Interleukin-2 in cancer therapy: uses and optimum management of adverse effects

Recombinant interleukin-2 (rIL-2) produces remissions in several human tumours, including metastatic renal cell cancer (RCC) and malignant melanoma. High-dose intravenous bolus rIL-2 is approved in the US in these 2 indications, based on evidence of rIL-2-induced durable remissions in a significant minority of patients. Due to the toxicity associated with high-dose rIL-2, alternative regimens were investigated in RCC, including low-dose intravenous bolus, subcutaneous outpatient regimens and continuous intravenous infusion, yielding similar response rates. A prospective randomised trial comparing different doses and routes of administration is underway. Because response rates to single agent rIL-2 are inadequate, combination therapies were studied. In RCC patients, a combination of rIL-2 and IFNalpha resulted in better response rates than either cytokine alone, with no apparent survival advantage. Combination with chemotherapy increased toxicity and had no proven benefit. Results of adoptive immunotherapy studies combining rIL-2 with either lymphokine-activated killer cells or tumour infiltrating lymphocytes were comparable to those of rIL-2 alone. In malignant melanoma, combination therapy of rIL-2 with chemotherapy was explored. Results of single-institution phase II combination studies of variable chemotherapy and rIL-2 and IFNalpha regimens were promising and randomised trials are underway. rIL-2 is being is evaluated in haematological malignancies. The rationale is based on pre-clinical evidence that a variety of leukaemic blasts are sensitive to cytolysis or growth inhibition mediated by rIL-2-activated immune effector cells. New immunotherapeutic strategies may ultimately improve the anti-tumour efficacy of rIL-2-based therapy. Early trials using rIL-2 as adjuvant therapy to vaccines or dendritic cell-based therapy have yielded promising results. rIL-2 therapy initiates a cytokine-mediated pro-inflammatory process leading to an adverse effect profile that is quite different from traditional chemotherapeutic agents. Dose-limiting toxicities are primarily cardiovascular and pulmonary and are dose-dependent in frequency and severity. Patients receiving high-dose regimens may require intensive care unit support, limiting its use to those with excellent performance status and adequate organ function. Patients receiving less intensive dose regimens may require less rigorous screening and monitoring. It has been postulated that rIL-2 related toxicity is mediated through the release of secondary cytokines, including TNF, IFNgamma, IL-6 and IL-1. With the increasing understanding of the pathophysiological mechanisms of the effects of rIL-2, it is possible that concurrent administration of selective cytokine antagonists may reduce the toxicity associated with rIL-2 without interfering with its anti-neoplastic activity.