Lymphokine-activated killer cells with interleukin-2: dose toxicity and localization in isolated perfused rat lungs

Lymphokine-activated killer (LAK) cells combined with recombinant interleukin-2 (rIL-2) can produce tumor regression in murine models and in patients with pulmonary metastatic disease. However, the dose escalations of rIL-2 required for optimal therapeutic effect often result in increased vascular permeability ("vascular leak syndrome") and other toxic systemic consequences. To avoid systemic distribution, lung perfusion was used to administer LAK and rIL-2 locally. Preliminary to using these agents to treat tumor-bearing lungs, we used a nonblood-perfused isolated rat lung model to study the localization of radiolabeled rIL-2 and LAK and to characterize effects on normal lung tissue of increasing dosages and exposure times of rIL-2 and LAK cells, individually and combined. Lung function or permeability was assessed by measuring lung weight gain and pulmonary arterial pressure during the perfusion, extravascular lung water by double indicator dilution techniques, and wet weight to dry weight ratio. After perfusion for 1 hour using 200,000 U (1,300 U/ml) rIL-2, injury was detected as visible pulmonary edema, weight gain and increases in wet to dry weight ratio, and extravascular lung water; no injury was detected at lower, clinically appropriate dosages. When 1 X 10(8) LAK cells combined with 100,000 U rIL-2 (666 U/ml) were perfused for up to 2 hours, no injury was ascertained. Uptake and distribution of the radiolabeled rIL-2 or LAK was uniform to all lung lobes and corresponded to the decrease of 12% of the rIL-2 or 50% of the LAK from the perfusate after 1-hour perfusion.