Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor beta chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7-53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3-44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 micrograms/ml were achieved in patients treated with 0.5 or 1.0 mg/kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.
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PMID:A phase I-II study evaluating the murine anti-IL-2 receptor antibody 2A3 for treatment of acute graft-versus-host disease. 236 50

The purposes of this work are to: review the biological activities of Interleukin-2 (IL-2); evaluate the reported therapeutic benefits and toxicity of IL-2/lymphokine activated killer (LAK) cells; and project the role of IL-2/LAK cells in cancer therapy. Interleukin-2 is a glycoprotein lymphokine (mw 15,000) produced naturally by mitogen or antigen stimulated T-lymphocytes. The activities of IL-2 include: enhancement of IL-2 receptor positive T-lymphocytes and a variety of other in vitro and in vivo alterations of T cell function. The IL-2 gene has been cloned from the Jurkat leukemia cell line and expressed by recombinant biotechnology in an E. coli vector. In vitro incubation of IL-2 with selected T-lymphocytes results in the formation of lymphocyte activated killer (LAK) cells. Rosenberg and colleagues, in 1983, demonstrated that both exogenous IL-2 and LAK cells were needed in order to get maximum tumor regression in a murine model and later humans. Patients selected for IL-2/LAK cell therapy have clinical metastases or advanced unresectable cancers. Almost all patients treated demonstrate some toxic effects, including chills, fever, nausea, vomiting, diarrhea and hepatic dysfunction. Approximately 75 percent of the patients have profound hypotension and require intensive nursing care. A review of the literature indicates that tumor responsiveness will range from negligible (adenocarcinoma of the lung with metastases) to a 30+ percent response in renal cell carcinoma when complete and partial responders are totalled. Interleukin-2/LAK cell therapy has promise for some wide spread tumors for which no other therapy is available.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-2 and lymphokine activated killer cells: promises and cautions. 264 90

The purpose of this study was to compare the toxicity, immunomodulatory changes, and antitumor efficacy of interleukin 2 (IL-2) and lymphokine activated killer (LAK) cell therapy with two durations of IL-2 infusion. Patients with progressive melanoma, non-Hodgkin's lymphoma, renal carcinoma, or colon carcinoma received IL-2 at 3 X 10(6) units/m2/day on days 1-5 and 13-17, either by bolus injection every 8 h (q8h) or by continuous i.v. (CIV) administration. Peripheral blood mononuclear cells were harvested by leukapheresis on days 8, 9, and 10, were incubated in vitro for 5 days for generation of LAK cells, and were infused on days 13, 14, and 15. The first 11 patients were treated with IL-2 q8h, and the subsequent 13 patients were treated by CIV infusion. Toxicity consisted primarily of fever, chills, emesis, diarrhea, weight gain, and edema but did not require intensive care unit support and did not differ significantly between treatment groups. IL-2-induced lymphocytosis on day 8 was higher with CIV than with q8h administration with a mean lymphocyte count/microliter of 5610 +/- 700 (SE) versus 3300 +/- 500. Immunomodulatory changes observed on days 8 and 20 were also greater with CIV IL-2 and included an increase in peripheral blood mononuclear cell IL-2 receptor expression as well as a marked rise in the number of Leu-11+ and Leu-19+ peripheral blood mononuclear cells. The total leukapheresis yield per patient and total number of LAK cells infused per patient were higher with CIV than q8h administration, with 49.8 +/- 4.9 X 10(9) versus 39.4 +/- 5.4 X 10(9) and 42.6 +/- 5.0 X 10(9) versus 34.0 +/- 5.4 X 10(9), respectively. The cells infused displayed phenotypic evidence of activation and exhibited marked lytic reactivity to Daudi, Raji, and HT-144 targets. One complete and one minimal response were observed in 2 of 8 patients with metastatic renal cell carcinoma who received CIV IL-2 and LAK cells. The results show that IL-2 is more biologically active by CIV than q8h administration, as demonstrated by greater rebound lymphocytosis, LAK cell yield, and in vivo immunostimulation.
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PMID:Influence of schedule of interleukin 2 administration on therapy with interleukin 2 and lymphokine activated killer cells. 278 43

Based on a preclinical study demonstrating the synergistic antitumor effect of recombinant interleukin 2 (rIL-2) and beta-interferon (IFN-beta) on mouse tumors and previous results of a phase I study of rIL-2, a phase I study of combination therapy with human rIL-2 and IFN-beta was conducted in 26 patients with advanced malignancy. Patients were given rIL-2 by 24-h continuous i.v. infusion and IFN-beta by 2-h i.v. infusion for 5 days each week for 4 weeks. The common side-effects were fever, malaise, chills, appetite loss, and diarrhea. Leukocytosis and eosinophilia were observed in 56% and 69% of the patients, respectively. Transient leukopenia and thrombocytopenia were also observed in some patients. Dose-limiting manifestations were intolerable fatigue and liver dysfunction, and it was concluded that the maximum tolerated doses of rIL-2 combined with IFN-beta were 1.1 x 10(6) U/m2/day for rIL-2 and 6.0 x 10(6) IU/m2/day for IFN-beta. No patients achieved complete and partial response to therapy in this study. One patient with pulmonary metastasis from pharyngeal cancer showed a minor response. Natural killer (NK) and lymphokine-activated killer (LAK) activities increased during the 5 days of treatment and decreased during the 2-day intermission. The percentage of IL-2 receptor-positive cells increased markedly until Day 12, and gradually decreased thereafter. The percentage of OKT 4-positive cells and the OKT 4/OKT 8 ratio increased. In contrast, the percentage of Leu 7- or Leu 11-positive cells decreased over the 4-week treatment. A phase II study of this combination therapy is ongoing against head and neck cancer, and renal cell carcinoma.
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PMID:Phase I study of combination therapy with interleukin 2 and beta-interferon in patients with advanced malignancy. 278 85

Recombinant human interleukin-2 (rIL-2) was administered to 34 patients with advanced malignancy. Three schedules of rIL-2 administration employed were as follows: (A) 2-hr iv infusion of 6.7 X 10(5) U/m2/day (A1, 6 cases) or 2.2 X 10(6) U/m2/day (A2, 8 cases) for five consecutive days; (B) 24-hr continuous iv infusion of 3.3 X 10(5) U/m2/day (B1, 3 cases), 6.7 X 10(5) U/m2/day (B2, 7 cases) or 1.1 X 10(6) U/m2/day (B3, 5 cases) for 28 consecutive days; and (C) 24-hr continuous iv infusion of 6.7 X 10(5) U/m2/day (C, 5 cases) for 5 consecutive days per week for four weeks. The common side effects were fever (79%), eosinophilia (61%), malaise (56%), erythema or rash (50%), chills (38%) and nausea or vomiting (35%), with the dose-limiting toxicities being hypotension in group A, and renal dysfunction with fluid retention in groups B and C. In the case of 2-hr iv infusion, rIL-2 was rapidly cleared from the plasma, with a half life of about 30 min, while in the case of 24-hr continuous infusion, more than 1 U/ml serum IL-2 activity was maintained for 14 days in group B3. Natural killer (NK) and lymphokine-activated killer (LAK) activities were augmented by rIL-2 administration in patients of groups A, B3 and C. In eight patients of group B, NK and LAK activities transiently decreased after rIL-2 administration, and recovered by day 3. The percentage of IL-2 receptor and Leu HLA-DR positive cells reached the peak level on day 7 in group B. In patients of group C, the percentage of Leu HLA-DR positive cells as well as NK and LAK activities increased upon rIL-2 administration and decreased during an intermission of two days. However, the percentage of rIL-2 receptor positive cells increased during the intermission of rIL-2. The most effective schedule of rIL-2 administration was considered to be the schedule of group C on the basis of this study.
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PMID:Three schedules of recombinant human interleukin-2 in the treatment of malignancy: side effects and immunologic effects in relation to serum level. 312 1

The purpose of this study was to investigate the effect of dose and duration of infusion of recombinant interleukin-2 (IL-2) on toxicity and immunomodulation. In a phase I/II study, IL-2 was administered intravenously (IV) daily for five consecutive days every other week for 4 weeks of treatment to 23 patients with progressive melanoma, renal, colon, or ovarian cancer by one of four regimens: groups I and II received 3 X 10(5) U/m2/d by two-hour or 24-hour infusion, respectively; groups III and IV received 3 X 10(6) U/m2/d by two-hour or 24-hour infusion, respectively. In a subsequent study, six patients (group V) received a single priming cycle of daily IL-2 for five days at 3 X 10(6) U/m2/d in divided 15-minute infusions every eight hours, before undergoing leukapheresis for lymphokine-activated killer (LAK) cell generation. Toxicity was mild with 3 X 10(5) U/m2/d, but severe chills and fever, moderate hypotension (not requiring IV pressors), and weight gain were observed with 3 X 10(6) U/m2/d. Toxicity was also related to the duration of infusion. In group IV (continuous infusion), fluid retention, weight gain, and azotemia were more frequent and severe than in groups III or V, in which the same total dose was administered by two-hour infusion or in three divided 15-minute infusions. IL-2 induced rebound lymphocytosis, which was directly dose-related and significantly higher in group IV (continuous infusion) than in groups III or V. Dramatic increases in the percentage and absolute number of cells expressing the IL-2 receptor were also most pronounced in group IV. With the higher dose of IL-2, LAK cells appeared in the circulation, and natural killer (NK) cytotoxicity was augmented. The results showed that the toxicity and immunomodulation by IL-2 are dose-dependent and are maximal by continuous infusion compared with two-hour or divided every eight hours infusions.
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PMID:Influence of dose and duration of infusion of interleukin-2 on toxicity and immunomodulation. 325 31

Humanized anti-Tac is a genetically engineered human IgG1 monoclonal antibody specific for Tac, the alpha subunit of the interleukin-2 (IL-2) receptor, and blocks IL-2-dependent activation of human T lymphocytes. The safety, pharmacokinetics, and immunosuppressive activity of humanized anti-Tac were evaluated in 20 patients who developed acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Patients had developed acute GVHD at 5 to 26 (median, 14) days after transplantation and had failed to respond to primary therapy with glucocorticoids. Sequential groups of 4 patients each received a single 1-hour infusion of antibody in escalating doses of 0.5, 1.0, or 1.5 mg/kg; 8 additional patients were then treated with 1.5 mg/kg. A second infusion of antibody was administered after 11 to 48 (median, 16) days in 8 patients who had transient improvement of GVHD after the first infusion. Acute side effects, limited to chills in 1 patient and diaphoresis in another, were observed during or shortly after the antibody infusion. Overall improvement of acute GVHD occurred in 8 patients, 6 of whom were treated with a single antibody infusion and 2 with two infusions. Four responses were complete and 4 were partial. Three additional patients had improvement in one organ but progression in another. Responses occurred in 9 of 16 cases with skin disease, 3 of 15 with liver disease, and 6 of 12 with gastrointestinal disease. Two patients survive at 529 and 645 days after antibody treatment. Two patients died after relapse of leukemia. Sixteen patients died of infection or organ failure between 5 and 211 (median, 55) days. The terminal elimination half-life of the antibody was 44 to 363 hours, with a harmonic mean of 79, 88, and 94 hours, respectively, for the three doses studied. Absolute peripheral blood T-lymphocyte counts remained unchanged during the 56 days after infusion of the antibody. A fraction of circulating T cells expressed the alpha chain of the IL-2 receptor that, in some patients, was bound by antibody in vivo up to 28 days after treatment. No patient developed a measurable antibody response to humanized anti-Tac. Humanized anti-Tac has a long half-life after intravenous injection in humans, superior to any rodent monoclonal antibody specific for human T cells, and does not appear to induce antibody formation in recipients of marrow transplants. Improvement of steroid-refractory GVHD in 40% of patients after only one or two antibody infusions indicates that humanized anti-Tac is immunosuppressive.
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PMID:Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor. 804 47

We evaluated adoptive immunotherapy using LAK cells combined with systemic administration of interleukin-2 (IL-2) in 11 patients with metastatic renal cell carcinoma. The LAK cells were generated by incubation in serum-free medium (AIM-V) supplemented with IL-2 (1,000 U/ml) for 4 days and were generally administered twice weekly (4 times/cycle). Daily administration of IL-2 (50 x 10(5) U) was started 3 days prior to the first LAK infusion and continued throughout the cycle. Each course of therapy comprised 1-6 cycles, with the total dose of LAK cells and IL-2 varying from 3.3-52.6 x 10(9) cells and 140-900 x 10(5) U, respectively. Clinical response was evaluated in terms of metastasis to specific organs (lung only: eight cases, lung and brain: one, lung and lymph nodes: one, lung and bone and pleuropericardium: one). The outcome was complete response in one patient, partial response in one, no change in six and disease progression in three. The response rate was 18.8%. This therapy was most effective against pulmonary metastases. Adverse reactions to LAK cell infusion included fever, headache, and chills. Eosinophilia and weight gain due to IL-2 administration were also observed. However, all of these symptoms were transient and no serious side effects occurred. In these patients, the proportion of natural killer (NK) cells (CD16) and cells with IL-2 receptor (CD25) among PBL was increased markedly in the early phase of therapy, and activated T cell (CD3+DR+) and suppressor T cells (CD8+11+) increased significantly at a later phase. It was suggested that the clinical response would be expected in case of increasing of CD16 cells or CD25 cells and augmentation of NK or LAK activity. Our results indicate that this regimen of adoptive immunotherapy shows some promise for the treatment of advanced renal cell carcinoma.
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PMID:[Study of adoptive immunotherapy for metastatic renal cell carcinoma with lymphokine-activated killer (LAK) cells and interleukin-2. II. Clinical evaluation]. 832 Aug 88

We conducted a Phase I trial of s.c. recombinant human interleukin 3 (rhIL-3) to evaluate the toxicity, maximal tolerated dose, pharmacokinetics, and in vivo biological effects of this cytokine. Thirty-one patients with refractory cancer were entered into the study between November 1991 and June 1993. Therapy consisted of s.c. rhIL-3 daily for 15 days administered to cohorts of three to nine patients at dose levels of 60-4000 microgram/m2/day. Cycles were repeated at intervals of 28 days. Seventy-five cycles of rhIL-3 were administered (median, two per patient) and the maximal tolerated dose was 2000 microgram/m2/day. Toxicity was moderate, with most patients developing chills, fever, and myalgia. Dose-limiting toxicity consisted of diarrhea (two patients) and headache (one patient). Hematological effects of rhIL-3 included significant dose-related increases of WBC (P < 0.001), neutrophils (P < 0.001), and eosinophils (P < 0.001). Platelet counts and absolute lymphocyte numbers also increased. Various CD3(+) lymphocyte subsets increased; however, lytic activity (natural killer and lymphokine-activated killer) of peripheral blood lymphocytes was not enhanced. Serum levels of the soluble IL-2 receptor increased in a dose-related fashion, and IL-2-induced lymphocyte proliferation also was increased variably. Pharmacokinetic studies were performed in 13 patients, and area under the curve and maximal concentration values increased with increasing rhIL-3 dose levels (P < 0.001) and correlated with maximal changes from baseline in WBC, neutrophils, and eosinophils. rhIL-3 antibodies were detected in 8% of patients by day 29 of cycle 1 but were not neutralizing. rhIL-3 is well tolerated when administered s.c. and has reproducible hematological and immunological effects. The pleiotropic effects of this cytokine on various in vivo biological parameters were demonstrated clearly. Further studies of its immunoregulatory effects are warranted.
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PMID:Phase I trial of subcutaneous interleukin 3 in patients with refractory malignancy: hematological, immunological, and pharmacodynamic findings. 981 78