INTERLEUKIN-2 - A REVIEW OF ITS PHARMACOLOGICAL PROPERTIES AND THERAPEUTIC USE IN PATIENTS WITH CANCER

Recombinant interleukin-2 (IL-2) products (e.g. aldesleukin, teceleuki n) are nonglycosylated, modified forms of the endogenous compound IL-2 acts as a pleiotropic mediator within the immune system, having a var iety of effects via specific cell surface receptors. The interaction o f IL-2 with the IL-2 receptor induces proliferation and differentiatio n of a number of T lymphocyte sub-sets, and stimulates a cytokine casc ade that includes various interleukins, interferons and tumour necrosi s factors. Antitumour effects of IL-2 appear to be mediated by its eff ects on natural killer, lymphokine-activated killer (LAK) and other cy totoxic cells. In vivo and in vitro effects of IL-2 seem to be depende nt to a large extent on the environment; many studies have reported co nflicting results, perhaps due to diverse populations of effector cell s, the availability of other cytokines that have synergistic or inhibi tory influences, and the dosage regimens used. The recombinant product s appear to be biologically indistinguishable from native IL-2 in vitr o and in vivo; the former induce minor antibody formation but this doe s not appear to alter functional properties. In patients with metastat ic renal cell carcinoma, IL-2 therapy achieves average objective respo nse rates of 20% (range 0 to 40%), with a complete response rate of ab out 5% (range 0 to 19%). Response duration varies considerably but can be durable (lasting for >12 months), with some patients remaining in complete response for >60 months. It is unclear at present whether hig her dosage regimens improve clinical response, or whether combination therapy with other agents and/or adoptive therapy is beneficial. Survi val duration may depend on the risk factors present, with poorer perfo rmance status and more than one site of metastases associated with sho rter survival times. Patients with metastatic malignant melanoma recei ving IL-2 as monotherapy show an average objective response rate of 13 % (range 3 to 24%); however, objective response rate averages 30% (ran ge 4 to 59%) when IL-2 is used in combination with other agents. Overa ll median survival appears to be about 10 months. Preliminary data ind icate that IL-2 produces a lower response rate in patients with refrac tory colorectal carcinoma, ovarian cancer, bladder cancer, acute myelo id leukaemia or non-Hodgkin's lymphoma. Adverse effects accompanying h igh dose, intravenous IL-2 therapy can be severe, with cardiovascular, pulmonary, haematological, hepatic, neurological, endocrine, renal an d/or dermatological complications frequently requiring doses to be wit hheld. Typically, these effects resolve rapidly with cessation of IL-2 therapy, and may be reduced considerably with regional or subcutaneou s administration. In conclusion, IL-2 offers hope to some patients wit h renal cell carcinoma, malignant melanoma and other neoplastic diseas e, but appropriate patient selection and optimum dosage regimens are a t present unresolved. Establishment of reliable predictors of clinical response, and optimum dosage schedules and methods of administration should enable a better assessment of the place of IL-2 in the treatmen t of these patients.