Immune Stimulants May Help Antibody-Based Drugs Fight Cancer

COLUMBUS , Ohio. January 1, 2006 - A new study suggests that antibody-based cancer drugs might help patients more if they are given with substances that stimulate the immune system.

This new study is the first to indicate that the drug trastuzumab, also known as Herceptin, may work better when it is followed by injections of interleukin (IL) 2 or IL-12. Both substances trigger the activity of immune cells known as natural killer (NK) cells.

The research, by scientists at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, is published in the Jan. 1 issue of the journal Cancer Research.

The drug trastuzumab consists of an antibody that targets the protein HER2, which is present on cancer cells of many breast tumors. NK cells are the body's first line of defense against many infections, and they also attack tumor cells.

NK cells rush into action when they encounter bacteria or other foreign agents in the body that are coated with antibodies, large proteins released by immune cells in response to the presence of foreign material in the body.

The investigators found that the combination of antibody-coated cells and IL-2 or IL-12 causes the NK cells to release substances that attract more potent immune cells -- mainly killer T cells -- thereby trigging a larger and more effective immune response against the tumor.

Trastuzumab is used to treat advanced breast cancer cases that over-produce the HER2 protein. The drug coats the tumor cells with antibodies, but it is unclear exactly what happens next.

Presently, researchers believe that when the trastuzumab antibodies join with the HER2 protein, they trigger changes within the tumor cells that cause the cells to die or to grow more slowly. In this scenario, the immune system plays a relatively minor role in slowing the tumor's growth.

"But our results show that the immune system really can play an important role in this therapy and that the outcome of patients treated with antibody-based drugs might be improved by activating the patient's immune system with agents such as IL-12," says principal investigator William E. Carson, III, associate professor of surgery and director for clinical research at the OSU Comprehensive Cancer Center.

First author Julie M. Roda, a graduate research associate in Carson 's laboratory, explained why this is so.

"The findings suggest that using trastuzumab and the IL-12 together makes the body think an infection is under way, and this activates cells of the immune system to eliminate tumor cells in the same way they would eliminate an infection," says Roda.

The investigators found that the combination of antibody-coated cells and IL-2 or IL-12 causes the NK cells to release substances that attract more potent immune cells -- mainly killer T cells -- thereby trigging a larger and more effective immune response against the tumor.

"Trastuzumab was not designed to mimic an infectious condition, but we think that's exactly what is happening," Roda says.

Carson, Roda and their colleagues came to their conclusions following several types of experiments.

For example, the researchers added human NK cells and IL-2 or IL-12 to cultures of breast-cancer cells with HER2 and coated with trastuzumab antibodies. In response, the NK cells produced a range of substances (known as cytokines and chemokines) known to attract killer T cells to sites of infection. When the experiment was repeated using cancer cells that lacked HER2 (and therefore were not coated with trastuzumab), however, the NK cells produced little of the T-cell-attracting substances.

The researchers also injected IL-12 and trastuzumab-coated mouse-tumor cells into mice and found that it raised the blood levels of the immune-stimulating substances produced by NK cells.

In addition, the researchers analyzed plasma samples from 15 patients with different types of cancer who were participating in a phase-I clinical trial of trastuzumab plus IL-12. The samples showed short-term increases in immune-stimulating substances produced by NK cells, and long-term increases in three patients who responded to the therapy.

"This is a preliminary study and the findings must be verified," Carson says, "but overall, the evidence supports the use of immune-stimulating agents in patients who receive antibody-based drugs such as trastuzumab."

Funding from the National Cancer Institute supported this research.