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

Neal J. Meropol, Grace M. Barresi, Todd A. Fehniger, James Hitt, Margaret Franklin, Michael A. Caligiuri

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

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 106 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 CD56(bright) 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 γ 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.

Original languageEnglish
Pages (from-to)318-326
Number of pages9
JournalCancer Immunology Immunotherapy
Volume46
Issue number6
DOIs
StatePublished - Sep 15 1998
Externally publishedYes

Keywords

  • Immunotherapy
  • LAK cells
  • Low-dose IL-2

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