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The immune system usually is thought of as our defense against foreign invaders, but the immune system also patrols against cancer in our own cells.

Cancer vaccines try to boost the immune system's response to cancer the same way infectious disease vaccines work. In their simplest forms, the vaccines introduce an antigen (a protein or piece of a protein that's unique to the virus or cancer) into the body, and the antigen primes the immune system to attack other cells that display the same protein. In cancer, the hope is that the immune system's T cells will recognize the antigen on tumor cells and kill the cells.

But researchers are finding that cancer cells have ways to evade destruction by the immune system and the simple vaccines are generally not strong enough to work in patients.

Now new methods to make cancer cells more vulnerable to the vaccine and how these methods work in patients are being studied in the laboratory of Dr. Howard Kaufman, associate professor of clinical surgery, vice chairman of surgical oncology, and director of the Center for Innovative Cancer Management.

One reason T cells may have difficulty finding and killing tumor cells is because cancer cells don't present the co-stimulatory molecules that T cells need to see before becoming activated to kill.

Dr. Kaufman's strategy is to deliver those co-stimulatory molecules into the tumor cells with a virus. One virus he's testing in clinical trials carries genes of three human co-stimulatory molecules. When the vaccine, made by Therion Biologics Corp. of Cambridge, Mass., is injected into the tumor, the virus infects the cancer cells and the cells produce and display the co-stimulatory molecules. T cells recognize the infected cells by the viral antigens displayed on the tumor and become activated to kill the cells after recognizing the co-stimulatory molecules.

To date, 10 patients with malignant melanoma treated in the phase I trial of the co-stimulatory vaccine have not experienced side effects to the vaccine and two of them have had a reduction in the size of at least one of their tumors.

Dr. Kaufman's lab also is designing virus-based vaccines that carry other molecules that may help the T cells kill tumor cells. Cytokines, including interleukin-2, help T cells grow and gain killer activity. In a study published last March in Vaccine, the lab found that a virus with two cytokines and the tumor-specific antigen doubled the survival of mice with lung cancer. They also are trying to construct a vaccine that will carry chemokines, a recently discovered group of molecules that are thought to attract T cells and other immune cells to sites of antigen priming. The lab has preliminary evidence that this approach may also activate the T cells.

Unlike infectious disease vaccines that are administered before exposure, cancer vaccines are only tested in people who already have advanced disease. But Dr. Kaufman believes vaccines may be more effective if given before cancer begins. "With genetics, we can identify some people at high cancer risk, such as women with BRCA1 and people with familial polyposis who develop colon polyps in their teens that turn cancerous in their 30s and 40s," Dr. Kaufman says. "These people are perfect candidates for a vaccine."

To investigate preventative cancer vaccines, Dr. Kaufman and his colleagues engineered a mouse that develops colon polyps, which then progress to cancer. The tumors the mice produce also make large amounts of human CEA, a protein overexpressed in many human cancers.

When young mice without polyps were injected with a vaccine that stimulated the mouse's T cells to recognize and kill tumor cells displaying CEA antigen, none of the mice developed polyps four months after injection while all of the control mice developed colon cancer.

The lab is now working with a preventative vaccine in people. "We're testing the vaccine in patients with metastatic colon cancer," Dr. Kaufman says, "and if the vaccine is shown to be safe, we hope to persuade the FDA to let us try it in high-risk patients."

Dr. Kaufman says cancer vaccines would improve if researchers can figure out better ways to stimulate the human immune system. "In clinical trials, we're finding about one in 10,000 T cells are specific for the cancer's antigen after vaccination," Dr. Kaufman says. "But in a viral infection, you'll have one in 500 or one in 1,000 T cells to fight the virus. I think vaccines will be effective when we can boost T cells to the levels seen after viral infection."

The research is being supported by the NIH, the Doris Duke Charitable Foundation, and Therion Biologics Corp.


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