title: Daily subcutaneous injection of low-dose interleukin 2 expands natural killer cells in vivo without significant toxicity.
abstract: We aimed to determine the toxicity and immunological effects of daily s.c. administered low-dose interleukin (IL) 2. Adult cancer patients received a single daily s.c. injection of IL-2 as outpatients for 90 consecutive days. Cohorts of four to nine patients were treated at escalating IL-2 dose levels until the maximum tolerated dose (MTD) was defined. Peripheral blood mononuclear cell phenotyping, IL-2 serum levels, and the presence of anti-IL-2 antibodies were investigated. Thirty-eight patients were treated at seven IL-2 dose levels ranging from 0.4 to 1.75 million International Units (mIU)/m2 daily. The MTD was 1.25 mIU/m2, with constitutional side effects, vomiting, and hyperglycemia dose limiting. Severe toxicity did not occur at or below the MTD, although mild local skin reaction and mild constitutional side effects were common. Objective tumor regressions were not observed during this Phase I trial. Low-dose IL-2 resulted in natural killer (NK) cell (CD3(-) CD56(+)) expansion at all dose levels. This effect was dose dependent (P < 0.01), ranging from a 154 to 530% increase over baseline. Peak NK levels were achieved at 6-8 weeks and sustained through 12 weeks of therapy. As predicted by in vitro studies of IL-2 receptor structure-activity relationships, the subset of NK cells that constitutively express high-affinity IL-2 receptors (CD3(-)CD56(bright+)) showed more profound dose-dependent expansion, with increases ranging from 368 to 2763% (P = 0.015). NK expansion occurred at peak IL-2 levels <10 pM (2.3 IU/ml). Three patients developed nonneutralizing anti-IL-2 antibodies. Thus, we concluded that selective expansion of NK cells may be achieved in vivo with daily s.c. injections of low-dose IL-2 with minimal toxicity.
authors.affiliation: Divisions of Medicine, Molecular Medicine, Molecular Immunology, and Biostatistics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: M
authors.initials: M
authors.lastname: Porter
authors.forename: L E
authors.initials: LE
authors.lastname: Blumenson
authors.forename: M J
authors.initials: MJ
authors.lastname: Lindemann
authors.forename: R P
authors.initials: RP
authors.lastname: Perez
authors.forename: L
authors.initials: L
authors.lastname: Vaickus
authors.forename: G M
authors.initials: GM
authors.lastname: Loewen
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: K A
authors.initials: KA
authors.lastname: Wilkes
authors.forename: M A
authors.initials: MA
authors.lastname: Giedlin
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000328:Adult; D000368:Aged; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D007376:Interleukin-2