By Mary Jean Pramik
Special To BioWorld Today
SAN FRANCISCO -- At the First International Congress on Proleukin, sponsored by Chiron Corp., researchers from around the world presented results of studies with interleukin-2 (IL-2) for treatment of AIDS and a variety of cancers, including hematologic malignancies and metastatic melanoma.
Chiron, of Emeryville, Calif., sells Proleukin, which is IL-2, for treatment of metastatic renal cell carcinoma. In April the company asked the FDA to expand the label to include metastatic melanoma.
Use of IL-2 has been limited by the inherent toxicity of the cytokine.
However, at the conference last week in San Francisco, Kendell Smith, of the New York Hospital-Cornell University Medical Center, in New York, said low doses of IL-2 appear to increase the body's natural defenses without causing the severe toxicity usually associated with the drug.
Smith described IL-2's side effects as the "cytokine syndrome" of severe fever, nausea, vomiting and serious hypotension.
Smith's research found that cytokine syndrome can be eliminated by administering just enough IL-2 to saturate the high-affinity IL-2 receptors. The Cornell scientist gave low doses of IL-2 to asymptomatic HIV-positive patients. The doses were about 500-fold lower than those used in cancer therapy and 50-fold lower than those given as intermittent therapy for HIV. No systemic side effects appeared during the six-month trial.
Results of Smith's studies showed the low-dose IL-2 treatment promoted a rise in CD4+ T cells and increases in natural killer cells, monocytes and eosinophils.
"We have begun more extensive clinical trials at our hospital to assess low-dose IL-2 with the triple-drug antiviral therapy that now appears so promising in treating HIV-positive patients," Smith said. "One randomized trial, to include about 50 HIV-positive patients, will compare the current triple antiviral therapy with the triple antiviral regimen combined with IL-2," he said.
Smith suggested IL-2 may have many therapeutic applications once researchers learn how it actually functions in the body and how to modulate dose levels to reduce side effects.
In other research, low doses of IL-2 combined with interferon-alpha (IFN-alpha) appeared to boost survival of patients with acute leukemic lymphoma, said Shimon Slavin, of the Cancer Immunotherapy & Immunobiology Research Center at Hadassah University Hospital, in Jerusalem. IL-2 and IFN-alpha were administered following autologous stem cell transplants.
In patients undergoing allogeneic blood and marrow transplantation, Slavin's group found that combining IL-2 and IFN-alpha promoted an "autoimmune-like" response against residual tumor cells after the bone marrow transplant. In combination with IFN-alpha, the IL-2 also appeared to have a reduced toxicity.
IL-2 May Be Chemotherapy Alternative
Slavin now is conducting a multinational, prospective, randomized clinical trial evaluating the IL-2 and IFN-alpha combination therapy in leukemia and lymphoma patients.
"Interleukin-2 is a good drug but we needed to learn how to use it correctly." said Slavin. "Many leukemias and other malignant blood diseases have grown resistant to conventional chemotherapy. We have to explore new ideas to treat cancer. We now have to go for a cure and not continue to just prolong the patient's life for a few months."
Additional clinical trials using IL-2 and IFN-alpha showed that when combined with standard chemotherapy, the collection of drugs improved response rates of malignant melanoma patients, reported Sewa Legha and colleagues at the M.D. Anderson Cancer Center, in Houston.
The M.D. Anderson Cancer Center group developed "biochemotherapy" regimens in which IL-2 and IFN-alpha were given with standard combination chemotherapy: cisplatin, vinblastine and DTIC.
"We had a 60 percent complete response rate in 24 patients with malignant melanoma after the first three weeks of this regimen," Legha said. "About 10 percent of our total patient population is still in complete remission for follow-up periods of over four years." However, Legha added, the treatment regimen is quite toxic.
French researchers also reported positive results using a combination of IL-2, IFN-alpha and chemotherapy. (See BioWorld Today, July 14, 1997, p. 1.) *