Interleukin-2 (IL-2) administered in pharmacologic doses to
renal cancer patients with intact organ function and good performance status induces durable complete responses in about 5% of patients and partial responses in an additional 10% to 15%. The mechanism of antitumor efficacy of
IL-2 is closely related to its ability to expand and activate cytotoxic lymphocytes of the natural killer (NK)- and thymic (T)-cell subsets that express
IL-2 receptors (IL-2R). There is also accumulating evidence that local or generalized effector cell dysfunction, which is characteristic of patients with advanced
cancer, can be reversed with
IL-2 exposure. The toxicities of
IL-2 are mediated by
cytokines and other small molecules secreted by IL-2R-expressing cells responding to the binding of this
ligand. The common mechanism for IL-2-induced multiorgan dysfunction appears to be a
capillary leak syndrome directly mediated by local production of
nitric oxide by cells of the monocyte-macrophage lineage. To date, efforts to improve on the antitumor activity of
IL-2 by the addition of IL-2-activated peripheral blood mononuclear cells (lymphokine-activated killer [LAK] cells) or cell subsets selected for proximity or potential
antigen-specificity (tumor-infiltrating lymphocytes [TIL]) have not led to improved therapeutic outcomes. Attempts to reduce the risks of
IL-2 therapy (which could potentially allow for increased IL-2 administration) by blocking one or more of the known mediators of toxicity have also been disappointing. Current research is directed at developing combination regimens with additive or synergistic antitumor effects and incompletely overlapping toxicities, as well as the identification of
tumor antigens that may be the target of more focused cellular
therapies. The role of high-dose
IL-2 in the adjuvant
therapy of resected
renal cancer at high risk of relapse is also under investigation.