title: In vivo induction of lymphokine-activated killer cells by interleukin-2 splenic artery perfusion in advanced malignancy.
abstract: In an effort to stimulate in vivo LAK cell activity at relatively nontoxic doses, 20 patients with advanced metastatic malignancy (13 renal cell carcinoma, 6 melanoma, 1 lymphoma) were treated with recombinant human interleukin-2 (IL-2) by continuous 5-day splenic artery perfusion using the femoral approach. Two treatment cycles were administered 3 weeks apart; IL-2 doses ranged from 1.5-4 x 10(4) Cetus units/kg/day. Peripheral blood lymphocyte cytotoxicity in a 4-h 51Cr release assay was measured using as tumor cell targets K562 for natural killer (NK) activity, Daudi for LAK, and Daudi plus in vitro IL-2 for inducible LAK (I-LAK). For the 20 patients, an increase in mean peak percent cytotoxicity from pretreatment levels was seen for NK (36% to 53%), LAK (8% to 37%) and I-LAK (20% to 53%) activity, all significant at P = 0.001. On day 43, 16 days after completing the second cycle of treatment, NK activity remained elevated at 47% and I-LAK at 40% (P = 0.008 and 0.01, respectively). Lymphocyte phenotype analysis by flow cytometry demonstrated increases from pretreatment levels in Leu 11+ (13 to 23%), Leu 19+ (10 to 21%), Leu 11+ 19+ (7 to 17%), IL-2r+ (4 to 17%), and HLA-DR+ (12 to 25%) subsets, all significant at P less than or equal to 0.01. Dose effect was studied at 3 dose levels: 1.5, 3, and 4 x 10(4) Cetus units/kg/day. At the higher doses mean peak NK (57%) and I-LAK (57%) activity were greater than at the low dose (42 and 31%, respectively), both significant at P less than 0.05. A trend to positive dose effect was seen in LAK activity (P = 0.08). Splenic artery perfusion with IL-2 can result in significant in vivo peripheral LAK cell generation as well as enhancement of I-LAK and NK activity that persists at least 16 days after the cessation of treatment. Such sustained activity would not be expected with conventional high dose i.v. therapy.
authors.affiliation: Department of Advanced Therapeutics, Cancer Control Agency of British Columbia, Vancouver, Canada.
authors.forename: R J
authors.initials: RJ
authors.lastname: Klasa
authors.forename: H K
authors.initials: HK
authors.lastname: Silver
authors.forename: S
authors.initials: S
authors.lastname: Kong
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D003602:Cytotoxicity, Immunologic; D004341:Drug Evaluation; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D007958:Leukocyte Count; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010477:Perfusion; D010641:Phenotype; D013157:Splenic Artery
chemical_list: D015703:Antigens, CD; D006684:HLA-DR Antigens; D007376:Interleukin-2