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In Vivo Induction of Lymphokine-activated Killer Cells by Interleukin-2 Splenic Artery Perfusion in Advanced Malignancy

Department of Advanced Therapeutics, Cancer Control Agency of British Columbia, Vancouver, British Columbia V5Z 4E6, Canada

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 10⁴ 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 0.01. Dose effect was studied at 3 dose levels: 1.5, 3, and 4 x 10⁴ 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 < 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.

¹ To whom requests for reprints should be addressed.

Received 9/18/89. Revised 4/27/90.