Abstract
Synopsis
Recombinant interleukin-2 (IL-2) products (e.g. aldesleukin, teceleukin) are nonglycosylated, modified forms of the endogenous compound. IL-2 acts as a pleiotropic mediator within the immune system, having a variety of effects via specific cell surface receptors. The interaction of IL-2 with the IL-2 receptor induces proliferation and differentiation of a number of T lymphocyte subsets, and stimulates a cytokine cascade that includes various interleukins, interferons and tumour necrosis factors. Antitumour effects of IL-2 appear to be mediated by its effects on natural killer, lymphokine-activated killer (LAK) and other cytotoxic cells. In vivo and in vitro effects of IL-2 seem to be dependent to a large extent on the environment; many studies have reported conflicting results, perhaps due to diverse populations of effector cells, the availability of other cytokines that have synergistic or inhibitory influences, and the dosage regimens used. The recombinant products appear to be biologically indistinguishable from native IL-2 in vitro and in vivo; the former induce minor antibody formation but this does not appear to alter functional properties.
In patients with metastatic renal cell carcinoma, IL-2 therapy achieves average objective response rates of 20% (range 0 to 40%), with a complete response rate of about 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 higher dosage regimens improve clinical response, or whether combination therapy with other agents and/or adoptive therapy is beneficial. Survival duration may depend on the risk factors present, with poorer performance status and more than one site of metastases associated with shorter survival times. Patients with metastatic malignant melanoma receiving IL-2 as monotherapy show an average objective response rate of 13% (range 3 to 24%); however, objective response rate averages 30% (range 4 to 59%) when IL-2 is used in combination with other agents. Overall median survival appears to be about 10 months. Preliminary data indicate that IL-2 produces a lower response rate in patients with refractory colorectal carcinoma, ovarian cancer, bladder cancer, acute myeloid leukaemia or non-Hodgkin’s lymphoma. Adverse effects accompanying high dose, intravenous IL-2 therapy can be severe, with cardiovascular, pulmonary, haematological, hepatic, neurological, endocrine, renal and/or dermatological complications frequently requiring doses to be withheld. Typically, these effects resolve rapidly with cessation of IL-2 therapy, and may be reduced considerably with regional or subcutaneous administration.
In conclusion, IL-2 offers hope to some patients with renal cell carcinoma, malignant melanoma and other neoplastic disease, but appropriate patient selection and optimum dosage regimens are at 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 treatment of these patients.
Pharmacological Properties
Interleukin-2 (IL-2) is an autocrine and paracrine biological response modifier, and recombinant IL-2 products (e.g. aldesleukin, teceleukin) appear to have essentially identical action to the endogenous molecule within the body. IL-2 promotes B and T cell proliferation and differentiation, and initiates a cytokine cascade that has both inhibitory and synergistic effects on IL-2 activity. Most effects are mediated via the IL-2 receptor, which is expressed in increased amounts on activated T cells. The in vitro antitumour effects of IL-2 are thought to occur via increased proliferation of natural killer, lymphokine-activated killer (LAK), and other cytotoxic cell populations. IL-2 has been co-administered with a number of other cytokines; however the results so far are inconclusive, and in many instances, conflict with the in vivo data.
In patients, the most common pharmacological effects of IL-2 therapy appear to be eosinophilia, acute lymphopenia followed by rebound lymphocytosis, and induction of LAK and natural killer cell activity. Increases in the levels of other cytokines have been reported, e.g. interleukins-3, -4, -5, -6 and -8, tumour necrosis factors-α and -β and interferon-γ, although other investigators dispute these findings, perhaps due to differing dosage schedules and sampling times. Changes in immune responses have been noted, but antibodies formed to recombinant products did not appear to interfere with biological activity. Other effects include alterations in plasma hormone levels (e.g. increase in atrial natriuretic factor and adrenocorticotropic hormone levels, decrease in melatonin levels) and other serum components (e.g. decrease in cholesterol, factor XII and prekallikrein levels, increase in biopterin levels).
The formulation of IL-2 may affect its pharmacokinetic properties; however, most non-glycosylated recombinant products appear to have similar pharmacokinetic profiles. Clearance occurs predominantly via the kidney, and appears to be biphasic.
Therapeutic Use
Approximately 20% of patients with metastatic renal cell carcinoma, and 13% of patients with malignant melanoma achieve objective responses with IL-2 monotherapy. Approximately 5% of patients with renal cell carcinoma achieve complete response (complete disappearance of all measurable disease), which is durable in many instances, persisting for >12 months, and in some patients for >60 months. Overall median survival approximates 10 months; however, it appears that survival may be correlated with the performance status of the patient, the duration from diagnosis to trial entry, and the number of metastatic sites.
Complete response rates in patients with malignant melanoma receiving IL-2 monotherapy are low (approximately 2.5%) but show a similar durability to those seen in patients with renal cell carcinoma. Adoptive immunotherapy, with autologous LAK cells or tumour-infiltrating lymphocytes (TIL) that have been activated ex vivo and then reinfused during IL-2 therapy, does not appear to improve the clinical response. Combination therapy of IL-2 with conventional chemotherapeutic agents or with interferon-α (IFN-α) does not appear to improve response in patients with renal cell carcinoma, but combination chemotherapy and immunotherapy with IL-2 and >1 agent appears to be advantageous in patients with malignant melanoma. Objective response rates average 36% (range 4 to 59%), with complete response rates of approximately 7%.
Patients with colorectal cancer are likely to respond to IL-2 therapy combined with chemotherapy with objective response rates of about 10%. The therapeutic value of IL-2 therapy in patients with bladder or ovarian cancer, non-Hodgkin’s lymphoma or acute myeloid leukaemia remains to be established. At present, there is little conclusive evidence to support an optimum dosage regimen or method of administration.
Although much research has attempted to detect reliable markers of clinical response, results of studies are conflicting. Levels of circulating IL-2 are unlikely to be associated with clinical response. The presence of raised levels of C-reactive protein and interleukin-6 (IL-6) have been associated with a poorer prognosis. It is thought that patients’ human leucocyte antigen (HLA) haplotype and lymphocyte subset population sizes may have a role in determining response, but further work is required to clarify this issue.
Tolerability
Adverse effects associated with IL-2 may be severe and affect most organ systems, but tend to be rapidly reversible with cessation of therapy. Toxicity appears to be dose-dependent, and can be reduced considerably with local or subcutaneous administration. A major concern, particularly with high-dose intravenous regimens, is capillary leak syndrome. This manifests with hypotension requiring vasopressor support in 70% of patients, weight gain that is often >10% of bodyweight, acute renal failure, pulmonary congestion and dyspnoea, and is reminiscent of early septic shock. Other complications include neurological abnormalities and psychiatric disorders, myocardial toxicity, hepatic and thyroid dysfunction, coagulation disorders and haematological complications, and dermatological effects. Patients receiving systemic IL-2 have an increased risk of infection, and sepsis was a major cause of death before the routine use of prophylactic antibiotics was implemented. Mortality has been 1 to 6% in reported trials; however, it is hoped that guidelines for patient selection will considerably improve tolerability in future trials.
Dosage and Administration
Many different dosage schedules and methods of administration have been used with IL-2 therapy. In the US in patients with renal cell carcinoma, 6 × 105 IU/kg given intravenously as a 15-minute bolus every 8 hours for up to a total of 14 doses is recommended, followed by a further cycle after a variable interval. The recommended rest period is 9 days, but intervals of 3 days to several weeks have been used in clinical trials. Doses are usually withheld rather than reduced when toxicity is evident. In Europe the approved dosage regimen is continuous infusion of 18 × 106 IU/m2/day for two 4.5- to 5-day cycles, with a rest period of about 6 to 8 days.
Subcutaneous and regional administration methods have been used in patients, but recommendations for dosage and scheduling have not been made. In combination therapy the dosages of IL-2 are often reduced. Although intensive monitoring is often required with bolus dosage regimens, IL-2 has been administered subcutaneously in an outpatient setting.
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Various sections of the manuscript reviewed by: E.W, Ades, National Center for Infectious Diseases, Centers for Disease Control, US Department of Health and Human Services, Atlanta, Georgia, USA; G. Bonadonna, Division of Medical Oncology A, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy; A. Butturini, Carter Dermatology Laboratory, The Rockefeller University, New York, New York, USA; J.P. Dutcher, Department of Oncology, Montefiore Medical Center, New York, New York, USA; R.A. Figlin, Department of Medicine, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, California, USA; M. Fresno, Centro de Biología Molecular ‘Severo Ochoa’, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain; T. Fujioka, Department of Urology, Iwate Medical University School of Medicine, Morioka, Japan; G Gambacorti-Passerini, Division of Experimental Oncology D, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy; M. Green, Department of Clinical Haematology and Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; E. Huland, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Hamburg, Federal Republic of Germany; S.H. Lim, Department of Haematology, Addenbrooke’s Hospital, Cambridge, England; P. Lissoni, Divisione di Radioterapia, Ospedale San Gerardo, Monza, Milano, Italy; W.C. Mertens, Department of Medical Oncology, London Regional Cancer Centre, Ontario Cancer Treatment & Research Foundation, London, Ontario, Canada; S. Négrier, Centre régional Léon Bérard, Lyon, France; D.Th. Sleijfer, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands.
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Whittington, R., Faulds, D. Interleukin-2. Drugs 46, 446–514 (1993). https://doi.org/10.2165/00003495-199346030-00009
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DOI: https://doi.org/10.2165/00003495-199346030-00009