In vivo activation of lymphokine-activated killer activity with interleukin-2: prospects for combination therapies

Administration of interleukin-2 (IL-2) in vitro or in vivo can activate a variety of immune effector functions involving T lymphocytes and natural killer cells. These immune cells and their secreted cytokines can potentially play a central role in the host antitumor response. With the isolation and cloning of the IL-2 gene, purified recombinant IL-2 has become available to test for clinical, immunologic, and antitumor effects. Early clinical studies suggest that the IL-2 doses required to induce antitumor effects are accompanied by severe life-threatening toxicity. Therefore, sustained treatment with lower doses of IL-2 has been developed that has a milder, acceptable toxicity. Most importantly, a small percentage of cancer patients experience significant shrinkage of their tumor with this IL-2 regimen alone. Further modification of this regimen is necessary. Preclinical studies indicate that combinations of IL-2 with other modalities may increase the therapeutic potential of the in vivo lymphokine-activated killer activity; combination therapy with other cytokines and monoclonal antibodies show significant promise. Furthermore, new technologic advances with the ability to produce human chimeric antibodies and bispecific hybrid antibodies has the potential to make combined IL-2 and antibody therapy more successful. IL-2 has been associated with overly optimistic expectations and overly negative reactions from physicians and the public. However, the immune activation induced by IL-2, the small number of clinical responses, and the preclinical data suggesting synergism with other approaches indicate that further development may make IL-2 part of a regimen that will enable better cancer treatment.