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Vaccines help the immune system uncover malignant cells.
William Coley, MD, a New York-based surgeon, never got over the death of one of his first patients. The 17-year-old girl had come to him with what turned out to be a sarcoma, a tumor on the bone on the back of her right hand. Although confident the cancer had not spread, Coley chose to amputate the girl’s arm just below the elbow. She died, painfully, a little more than two months later.
Determined to find a better treatment, Coley scoured patient records at New York Cancer Hospital, where he worked. There, he came across an account of a German immigrant who had come to the hospital with an egg-sized sarcoma just under his left ear. Surgeons operated twice. Each time the cancer rebounded. After the third operation, the man’s wound swelled and reddened, and he suffered attacks of high fever. And then, remarkably, the irrepressible tumor started to shrink. A few months later, the patient left the hospital apparently cancer-free.
Coley spent weeks relying on his broken German to search New York’s Lower East Side until he finally found the man, still healthy seven years after his cancer. Coley suspected that the man’s immune system had attacked the tumor along with the infection. He eventually developed a treatment, which became known as “Coley’s Toxins,” of killed bacteria to provoke an immune reaction in cancer patients. The year was 1893. Coley used his toxin, with mixed success, until his death in 1936.
More than 100 years after Coley’s 19th century insight, physicians are again trying to enlist the body’s immune system to get rid of cancer. That old idea has become one of the hottest new fields in cancer research. One such product has already entered the market, the vaccine Provenge (sipuleucel-T) for prostate cancer, and many others are in development. New immune boosters for brain tumors, multiple myeloma, lung cancer and others are undergoing the final stages of testing.
“There is a lot of enthusiasm because we’ve seen nuggets of success,” says Candace Johnson, PhD, deputy director of the Roswell Park Cancer Institute in Buffalo, N.Y. But she and others caution that much remains unknown, and no immuno-based therapy can yet claim to be a sure shot against cancer. If anything has become apparent in the past two decades, it is that the immune system not only struggles to recognize cancerous cells—because, after all, they were once as ordinary as any other cells—but that even when the immune system responds in force, tumors have a whole bag of tricks to evade an attack. “Tumor cells by nature are pretty crafty,” Johnson says. “That’s why they are tumor cells. They learn to adapt for their own survival.”
Which means science has to find ways to outmaneuver them.
Tumor cells by nature are pretty crafty. That’s why they are tumor cells. They learn to adapt for their own survival.
The immune system is made up of different kinds of white blood cells that patrol the blood, ready to detect any kind of antigen that didn’t arise from the body itself. The exact mechanism depends on what kind of threat is detected, be it viral, bacterial, fungal or of some other origin. Classic vaccines, which prevent disease, use just enough of a foreign substance (like the antigens from pathogens) to provoke an immune response without causing illness. The idea is that when the real infection occurs, immune cells are trained and ready to act.
Vaccines against cancer work on the same general principle—educating the immune system about something dangerous—but with the goal of treating disease, not preventing it. The theory is to amplify an immune reaction that would occur naturally or drive a weak response into something formidable. One of the biggest challenges, however, is that unlike the proteins of infections, the molecules produced by a cancer cell are often too similar to ones the body makes normally. (Cancer cells, at some point in their existence, were once normal tissue.) So the immune system must react aggressively to something it had been programmed to see as familiar.
And there are other challenges. Most vaccines that prevent disease work by prompting the immune system to make antibodies, which are large proteins made by white blood cells called B cells. The B-cell system, which in effect is an antibody factory, plays a significant role in the protection conferred by childhood immunizations, but only a lesser role in immune effects against cancer. The immune cells that naturally fight cancer tend to be killer T cells and other types of white blood cells. When fighting infection, T cells work like trained assassins, destroying cells that are infested with pathogens. When you catch a cold, you recover because T cells have gone around and obliterated your own cells harboring (or carrying) the virus.
“In animals, you can take tumors that are growing and implant them into mice and give the mice vaccines,” says James Gulley, MD, PhD, director of the clinical immunotherapy group at the National Cancer Institute. “If we wipe out their B cells, they can still have a good response.” In other words, stimulating the production of antibodies, which is the mainstay of traditional vaccines, is of little help against certain types of tumors. This makes vaccine development more complex.
Researchers developed Provenge with the idea of focusing the T cells specifically on cancer. The vaccine works by harvesting a component of a patient’s immune system known as antigen-presenting cells, or APCs. Antigens are any foreign invader targeted by the immune system. An APC swallows antigens, and then displays them on its surface to provoke T cells, like a matador flapping a cape. For Provenge, scientists incubated an antigen common to prostate cancer cells with a patient’s own APCs, and then returned the APCs—now waving the cancer-specific proteins—back to the patient.
In clinical trials, men with advanced castration-resistant prostate cancer who used the vaccine experienced a life expectancy that was about four months longer than men who did not use the vaccine. The results were good enough that the U.S. Food and Drug Administration approved the drug in 2010, though a recent paper in the Journal of the National Cancer Institute questioned whether the survival benefit might be simply an artifact of the study’s design. (With a full round of treatment costing nearly $95,000, it became one of the most expensive cancer drugs on record.)
One reason Provenge might not have had stronger results is that some men benefitted greatly while others hardly responded at all, Gulley says. This is one of the problems with current vaccines: it’s still unclear who best responds to them. One complicating factor in the development of treatment is that experimental vaccines have been mostly tested in men who have received more than one therapy, which could have weakened their immune system’s ability to respond to the vaccine. “As we go on, we’re going to see an improvement in our ability to define which patients would be best treated,” Gulley says.
The best use for vaccines may turn out to be in patients at the other end of the spectrum: those who have the smallest amount of cancer. “What I see in the future is that if you have a small lesions, you have them surgically removed, and then you have a vaccine,” Gulley says. The vaccine would have the job of mopping up any stray cancer cells that remain undetected.
That’s what Terry Page is banking on. The 60-year-old railroad conductor from Tigard, Ore., received a diagnosis of early-stage prostate cancer in 2010. There was no evidence that the cancer had spread beyond his prostate, but because there was a significant risk of the cancer reappearing in the future, his doctors offered him a chance to participate in a study of Provenge as a way to help prevent the cancer from returning. Before his surgery, he underwent three outpatient treatments—which involved sitting for almost three hours in a recliner as APCs were filtered out of his blood through a special intravenous catheter. After the white cells were trained to display the cancer antigens, they were then infused back into his system a week later.
“It may help my immune system fight any floating cancer,” he says, since doctors don’t have a way to detect any stray cells that could sow the seeds of a recurrence.
Page also likes the idea that his participation may help provide answers for other men. But those answers will take years to obtain, says Gulley, who is coordinating a study of another type of prostate cancer vaccine, called Prostvac, or PSA-Tricom.
“You have to follow patients for years and years to see if the drug is working,” he explains.
As those studies continue, scientists are conducting investigations of new immune-boosting methods for other types of cancers, such as targeting the way the tumor defends itself.
“Getting the T cells activated is not the limiting step in all cases,” says Thomas Gajewski, MD, PhD, of the University of Chicago. “Sometimes the tumor walls itself off and cannot be attacked,” he says, like a medieval city.
In melanoma, for example, T cells are often active against the cancer, but are either unable to get inside the tumor or are neutralized once they do get in, he adds. The challenge has not been in just mounting an immune response but figuring out how to make the tumor succumb to it.
Federal regulators approved one treatment last year for advanced melanoma that tries to knock out a tumor’s defenses. Called Yervoy (ipilimumab), the drug targets a protein that works as a kind of on-off switch on T cells, turning on a mechanism that the tumor has shut down.
[Read more on advancements in melanoma in "Melanoma: Ready for Takeoff"]
Studies found an improvement in median overall survival of about four months. Although it seems to bring about only a modest improvement, the drug was groundbreaking because it was the first time that any drug prolonged life in patients with advanced melanoma.
Like other researchers, Gajewski says the goal is to figure out which patients will benefit and why. “In a subset of patients with immune therapy, when there is shrinkage, it can be complete and very durable,” he says.
Christine Sable of Lancaster, Pa., knows this. A commercial real estate broker who received a diagnosis of ovarian cancer in 2003, she was told after chemotherapy that she had a 75 to 80 percent chance of recurrence. At the time she had just turned 44 and had two young children. One night, her husband happened to see a news story about an experimental vaccine for ovarian cancer being used at Roswell Park Cancer Institute. “Come in here!” he shouted to her. The vaccine was targeting a cancer protein called NY-ESO-1. She qualified for the study and underwent a series of 15 injections, which bothered her even less than flu shots, she says.
In a subset of patients with immune therapy, when there is shrinkage, it can be complete and very durable.
Eight years later, she remains free of recurrence, witnessing all the family milestones she once thought she would miss. She was lucky—most of the other women in the study eventually experienced a progression of disease.
“For me, it worked because I did have a match for this NY-ESO-1 protein,” she says, and she also had other allies in her immune system that gave her a robust reaction. The NY-ESO-1 targeting vaccine is still evolving. A safety study of a new combination of the vaccine with Rapamune (sirolimus) launched earlier this year, designed to extend the life of immune cells once they recognize the tumor.
Vaccines for other types of cancer are also reaching the final stages of testing. Researchers hope that, as studies continue, they will solve many mysteries, and see more patients like Sable.
[Read "First Steps: Vaccine Research" on how breast, lung, brain and blood cancers are benefiting from vaccine therapy research.]
“Under the proper circumstances, the immune system can control cancer for a long period of time,” says Jedd Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center—William Coley’s New York Cancer Hospital as it stands today. “We are very committed to uncovering why some people benefit and others don’t,” he says.
In pursuing Coley’s old mystery, researchers could help patients in the century he never lived to see.
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