Intravenous Interleukin-2 Therapy Research Articles

Pharmacokinetic Study of Interleukin‐2 Following Intravenous Injection in Hemodialysis Patients With Renal Cell Carcinoma

The purpose of the present study is to determine the change in blood concentration of interleukin-2 (IL-2) after intravenous injection in hemodialysis patients and to assess its safety. Four hemodialysis patients who underwent nephrectomy due to renal cell carcinoma were treated with IL-2 at a dose of 350 000-700 000 JRU by intravenous injection. Pharmacokinetic parameters were analyzed from the serum IL-2 concentration, which reached its peak just after the end of infusion, followed by biphasic elimination, and was below the detection limit in all patients at 24 h postinfusion. In comparison with patients with normal renal function, the volume of distribution in the serum compartment was almost comparable (3820 +/- 2020 mL). Clearance (50.47 +/- 11.50 mL/min) decreased to 40%, and the half-life of the distribution phase (0.45 +/- 0.19 h) and that of the terminal phase (1.72 +/- 0.20 h) were distinctly longer. The area under the blood concentration-time curve was about two-fold higher than that of non-hemodialysis patients. In all patients, there were no serious adverse reactions. The results of the present study suggest that intravenous IL-2 therapy can be safely performed in hemodialysis patients.

Response rates of patients with metastatic melanoma to high-dose intravenous interleukin-2 after prior exposure to alpha-interferon or low-dose interleukin-2.

We evaluated 567 patients with metastatic melanoma who were treated with high-dose intravenous interleukin-2 (IL-2) to determine whether prior treatment with either alpha-interferon or low-dose IL-2 altered the rates of response to subsequent high-dose IL-2. Of the 567 patients treated, 46 patients had received low-dose IL-2 before, and 78 had received alpha-interferon before. The response rate for patients who had received IL-2 before compared with IL-2 naïve patients was 15% versus 21% respectively (p = 0.39). The response rate for patients who had received alpha-interferon before compared with patients who had not was 13% versus 21% (p = 0.084). Therefore, prior low-dose IL-2 therapy does not appear to prevent a subsequent response to high-dose IL-2. There is a trend for patients who received alpha-interferon before to have a lower-response rate to subsequent high-dose IL-2, but the number of patients evaluated in this study is too small to definitively answer this question.

Comparison between subcutaneous and intravenous interleukin‐2 treatment in HIV disease

Therapy of HIV-infection using intravenous interleukin-2 (IL-2) is known to be effective in terms of increasing CD4-counts but is associated with significant side-effects and hospitalization. However, the combination with protease-inhibitor therapy has not been tested yet. The aim of the present study was to investigate the safety and efficacy of intravenous vs. subcutaneous IL-2 regimes using 9 Mio I.U. of IL-2, in combination with protease-inhibitor therapy. All patients were treated with a combination of two reverse transcriptase inhibitors and a protease-inhibitor prior to IL-2 administration for at least 6 weeks. Ten patients were assigned to the intravenous IL-2 group (group A). 10 to the subcutaneous group (group B). In both treatment groups, CD4 count significantly increased shortly after the end of therapy (group A: 223% over baseline [day 7]; group B: 264% over baseline [day 7]). During the follow-up CD4 counts slowly decreased thereafter but remained above baseline 3 months following IL-2 treatment. The CD8 lymphocytes showed a similar but less pronounced pattern with a maximum at day 7 (group A: 116% over baseline, group B: 158% over baseline) and reached baseline earlier in the follow-up-period. Altogether the CD4/CD8-ratio was elevated through long periods on follow-up. Throughout follow-up, there were no apparent changes in viral load during IL-2 therapy in either groups. IL-2 therapy was administered for a mean time of 4.2+/-0.1 days in the intravenous group and of 4.8+/-0.1 days in the subcutaneous group until therapy was terminated at day 5 or due to side-effects. Only 1/10 patients completed the 5-day course of intravenous therapy in contrast to 6/10 in the subcutaneous group. Subcutaneous interleukin-2 using 9 Mio IU day(-1) in combination with protease-inhibitors showed equal efficacy as intravenous therapy and was associated with less side-effects.

Interleukin-2 therapy in HIV infection.

Immune cells secrete a variety of cytokines that have a profoundly significant influence on the immune system. For example, cytokines secreted by T-helper cells have a role in cellular immune response (Th1 cytokines) and in antibody production (Th2 cytokines). Interleukin 2 (IL-2) is used therapeutically for immune modulation, most specifically in cancer therapy. The following report describes the mechanisms of IL-2/IL-2 receptor interaction and summarizes the rationale for using IL-2 in HIV-infected patients and briefly describes recent and ongoing clinical trails using IL-2 in HIV/AIDS disease (intravenous IL-2 therapy and subcutaneous IL-2 therapy). In one study of patients with moderate stage HIV disease, subjects taking a maximum tolerated dose of IL-2 at 12 to 15 MIU/day demonstrated durable increases in CD4 counts and a near normal return in value. Relative to the published reports, low circulating CD4 counts and high HIV viral burden appeared to be independent determinants of a poor response to IL-2. However, aggressive combination therapy with IL-2 and highly active anti-retroviral therapy (HAART)(e.g., ACTG 328) holds promise for an improved immune restorative response even in patients with advanced disease.

Generation of the complement activation product C5a precedes interleukin-2-induced capillary leakage syndrome.

Capillary leakage syndrome (CLS) is a severe side effect of intravenous interleukin-2 (IL-2) therapy. Twenty-seven cycles of IL-2 therapy [six (day 1), nine (day 2), and 12 >( 10(6) U/m(2) body surface (days 3 to 5), given as continuous infusion] were analyzed in children and adolescents. The anaphylatoxin C5a was assessed as an early predictor for CLS. CLS developed in 11 of 27 cycles of IL-2 infusion. C5a at day 2 of IL-2 infusion (0.8-9.43 mu g/L; median, 1.8 mu g/L) was increased in CLS patients when compared with baseline values (0.21-0.74 mu g/L; median, 0.40 mu g/L; p = 0.01) and when compared with C5a at day 2 in non-CLS patients (0.44-1.2 mu g/L; median, 0.62 mu g/L; p <0.01). Ten of 11 CLS patients showed C5a levels >1.0 mu g/L, whereas 14 of 16 patients who did not develop CLS showed C5a <1.0 mu g/L (predictive value positive 83% for CLS).

Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer.

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 leukemia 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Interleukin-2-administration intravenously and intrapleurally in a patient with primary pulmonary adenocarcinoma. Cellular responses in peripheral blood, intrapleural fluid and bronchoalveolar lavage

A case report of a patient who suffered from a rapidly progressive lung adenocarcinoma with malignant pleural effusions, is given. The patient failed to respond on two series of conventional cytotoxic drug therapy (Carboplatin, Etoposide). Interleukin-2 (IL-2) treatment was first started as intrapleural instillations (3.0 million IU per day in 6 days). A clear clinical response was achieved with ceasing of the pleural effusion, and the overall disease became stable. In the peripheral blood, there was an increase of CD4 positive lymphocytes that remained elevated after finishing the installation period. Both in bronchoalveolar lavage (BAL), and in the pleural fluid, there was a marked decrease of cells recovered, possibly due to an enhanced tissue attachment of activated cells. A second analysis with subtyping of lymphocytes in BAL was impossible due to the low cell number. In the pleural fluid, the fractions of CD3 positive cells increased from 20 to 71% while the ratio between CD4 and CD8 remained persistently elevated at 6.1:1. Because of the disappearance of the pleural effusion, the patient was thereafter treated with IL-2 given as a continuous infusion (18 million IU per square-metre during 24 hours for 5 days). Hereby a more pronounced cell response was achieved in the peripheral blood. In contrast to the intrapleural treatment route, not only CD4 positive cells, but also the numbers of natural killer cells (NK) increased. However this treatment was also associated with a much higher degree of side effects. It can be concluded from both intrapleural and intravenous IL-2 therapy, that a clinical and immunological response was achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine Effects of Subcutaneous Interleukin-2 Injection in Cancer Patients

Intravenous interleukin-2 (IL-2) administration has been shown to influence several hormonal secretions. The present study was carried out to investigate the endocrine effects of subcutaneous therapy with IL-2. Six patients with advanced renal cancer were studied. They were treated subcutaneously with IL-2 according to the schedule proposed by Atzpodien et al. Venous blood samples were collected at O-time and 1, 8 and 12 hours after the first IL-2 pulse of 9 X 10(6) IU/m2 at 8.00 a.m.; on a separate occasion, samples were collected during a saline infusion only. In each blood sample, serum levels of cortisol, beta-endorphin, GH, PRL, FSH, LH, TSH and the pineal hormone melatonin were measured by RIA. Both cortisol and beta-endorphin significantly increased after IL-2 injection. GH rose but not to a significant extent. PRL, FSH, LH and TSH did not change after IL-2. Finally, melatonin levels markedly decreased after IL-2 injection in the only 2 patients with elevated concentrations of this hormone before the start of immunotherapy. These results suggest that the endocrine effects of subcutaneous IL-2 therapy are similar to those previously described with intravenous administration.

Appearance of neuropeptides in ascitic fluid after peritoneal therapy with interleukin-2 and lymphokine-activated killer cells for intraabdominal malignancy

Administration of intravenous interleukin-2 (IL-2), followed by intraperitoneal IL-2 and autologous lymphokine-activated killer (LAK) cells to six patients with colonic, ovarian, or endometrial carcinoma restricted to peritoneal spread increased significantly the ascitic fluid concentrations of the neuropeptides substance P (SP) and calcitonin-gene related peptide (CGRP). After intravenous IL-2 alone, the level of SP rose 10- to 140-fold, without a change in that of CGRP. Intraperitoneal IL-2 and LAK cells led to elevations in the concentrations of SP and CGRP to respective maximal means of 319 and 175 pM after 8 hr, which were maintained for 24-48 hr without alterations in the levels of vasoactive intestinal peptide or somatostatin. SP and CGRP from peritoneal fluid were chromatographically indistinguishable from synthetic neuropeptides. The increases in concentrations of SP and CGRP after IL-2 and LAK-cell therapy are the first demonstration of a neural response to a human cellular immunological reaction. The time course and magnitude of the neuropeptide response suggest a role in the vascular side effects of this form of treatment.