The role of interleukin-2 in cancer therapy

Despite the abundance of evidence from murine models suggesting a powerful immunological approach to the treatment of cancer, the available data on clinical response have not been as dramatic. The use of interleukin-2 (IL-2) either alone or in combination with lymphokine activated killer (LAK) cells clearly is therapeutic for some patients, albeit a minority. It does not appear from the available evidence that the regimens tested show major differences in antitumour activity, although there is a sense that higher doses may be slightly more effective. Nor is it clear that the addition of LAK cells significantly or sufficiently enhances clinical responses to warrant their widespread use. It must therefore be concluded that other patient and tumour related factors must have an undefined role in the ability to attain meaningful responses. Immunological response to IL-2 and tumour burden are factors which can be examined given the available clinical data. While animal studies have shown that antitumor effects are related to the dose and number of LAK cells given, this is not as clear in patient studies. Some reports have suggested a correlation between clinical response and the in vivo induction of LAK activity or the magnitude of the rebound lymphocytosis. Clinical trials at the University of Wisconsin have shown striking increases in both the number of peripheral blood lymphocytes and LAK induction in patients who showed no clinical response. This in vivo LAK induction, as expected, is not the sole determinant in achieving a measurable response. Whether it is a necessary biological response needed to achieve antitumour effects remains uncertain. The role of tumour burden in response to IL-2 remains elusive. In many trials, including our own, patients with bulky disease have responded to therapy that was ineffective in other patients with what appeared to be a minimal tumour burden. Despite the disappointment that initial expectations have not quite been met, something extremely important has occurred in the treatment of cancer. For the first time, the controlled activation of a patient's endogenous immune system has been shown to have some promise as an antitumour treatment. Clearly, if the response rates reported to date are the best attainable its role will be limited. This remains doubtful as investigators are actively exploring combinations of IL-2 with other biologicals, cytokines, monoclonal antibodies and chemotherapeutic agents. Preclinical data suggest enhanced antitumour effects will be mediated by these combinations. While the magic bullet has not yet been found, there has been a major step forward since IL-2 was first described.