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Twice Weekly IL-12 Shows Promise in Kidney Cancer

Twice Weekly IL-12 Shows Promise in Kidney Cancer

WASHINGTON—“Enough evidence has accumulated to suggest that interleukin-12 [IL-12] deserves continued study in kidney cancer and other malignancies, even though it has had a difficult track record so far,” Janice P. Dutcher, MD, said at the 1999 Kidney Cancer Association Annual Convention. Dr. Dutcher is associate director for clinical affairs, Our Lady of Mercy Cancer Center/New York Medical College.

While problems with dose and toxicity emerged in past clinical studies of IL-12, researchers at Beth Israel Deaconess Hospital, Boston, may have hit upon a useful balance by giving the drug twice a week, Dr. Dutcher said.

“I’m not saying this is the answer to this disease,” she said. “I’m just saying it bothers me if we don’t fully explore every new drug that has a glimmer, because we need anything we can find.”

Researchers also need to explore every angle of a possible new drug before they discard it from their candidate list, she said. The fact that the immune system’s role in kidney cancer is unclear has not stopped scientists from investigating a number of immunomodulators and their potential for treatment of the disease.

“It is a lot of trial and error,” Dr. Dutcher said. “Unfortunately, that’s how we’ve made advances in cancer. Nobody has waited to have the whole picture. Still, with a little bit of theory and hypothesis and a lot of real hard work, we have made steps forward by learning to control the immune system and to activate the immune system.”

A Rocky Path

Interleukin-12’s rocky path in kidney cancer research began with testing in mice showing the drug was extremely active, more so than interleukin-2, Dr. Dutcher said. But in early testing, subcutaneous and intravenous injection of IL-12 produced mouth sores, flu-like symptoms, and elevated liver enzymes.

“Later phase I studies, in which the dose was reduced, produced responses in kidney cancer and melanoma,” she said. In a phase II study, doses were given over 5 days but the study was stopped because of toxicity—nevertheless, one patient had a partial response lasting a year.

Other institutions gave IL-12 as a weekly dose, which caused decreases in toxicity but no response. “So what’s in between?” Dr. Dutcher asked. “Maybe twice a week. The biology and pharmacology tell us that maybe twice a week dosing makes more sense.”

Researchers are currently investigating IL-12 given on a twice-a-week schedule for 6 to 18 months in Kaposi’s sarcoma in AIDS patients and in cutaneous T-cell lymphoma, which is also associated with an immune deficiency. “So far, some of the patients are experiencing a response to the drug,” she said.

In the study of kidney cancer at Beth Israel Deaconess, the drug is being given twice a week for 36 weeks or more. “Patients are tolerating the drug with only some minor side effects,” Dr. Dutcher said. Early results indicate the treatment is leading to sustained gamma interferon levels, and some responses have been seen, she said, emphasizing that these results are preliminary and have not been published. The Boston team also plans other studies of the cytokine, among them a trial of IL-12 in combination with IL-2.

The research results to date are “sort of a wake-up call to you, to me, to all of us, that we want to push further for this drug,” Dr. Dutcher concluded.

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