An Uphill Battle
to Undermine Cancer
words by eve jacobs / photograph by andrew hanenberg
left to right: Members of the cancer vaccine-team (l-r): David August, MD, professor of surgery, chief, Division of Surgical Oncology; Tamir Ben-Menachem, MD, associate professor of medicine, Division of Gastroenterology; Edmund Lattime, PhD, professor of surgery, Division of Surgical Oncology; Deputy Director, CINJ; Mark Stein, MD, assistant professor of medicine, Division of Medical Oncology; Elizabeth Poplin, MD, professor of medicine, Division of Medical Oncology. All are on faculty at RWJMS and are members of The Cancer Institute of New Jersey.
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here would we be without vaccines? Babies get them almost from go; toddlers, school-age kids and teens get them; young, middle and older adults do, too. Vaccines against infectious diseases have changed the face of medicine — and saved countless lives. Smallpox — gone; polio, measles, mumps, diphtheria, and whooping cough — almost gone; flu, hepatitis and shingles — on their way down. The list of vaccine-preventable diseases is long and growing.
But not much has changed in the arsenal against cancer in decades. Surgery, more and better drugs and more targeted and potent radiation have made inroads, but gained not nearly enough victories. This is a wily enemy with many tricks under its belt, chief and foremost how to evade or undermine the body’s potent defense system. However, recent insights on just how it does this may help make cancer vaccines a real player in this war without seeming end.
The first two vaccines aimed at preventing cancers are already out there and are huge successes, although they are not technically “cancer vaccines.” The HPV vaccine to thwart human papilloma virus types 16 and 18, which are responsible for approximately 70 percent of cervical cancer, and a vaccine against the hepatitis B virus, which can cause liver cancer, prevent disease by targeting foreign viruses that can lead to malignancy.
Cancer vaccine research is moving full steam ahead at The Cancer Institute of New Jersey (CINJ), where two vaccine researchers — Edmund Lattime, PhD, and Mark Stein, MD — talk about their teams’ work on the next generation of cancer therapies.
Pancreas Cancer is a Formidable Foe
Most cancer vaccines currently in the works are therapeutic vaccines geared to stimulating a more powerful immune response to the encroaching tumor or stopping the immune-inhibitory response that the tumor sets in motion, according to Lattime, Deputy Director of CINJ. “A tumor doesn’t just sit there,” he explains. “It stimulates inhibitory pathways that block the immune response to the cancer. We are studying how to block the pathways that turn on the inhibition.”
Scientists are just beginning to appreciate the complexity of the interaction between a tumor and the immune system, says Lattime, whose team launched a clinical trial on a pancreas cancer vaccine several months ago and just finished a trial on a bladder cancer vaccine. “These tumors are a lot smarter than we ever gave them credit for.”
Patient interest in the pancreas vaccine has been strong. With no good treatments available, any new option is golden. “Unfortunately, many of the more than 100 callers did not meet the study criteria. So far, four patients have been treated, and there will be a total of 12 to 20 by the end of the trial,” he says. “We are looking for individuals with inoperable, locally advanced disease who have had only limited treatment. Chemotherapy and radiation may change the body’s immune response.”
“Only 10 percent of those with pancreas cancer are operable,” he states, explaining that the pancreas sits on top of the stomach, the site of many important blood vessels, and the cancer moves quickly.
For those accepted into the trial, the first step entails taking a sampling of the tumor endoscopically and giving the first dose of vaccine, which is injected directly into the pancreas tumor, during that same procedure. That is followed almost immediately by step 2 — a shot of vaccine in the arm — to enhance its action. Step 3 happens two weeks later, when vaccine is injected again directly into the tumor, and another sample of the tumor is taken endoscopically. A total of seven treatments are given, five of them in the arm. On day 39 of the protocol, the patient goes on the standard of care, which often includes chemotherapy and radiation.
The team will have results of this Phase 1 study — designed to determine toxicity and dosing — in 12 months. If all goes well and they get the green light from the NCI, and there is vaccine available, they will start Phase 2. “We want to move on to borderline operable patients, use the vaccine to enhance the patient’s immunity and then take the tumor out. This may give us even better results,” states Lattime.
So far, he says, “There are promising results with a number of vaccines that appear to prolong survival. Targeted drug therapy combined with immunity-enhancing vaccines is where the cancer field is going.”
“Chemotherapy has increasingly been shown to be effective,” he describes, “but it often can’t get everything. It’s that last bit that’s worrisome. While cancer vaccines may be less able to kill big, bulky tumors, we are hopeful that they could kill the cells that are left behind. We are figuring out how to use these two together.”
A Therapeutic Cancer Vaccine is Born. Will Others Follow?
It’s hard to catch up with prostate cancer specialist Mark Stein these days — it seems that everybody wants to talk with him about Provenge. “The entire field changed about four months ago,” he says, “when the FDA approved Provenge — the first therapeutic vaccine for cancer.”
Stein calls it a new paradigm. But is it a vaccine? “Technically yes,” he says. “It’s fair to call any therapy to stimulate the immune system a vaccine.”
Provenge got the green light on May 1 after many years of clinical trials including more than 500 men with advanced prostate cancer that had metastasized. Of those in the Provenge group, almost one third were still alive after three years, while less than one quarter of men who got placebos were alive at that time. The vaccine extended median survival by four months. Provenge is an individualized immune therapy created by harvesting a patient’s own immune cells (a three hour process), genetically engineering them to fight prostate cancer, and then infusing them back into the patient in three batches over a period of a month. About 100,000 men a year with this type of prostate cancer are eligible for the treatment.
“This may seem like a small step,” Stein states, “like pushing a football a few feet down the field, but you’ve moved the ball. We’ve proved that this works in a large validated way. It’s a milestone.”
Stein, a medical oncologist at CINJ and an assistant professor of medicine at RWJMS, says the challenge is how to take Provenge to the next stage. “How will we combine this with other therapies to increase its benefit?”
The vaccine was tested on men with asymptomatic metastatic disease — meaning the tumor has stopped responding to hormonal therapy and the cancer has spread, he explains. “This is the healthiest group of men in a population with advanced disease. One of the challenges will be to try to expand the therapy into different populations.”
“What about giving it earlier?” he asks. “What about trying immune-stimulation even before the tumor is detectable on scans? Who is most likely to benefit from this therapy? Are there markers to indicate this?” That will be the focus of his future investigations, he hopes.
“Vaccines are very well tolerated,” he explains. “The problem with chemotherapy is the toxicity. Each added agent can cause more toxicity.”
One point of interest is that scientists do not know why people on Provenge live longer. “We don’t actually see the tumors shrinking on scans or measure less prostate cancer protein in the blood,” Stein says. “How does the drug really work? We know how it works in the test tube but not in people.”
On June 15, CINJ announced the launch of a new clinical trial to test a combination of radiation therapy and vaccine. Samarium 153, a standard radiation treatment for prostate cancer that has metastasized to the bones, will be administered by injection in conjunction with a series of PROSTVAC-VF injections, a vaccine to stimulate the body’s own immune response. The control group will receive only Samarium 153.
PROSTVAC-VF is a vaccine made up of poxviruses that have been genetically altered to produce slightly irregular versions of PSA (prostate specific antigen) — a protein found on the surface of prostate cells, which is abnormal in many prostate cancers — and three molecules that spur the immune system to attack prostate tumor cells. In prior clinical trials that included 125 men with metastatic prostate cancer who did not respond to hormone therapy — 82 who received the vaccine and 40 who received a placebo — patients receiving the vaccine lived longer than patients who received a placebo. Thirty percent of the PROSTVAC-VF patients were alive, versus 17 percent of the control group, after three years. The vaccine group had a median survival increase of 8.5 months compared with the controls. A Phase III trial to enroll 600 patients is planned. Robert DiPaola, MD, director of CINJ, led the NJ arm of early clinical trials of PROSTVAC.
Stein says that PROSTVAC-VF, which has not yet been approved by the FDA, has been tested on the same population as Provenge, and that results were similar.
“For now, with immunotherapies, the only way to tell if the therapy is effective is determining if it results in longer life,” Stein says. “You can’t use the same benchmarks as chemotherapy. What we need now is to test PROSTVAC-VF on a larger population.” He would also like to test the vaccine on men at an earlier disease-stage.
The current, active PROSTVAC-VF plus chemotherapy trial will enroll a total of 40 men at three locations — at CINJ in New Brunswick, at the National Cancer Institute, and at the University of Chicago. “We are part of an elite network of 12 to 14 sites linked together to do clinical trials of mutual interest. We can get the right patients, get faster answers and get therapies to patients quicker,” he states.
“I’ve been at CINJ six years and it has taken that long for new drugs to come on the scene. They tend to come in a burst,” says Stein. “But extending survival an additional four months beyond the usual 21 months for advanced disease is just not enough — it’s inadequate for a 52-year-old but it’s also inadequate for a healthy 80-year-old. We can’t afford to get complacent.”
What does he hope to see in the next three to five years? “I hope that advances will come faster. I think chemo will always be part of the picture, but our challenge for the future is to come up with novel combinations of therapies that will make prostate cancer into a chronic disease.”