Pharmaceutical analogues Aldesleukin is a form of recombinant interleukin-2. It is manufactured using
recombinant DNA technology and is marketed as a
protein therapeutic and branded as Proleukin. It has been approved by the
Food and Drug Administration (FDA) with a
black box warning and in several European countries for the treatment of cancers (
melanoma,
renal cell cancer) in large intermittent doses and has been extensively used in continuous doses. Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects. However, clinical trials into this candidate were discontinued.
Dosage Various dosages of IL-2 across the
United States and across the world are used. The efficacy and
side effects of different dosages is often a point of disagreement. The commercial interest in local IL-2 therapy has been very low. Because only a very low dose IL-2 is used, treatment of a patient would cost about $500 commercial value of the patented IL-2. The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy.
United States Usually, in the U.S., the higher dosage option is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects. A lower dose regimen involves injection of IL-2 under the skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of
chemotherapy.
Local application In preclinical and early clinical studies, local application of IL-2 in the tumor has been shown to be clinically more effective in anticancer therapy than systemic IL-2 therapy, over a broad range of doses, without serious side effects. Tumour blood vessels are more vulnerable than normal blood vessels to the actions of IL-2. When injected inside a tumor, i.e. local application, a process mechanistically similar to the vascular leakage syndrome, occurs in tumor tissue only. Disruption of the blood flow inside of the tumor effectively destroys tumor tissue. In local application, the systemic dose of IL-2 is too low to cause side effects, since the total dose is about 100 to 1000 fold lower. Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients. In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy
Toxicity Systemic IL-2 has a narrow
therapeutic window, and the level of dosing usually determines the severity of the side effects. In the case of local IL-2 application, the therapeutic window spans several orders of magnitude. Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses. This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing the cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the
U.S. Food and Drug Administration (FDA) for treatment of
cutaneous T cell lymphoma (CTCL). == Preclinical research ==