Harness the Power

Researchers are investigating vaccines that stoke the body's own immune system to battle cancer.

by Alicia Di Rado


Consider the power of a patient, gaining control over his cancer by using his own body’s sentry—his immune system. The steadfast white blood cells attack the malignant tumors budding inside him, pummeling cancer cells much as they would fight an infection.


That power remains the ultimate hope of cancer vaccine investigators.


Dedicated scientists have toiled for decades to create vaccines that harness the immune system to kill off cancer. While investigational vaccines have helped some cancer patients live longer and better lives, investigators acknowledge the march toward a proven vaccine solution against cancer has been a slow one.


“There are a lot of obstacles to overcome in developing vaccine therapy,” says Jeffrey S. Weber, M.D., Ph.D., associate professor of medicine and microbiology and immunology at the Keck School of Medicine of USC. “But we have to keep going.”


Weber knows that breakthroughs will come as part of a long scientific road of faith full of wrong turns, serendipitous discoveries and, most of all, determination.


Fortunately, Weber and his colleagues in quest of cancer vaccines have some reason for renewed optimism. They are taking the lessons learned from earlier clinical trials and applying them to promising vaccine therapies. New trials using increasingly focused strategies open every year.


Several of those are underway at the USC/Norris Comprehensive Cancer Center.


Targeted Attack
Weber, the Lucille and Berle Adams Chair in Cancer Research at USC/Norris, is waging war on cancer. Literally.


Nestled in his Cancer Center office—amid filing cabinets topped with models of World War II-era aircraft, from Corsairs to Spitfires—Weber envisions aerial warfare as a metaphor for the immunologic fight against cancer. If a tumor is the target, he proposes, the contents of the vaccine itself is the bomb meant to wipe out cancer. The vaccine’s delivery system is like an airplane, carrying the bomb right to the target.


“There are potential pitfalls in trying to attack the target. Cancer can throw up passive defenses to hide. Even if you have a powerful bomb in the plane, if you can’t see the target, it’s useless,” Weber says.


“But now, finally, we’re at the point where we’ve got the airplane, we’ve got the bomb, and we’re looking right at the target.”


It is an immunologic war proving far more tangled than the fight against diseases tamed by earlier generations of vaccines.


These vaccines connote memories from childhood: shots in the arm against smallpox, measles and other contagious diseases. The inoculations prevent diseases before they can happen by priming the immune system for a possible attack.


That idea came about quite by accident—some 200 years ago—when English physician Edward Jenner noticed something peculiar in the western farmlands of Britain. Milkmaids who contracted the mild disease known as cowpox, after handling materials from cows, were immune to smallpox, a related but more serious disease. Jenner developed a successful vaccine using cowpox matter to stoke the immune system into building resistance against smallpox (and in fact, the word “vaccinate” originates from “vacca,” the Latin word for cow). Vaccines against other viruses followed.


“These vaccines work by getting the body to create antibodies against an organism,” Weber says. A type of white blood cell called a B cell makes antibodies—specific, special proteins—in response to invaders such as viruses. Antibodies help kill those invaders.


“Flu vaccines are essentially an injection of proteins from a dead virus, which spurs an antibody response,” Weber says. “In cancer, though, generating an antibody response doesn’t do you much good.”


Here is why: Antibodies recognize simple, repeating structures such as parts of the cell wall of bacteria or the coat proteins of viruses, Weber says, “but cancer cells don’t have too many repeating structures—they’re just too complex.”


Instead of using antibodies, researchers such as Weber want to harness the power of white blood cells called T cells and their immunologic comrades, the antigen-presenting cells, to blast cancer.


And that is where the battle begins.


Peptide Rally
While the immune system can respond to invading bacteria, attacking and ridding the body of them, it may overlook cancer cells because they arise from the body’s own tissue. They seem to belong.


Researchers must help the immune system recognize cancer cells as targets. Scientists are trying several techniques, among them using viruses as vaccine delivery vehicles and engineering potent immune cells that are primed to lock on to cancer (see sidebar, “Vaccine Variations”).


“Nobody today knows what’s the best way to do it,” says Weber, though many techniques have shown usefulness in models.


At their most basic, many vaccines consist of one or more proteins, called antigens, that are found on cancer cells.
The immune system’s T cells each recognize only one specific antigen from a universe of thousands. When the T cell encounters its antigen target, the T cell makes many identical copies of itself.


Investigators hope that injecting these antigens will result in more T cells and more immune-boosting chemicals called cytokines in the body, and that the T cells will then attack and kill the cancer cells marked with an antigen they recognize.
USC/Norris oncologists are offering a clinical trial of an investigational vaccine that employs this strategy for colon cancer, for example. Rather than whole antigens, though, the EP-2101 phase I trial uses pieces of antigens. The pieces are composed of peptides.


“The latest development in vaccines for cancer is peptide vaccines,” says medical oncologist Heinz-Josef Lenz, M.D., associate professor of medicine at the Keck School and principal investigator for the trial at USC/Norris.


EP-2101 includes 10 different peptides associated with four antigens.


These four antigens may sound familiar to cancer patients: CEA, or carcinoembryonic antigen; p53, one of the nuclear regulatory proteins; MAGE, a family of antigens often found on melanoma and other tumors; and HER-2/neu, or human epidermal receptor-2/neu, an antigen often discussed in relation to breast cancer, but also found on other tumors.


The study is open to patients who were diagnosed with a single colon tumor, with sign of some cancer cells in nearby lymph nodes but no cancer spread beyond that. Such cancers are usually removed through surgery and followed up with chemotherapy.


The vaccine does not replace the usual therapy for cancer; instead, it is being tested as an accompanying therapy. Participants must have already completed their standard cancer treatment, with no sign of the cancer’s return.


Most investigational vaccines have been tested in patients with advanced cancers, but the EP-2101 vaccine, developed by San Diego-based Epimmune Inc., is in testing for earlier-stage cancer. Scientists hope it can boost the immune system so it will kill any cancerous cells that remain after standard treatment.


Getting an immune response in late-stage cancers may be difficult. Not only do cancers put up a passive defense—masking themselves as normal cells to the immune system—but also, as cancers grow and spread, they defend themselves aggressively, pumping out proteins that suppress the immune system.


“The immune system becomes damaged,” Lenz says. “But if you can provide the vaccine before the cancer advances, as we are doing with this vaccine, the immune system may have more of a chance to work.”


Participants in the trial will receive a total of six injections, with one injection every three weeks for 18 weeks.


Custom Shot
The more researchers learn about fighting cancer with vaccines, the more complicated the battle becomes.


For example, investigators found that the success of some vaccines appears linked to a special signature, similar to a blood type, found on the surface of human cells.


Each human being has a specific set of human leukocyte antigens, or HLA, on their cells. HLA comes in numerous possible combinations. Many know about HLA through the world of organ transplantation, because physicians use it to determine whether donor organs will match well with a transplant candidate.


In the case of the EP-2101 trial, only patients with the A2 type of HLA are eligible, says Lenz. About half the population has HLA-A2 type.


Weber hopes to take HLA typing to the next level. He is creating a clinical trial for advanced melanoma in which patients could get as many as 11 different peptides in a vaccine, depending on their HLA profile, which is determined through a blood test.


“The idea is that we will give a combination of peptides, tailored to your HLA type,” Weber says, “and these will be combined with two immune boosters.”


It will be the first vaccine trial to employ two separate classes of peptides, which are recognized by entirely different kinds of immune cells, Weber says. In his warfare analogy, the result might be not only a smarter anti-cancer bomb, but also one that packs a bigger wallop.


And it all got going, Weber says, with his patient Kaye Coleman.


Coleman, a witty, one-lining waitress from Nate n’ Al’s deli in Beverly Hills, had been diagnosed with malignant melanoma, and it was spreading. But one of Coleman’s many friends, Arlene Ray, was the founding president of the fundraising group STOP CANCER. Ray asked Weber what it would take to create something that might help Coleman and other patients. The answer: funding.


Ray helped raise more than $100,000 for the trial from customers at the deli alone. Soon, the National Institutes of Health agreed to cover other expenses; Weber hopes the trial will be open to about six dozen melanoma patients by late 2003.


Shots will be given every two weeks for six weeks, every four weeks for 16 weeks, and then followed up with boosters every three months. “No one has done this so far,” says Weber, “and it will only be available here.”


Battle Weary
Weber thinks fondly about the melanoma patients who have made seemingly miraculous recoveries when given an experimental vaccine. But so many also underwent treatments and eventually succumbed to the ravaging disease.


“The $64,000 question is, what distinguishes the patients who’ve had great results from those who haven’t? We just don’t know,” Weber says.


The vaccine war against cancer has been so challenging that Weber admits he and his fellow cancer-fighters get frustrated at times. He says his former boss has a statue of Sisyphus on his desk. “You know, the mythical man pushing a boulder up a hill for eternity only to have it roll back down. That’s his self-image.”


Weber adds, “Do I think a vaccine approach will eventually work? Absolutely, or I would not be doing this. We just have to acknowledge it’s an uphill struggle.”