Cancer Vaccines: Immune Response

by Food and Drug Administration (FDA)

Vaccines traditionally have been used to prevent infectious diseases such as measles and the flu. But with cancer vaccines, the emphasis is on treatment, at least for now. The idea is to inject a preparation of inactivated cancer cells or proteins that are unique to cancer cells into a person who has cancer. The goal: to train the person's immune system to recognize the living cancer cells and attack them. (See "The Immune System and How It Works.")

"The best settings are for treating people who have minimal disease or a high risk of recurrence," says Jeffrey Schlom, Ph.D., chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute (NCI). "But at this time, most therapeutic cancer vaccines are being studied in people who have failed other therapies."

Cancer vaccines are experimental; none have been licensed by the Food and Drug Administration. But there are about a dozen cancer vaccines in advanced clinical trials, says Steven Hirschfeld, M.D., a medical officer in the FDA's Center for Biologics Evaluation and Research. "Research has shown us that the fundamental approach to cancer vaccines is right; we are moving in the right direction," he says.

The three standard cancer therapies are surgery to remove tumors; chemotherapy, which modifies or destroys cancer cells with drugs; and radiation, which destroys cancer cells with high-energy X-rays. Immunotherapy, which includes cancer vaccines, is considered a fourth, and still investigational, type of therapy. Cancer vaccines are sometimes used alone, but are often combined with a standard therapy.

While standard treatments alone have proven effective, they also have limitations. Radiation and chemotherapy can wipe out a person's cancer cells, but they also damage normal cells. "We want to find treatment that is more targeted and less toxic," says Hirschfeld. "Cancer vaccines are designed to be specific, targeting only the cancer cells without harming the healthy ones."

The approach has made cancer vaccines generally well tolerated, allowing them to be used in outpatient settings. And they can be added to standard therapy with a low likelihood of causing further serious side effects.

How Cancer Vaccines Work

Cancer is a term for more than 100 diseases characterized by the uncontrolled, abnormal growth of cells. To the immune system — the body's natural defense system against disease — cancer cells and normal cells look the same. The immune system tends to tolerate the cancer cells, just as it tolerates the normal cells. That's because the immune system doesn't recognize cancer cells as something foreign, Hirschfeld says. Rather, cancer cells are once-normal cells that have gone awry. Cancer vaccines try to get the immune system to overcome its tolerance of cancer cells so that it can recognize them and attack them.

All cells have unique proteins or bits of proteins on their surface called antigens. Many cancer cells make cancer-specific antigens. The goal of using cancer antigens as a vaccine is to teach the immune system to recognize the cancer-specific antigens and to reject any cells with those antigens. The antigens activate white blood cells called B lymphocytes (B cells) and T lymphocytes (T cells). B cells produce antibodies that recognize a particular antigen and bind to it to help destroy the cancer cells. T cells that recognize a particular antigen can attack and kill cancer cells. In 1991, the first human cancer antigen was found in cells of a person with melanoma, a discovery that encouraged researchers to search for antigens on other types of cancer, according to the NCI.

The two main approaches for cancer vaccines are whole-cell vaccines and antigen vaccines. Whole-cell vaccines may take whole cancer cells from a patient or sometimes several patients, or use human tumor cell lines derived in a laboratory. "Some cell-based vaccines use tumor cells from the patient, some contain something that looks like a tumor cell but was created in a lab, and others are personalized vaccines that use some cells from the patient and some from the lab," Hirschfeld says. Cells that are taken from people with cancer are altered in a lab to inactivate them so that they are safe to re-inject.

Regardless of the exact source of the cells, whole cell vaccines potentially use all the antigens found on the tumor cells. Antigen vaccines try to trigger an immune response by using only certain antigens from cancer cells. Hirschfeld says antigens may be particular to an individual, to a certain type of cancer, or to several types of cancers.

Boosting the Immune Response

In the early 1990s, Steven Rosenberg, M.D., one of the pioneers of immunotherapy and chief of surgery at the NCI, wrote that trying to use the immune system to fight cancer is so difficult that it made him feel "like a dog trying to bite a basketball." Among Rosenberg's contributions was identifying the antigens that trigger an immune response, and cloning genes that look for, or "code for," those antigens.

Researchers have been working to develop cancer vaccines for more than 100 years in one form or another, and the main mission has always been to make the immune system's response to the cancer antigens as strong as possible.

One major strategy involves combining vaccines with additional substances called adjuvants, which act as chemical messengers that help T cells work better. An example of one type of adjuvant, called a cytokine, is interleukin-2. This protein is made by the body's immune system and can also be made in a lab.

There have also been improvements in vaccine delivery. For example, Schlom developed a vaccine in which genes for tumor antigens are put into a weakened virus called a "vector" that delivers genetic materials to cells. This makes the tumor antigen more visible to the immune system. The CEA-TRICOM vaccine was developed at the NCI through a cooperative research and development agreement with Therion Biologics in Cambridge, Mass. Researchers use the vaccinia virus, the same virus in the smallpox vaccine, as the vector. The carcinoembryonic antigen (CEA), which is found on most breast, lung, colon, and pancreatic tumors, is added to the virus. Researchers also add three molecules, called "costimulatory molecules," which serve as signals that make the vaccine more potent than it would be if the antigen were used alone. A similar vaccine developed under the NCI agreement with Therion is the PANVAC vaccine, which has now entered advanced study as a treatment for pancreatic cancer.

In addition to studying this type of virus-based technique, researchers at Duke University's Cancer Center in Durham, N.C., have been studying vaccines that mix white blood cells called dendritic cells with genetic material from a person's tumor.

Dendritic cells, which can activate T cells, work by looking around, finding antigens, and showing them to the fighter T cells. Researchers have found ways to increase the number of dendritic cells in a vaccine. "Employing millions of 'pumped up' dendritic cells can help elicit a strong immune response," says H. Kim Lyerly, M.D., director of the Duke cancer center.

Recent work by Lyerly and Duke investigators Michael Morse, M.D., and Timothy Clay, Ph.D., has focused on modifying dendritic cells with viruses so that they activate even stronger T cell responses against cancer antigens.

"This is an evolving area, and it's exciting to be able to make progress," says Lyerly. "For decades, people thought it wasn't even fundamentally possible to develop cancer vaccines, and here we are. The science behind cancer vaccines is leading us to believe that we will find the answers."

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