New results from NCI's Center for Cancer Research (CCR), reported in the November 15 Cancer Research, show promise for interleukins (IL) to enhance the body's natural ability to fight cancer that has spread to the liver. A combination of IL-12 and IL-18 increased the concentration of natural killer (NK) cells in animals and triggered therapeutic levels of interferon-gamma (IFN-γ), a key messenger molecule that regulates the immune system defenses against cancer in the liver, a common site of tumor metastasis.

NK cells are key players in the immune process, and are aptly named because they act like commandos on a search-and-destroy mission for virally infected and cancerous cells.

"This combination of interleukins significantly modifies the microenvironment in the liver and has potent antitumor activity," said Dr. Robert H. Wiltrout, director of CCR and head of the lab where the work was done. "Immunotherapeutic approaches using this strategy represent a novel approach to treating tumors in the liver." Current treatments to surgically resect or transplant the liver are only effective in a minority of patients.

Interleukins and other cytokines occur naturally in the body as signaling molecules, which are part of the immune system, but they may also be reproduced in recombinant form in the lab. "We knew that both IL-12 and IL-18 each ramp up NK cell production separately, but now we find that when given together, they have a synergistic effect," said Jeff Subleski of CCR, lead author.

The combination of IL-12 and IL-18 not only increased the number of NK cells, but also continued to populate the liver microenvironment and mediate IFN-γ for at least 2 weeks. Previous work with each interleukin alone had shown the IFN-γ effect to drop significantly within 4 days or less. "This means that IFN-γ appears to play a key role in triggering immune cells to attack cancer cells," said Mr. Subleski.

The key to sustaining high levels of IFN-γ, noted Dr. Wiltrout, was turning down the number of natural killer T (NK-T) cells, another immune system operative. Even though NK-T cells in the liver similarly increase IFN-γ, they also can suppress antitumor immune system activity, he explained.

"NK-T cells are heavily expressed in the liver because it is the junction between the blood stream and the gut where foreign antigens and bacteria are common, and where initial immune defenses are strategically effective. But NK-T cells may also serve as sentinels by initially suppressing immune reactions that would be excessive," said Dr. Wiltrout.

He further explained, "You don't want immunosuppression to contribute to tumor spread or progression." In this experiment, the novel combination of IL-12 and IL-18 reduced the regional NK-T cell population to undetectable levels before they could suppress the IFN-γ impact on the tumors.

Initiation of an immune response against a tumor requires a complex set of events. Information gained from animal studies will likely provide insight into how the power of the immune system can be harnessed to develop new anticancer therapies.

"These are very promising findings for the immunotherapy of any type of cancer that is sensitive to killing by NK cells, as it does not require identification of molecules unique to the tumor," said Dr. Jay A. Berzofsky, chief of CCR's Vaccine Branch. "By diminishing the suppressive effects of NK-T cells, the IL-12/IL-18 combination treatment could provide a one-two punch needed to immunologically control cancer."

By Addison Greenwood