Interleukin-2

cancerous kidney had been successfully removed. Although she felt fine, the x-ray showed several ominous spots in both lungs, some as large as grapes. The cancer had spread. It wasnít a complete surprise, though.

Her doctors had said that despite surgery, kidney cancer eventually spreads, usually to the lungs, in about half of the 20,000 new cases diagnosed yearly in the United States. In the past when this happened, there was virtually no treatment.

"Conventional chemotherapy has a very unsuccessful response rate for advanced, metastatic [spread] kidney cancer of only about 4 percent, and radiation doesnít work," says Eugene Schonfeld, Ph.D., president of the National Kidney Cancer Association in Chicago.

But in this case, the woman was luckyñshe participated in a clinical trial of interleukin-2 (IL-2), and got a second chance at life. Her success with the treatment contributed to FDAís licensing in May 1992 of IL-2 for the treatment of kidney cancer. IL-2 is a naturally occurring protein that stimulates an immune response. The biological product is marketed under the brand name Proleukin (generic name, aldesleukin).

The route to recovery with IL-2 isnít easy. Two months after the devastating chest x-ray, after tests showed her heart, lungs, and remaining kidney to be functioning well and her head, bones and abdomen to be free of tumors, the woman began her first treatment cycle with IL-2. In the hospital, every eight hours, for five consecutive days, she received the medication intravenously. The IL-2 caused her immune system to produce more cancer-fighting lymphocytes (a type of white blood cell), along with other biochemicals, called cytokines, that cause some of the long list of side effects she experienced.

She lost her appetite, developed a rash, was very tired, and her urine was scant and contained protein, signs of strain on her kidney. But these problems vanished days after stopping treatment. Her second IL-2 cycle (two five-day treatments nine days apart) seven weeks later brought the same side effects, but so much more severe that her doctors halved the doses in the remaining cycles of the six-month regimen.

But more was happening in her body than temporary misery. After only two treatment cycles, the spots in her lungs began to shrink; by six months, her chest x-ray was clear! When the womanís case was reported in a medical journal, Seminars in Oncology Nursing, in August 1993, she had been completely free of cancer for 10 months.

IL-2 is now the state-of-the-art, conventional treatment for advanced, metastatic kidney cancer, says Schonfeld, who underwent surgery for kidney cancer himself four years ago and who presented FDA with evidence in support of the treatment at various points along the road to approval.

In 1990, the agency concluded evaluation of data submitted by the manufacturer, Cetus Oncology of Emeryville, Calif., from several clinical trials, including a total of 106 kidney cancer patients who received the proposed regimen of interleukin-2. Although results looked promising, the agency requested more information. The number of favorable responses was small, most occurred in one medical center, and toxicity was substantial. This made it difficult to judge the value of the therapy.

By 1992, Cetus had submitted more cases, showing "significant clinical benefit in a minority of 255 patients," according to Richard Fisher, professor at Loyola University Medical School in Chicago, who presented the data at an FDA meeting. Fifteen percent of the patients showed a partial response (tumor shrinkage), and 4 percent showed a complete response (no sign of tumor)ñbut 4 percent died from the treatment.

Side effects seem to be part and parcel of taking IL-2. The patient brochure from the manufacturer says that everyone has some side effects, but the nature and severity vary. Nearly everyone experiences fever, shaking and chills shortly after receiving the first dose. This is an expected response to the bodyís receiving a huge dose of interleukin-2, which is normally present in the body in only very small amounts.

Other side effects stem from a phenomenon called "capillary leak syndrome." Capillaries are microscopic blood vessels, their walls only a single cell thick, joined like bathroom tile and folded to form tiny tubules. IL-2 causes the fluid portion of blood to leak from inside capillaries to the tissue spaces outside, the areas between organs. This both robs organs of their blood supply, and swells the body. As a result, the patient gains weight and has lower blood pressure, kidney strain, and respiratory distress.

Patients usually require fluids and drugs to support their blood pressure and occasionally require dialysis or mechanical ventilation (machines to assist kidneys and lungs). They may also experience neurological changes such as mood alteration, lethargy, agitation, coma, or seizures. Fortunately, IL-2 toxicities usually clear up within a few days after IL-2 treatment stops, although fatigue may linger for a few weeks.

Researchers still arenít sure precisely how IL-2 combats kidney cancer, because its role in the immune system is quite complex.

IL-2 is a cytokine, a hormone-like substance secreted by the cellular branch of the immune system, which also includes T lymphocytes, or T cells. (The other branch, the humoral immune system, includes B lymphocytes, or B cells, and their secreted substances, antibodies.) There are many different types of cytokines, which interact together, so teasing apart the role of just one is difficult.

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.

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 FDAís Center for Biologics Evaluation and Research. "We had considerable concerns. How should IL-2 be givenñsubcutaneously 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 accessibleñpeople who couldnít 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 patientsí 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 wasnít. 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.

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 patientís 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 directlyñby aerosol in a device similar to those that deliver asthma medicationñto 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 responseñtheyíve walked away, after IL-2 treatment, cancer free."

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