Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0424790 (rigors)
 822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 2 (IL-2) and interferon-alpha (IFN-alpha) are cytokines with synergistic antitumor effects in mouse models. The biological effects of this combination, however, have not been directly compared to each agent alone in humans. We conducted a Phase 1B trial of IL-2 plus or minus IFN-alpha in 38 cancer patients. The objectives of this trial were to determine which doses of IFN-alpha and IL-2 maximally enhanced biological responses, and to determine whether the combined administration of IFN-alpha and IL-2 would result in a potentiation of biological responses over IL-2 alone. Patients received 4 days of IL-2 (1.5 x 10(6) units/m2/day or 3.0 x 10(6) units/m2/day) as a continuous infusion followed by a 3-day rest period, weekly for 3 weeks, with a 3-week rest period between 2 treatment courses. IFN-alpha (0.5 x 10(6) or 5 x 10(6) units/m2/day) was administered s.c. on days 1-4 weekly for 3 weeks with one of the 3-week courses. Patients were randomized to receive either IL-2 alone for course 1, followed by IL-2/IFN-alpha for course 2, or IL-2/IFN-alpha in course 1, followed by IL-2 alone. Immunological parameters were evaluated before treatment, and 24 h after completion of the third week of IL-2. A statistically significant increase in the percentage of circulating natural killer cells (CD56), natural killer cells bearing the Fc receptor (CD16), and activated T cells (CD25) was observed following IL-2 alone, and following IL-2 plus IFN-alpha. Significant increases in lymphocyte-activated killer cell cytotoxicity, antibody cellular cytotoxicity, and serum IL-2 receptor were also observed following both IL-2 and IL-2 plus IFN-alpha. However, no significant differences were observed in the magnitude of the increase in the IL-2-alone group when compared to the IL-2 plus IFN-alpha group. The mean fluorescent intensity of monocytes positive for HLA-DR and Fc receptor expression also increased significantly in both groups, as did serum beta 2-microglobulin expression and indoleamine 2,3-dioxygenase activity. However, increases were not significantly different between patients receiving IL-2 alone and IL-2 plus IFN-alpha. No dose response effect for IFN-alpha was observed for any of the parameters assessed. Toxicities consisted primarily of constitutional toxicities, including fever, rigors, malaise, headache, anorexia, and a decrease in performance status. No clinically significant differences in toxicities were observed between courses consisting of IL-2 and those consisting of IFN-alpha and IL-2.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:A direct comparison of immunological and clinical effects of interleukin 2 with and without interferon-alpha in humans. 844 8

HuM195 is a recombinant humanized IgG1 monoclonal antibody reactive with CD33, a Mr 67,000 glycoprotein expressed on early myeloid progenitor cells and myeloid leukemia cells. HuM195 has been shown to rapidly target and saturate acute myeloid leukemia (AML) cells after i.v. infusion into patients and is capable of mediating antibody-dependent cellular cytotoxicity. This activity is enhanced in vitro when natural killer (NK) effector cells are preincubated with low concentrations of interleukin 2 (IL-2). Previous Phase I trials of HuM195 in patients with relapsed AML demonstrated safety and attainment of complete responses, but significant antileukemic activity appears limited to patients with low leukemia tumor burdens. Therefore, in the present trial, we sought to determine whether low-dose IL-2 could safely enhance the numbers of NK cells and therefore the cytotoxic capability of HuM195 via presumptive NK cell antibody-dependent cellular cytotoxicity in vivo against myeloid leukemia cells. Thirteen patients with relapsed or refractory AML and one patient with advanced myelodysplastic syndrome were treated with 0.6x10(6) IU/m2 of s.c. IL-2 daily for 35 days. Starting on day 15, patients received twice weekly i.v. infusions of HuM195 (3.0 mg/m2) for 3 weeks. Immediately after the HuM195 infusion, the patients received IL-2 i.v. infusions over 2 h at one of three escalating dose levels of 0.5x10(6), 1.0x10(6), and 2.0x10(6) IU/m2. Peripheral blood mononuclear cells were quantitated and immunophenotyped by flow cytometry. Safety, tolerability, bone marrow mononuclear cell morphology, and immunophenotype, as well as responses were assessed. Of the 14 patients who entered the study, 10 were able to complete at least one cycle of therapy. Adverse effects to the s.c. IL-2 were relatively mild and included erythema and induration of the skin at the injection site and low-grade fever. Toxicity from the sequential HuM195 and i.v. IL-2 infusions included nausea, rigors, and fever. Toxicity was IL-2 dose related with dose-limiting toxicity seen at the 2.0x10(6) IU/m2 dose level. Three patients had stable disease at the completion of the first cycle and went on to receive a second cycle of treatment. CD3-positive, CD56-positive, and CD33-positive cells were generally found to significantly decrease immediately after each administration of i.v. IL-2 and HuM195. CD56-expressing cells increased in 6 of 10 patients from the beginning to the end of therapy. Among the 10 evaluable patients, 2 patients had significant decreases in the percentage of blasts in the bone marrow (one of which achieved a complete bone marrow remission), 5 patients had stable levels of bone marrow blasts, and 3 had progression of disease on therapy. The combination of IL-2 and HuM195 shows modest biological activity and clinical antileukemic activity but also produced significant toxicity.
 ...
PMID:A phase I trial of humanized monoclonal antibody HuM195 (anti-CD33) with low-dose interleukin 2 in acute myelogenous leukemia. 1053 38