Evaluation of natural killer cell expansion and activation in vivo with daily subcutaneous low-dose interleukin-2 plus periodic intermediate-dose pulsing

Cancer Immunol Immunother. 1998 Aug;46(6):318-26. doi: 10.1007/s002620050493.


Natural killer (NK) cells may be expanded in vivo with a prolonged course of daily subcutaneous interleukin-2 (IL-2). However, cellular activation requires higher concentrations of IL-2 than are achieved with low-dose therapy. The objective of the current trial was to determine the toxicity and immunological effects of periodic subcutaneous intermediate-dose IL-2 pulses in patients receiving daily low-dose therapy. A group of 19 patients were treated with daily subcutaneous low-dose IL-2 at 1.25 x 10(6) International Units (1.25 MIU) m(-2) day(-1). After 4-6 weeks, patients received escalating 3-day intermediate-dose IL-2 pulses administered as single daily subcutaneous injections, repeated at 2-week intervals. The maximum tolerated pulse dose was 15 MIU m(-2) day(-1), with transient hypotension, fatigue, and nausea/vomiting dose-limiting. Subcutaneous IL-2 resulted in in vivo expansion of CD56+ NK cells (796+/-210%) and CD56bright natural killer (NK) cells (3247+/-1382%). Expanded NK cells coexpressed CD16, and showed lymphokine-activated killer activity and antibody-dependent cellular cytotoxicity in vitro. Intermediate-dose pulsing resulted in serum IL-2 concentrations above 100 pM. Cellular activation was suggested by rapid margination of NK cells following pulsing, coincident with peak IL-2 levels, with return to baseline by 24 h. In.addition, interferon gamma production in response to lipopolysaccharide was augmented. Subcutaneous daily low-dose IL-2 with intermediate-dose pulsing is a well-tolerated outpatient regimen that results in in vivo expansion and potential activation of NK cells, with possible application in the treatment of malignancy and immunodeficiency.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antibody-Dependent Cell Cytotoxicity
  • CD56 Antigen / analysis
  • Cell Division / drug effects
  • Cell Line
  • Drug Administration Schedule
  • Female
  • Humans
  • Immunologic Factors / administration & dosage
  • Immunologic Factors / adverse effects
  • Immunologic Factors / pharmacology*
  • Immunologic Factors / therapeutic use
  • Immunophenotyping
  • Injections, Subcutaneous
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / administration & dosage
  • Interleukin-2 / adverse effects
  • Interleukin-2 / pharmacology*
  • Interleukin-2 / therapeutic use
  • Killer Cells, Lymphokine-Activated / immunology
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / drug effects*
  • Male
  • Middle Aged
  • Neoplasms / therapy


  • CD56 Antigen
  • Immunologic Factors
  • Interleukin-2
  • Interferon-gamma