Interleukin-2: Therapy For Kidney Cancer

by Food and Drug Administration (FDA)

The 59-year-old woman was in for a distressing surprise when she returned to the hospital for a routine chest x-ray 10 months after her 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 wasn't 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 doesn't work," says Eugene Schonfeld, Ph.D., president of the National Kidney Cancer Association in Chicago.

But in this case, the woman was lucky — she participated in a clinical trial of interleukin-2 (IL-2), and got a second chance at life. Her success with the treatment contributed to FDA's 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).

Rough Road

The route to recovery with IL-2 isn't 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 woman's case was reported in a medical journal, Seminars in Oncology Nursing, in August 1993, she had been completely free of cancer for 10 months.

A Treatment Where There Was None

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) — but 4 percent died from the treatment.

Controlling Side Effects

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 body's 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.

How IL-2 Works

Researchers still aren't 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.

About the Author

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