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Repetitive Weekly Cycles of Interleukin 2: Effect of Outpatient Treatment with a Lower Dose of Interleukin 2 on Non-Major Histocompatibility Complex-restricted Killer Activity¹

Departments of Human Oncology, Statistics, Pediatrics, and Genetics, University of Wisconsin, Madison, Wisconsin 53792; and the Clinical Investigation Section, Hoffmann-LaRoche Inc., Nutley, New Jersey

Fifteen patients with advanced malignancy who had failed conventional therapy were entered into a protocol consisting of 1 inpatient mo of repetitive weekly cycles of interleukin 2 (IL-2) at 3 x 10⁶ units/m²/day by constant infusion for the first 4 days of each week. This was followed by IL-2 administered on an outpatient basis at the same schedule but at a dose of 1 x 10⁶ units/m²/day for the next 1 to 6 mo. Nine patients had renal carcinoma, four had melanoma, and two had lymphoma. Thirteen patients completed the induction month, and ten patients completed 1 mo of outpatient therapy.

Only one patient had therapy discontinued because of toxicity due to IL-2. No major toxicities occurred during outpatient therapy. After 1 mo of IL-2 at 3 x 10⁶ units/m²/day, profound changes similar to those previously documented were seen in peripheral blood lymphocyte (PBL) counts (4.7-fold increase), lymphokine-activated killer activity (16-fold increase), and the percentage of PBL with natural killer-associated markers including a 3.6-fold increase in the percentage of PBL expressing the Leu 19 (NKH-1) marker, a 3.7-fold increase in Leu 11 (FcIgGR), and a 3.0-fold increase in Leu 17 (OKT10).

These indicators of IL-2 effect all remained elevated relative to the baseline at the end of 1 and 2 mo of outpatient therapy at the lower dose. However, lymphokine-activated killer activity and Leu 17 percentage were significantly reduced relative to the effect of the higher induction dose. PBL taken from patients while receiving maintenance therapy showed strong and rapid responses to IL-2 in vitro, confirming the in vivo effects of prolonged IL-2 treatment. Nevertheless, there were no complete or partial antitumor responses seen.

This study demonstrates that an immunologically active dose of IL-2 can be given long term as outpatient therapy with tolerable toxicity and results in highly IL-2-responsive "primed" lymphokine-activated killer cells.

¹ This research was supported by Hoffmann-LaRoche Inc.; NIH Grants CA 20432, CA 32685, and RR-03186; and American Cancer Society Grant CH-237D.

² To whom requests for reprints should be addressed, at K4/448 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.

Received 1/ 5/89. Revised 4/ 8/89. Revised 7/14/89. Accepted 9/ 1/89.