Interleukin-2: Therapy For Kidney Cancer : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 2)

Birth of a Therapy

IL-2 was discovered in 1976 and described as a protein that supports the growth of certain T cells in culture. In 1983, researchers identified the gene encoding IL-2, making it possible to mass-produce the protein in genetically engineered bacteria, a technology that avoids the contamination that can happen when biological substances are collected from human donors and increases productive capacity.

Between 1984 and 1986 came the groundbreaking work that placed IL-2 on the pathway to clinical use. Steven A. Rosenberg, M.D., and his colleagues at the National Cancer Institute showed that IL-2, given to mice either alone or with the lymphocytes that they stimulate (called lymphokine-activated killer cells, or LAK cells), shrunk tumors that had spread to the lungs, liver and skin. (The effect of IL-2 on tumors was not direct. Instead, the lymphocytes, whose numbers they increase, attack the tumor.) So spectacular were the results of IL-2 on mice that phase I clinical trials began in 1984 and 1985 in patients with advanced cancer who had exhausted existing treatments. These trials established safety and the maximum tolerable dose of IL-2.

A 1987 study by Rosenberg compared IL-2 alone to IL-2 given with LAK cells. The cells were removed from the patients, cultured with IL-2 in the laboratory, and then injected into the patients. For kidney cancer, there appeared to be little or no difference in receiving IL-2 alone or with LAK cells.

Refining IL-2 Therapy

The story of IL-2 is still in its opening chapter. Researchers are attempting to tame the toxicities so that the cancer-fighting effects can be brought to more patients.

"The FDA approval is for the high-dose regimen, which is very toxic," says Jay Siegel, acting director of the division of clinical trials at FDA's Center for Biologics Evaluation and Research. "We had considerable concerns. How should IL-2 be given — subcutaneously or intravenously? Intermittently or continuously? There were a range of trials, and a lot was looked at." The approval was for a high-dose regimen, Siegel adds, because the largest experience was with the high-dose regimen and the available data suggested that response rates were considerably lower at lower doses.

Physicians around the world are now experimenting with variations on the high-dose theme of IL-2 therapy. Many physicians, say McDonald and Schonfeld, are giving patients lower doses than that approved by FDA, which is legal. "More physicians are giving IL-2 in moderate-dose protocols. This has made it a lot more accessible — people who couldn't tolerate the high-dose regimen are getting low-dose IL-2, and some are benefiting," says Schonfeld.

However, Siegel points out that little data documenting an effect at lower doses has been reported to FDA.

But lower-dose IL-2 protocols can be given on an outpatient basis. The approved high-dose plan requires hospitalization, usually in a cancer unit, but sometimes in intensive care if side effects are severe. Jerome Ritz and co-workers at the Dana-Farber Cancer Institute in Boston conducted a phase I clinical trial in which 21 kidney cancer patients received IL-2 as outpatients for three months. The researchers noted minimal toxicity, and an increase in the number of a certain type of lymphocyte in the patients' blood, concluding, "therapy with low-dose IL-2 can be given safely in an uninterrupted fashion for prolonged periods of time in an outpatient setting." A phase II trial will evaluate whether outpatient IL-2 therapy shrinks tumors.

What about altering the rate at which IL-2 enters the body? The Extramural IL-2/LAK Working Group at the University of Texas Health Science Center in San Antonio compared IL-2 given in three injections daily to continuous infusion. Would a continuous supply of the toxic treatment be more tolerable? It wasn't. Data from studies submitted to FDA indicated that patients receiving the continuous infusion regimen had comparable side effects but fewer responses to treatment than those on a three-times-a-day regimen.

Similarly, a large group of investigators led by Michael B. Atkins at the New England Medical Center in Boston suspected that combining IL-2 with another cytokine, alpha interferon, might be more effective, because interferon attacks cancer cells differently than does IL-2. But IL-2 alone was more effective, with a 17 percent response rate, compared to only 11 percent for the combined cytokine approach.

Other Approaches

In another approach, researchers at the Surgery Branch of the National Cancer Institute are combining IL-2 with white blood cells called "tumor infiltrating lymphocytes," or TILs. These cells are found within a specific tumor, and theoretically fight only that tumor. They are not the same as LAK cells, which circulate in the blood and have a much more general effect. TILs are up to 100 times more effective than LAK cells in killing certain tumor cells.

NCI researchers reported in the November 1992 issue of Contemporary Urology that they are developing a "tumor reimplantation protocol." When the cancerous kidney is removed, a small piece of it will be implanted underneath the skin of the patient's thigh. (The skin is a site of intense immune system activity.) Three weeks later, the researchers will collect lymphocytes from a lymph node near the tumor implant. They will separate out the tumor-specific TILs, grow them to larger numbers in the laboratory using IL-2, and then reinfuse them into the patients. The hope: that the nurtured and boosted TILs will seek and destroy any remaining cancer cells in the body, while the implanted bit of tumor continues to alert the immune system.

Yet another approach is to add IL-2 genes to TILs in the lab, so that they make their own IL-2 when reintroduced into the body.

In the February 1992 issue of the Journal of Urology, German researchers Edith Huland, M.D., and colleagues reported on administering IL-2 more directly — by aerosol in a device similar to those that deliver asthma medication — to patients whose kidney cancer has spread to the lungs.

"They apply IL-2 directly to lung tumors, where it activates TILs locally that are the most sensitive to the tumor because they are already there," says Schonfeld. Clinical trials of this approach in the United States have just begun, he adds.

With a demonstrated ability to treat an untreatable cancer and many new variations in the works, IL-2 therapy for advanced kidney cancer has begun to show its value.

Concludes Schonfeld, who may one day undergo the treatment himself for his kidney cancer, "When IL-2 works, it really works well. Some of our members with advanced disease in both lungs had a total response — they've walked away, after IL-2 treatment, cancer free."

About the Author

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