "Then," said Alfke, "it didn't." And the disease had moved into his bones. Other than chemotherapy, there was nothing left to try except something that physicians had been thinking about for decades a way to enlist the immune system to see cancerous cells as an enemy. Cancer's greatest protection has always been its origin in our own cells, a cloak that masks its deadly behavior from attack.

This winter, Alfke has sat patiently in a chair at the Stanford Cancer Center watching a very select type of his own immune system cells, power-boosted and sensitized to eradicate a certain prostate cancer protein, being pumped into his body. The process and its components are a brand-new treatment package called Provenge, the first-ever FDA-approved therapeutic cancer vaccine. For men like Alfke, who have no other options left, Provenge can mean extra months of life where none seemed possible.

The Stanford Cancer Center is one of a limited number of health care sites to offer the very limited amount of Provenge available this year.

Stanford is distinguished, too, as the institution whose physician-scientists discovered much of the core scientific knowledge to enable Provenge and other individualized manipulations of the immune system: Ed Engleman, MD, Ronald Levy, MD, and Samuel Strober, MD, each unraveled a crucial thread in the intricate workings of the immune system. Levy discovered that antibodies could be made to recognize cancer cells. Engleman tracked down one of the immune system's key order-giving cells. Strober developed a technique to enrich and purify immune system cells.

The combination of that knowledge offers an effective cancer treatment with a vast cellular army that has none of the often debilitating side effects of surgery or radiation or chemotherapy. It's a radical departure from the past. "What we taught for half a century was that our immune system is irreversibly trained during embryonic development not to attack our own tissues, including tumors," said Engleman, a cellular immunologist and professor of pathology. "We now know that is not true. We were so naïve. Our knowledge is much greater now."

Engleman's research gaze focused on dendritic cells, proportionately small in number, less than one percent of all white blood cells, but inversely powerful commanders of the immune system's behavior. The earliest thinking about them suggested that they were powerful immune cells. Engleman first learned how to obtain them from blood. The trick, of course, was how to turn them on against cancer. "The immune system has the potential to recognize almost anything, and now we can manipulate its response," he said, to ultimately treat all forms of cancer.

While the concept of immune system control has clearly been proven, the devil is in the details. There are many kinds of cancer, and each has its own biochemical profile.  Researchers know the encyclopedia of cancer information is still at a very basic stage. One example: Provenge's clinical studies showed that patients with prostate cancer who received treatment did live longer than those who did not, yet their tumors did not change in size, nor was there a change in the patients' levels of PSA, the prostate-specific antigen that reflects the prostate cancer's activity.

"The thing with PSA is that it's a single protein that's used as a marker and does not correlate perfectly with tumor growth rate,” said Russell Pachynski, MD, Alfke's physician, a tumor immunologist focused on investigating novel therapies. "PSA is a good marker, but it's not perfect. Provenge is immunotherapy and works through radically different mechanisms than the traditional ones used for years,  so we're having to get used to new things like this."

"The ultimate standard is overall survival," said Stanford oncologist Sandy Srinivas, MD. There are similar mysteries in medicine, she said, especially with immunotherapy treatments. "You're stimulating your immune system and you're not seeing immediate benefits, but over time, something changes. It's unique in oncology in that we're doing something that doesn't have immediate gratification."

What needs to be carefully tested and proven in clinical trials, Levy said, is the benefit of combining Provenge with other treatments.

Prostate cancer is the second leading cause of cancer-related death in men in the U.S.; last year, that was 32,000. More than 200,000 new cases will likely emerge this year. Risk of the disease increases with age. African-American men more often suffer from it and die at double the rate of other ethnic and racial groups. The FDA has restricted Provenge's use to those men whose cancer has metastasized and become resistant to the standard testosterone-reducing hormonal therapies and is either without symptoms or mildly symptomatic.

That would be about 30% of the current patients, Srinivas said, or about 100,000 men. Dendreon, which makes Provenge, will only have enough this year for 2,000 patients. Stanford will be one a few health care facilities to offer the treatment. The FDA approved Provenge this spring, based on the results of a final clinical trial which followed 512 men. At its end, researchers found that the men treated with Provenge had lived a median length of 25.8 months, four more months than those who received a placebo treatment. After three years, 32% of those who got Provenge were alive compared with 23% of those who got the placebo.

One major benefit of Provenge is how patients feel after treatment. "Provenge does not have the side effects that the current chemotherapy does," Srinivas said.

Provenge treatment begins with the patient giving blood whose dendritic cells are then removed. They are cultured with a protein found in 95% of all prostate cancers, then mixed with a protein that enhances the immune cell's vigor. Finally, the combination is put back into the patient's blood stream, creating an immune system that is more reactive against the cancer protein.

Engleman and Strober founded Activated Cell Therapy, Inc., in 1992. It later became Dendreon, but neither man has been involved in the company for a decade. Engleman still owns shares of company stock.

The company chose to target prostate cancer as its first priority because there was less risk that activating the immune system against the prostate would cause serious complications. "The prostate is not a very useful organ so if it is destroyed by an immune attack, there should be little or no harm to the patient, whereas with something like lung cancer, you would want to be more cautious because damaging normal lung tissue could compromise our ability to breathe." Prostate cancer is quite common, he said, "and once it spreads, it's almost universally fatal. Nor was there any other effective treatment."

Engleman, Levy, Strober and other Stanford physician-scientists have moved deeply into the next steps: using a bone marrow transplant in combination with a cancer-specific immune boost—an immunotransplant that eliminates a portion of the original immune system cells to make space for the new power-boosted and cancer-recognizing cells. It's a way to get at non-solid cancers like leukemia. "Our rate of discovery has increased and our level of sophistication is enormously better," Engleman said. He believes immunotherapy-based cancer vaccines will be a mainstay of treatment in the future. "So many things are going forward at full steam," he said.

Alfke will be 80 this November. He’s trying hard to live his life without thinking too much about his illness. "But I do trust these doctors that this treatment makes sense. I won’t know for some time," he said. In the meantime, "I'm not sitting at home crying."