Low-Dose IL-2 Promising in AIDS Cancers

December 1, 1995

SAN ANTONIO--Physicians who treat HIV-infected patients may need to brace for patient inquiries in light of evidence that low-dose inter-leukin-2 (IL-2, Proleukin) may boost immune function following remission-inducing chemotherapy for AIDS-related malignancies.

SAN ANTONIO--Physicians who treat HIV-infected patients may needto brace for patient inquiries in light of evidence that low-doseinter-leukin-2 (IL-2, Proleukin) may boost immune function followingremission-inducing chemotherapy for AIDS-related malignancies.

The IL-2 therapy led to increased production of eosinophils andnatural killer (NK) cells in AIDS patients with non-Hodgkin'slymphoma or Kaposi's sarcoma, Dr. Michael Caligiuri said at alymphoma symposium sponsored by the University of Texas M.D. AndersonCancer Center.

No patient in the study developed opportunistic infections whileon 90-day courses of IL-2 therapy during 50 accumulated months,and the treatment caused no grade 3 toxicities at the maximumtolerated dose.

Also important in today's cost-containment environment, the researchshowed that low-dose IL-2 can be safely self-injected in the homesetting, whereas patients must be hospitalized for administrationof moderate to high IL-2 doses, due to toxicities.

"We know that we can administer this therapy in the absenceof any significant toxicity. The question remains open as to whetheradministration of such cytokines as IL-2 will help maintain remissionsor ultimately prevent development of lymphoma in immunocompro-misedpatients," said Dr. Caligiuri, associate professor of medicine,Roswell Park Cancer Institute, Buffalo, NY.

Reflecting physicians' anticipation of patient reaction to thenews, Dudley Youman, an oncologist from Austin, Texas, asked,"Are we going to have AIDS patients coming to us wantingto be on IL-2 to prevent lymphoma, and, if so, what's the downside?"

"I would imagine there will be patients who inquire aboutthis," Dr. Caligiuri responded. "The downside is thatthe jury is still out, so we should encourage patients as muchas we can to participate in the phase II and III clinical trialsthat will answer the questions."

Phase II Trial

Enrollment for a phase II trial at Roswell Park has just started,he added, and will be conducted through the new AIDS MalignancyConsortium, the Cancer and Leukemia Group B (CALGB), and possiblyother cooperative groups. The trial will assess the effectivenessof IL-2 in preventing opportunistic infections and/or cancer progressionin HIV-infected patients.

Dr. Caligiuri noted that since AIDS-related lymphomas are associatedwith a progressive decline in immune function and emergence ofa variety of infections, it is hoped that administration of Thelper 1 (Th1) cytokines such as IL-2 in low doses will forestallthe development of malignancies or help sustain remissions afterchemotherapy in these patients.

The clinical trial (reported in Blood 86:3287, 1995) grew outof previous observations in immunodeficient (SCID) mice that developfatal EBV+ human lymphoproliferative disease when injected withlymphocytes from healthy human donors.

"Instead of treating with more CD4 cells, we wondered whetherwe could do replacement therapy with low levels of the hormonesthe cells make," he said. When the SCID mice were treatedwith low-dose IL-2, about 80% had long-term cancer-free survival,whereas placebo-treated animals died of overwhelming lymphoproliferativedisease.

Results in 10 Patients

The 10 patients in the clinical trial consisted of five with non-Hodgkin'slymphoma and five with Kaposi's sarcoma. All lymphoma patientshad achieved complete or partial remissions with chemotherapy.Seven of the 10 had a poor prognosis, as judged by CD4 countsof less than 200 at diagnosis of malignancy.

A team headed by Roswell Park oncol-ogist Zale P. Bernstein treatedthe patients with "near physiologic" IL-2 doses thatranged between 0.4 × 106 and 1.4 × 106 U/m²/day.

Treatment continued for 90 consecutive days. Completion of a 90-daycourse was followed by a 2-week drug holiday. Then another 90-daycourse began, using a higher dose.

The patients completed a total of 17 courses. T-cell subsets didnot change in response to therapy. However, levels of NK cellsincreased an average of 247% at the three highest tolerated doses(0.6, 0.9, and 1.2 × 106), comprising 13 of the 17 evaluablecourses. Eosinophil counts increased during nine of the 17 courses,and these increases were independent of IL-2 dose, prior IL-2dose, or NK-cell expansion.

Two patients developed grade 3 fever 3 weeks into a course witha dose of 1.4 × 106 U/m²/day. One of the two also developedgrade 3 fatigue. These patients were switched to a 1.2 ×106 dose and completed the course. Otherwise, no grade 3 toxicitiesoccurred. Headache, fatigue, and erythema were the most commonlyreported side effects.