title: Expansion and manipulation of natural killer cells in patients with metastatic cancer by low-dose continuous infusion and intermittent bolus administration of interleukin 2.
abstract: Interleukin 2 (IL-2) administered at low doses for prolonged periods can markedly expand the number of CD56(+) natural killer (NK) cells in patients with metastatic cancer. The cytotoxic capacity of NK cells obtained from patients receiving IL-2 in vivo can be dramatically augmented by additional exposure to IL-2 in vitro. These observations formed the basis of a clinical trial in which patients with metastatic cancer were treated with low-dose continuous daily infusions of IL-2 to increase the number of their NK cells in conjunction with intermittent boluses of additional IL-2 to stimulate this expanded pool of cytotoxic cells. Twenty-three patients were registered to receive IL-2 at 4.5 x 10(5) units/m2/day for 8 weeks by continuous i.v. infusion. After 4 weeks of "priming" with low-dose continuous infusion IL-2, cohorts of three to five patients received 5 weekly 2-h boluses of IL-2 at doses ranging from 2.5 x 10(5) units/m2 to 1.0 x 10(6) units/m2. Low-dose continuous infusion IL-2 was usually well tolerated; 2-h bolus infusions of IL-2 were often associated with high fevers and constitutional symptoms that resolved after several hours. Low-dose continuous infusion IL-2 resulted in the progressive expansion of circulating CD56(+)CD3(-) NK cells. In contrast, each bolus infusion of IL-2 resulted in an immediate dramatic decrease in both the number of NK cells and activated T lymphocytes with recovery noted within 24 h. Bolus doses of IL-2 as low as 2.5 x 10(5) units/m2 were capable of producing these effects. Cytolytic activity against NK-sensitive and -resistant targets correlated with the presence of circulating activated NK cells. Our results demonstrate that NK cells expanded by low-dose continuous infusions of IL-2 can be further activated in vivo by exposure to very low doses of IL-2 as a 2-h i.v. bolus. This capacity to manipulate human NK cells in vivo through varying the dose and schedule of IL-2 administration may help in defining the therapeutic potential of these cytotoxic effectors in the treatment of both neoplastic and infectious diseases.
authors.affiliation: Divisions of Hematologic Malignancies and Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: C
authors.initials: C
authors.lastname: Murray
authors.forename: C
authors.initials: C
authors.lastname: Shapiro
authors.forename: H
authors.initials: H
authors.lastname: Collins
authors.forename: S
authors.initials: S
authors.lastname: Chartier
authors.forename: S
authors.initials: S
authors.lastname: Lazo
authors.forename: J
authors.initials: J
authors.lastname: Ritz
mesh_terms: D000328:Adult; D000368:Aged; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins