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Boosting Killer Cells Might Improve Breast Cancer Drug [Ohio State University]
COLUMBUS, Ohio - Preliminary research suggests that a drug that targets a particular type of breast cancer might be more effective if patients are also given a substance made by the body that stimulates certain immune cells.

The laboratory and animal study suggests that the substance interleukin 21 (IL-21) might improve the effectiveness of the drug Herceptin. The findings suggest that this happens because the IL-21 boosts the cancer-killing activity of immune cells called natural killer (NK) cells, which attack the tumor.

The findings by researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute are published in the July 1 issue of The Journal of Immunology. The researchers hope to begin a clinical trial to test the strategy in humans soon.

Herceptin is used to treat HER2-positive breast cancer — about 20 percent of all breast-cancer cases. HER2 breast cancers have a protein called HER2 on the surface of the tumor cells. Herceptin attaches to the HER2 protein and coats the cells.

The findings indicate that IL-21 stimulates NK cells to attack and destroy the Herceptin-coated cells.

"Only 25 to 35 percent of patients with this form of breast cancer respond to Herceptin," says principal investigator William E. Carson, III, associate professor of surgery and associate director for clinical research at the OSU Comprehensive Cancer Center .

"Our results suggest that giving IL-21 along with the Herceptin might increase the patient's immune response to the tumor and perhaps boost the drug's effectiveness."

Many researchers believe that Herceptin works because it stops tumor cells from growing and causes them to self-destruct through a natural process called programmed cell death, explains first author Julie M. Roda, a graduate research associate in Carson 's laboratory.

But, Roda says, "our findings provide new evidence that Herceptin works at least in part by stimulating NK cells activity, and that IL-21 enhances that action."

Carson, Roda and their collaborators chose to study IL-21 because the substance is known to activate NK cells and causes them to release substances that attract other immune cells to a tumor site.

This study's findings came from several experiments. First, the scientists exposed NK cells in Petri dishes to both Herceptin and IL-21. This caused the cells to release three to 10 times more of a substance called interferon gamma than would cells exposed to either agent alone.

Interferon gamma is an immune-system signaling agent that causes the NK cells to become more active. It also increases the activity of other immune cells and forces tumor cells to self-destruct.

The researchers then repeated this experiment in mice. They found that animals given both IL-21 and Herceptin-coated tumor cells had nearly three times more interferon gamma in their blood than did animals injected with either of those items alone.

Still another experiment used mice with HER2-positive tumors. When the animals were treated with both the mouse version of Herceptin and IL-21, the tumors shrunk by nearly half compared to those in mice receiving either agent alone.

Last, to test whether the interferon gamma was important for causing the tumors to shrink, the researchers repeated this experiment using mice that cannot make the substance.

The researchers were surprised to find that when interferon gamma was missing, the mouse drug and IL-21 combination had no effect on the tumors.

"We thought if we took out interferon gamma, the NK cells would still be able to kill the tumor cells," Roda says.

But that didn't happen

"This is very interesting because it suggests that interferon gamma production might be critical to the response to Herceptin, and I believe that we are the first to show this."

Overall, says Carson , "Our results suggest that IL-21 might enhance the effectiveness of Herceptin, and perhaps similar anticancer drugs."


ABSTRACT: Interleukin-21 Enhances NK Cell Activation in Response to Antibody-Coated Targets [Journal of Immunology; Subscribe]
NK cells express an activating FcR (Fc?RIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modulatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-? secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-?. Increased secretion of TNF-? and the chemokines IL-8, MIP-1?, and RANTES was also observed under these conditions. NK cell IFN-? production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-? by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-?. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.