EXPANSION AND MANIPULATION OF NATURAL-KILLER-CELLS IN PATIENTS WITH METASTATIC CANCER BY LOW-DOSE CONTINUOUS-INFUSION AND INTERMITTENT BOLUS ADMINISTRATION OF INTERLEUKIN-2

Interleukin 2 (IL-2) administered at low doses for prolonged periods c an markedly expand the number of CD56(+) natural killer (NK) cells in patients with metastatic cancer. The cytotoxic capacity of NK cells ob tained from patients receiving IL-2 in vivo can be dramatically augmen ted by additional exposure to IL-2 in vitro. These observations formed the basis of a clinical trial in which patients with metastatic cance r were treated with low-dose continuous daily infusions of IL-2 to inc rease the number of their NK cells in conjunction with intermittent bo luses 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/m(2)/day for 8 weeks by continuous i.v. infusion. After 4 weeks of ''priming'' with low-dose continuous infusion IL-2, cohorts o f three to five patients received 5 weekly 2-h boluses of IL-2 at dose s ranging from 2.5 x 10(5) units/m(2) to 1.0 x 10(6) units/m(2). Low-d ose continuous infusion IL-2 was usually well tolerated; 2-11 bolus in fusions of IL-2 were often associated with high fevers and constitutio nal symptoms that resolved after several hours. Low-dose continuous in fusion IL-2 resulted in the progressive expansion of circulating CD56( +)CD3(-) NK cells. In contrast, each bolus infusion of IL-2 resulted i n an immediate dramatic decrease in both the number of NK cells and ac tivated T lymphocytes with recovery noted within 24 h. Bolus doses of IL-2 as low as 2.5 x 10(5) units/m(2) were capable of producing these effects. Cytolytic activity against NK-sensitive and -resistant target s correlated with the presence of circulating activated NK cells. Our results demonstrate that NK cells expanded by low-dose continuous infu sions 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 adminis tration may help in defining the therapeutic potential of these cytoto xic effecters in the treatment of both neoplastic and infectious disea ses.