Cancer Vaccines : Promising, But Still Early, Clinical Trial

by Food and Drug Administration (FDA)

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Promising, But Still Early

As with any new treatment, cancer vaccines must be first studied in lab animals and then tested for safety and effectiveness in three phases of human studies, called "clinical trials," before they can be approved by the FDA. In Phase 1 clinical trials, cancer vaccines are used alone and studied for safety and to determine the proper dose. In Phase 2 trials, they are tested for effectiveness and may be used alone or in combination with another therapy. Phase 3 trials are large-scale studies testing effectiveness and usually comparing a vaccine with some standard therapy. Researchers are testing vaccines using various adjuvants, delivery methods, and types of antigens.

Cancer vaccines have shown promise in clinical trials with many types of cancer. According to Howard Streicher, M.D., a senior investigator with the NCI's Cancer Therapy Evaluation Program, it's too soon to say which cancers will be treated with vaccine therapy. The types of tumors that have proven most susceptible to vaccines so far, he says, are: skin cancer (melanoma); kidney cancer (renal cell); a group of cancers that affect the lymphatic system (lymphoma); a malignant tumor of the bone marrow (myeloma); and solid tumors, such as lung cancer. The most work has been done in the area of melanoma, a type of skin cancer in which treatment options are limited when the disease is in advanced stages.

"After having a tumor removed, about half of patients with stage III melanoma may have a recurrence, and we want to prevent that," Streicher says. "Chemotherapy doesn't work in this area, so our hope is that this could be just the right place for a vaccine."

James Mulé, M.D., Ph.D., associate director of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., says, though some early studies have shown that some people's tumors shrank or even disappeared in response to a cancer vaccine, it's still early. Mulé was an investigator on the first study that tested dendritic cells in children. In the Phase 1 study, one 16-year-old with cancer that had spread to her lungs and spine showed significant shrinkage of tumors.

"There is promise in the sense that some of these vaccines can illicit a powerful immune response in some patients, but I think we have to be careful about getting too excited over early studies that can't be reproduced," Mulé says.

Jeffrey Weber, M.D., Ph.D., director of the Norris Melanoma Center at the University of Southern California, says there is also still a lot of work to be done in discovering new antigens and adjuvants and more sophisticated strategies to overcome the immune system's tolerance of cancer cells. "We are still discovering molecules that regulate the immune system such as CTLA-4, so we're still in the dark in some areas," Weber says. Recent research has found that inhibiting CTLA-4 can help the immune system attack some tumors.

Experts say that no therapeutic cancer vaccine has been licensed yet because few Phase 3 studies have been completed, and those that have been completed did not meet their goals of demonstrating safety and effectiveness of the vaccine. "We are still working with industry to define the characteristics, including potency," says the FDA's Hirschfeld. "So a trial may look promising early on, but our job is to make sure it can be reproduced. We have to ask: 'Will this treatment work in the larger population?'"

One of the challenges is that cancer vaccines may produce different effects than those caused by cancer drugs. With cancer drugs, experts ask whether there is an objective, measurable response, such as tumor shrinkage. A cancer drug may cause tumors to shrink, but a person still may not live longer. With a cancer vaccine, there may be fewer signs of tumor shrinkage, but a person might live longer.

There aren't the same landmarks that you would see with traditional therapies, says Natalie Sacks, M.D., medical director in the clinical research division at San Francisco-based Cell Genesys, which is studying its vaccines, called GVAX, in people with prostate cancer, pancreatic cancer, leukemia, and myeloma. These whole-cell vaccines all use a hormone that stimulates immune response, called granulocyte macrophage colony stimulating factor (GM-CSF).

"As sponsors, we want to develop treatments and get them out to the market and help patients," Sacks says. "In the case of cytotoxic chemotherapies, the traditional endpoints used in drug development are shorter-term outcomes, such as tumor response and progression-free survival. Where I expect immunotherapy to be successful is in longer-term outcomes and increased survival. Because of the mechanism of action, the patient may not show an immediate response as is generally observed with standard chemotherapies, and the trial may take longer."

Finding a Clinical Trial

Cancer researchers say their work won't mean much if more people don't enroll in clinical trials. According to the NCI, less than 3 percent of U.S. adults with cancer participate in clinical trials.

If there is a standard treatment available for a type of cancer, the NCI recommends choosing it over an experimental therapy. Cancer vaccines show the most promise at preventing a recurrence of cancer after surgery, radiation, or chemotherapy because the immune system will need to recognize and attack a smaller number of cancer cells. Cancer vaccines are also being tested as a treatment for advanced cancer.

Gary Montgomery, 66, of Redmond, Wash., enrolled in a cancer vaccine trial in 2002 to treat a rare form of abdominal cancer called pseudomyxoma peritonei. According to the National Organization for Rare Disorders, the disease is characterized by the accumulation of mucus-secreting tumor cells in the abdomen and pelvis. As the mass of tumor cells grows, the abdomen swells and digestive function becomes impaired.

Montgomery first had the standard therapy of surgery to remove the tumors in 2000. "They opened me up like a sardine can — from the sternum to the abdomen — and took out as many tumors as possible," Montgomery says. Then they inserted a tube into the abdomen, which delivered chemotherapy for six months. He experienced no tumor growth for about a year, but then the tumors came back. "It's known as a relentless form of cancer that wears you down," he says. "The doctor said that with the exception of another surgery, there was really nothing else they could do."

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