摘要:

Summary:The proto‐oncogene HER2/neu encodes a protein tyrosine kinase (p185HER2) that is homologous to the human epidermal growth factor receptor. Amplification and/or overexpression of HER2/neu occurs in multiple human malignancies and appears to be integrally involved in progression of some breast and ovarian cancers. Because of this fact, HER2/neu is an intriguing target for specific cancer therapeutic strategies. One such strategy is active specific immunotherapy, in which the immune system is targeted at specific antigens expressed by tumor cells. We have employed a transfected cell line that secretes the extracellular domain of p185HER2as a source of HER2‐derived immunogen in a guinea pig model. The immunized animals developed a cellular immune response, as monitored by delayed‐type hypersensitivity, and antisera derived from immunized animals specifically inhibited the in vitro growth of human breast tumor cells overexpressing p185HER2. These data provide support for an immunotherapeutic approach to cancers characterized by overexpression of the HER2/neu pro‐to‐oncogene.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Eleven patients receiving weekly cycles of therapy with recombinant interleukin‐2 (IL‐2) were evaluated with a sensitive limiting dilution analysis to determine lymphokine‐activated killer (LAK) cell precursor frequencies in peripheral blood lymphocytes. An increase in LAK precursor frequency above baseline was suggested by day 6 of this protocol and was clearly significant by day 20, indicating an expansion of the circulating precursor pool results from in vivo IL‐2 administration. Correlations were not significant between LAK precursor frequency during IL‐2 therapy and the total number of circulating lymphocytes, the percentage of CD56+ lymphocytes, IL‐2 proliferative responses, or LAK activity of peripheral blood lymphocytes, indicating that the precursor frequency identification based on functional testing of individual cells is not accurately reflected by these analyses of heterogeneous bulk populations. Selective cell depletion analyses revealed that the majority of LAK precursors after in vivo IL‐2 therapy were cells with the natural killer phenotype. Analysis of LAK precursors may help define the in vivo IL‐2 administration, alone or in combination with other hematopoietic or immuno‐differentiative cytokines, necessary to further augment in vivo effector cell numbers and activity for patients with cancer.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:A direct positive panning technique was developed in order to achieve highly purified CD4+and CD8+cells. Fresh peripheral blood mononuclear cells or tumor‐infiltrating lymphocytes derived from bulk cultures were applied to modified polystyrene surfaces to which anti‐CD4 or anti‐CD8 monoclonal antibodies were covalently attached. Adherent cells were allowed to grow in the original flask and were then harvested and cultured in IL‐2‐containing medium. This positive immunoselection technique resulted in CD4+and CD8+cell subsets with high cell viability and a high degree of purity. In several samples, the isolated cell subsets were subsequently subjected to a negative immunomagnetic bead selection in order to remove reciprocal cell subset contamination or double‐positive CD4+/CD8+cells. The isolated cells maintained their ability to proliferate, kept their phenotypic profiles, and remained functionally intact after long‐term growth in culture without the further addition of mitogenic or allogeneic cell stimulation. This approach is a simple, rapid, and reproducible technique that might be useful on a large scale to isolate and to grow T‐cell subsets for research and for clinical use.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:We administeredEscherichia coli‐derived recombinant human granulocyte‐macrophage colony‐stimulating factor to 61 patients with malignancy, 36 of whom had normal peripheral blood counts and 25 of whom had peripheral cytopenia due to underlying bone marrow disease, to compare the efficacy of two different routes of administration to stimulate the in vivo granulopoiesis: i.e., continuous i.v. infusion and s.c. injection. Three well‐tolerated dose levels were investigated. Application of granulocyte‐macrophage colonystimulating factor resulted in dose‐dependent increases in circulating neutrophils, eosinophils, and monocytes and an increase in bone marrow cellularity, irrespective of route of administration. In some patients, mild side effects, including bone pain, dyspnea, flu‐like symptoms, and a decrease of platelet counts, were recorded, but they were less pronounced when the hormone was administered subcutaneously.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:The purpose of the study was to evaluate the toxicity and biological activity of highly purified lipopolysaccharide (LPS) administered intravenously to cancer patients in order to establish an optimum dosage scheme. An initial subtoxic dose was increased in weekly increments in accordance with individual regimens that maintained patient reaction at a safe and acceptable level. Purified LPS fromSalmonella abortus equiwas administered to 11 patients with advanced solid tumors on a weekly schedule with intraindividually escalating dosage as determined by patient response. Biological response was monitored by complete blood count, C‐reative protein, and cytokine measurements at different time points after LPS injection. Tumor necrosis factor‐&agr; (TNF) and interleukin‐1&bgr; serum levels were measured by enzyme‐linked immunosorbent assay and interleukin‐6 (IL‐6) by bioassay. Dose‐limiting toxicities including chills and fever (WHO grade III) were reached at 1.0 ng/kg of body weight (maximal tolerated dose‐1, MTD‐1). Pretreatment with ibuprofen (1,600 mg) abrogated these side effects, allowing further escalation of LPS doses up to 10 ng/kg of body weight. At dose levels >8.0 ng/kg of body weight (MTD‐2), the aforementioned side effects occurred again and, additionally, hepatic toxicity (WHO grade III) was observed. Hematological changes included neutropenia followed by a pronounced neutrophilia contributed to by up to 30% bands, marked monocytopenia for 3 h, and retarded lymphopenia. By 24 h, all hematological parameters returned to pretreatment values. TNF serum levels increased from 10 pg/ml before treatment to 7,000 pg/ml as a function of dosage. Maximum serum levels were reached at 60 to 90 min after LPS injection. Similarly, IL‐6 serum concentrations increased from <4 to 2,500 U/ml; peak levels were obtained 30 min after TNF peak values. Prior administration of ibuprofen had no effect on the above‐mentioned hematological changes nor on cytokine release. LPS can be administered intravenously in weekly intervals at escalating doses from 0.15‐10.0 ng/kg of body weight, when patients are protected by pretreatment with ibuprofen at dose levels above 1.0 ng/kg of body weight. Cytokine release as measured by TNF and IL‐6 increased in a dosedependent manner although the constitutional symptoms are completely attenuated.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:A phase I clinical trial of the macrophage activator, muramyl tripeptide‐phosphatidylethanolamine has been carried out in 37 patients (47 courses) at doses of 0.01‐6.0 mg/m2intravenously twice weekly for 4 weeks. Activation of peripheral blood monocytes and drug toxicity were used as the parameters to monitor the trial. Toxicity was acute systemic responses of fever, chills, and hypertension without a clear dose response. No major organ‐related toxicity was seen. A dose of 4.0 mg/m2biweekly produced activation of blood monocytes; a dose of 6.0 mg/m2produced inhibition. There was one complete response of 3 months duration in a patient with renal cell carcinoma with pulmonary metastases. The optimum dose for phase II studies is in the range of 1‐4 mg/m2twice weekly for 4 weeks, a dose that is well tolerated.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:We have shown that a T‐cell clone derived from murine tumorinfiltrating lymphocytes (TILs) can be established that mediates in vitro and in vivo antitumor effects. Utilizing this clone as a model, we examined the effect of cytokines on T‐cell antitumor effector mechanisms in vitro and in vivo. This clone, termed BF‐1, was generated by limiting dilution culture of a freshly excised MC‐38 tumor, growing it in low levels of interleukin‐2 (IL‐2), and has been maintained for over 600 days. This clone became specifically cytotoxic for the MC‐38 tumor during its first 100 days of culture. Pretreatment of the parental MC‐38 tumor cell line with tumor necrosis factor (TNF) and interferon‐&ggr; (IFN‐&ggr;) increased its susceptibility to lysis by the BF‐1 TIL line, but not to lysis by lymphokine‐activated killer cells, in in vitro cytotoxicity assays. This increased susceptibility of the cytokine‐pretreated targets was restricted to the parental tumor (MC‐38), since similar pretreatment of MCA‐102, MCA‐105, or MCA‐106 tumors did not render them susceptible to lysis by BF‐1 TILs. This increased sensitivity to lysis in vitro was not the result of a change in the expression of major histocompatibility complex class I molecules. In experiments testing the ability of TILs to treat established lung metastases, the combination of TNF, IFN‐&ggr;, IL‐2, and TILs was shown to increase significantly the antitumor properties of this therapy when compared to TILs and IL‐2. This result demonstrates that combinations of lymphokines, which when administered alone do not affect micrometastatic tumor burdens (TNF, IFN‐&ggr;), can synergize with cellular immunotherapy in the treatment of established tumor burdens and may have applicabilities to the treatment of cancer in humans.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:A prospective phase I clinical trial with recombinant interferonalpha‐2b as maintenance therapy after cytotoxic chemotherapy was conducted. Twenty‐one homosexual and bisexual males with extensive mucocutaneous or visceral epidemic acquired immunodeficiency syndrome (AIDS)‐Kaposi's sarcoma (KS) were studied. After a complete response (6 patients) or partial response (15 patients) from chemotherapy consisting of Adriamycin (20 mg/m2), bleomycin (10 U/m2), and vincristine (1.4 mg/m2; 2 mg maximum), patients were given interferon‐alpha (IFN‐alpha) in an attempt to prolong disease‐free survival. Three dose levels of daily IFN‐alpha were tested: 5, 10, and 15 million U. The maximum tolerated dose was 10 million units. Dose‐limiting toxicities included recurrent grade 3 fatigue, diarrhea, and fever, which resulted in the termination of therapy in eight patients (38%). Hematologic toxicities were infrequent (four patients; 19%). Responses were observed in two patients on IFN‐alpha, both at the 10‐million‐U dose level. The median duration of response on IFN‐alpha therapy following chemotherapy was 8 weeks (range, 3‐11). We conclude that the duration of IFN‐alpha maintenance response following cytotoxic chemotherapy is short with response to residual disease observed in a minority of cases at this dose and schedule. Additional trials of maintenance therapy in patients with advanced AIDS‐KS combining antiretroviral agents are in progress.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:To develop effective interleukin‐2 (IL‐2) protocols for pediatric malignancies, it is important to define IL‐2 pharmacokinetics in children. In a phase I trial, we studied IL‐2 pharmacokinetics in seven children, aged 6‐18, five with leukemia, one with neuroblastoma, and one with rhabdomyosarcoma. IL‐2 was administered as a 15‐min i.v. infusion of either 1 × 106CU/m2/dose or 3 × 106CU/m2/dose (every Monday, Wednesday, and Friday for 3 weeks). IL‐2 levels were determined using an IL‐2‐dependent murine T lymphocyte cell line bioassay. Peak IL‐2 levels of 120‐426 and 330‐740 CU/ml were achieved after the lower and higher doses, respectively. Pediatric IL‐2 kinetics resembled data reported for adults, fitting a two‐compartment model (least‐squares‐regression technique), with an alpha half‐life of 14.0 ± 5.6 min (range, 6.3‐23.1) and a beta half‐life of 51.4 ± 10.7 min (range, 33.0‐66.0). The volume of distribution approximated total extracellular fluid (mean, 0.18 L/kg). Further clinical trials are needed to identify which pediatric malignancies are sensitive to immunotherapy and to establish the optimal treatment regimens.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Summary:Recombinant human tumor necrosis factor and recombinant human interferon‐gamma are two representatives of a novel class of antineoplastic agents. Evaluation of these agents in vitro has suggested that the combination would be more effective than either agent alone. A prior phase I study demonstrated that the maximum tolerated dose for each agent was 150 &mgr;g/m2/day for 5 days when administered concomitantly. Based on this experience, a phase II trial of patients with biliary tract, pancreatic, and colorectal cancer was planned. Our goal was to treat a minimum of 14 patients with each tumor type. However, in the first 13 patients entered into this trial the toxic effects at the starting doses of 125 &mgr;g/m2/day for 5 days for each agent were intolerable, with four patients unable to complete planned therapy. In this cohort of patients, no objective responses were observed. Further clinical investigation of this combination should consider alternative treatment schedules to reproduce the in vitro synergistic cytotoxicity of this combination while minimizing host toxicity.

ISSN:0732-6580    

出版商:OVID    

年代:1990

数据来源: OVID