Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2

Michael A. Caligiuri, Christine Murray, Michael J. Robertson, Eunice Wang, Keith Cochran, Christine Cameron, Peter Schow, Mary E. Ross, Thomas R. Klumpp, Robert J. Soiffer, Kendall A. Smith, Jerome Ritz

Research output: Contribution to journalArticle

200 Scopus citations

Abstract

The immunologic consequences of prolonged infusions of rIL-2 in doses that produce physiologic serum concentrations of this cytokine were investigated. rIL-2 in doses of 0.5-6.0 × 106 U/m2 per d (3.3-40 μg/m2 per d) was administered by continuous intravenous infusion for 90 consecutive days to patients with advanced cancer. IL-2 concentrations ( 25±25 and 71±64 pM, respectively) that selectively saturate high-affinity IL-2 receptors (IL-2R) were achieved in the serum of patients receiving rIL-2 infusions of 10 μg/m2 per d and 30 Mg/m2 per d. A gradual, progressive expansion of natural killer (NK) cells was seen in the peripheral blood of these patients with no evidence of a plateau effect during the 3 mo of therapy. A preferential expansion of CD56bright NK cells was consistently evident. NK cytotoxicity against tumor targets was only slightly enhanced at these dose levels. However, brief incubation of these expanded NK cells with IL-2 in vitro induced potent lysis of NK-sensitive, NK-resistant, and antibody-coated targets. Infusions of rIL-2 at 40 Mg/m2 per d produced serum IL-2 levels (345±381 pM) sufficient to engage intermediate affinity IL-2R p75, which is constitutively expressed by human NK cells. This did not result in greater NK cell expansion compared to the lower dose levels, but did produce in vivo activation of NK cytotoxicity, as evidenced by lysis of NK-resistant targets. There was no consistent change in the numbers of CD56- CD3+ T cells, CD56+ CD3+ MHC-unrestricted T cells, or B cells during infusions of rIL-2 at any of the dosages used. This study demonstrates that prolonged infusions of rIL-2 in doses that saturate only high affinity IL-2R can selectively expand human NK cells for an extended period of time with only minimal toxicity. Further activation of NK cytolytic activity can also be achieved in vivo, but it requires concentrations of IL-2 that bind intermediate affinity IL-2R p75. Clinical trials are underway attempting to exploit the differing effects of various concentrations of IL-2 on human NK cells in vivo.

Original languageEnglish (US)
Pages (from-to)123-132
Number of pages10
JournalJournal of Clinical Investigation
Volume91
Issue number1
DOIs
StatePublished - Jan 1993

Keywords

  • Cytotoxicity
  • IL-2
  • IL-2 receptor
  • Immunotherapy
  • Natural killer cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Caligiuri, M. A., Murray, C., Robertson, M. J., Wang, E., Cochran, K., Cameron, C., Schow, P., Ross, M. E., Klumpp, T. R., Soiffer, R. J., Smith, K. A., & Ritz, J. (1993). Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. Journal of Clinical Investigation, 91(1), 123-132. https://doi.org/10.1172/JCI116161