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

Citation
T. Mekhail et al., Interleukin-2 in cancer therapy - Uses and optimum management of adverse effects, BIODRUGS, 14(5), 2000, pp. 299-318
Citations number
144
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Pharmacology
Journal title
BIODRUGS
ISSN journal
1173-8804 → ACNP
Volume
14
Issue
5
Year of publication
2000
Pages
299 - 318
Database
ISI
SICI code
1173-8804(200011)14:5<299:IICT-U>2.0.ZU;2-Q
Abstract
Recombinant interleukin-2 (rIL-2) produces remissions in several human tumo urs, including metastatic renal cell cancer (RCC) and malignant melanoma. H igh-dose intravenous bolus rIL-2 is approved in the US in these 2 indicatio ns, based on evidence of rIL-2-induced durable remissions iii a significant minority of patients. Due to the toxicity associated with high-dose rIL-2, alternative regimens were investigated in RCC, including low-dose intraven ous bolus, subcutaneous outpatient regimens and continuous intravenous infu sion, yielding similar response rates. A prospective randomised trial compa ring different doses and routes of administration is underway. Because resp onse rates to single agent rIL-2 are inadequate, combination therapies were studied. In RCC patients, a combination of rIL-2 and IFN alpha resulted in better response rates than either cytokine alone, with no apparent surviva l advantage. Combination with chemotherapy increased toxicity and had no pr oven benefit. Results of adoptive immunotherapy studies combining rIL-2 wit h either lymphokine-activated killer cells or tumour infiltrating lymphocyt es were comparable to those of rIL-2 alone. In malignant melanoma, combinat ion therapy of rIL-2 with chemotherapy was explored. Results of single-inst itution phase II combination studies of variable chemotherapy and rIL-2 and IFN alpha regimens were promising and randomised trials are underway. rIL-2 is being is evaluated in haematological malignancies. The rationale i s based on pre-clinical evidence that a variety of leukaemic blasts are sen sitive to cytolysis or growth inhibition mediated by rIL-2-activated immune effector cells. New immunotherapeutic strategies may ultimately improve the anti-tumour eff icacy 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 leadin g to an adverse effect profile that is quite different from traditional che motherapeutic agents. Dose-limiting toxicities are primarily cardiovascular and pulmonary and are dose-dependent in frequency and severity. Patients r eceiving high-dose regimens may require intensive care unit support, limiti ng its use to those with excellent performance status and adequate organ fu nction. Patients receiving less intensive dose regimens may require less ri gorous screening and monitoring. It has been postulated that rIL-2 related toxicity is mediated through the release of secondary cytokines, including TNF, IFN gamma, IL-6 and IL-I. With the increasing understanding of the pat hophysiological mechanisms of the effects of rIL-2, it is possible that con current administration of selective cytokine antagonists may reduce the tox icity associated with rIL-2 without interfering with its anti-neoplastic ac tivity.