An early-phase clinical trial of interleukin-12 (IL-12) published online February 28 in Blood has shown promising results in patients with AIDS-related Kaposi's sarcoma (KS).

KS involves the abnormal growth of blood vessels and can develop in the skin or internally. Unlike most cancers, KS is caused by a virus - Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8. This virus is relatively common in certain countries with a high incidence of KS. In most people, the virus is kept in check by the normal functioning of the immune system. However, patients with severely suppressed immune systems, such as people living with HIV, are vulnerable to the development of KS.

Because IL-12 can act as both an immunostimulator and an antiangiogenesis agent - a drug that can suppress the growth of new blood vessels - investigators lead by Drs. Robert Yarchoan and Richard Little from NCI's HIV and AIDS Malignancy Branch saw potential for the drug in the treatment of AIDS-related KS.

"We initially became interested in IL-12 with the idea of correcting the immunodeficiency of HIV," explains Dr. Yarchoan. "Then it was reported that it had antiangiogenesis activity, and this stimulated our interest in AIDS-associated KS. Kaposi's is essentially a tumor of endothelial cells, which are important in angiogenesis. Yet another reason for our interest was the idea that we might be able to boost the immune system's ability to fight the KS virus. So we thought that this was a potentially interesting tumor in which to test IL-12."

Their phase I study enrolled 32 patients who had received a stable regimen of antiretroviral therapy for at least 3 months prior to entry and who had worsening KS on this regimen. They chose to test the drug in patients whose KS was no longer kept in check by highly active antiretroviral therapy (HAART) in order to ensure that observed responses were not due to activity of HAART. Cohorts of 3 to 6 patients received IL-12 subcutaneously twice a week at doses of 100, 300, 500, or 625 nanograms per kilogram (ng/kg) of body weight. Additional patients were enrolled on the 500 ng/kg dose when it was established as the maximum tolerated dose of IL-12.

Of the 28 patients from all cohorts who could be evaluated for tumor response, 4 experienced a complete response, and 13 experienced a partial response. The overall response rate was 61 percent. For patients in the 300 and 500 ng/kl dose cohorts, the response rate was 71 percent. Among patients receiving doses of 300 ng/kg or higher who could be evaluated for tumor response, the median progression-free survival was not reached by the end of the study, and the probability of progression-free survival at 4 years was 82 percent.

Most side effects were mild, although some patients did develop more severe toxicities including joint pain, vomiting, and headaches. Interestingly, the investigators also noted a high incidence of depression that was apparently linked to administration of the drug. However, as Dr. Yarchoan noted, a number of the patients had a history of depression, and this had not emerged as a problem in previous studies of IL-12 in other tumors. Nonetheless, he commented, "Depression can be difficult to detect, and investigators need to be on the lookout for it in future studies of IL-12."

IL-12 has been previously tested against various tumors in several phase II trials, but relatively little activity was observed. According to Dr. Little, the KS results suggested that it was worth taking a second look at this drug, especially in tumor types that might respond to improved immunity or be very sensitive to the inhibition of angiogenesis. He also noted that IL-12 was an excellent candidate for a randomized clinical trial in patients with AIDS-related KS that no longer responds to HAART.