Evaluation of natural killer cell expansion and activation in vivo with daily subcutaneous low-dose interleukin-2 plus periodic intermediate-dose pulsing |
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Authors: | N J Meropol Grace M Barresi Todd A Fehniger James Hitt Margaret Franklin Michael A Caligiuri |
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Institution: | (1) Division of Medicine, Roswell Park Cancer Institute, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA e-mail: NJ-Meropol@Fccc.edu Tel. +1-215-728-2450; Fax +1-215-728-3636, US |
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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 1.25×106 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 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 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.
Received: 31 December 1997 / Accepted: 20 April 1998 |
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Keywords: | Immunotherapy LAK cells Low-dose IL-2 |
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