摘要:

SummaryA single rising dose tolerance trial of rDNA interferon-α2, (IFN-α2) was conducted in eight patients with the diagnoses of non-Hodgkin's lymphoma (NHL), multiple myeloma, and chronic lymphocytic leukemia (CLL). Patients received a total of six i.m. doses at weekly intervals as follows: 1, 3, 10, 30, 60, and 100 X 106IU. Patients were monitored at each dose level for serum IFN activity, anti-IFN antibodies, immunomodulation, clinical toxicity, and response. All patients exhibited clinical toxicity, including fever, chills, fatigue, headache, anorexia, mild-to-moderate leukopenia, nausea, and vomiting. Toxicity was dose-related, with significant side effects occurring in all patients at levels of 10 X 106IU and above and some evidence of tachyphylaxis at higher doses. All side effects, including leukopenia and thrombocytopenia, were of short duration and were resolved within 3–5 days. Fevers, rigors, myalgias, and fatigue were partially alleviated by premedication with acetaminophen or hydrocortisone. Pharmacokinetic data indicated mean peak serum IFN titers >90 at a dose of 10 X 106IU and ≥200 at doses ≥30 X 106IU 8 h after injection. No anti-IFN antibodies were detected. However, the serum levels achieved at higher doses were not linear, possibly indicatingin vivodegradation. Total T cells, B cells, monocytes, and T subsets monitored by flow cytometry with monoclonal antibodies remained essentially constant throughout the trial. Although some patients demonstrated minor augmentations of antibody-dependent cellular cytotoxicity (ADCC) and natural killing (NK) activity at the lowest IFN-α2doses, the majority of patients demonstrated decreases in NK activity after higher IFN doses. No correlation between immunomodulation and clinical response to IFN was observed. At higher dose levels, the predominant immunomodulatory effect of IFN-α2was suppression of NK, ADCC, and blastogenic responses to T-cell mitogens and recall antigens. B-cell functional deficits as well as radioresistant T-helper and radiosensitive T-suppressor function assessed in a pokeweed mitogen–driven immunoglobulin secretion assay appeared unaffected by IFN administration. One myeloma patient showed progression and was discontinued after 60 X 106IU. There were four patients (3 NHL, 1 myeloma) who achieved partial remission (≥50% tumor reduction) and three (1 CLL, 2 NHL) who showed objective tumor responses of <50%. These data suggest that rDNA IFN-α2is well-tolerated and may have significant antitumor activity against lympho-proliferative malignancies. Clinical responses occur independent of any immunomodulatory activity of IFN-α2.

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

摘要:

SummaryFifteen patients with various types of cancer, resistant to conventional therapy, were entered into a phase I trial of pure interferon-α2(IFN-α2) produced by recombinant DNA technology. Groups of patients received either 3, 10, 30, or 50 X 106units (U) of IFN-α2subcutaneously daily for 4 weeks and were closely followed for possible toxicity. At the higher doses, toxicity was encountered, which led to reduction in the frequency of administration. For immunological testing, peripheral blood mononuclear cells were obtained before treatment on day 1, on day 2, and during the 2nd, 3rd, and 7th weeks of the study. The cells were tested for natural killer (NK) activity, antibody-dependent cellular cytotoxicity (ADCC), monocyte-mediated antibody-dependent cellular cytotoxicity (MMADCC), and spontaneous monocyte-mediated cytotoxicity (SMC). ADCC was augmented at all doses in 9 of 15 patients, 6 of whom exhibited elevated levels by day 2. In direct contrast, MMADCC was decreased in 12 of 14 patients 7–20 days after beginning treatment. SMC was increased on day 2 in 1 of 2 patients given 3 X 106U and in 3 of 4 patients given 10 X 106U. SMC in the other patients given these doses was unchanged on day 2, with no decreases noted. In contrast, SMC was decreased in 2 of 4 patients given 30 X 106U and in 2 of 3 patients given 50 X 106U. NK cell activity was increased in 2 of 3 patients given 3 X 106U, but was either unchanged or decreased in patients given higher doses. The only exception was an increase found in a patient given 50 X 106U, whose renal cell carcinoma responded significantly to treatment. Data on NK and SMC from a phase II study of breast cancer treated daily with 3 X 106U IFN-α2support our phase I observations. NK-cell activity was increased on day 2 in 3 of 8 patients, and SMC increased in 2 of 8 patients. As in the phase I study, no decreases in these functions occurred. In summary, for those responses that were dose dependent, such as NK and SMC, lower doses of recombinant IFN-α2(3 X 106and possibly 10 X 106U) may be more effective in increasing these anti-tumor activities than are higher doses.

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

摘要:

SummaryThe antitumor mechanisms of the interferons (IFN) have yet to be fully elucidated. Augmentation of natural killer (NK) cell activityin vitroandin vivoby IFN has regularly been assessed in clinical trials. We have measured NK activity against K562 target cells at various effector-to-target ratios, in patients receiving leukocyte IFN-α (HuLeIFN) in various schedules, as well as T-cell subsets determined by indirect immunofluorescence using Leu series monoclonal antibodies (Becton-Dickinson). The effect of HuLeIFN on the endocrine system has also been examined in selected trials. The preliminary results of these studies reveal that NK activity rose during the first 8 days of HuLeIFN therapy in patients with initially low levels of target cell lysis (<50% NK activity at either 50:1 or 25:1 ratios). Tachyphylaxis, with a decremental effect of HuLeIFN on NK activity, ensued during treatment, whether at the same or escalated doses. NK activity rose repeatedly during intermittent schedules of i.m. HuLeIFN given daily X 5 every 21 days with escalation cycles. A decreasing trend in the ratio of Leu 3a to Leu 2a (helper phenotype/ suppressor phenotype) was also seen overall. Of the endocrine parameters evaluated, the only remarkable finding was an increase in serum cortisol level following ACTH stimulation following HuLeIFN. Intramuscular HuLeIFN has been shown to augment NK activity, to perturb the T-cell-lymphocyte balance, and to affect the pituitary-adrenal axis invivo.

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

摘要:

SummaryTwenty-nine patients receiving recombinant interferon (IFN-α2; Schering Plough Corp., Bloomfield, NJ) were studied for changes in natural killer (NK) activity measured by a 4-h51Cr release assay against K562 cells, and T-cell subsets were determined by indirect immunofluorescence of Leu series monoclonal antibodies (Becton-Dickinson, Mountain View, CA). Seventeen cancer patients received daily i.m. injections of IFN-α2from 3 to 100 X 106U/day for 28 consecutive days or to tolerance. Twelve of an anticipated 16 melanoma patients have been studied during a phase I trial using the i.v. route with the same recombinant IFN-α2. NK activity rose during the first week of i.m. therapy from 49 ± 6.5 to 67 ± 6.2 (mean ± SE, day 8) at both high (≥30 X 106U/day) and low (≤10 X 106U/day) doses. This trend was not observed during therapy by the i.v. route at similar doses, in which NK activity tended to decrease in patients receiving 30 X 106U/day or more. Changes in T-cell subsets were observed in both trials; Leu 3a/2a (helper phenotype/suppressor phenotype) ratio rose twofold in patients receiving i.m. IFN-α2at higher doses. A rise in Leu 3a+and a fall in Leu 2a+T cells account for the change. No change in T-cell subsets was seen in patients treated at low doses (≤107U/day) by the i.m. route. By contrast, the Leu 3a/2a ratio fell by 50% in patients who received 30 X 106U/day or more of IFN-a, by the i.v. route, reflecting a fall in Leu 3a+cells and a rise in Leu 2a+cells. Thus, opposite changes in several parameters of immune competence occurred during treatment of patients with melanoma and other cancers, with a single recombinant IFN subspecies given by two different routes. These findings suggest that immunological monitoring may be critical to the optimal use of interferon.

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

摘要:

SummaryMethisoprinol (MIP) was found to augment natural killer (NK) activity of peripheral blood mononuclear cells (PBMC), as measured in a 4-h51Cr release assay using K562 cells as targets. Overnight incubation of PBMC with 0.1 μg/ml MIP, followed by removal of the drug, resulted in significant increases in the NK activity of all 17 donors studied. Augmentation of NK, expressed as lytic units (LU)/107effector cells, was generally two- to fourfold, and was manifest as early as 1 h after incubation with the drug, but was maximal after 4 h. The effect of MIP was dose dependent up to 0.1 μg/ml and remained at a plateau up to 10 μg/ml, where cytotoxicity to the effectors was observed. The effect of MIP was exerted on the effector cells and was not due to an increased susceptibility of target cells to lysis. In addition, this phenomenon was probably independent of interferon (IFN) production. Binding and killing at the single-cell level were shown to be unaffected by prior treatment with MIP. Rather, the analysis of the kinetics of NK activity indicated that MIP increased the recycling ability of NK effector cells. Augmentation of NK by MIP was dependent on the presence of adherent cells in PBMC fractions. Populations depleted of plastic adherent cells or populations enriched for adherent cells themselves could not undergo boosting by MIP, indicating that MIP did not act to recruit functional cells from inactive precursors. These studies suggest that the observed antiviral and/or immunoregulatory actions of MIP might be mediated through an increased NK cell activity.

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

摘要:

SummaryA preliminary trial was designed as a toxicity/feasibility study using a fixed dose of vaccinia melanoma oncolysates (VMO) to treat recurrent stage II and stage III (skin, subcutaneous, and nodal metastases only) melanoma. There were no adverse consequences of the therapy, and 4 of the 12 patients treated seemed to have responded to the treatment by the criteria of the study. Sera from the six patients with the longest survival showed immunoreactivity to human melanoma lines in aStaphylococcusprotein A assay (SpA) after 3 months of therapy. While the specificity of this immunoreactivity remains to be determined, the discovery of posttreatment serologic activity in a SpA assay permits investigation of the degree of VMO immunostimulation at different dose levels of the biologic. This assay may provide the means to quantitate optimal biologic dose for future melanoma oncolysate trials. The Southeastern Cancer Study Group is now conducting a phase I/II trial with these vaccinia melanoma oncolysates using the SpA assay to monitor this trial.

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID

ISSN:0732-6580    

出版商:OVID    

年代:1983

数据来源: OVID