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Researchers Use ‘Trickery’ To Create Immune Response Against Melanoma

Dendritic cell-based therapy uses tumor cells and ‘danger’ signals to stimulate tumor immunity

PITTSBURGH, November 1, 2005 — A new type of immunotherapy in which dendritic cells are tricked into action against cancer when they are exposed to harmless pieces of viruses and bacteria is described in the November issue of Cancer Research. Dendritic cells, the pacemakers of the immune system, are known to play a vital role in the initiation of the immune response but are often eluded by cancer.

In the study, University of Pittsburgh researchers describe the creation of an animal model of an immunotherapy approach that, first used in cancer patients, uses a patient’s own tumor cells to stimulate anti-tumor immunity. The discovery of the animal model will enable researchers to more fully understand and develop the approach.

“Cancer cells are very adept at camouflaging themselves and hiding from the immune system and this makes most cancers, including melanomas and lymphomas of the skin, extremely challenging to treat with existing immunotherapies,” said Louis D. Falo, M.D., Ph.D., professor and chairman of the department of dermatology at the University of Pittsburgh School of Medicine. “While we know that dendritic cells are necessary to activate a response against cancer as the first cells to present antigens to other cells of the immune system, they are often ineffective because they fail to recognize growing cancers as dangerous. What we describe is an immunotherapy approach that activates dendritic cells by using an external stimulus that mimics danger. This alerts the cells to activate a type of immune response that is particularly important for fighting cancer.”

In the study, melanoma cells and dendritic cells from mice were removed, combined together in a culture dish and exposed to pieces of viruses and bacteria. The researchers used the most aggressive mouse melanoma tumor, B16, which has multiple mechanisms to escape the immune system that are similar to those used by human cancers. They found that the dendritic cells were able to extract antigens directly from tumor cells. By exposing the antigen-bearing dendritic cells to harmless pieces of bacteria and viruses that they perceived as dangerous, the researchers “tricked” them into recognizing the tumor as dangerous as well. The alerted cells were then injected back into the mice where they successfully activated a particular T-cell response important for fighting tumors. That response, called Th1, led to a significant reduction in tumor growth in the mice.

“Typically, tumors are able to grow in part by convincing the immune system that they are normal. Our goal was to mimic danger to wake up the dendritic cells and program them to stimulate the right type of immune response against the patients’ own tumor cells,” said Dr. Falo.

The researchers further discovered that the Th1 response was enough to stop tumor growth on its own, indicating the importance of Th1-type immunity for tumor therapy. Prior to their discovery, researchers believed that a Th1 response was important, but that it worked primarily by activating another type of T-cell called a cytotoxic T-cell (CTL). These results suggest that it may be important to monitor Th1-type immunity in addition to CTL immunity when evaluating patients’ responses to immunotherapy.

Interestingly, Dr. Falo has already found this approach to be successful in a preliminary study in cancer patients. But further progress has been hindered by the length of time and expense involved in such a clinical trial. Unlike most therapy advances that are developed in animal models and then translated to patients, the “danger” signals used in this approach were developed using models based on human tissue. He believes that the creation of this animal model will enable further development of immune approaches to melanoma and other cancers, bringing new treatment options to patients who have failed available therapies.

Melanoma is the most serious form of skin cancer. Although it accounts for only 4 percent of all skin cancer cases, it causes most skin cancer-related deaths. Lymphomas of the skin, including cutaneous T-cell lymphomas, are diagnosed in approximately 16,000 to 20,000 people in the United States each year and are often difficult to diagnose in early stages.

This study was funded by a grant from the National Cancer Institute. Collaborators on the study include University of Pittsburgh researchers David A. Hokey; Adriana T. Larregina, M.D., Ph.D.; Geza Erdos, Ph.D.; and Simon C. Watkins, Ph.D.

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