Recombinant interleukin-2 in combination with recombinant interferon-γ in patients with advanced malignancy: A phase 1 study

Because interleukin-2 (IL-2) and interferon-gamma (IFN-γ) act synergistically in vitro in the generation of lymphokine-activated killer (LAK) cells, we initiated a clinical trial of these lymphokines in combination. Twenty patients with advanced malignancy were treated at fixed dose levels of recombinant IFN-y given by intramuscular (i.m.) injections once a day and recombinant IL-2 given by an intravenous (i.v.) bolus injection 3 times a day for 7 days after a 3-day tre a tm en t with fixed doses (250 µg/m²/day) of IFN-γ alone. A minimum of four patients were treated a teach of the four dose levels studied. The side effects of the combination therapy were similar to those seen with individual lymphokines and included fever and chills, myalgia, headache, fatigue, nausea, vomiting, peripheral edema, skin rash, and hypotension. The maximum tolerated dose for th e combination after a fixed dose of IFN-γ was 2 × 105 U/m²/day (10 /xg/m²/day) of IFN-γ and 3 × 106 U/M²/day of IL-2, with fluid re ten tio n as the dose-limiting toxicity. Whereas n atural killer (NK) or LAK activity or both were significantly increased in four of eight patients studied, only one patient with renal cell cancer had a minor response for four tre a tm en t cycles. We conclude th a t combination therapy with cytokines IL-2 and IFN-γ given in this schedule had manageable toxicity and exhibited immunomodulatory effects in some patients but had no significant antitumor activity in this patient population.