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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we evaluated human pancreatic cancer xenotransplanted into nude mice as a model suitable for adoptive immunotherapy studies. A pancreatic cancer cell line (MIA PaCa-2) was chosen and its growth in nude mice and sensitivity to lysis by human lymphokine-activated killer (LAK) cells were characterized. This line grew in 96% of the cases when young (4- to 6-week-old) Swiss/NIH nude mice were used. The line was highly sensitive to lysis by LAK cells in a standard chromium-51 release assay (67.8%), similarly to other cell lines known to be highly sensitive, such as K562 (75.6%) and the melanoma cell line SU.102 (53.1%). To assess their in vivo distribution, human peripheral blood lymphocytes (PBLs) and LAK cells were adoptively transferred into nude mice after labeling with indium-111 oxine. The results of this study show that adoptively transferred PBLs and LAK cells localize in this heterologous system as they do in autologous systems. PBLs are taken up mostly by the liver and spleen. The percentage of the administered dose of radioactivity taken up corrected by weight (percent dose per gram tissue) is 64.3 +/- 15.6%d/gm (liver) and 43.5 +/- 9.5%d/gm (spleen). LAK cells are taken up by liver (43.2 +/- 5.3%d/gm) and spleen (28.0 +/- 4.9%d/gm) but also localize significantly more than PBLs in other organs such as lungs (12.9 +/- 3.5%d/gm vs 1.4 +/- 0.3%d/gm, p less than 0.01), kidneys (19.1 +/- 2.1%d/gm vs 6.3 +/- 1.5%d/gm, p less than 0.001), and pancreatic tumors growing in orthotopic position (1.93 +/- 0.36%d/gm vs 0.56 +/- 0.06%d/gm, p less than 0.05). When the nude mice are pretreated with human recombinant tumor necrosis factor, localization of LAK cells compared with PBLs is even further enhanced both in tumors implanted in the pancreas (3.1 +/- 0.5%d/gm vs 0.56 +/- 0.06%d/gm, p less than 0.01) and in the subcutis (12.5 +/- 8.3%d/gm vs 0.95 +/- 0.29%d/gm, p less than 0.001).
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PMID:The in vivo distribution of human peripheral blood lymphocytes and lymphokine-activated killer cells adoptively transferred in human pancreatic cancer-bearing nude mice. 249 21

In the course of a phase I trial, in which recombinant IL-2 (rIL-2) was infused intraperitoneally (i.p.) in patients with peritoneal carcinomatosis, we evaluated the effect on "tumor-associated lymphocytes" (TAL) isolated from the ascitic fluid. No major changes in the percentages of cells expressing the CD3, CD4, CD8, Leu-7, OKM1 and WT-31 antigens were detected either in TAL or in peripheral blood lymphocytes (PBL) after 7 days of rIL-2 infusion. In contrast the percentages of TAL (but not PBL) expressing surface IL-2 receptor (Tac), or LAK-1 antigen were sharply increased. Analysis of cytolytic functions showed a potentiation of the lytic activity against natural-killer (NK) sensitive K562 target cells and the de novo appearance of lytic activity against fresh melanoma cells. In one patient IFN-gamma was detected in the ascitic fluid following rIL-2 infusion. T-cell clones derived from the patient were analyzed for the IFN-gamma production. While only approximately 40% of PB-derived control clones produced medium to low amounts of IFN-gamma, all of the TAL-derived clones produced medium to high amounts of the lymphokine.
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PMID:Phenotypic and functional characteristics of tumor-associated lymphocytes in patients with malignant ascites receiving intraperitoneal infusions of recombinant interleukin-2 (rIL-2). 249 78

Interleukin 2 (IL-2) is a secreted glycoprotein which acts as an activation and proliferative signal for lymphocytes expressing membrane-bound glycoprotein IL-2 receptors. We have recently established that swainsonine (SW), an inhibitor of mannosidase II during N-linked glycoprotein processing, augmented mitogen-induced mononuclear leukocyte IL-2 receptor expression and IL-2-induced proliferation. The objective of the present investigation was to examine the effect of SW on lymphokine-activated killer (LAK) cell induction. Human mononuclear leukocytes were treated with various concentrations of SW (0.1-10 micrograms/ml) and IL-2 (1-100 units/ml) for up to 72 h. SW augmented IL-2-induced LAK activity directed against human lung carcinoma, melanoma, and leukemia cells 2-3-fold. LAK activity generated in the presence of SW at suboptimal doses of IL-2 (10 units/ml) was similar to that observed with higher concentrations of IL-2 (100 units/ml) alone. SW treatment alone or in combination with IL-2 increased the percentage of IL-2 receptor-positive cells. Furthermore, pretreatment with SW subsequently enhanced IL-2-induced lymphocyte proliferation. SW-treated mononuclear leukocytes exhibited an increase in high-mannose type glycoproteins based upon [3H]mannose labeling, susceptibility to alpha-mannosidase, and binding to concanavalin A-Sepharose. These results indicate that modulators of glycoprotein processing may be useful in lowering the concentrations of IL-2 required for LAK induction and maintenance.
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PMID:Potentiation of human lymphokine-activated killer cell activity by swainsonine, an inhibitor of glycoprotein processing. 250 Oct 20

Clones were isolated from the cultured human melanoma cell line MeM 50-10, which metastasizes in nude mice with a pattern similar to that in patients with melanoma. Analysis with monoclonal antibodies detected heterogeneity among the clones in the expression of HLA class I antigens, HLA class II antigens, intercellular adhesion molecule 1 and high molecular weight melanoma associated antigen. The clones MeM A16 and MeM A18 were also shown to display differential susceptibility to modulation by immune interferon (IFN-gamma) and/or tumor necrosis factor (TNF-alpha) of the expression of the four types of antigens analyzed. In spite of differences in the antigenic profile, the two clones did not differ in their susceptibility to lysis by lymphokine-activated killer (LAK) cells and by anti-HLA-A2 cytotoxic T cells. The increase in the expression of HLA class I antigens induced by IFN-gamma and/or TNF-alpha on the two clones was associated with an increased susceptibility to lysis by anti-HLA-A2 cytotoxic T cells. Because of the metastasizing properties of cultured melanoma cells MeM 50-10, the clones we have isolated, with their distinct antigenic profile and differential susceptibility to modulation by cytokines, may represent useful models to investigate the role of distinct antigenic structures in the metastatic process.
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PMID:Modulation by cytokines of HLA antigens, intercellular adhesion molecule 1 and high molecular weight melanoma associated antigen expression and of immune lysis of clones derived from the melanoma cell line MeM 50-10. 251 11

Adoptive immunotherapy of cancer consists of using interleukin-2 to induce the formation of lymphokine-activated killer (LAK) cells which are toxic to tumoral cells. Six patients, 3 with hypernephroma and 3 with melanoma, were treated with interleukin-2. Drug toxicity consisted of capillary leakage syndrome in one case and reversible renal impairment in another. One patient showed an objective response; transient subjective improvement was observed in all patients.
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PMID:[Adoptive immunotherapy with interleukin 2. Initial results of a pilot study in 6 cancer patients]. 252 48

We have studied the effects of low-dose recombinant interleukin-2 preceded by low-dose cyclophosphamide on malignant melanoma. Thirty eight outpatients aged from 25 to 75 years were treated with interleukin-2, 3.6 million Cetus units/m2 i.v. daily for five days on two successive weeks beginning three days after 350 mg/m2 of intravenous cyclophosphamide. This schedule was repeated at least twice more with a one-week interval between cycles, usually at the same dosage level. Ten of the 38 patients (26.3%) had clinically significant remissions: two complete (5.3%), seven partial (18.4%), and one ongoing, long-term (greater than 18 mo) "minor" response (2.6%). Four others (10.5%) had shorter minor responses and four (10.5%) a mixed response. One patient with disease restricted to the skin had a complete remission, while the other patient with a complete remission had had three lung nodules and an enlarged hilar lymph node. It was gratifying that one of the major sites of disease responding to treatment was the liver. Two complete and two partial remissions (i.e., greater than 50% regressions for greater than four weeks at this site) were obtained in 10 patients with liver involvement. Lung metastases also responded in four of 16 patients (one complete and three partial remissions). Subcutaneous nodules responded in seven of 21 patients (two complete, five partial remissions), while lymph node metastases diminished significantly in four of 14 patients (one complete, three partial remissions). The median duration of response was nine months (range, 1.5-20 months), with four patients treated for more than one year. Toxicity was moderate and controllable, and only two patients required hospitalization, both overnight. Lymphokine activated killer cell activation was induced in 24 of 38 patients, including all nine of the major responders. Conversely, none of 14 patients without lymphokine activated killer cell activation had a significant clinical remission. This regimen appeared to be as effective in melanoma as those involving ex vivo activation of lymphokine activated killer cells, and was more tolerable than therapy with high doses of interleukin-2.
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PMID:Low-dose cyclophosphamide and low-dose interleukin-2 for malignant melanoma. 253 54

The recombinant lymphokine interleukin-2 (IL-2) has activity in renal cell carcinoma, melanoma, and other cancers. A side effect of IL-2 use is a "capillary leak phenomenon" which is purported to be related to endothelial effects of IL-2 itself or to cells activated by IL-2. We studied IL-2 effects on rat lung lavage parameters to determine whether endothelial damage occurred. The specific endpoints were 125I-albumin extravasation, lavage protein, and lavage angiotensin-converting enzyme (ACE) activity. To ensure sensitivity of these endpoints, we used the known endothelial toxicant thiourea, which increases lung lavage protein and lavage ACE. We found that both PEG IL-2 and thiourea increased the amount of protein and 125-I flux into the lavage. However, although thiourea increased lavage ACE, PEG IL-2 did not. These results suggest that PEG IL-2 can increase protein and iodine flux across the endothelium without causing cell injury.
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PMID:Effects of PEG-coupled interleukin-2 on rat lung lavage parameters. 256 75

While preclinical studies suggest a steep dose-response relationship for the anti-cancer effect of recombinant interleukin-2 (rIL-2), translation of dose-intense rIL-2 to humans can be complicated by known toxicities, including hypotension, capillary leak phenomena and fluid retention. In an attempt to develop a manageable approach to dose-intense rIL-2, we have employed a continuous infusion schedule, 18 X 10(6) IU rIL-2/m2/day for five days. This treatment results in marked biological effect, and continuous infusion of rIL-2 alone or in conjunction with lymphokine-activated killer cells can result in complete remission of metastatic renal carcinoma. Treatment with continuous infusion tumour necrosis factor at 60 micrograms/m2/day for three days prior to rIL-2 may be of possible benefit in isolated cases of colon and lung carcinoma, but has not appeared to produce results superior to rIL-2 alone. Addition of tumour-infiltrating lymphocytes has been of benefit in selected cases of melanoma. The most promising combination of biological agents may be rIL-2 in conjunction with alpha-interferon. Ongoing studies involving subcutaneous alpha-interferon during continuous infusion rIL-2 suggest clinical synergy with acceptable toxicity.
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PMID:Clinical application of continuous infusion of recombinant interleukin-2. 262 85

The large granular lymphocyte (LGL) population includes such heterologous effector cells as the natural killer (NK), lymphokine activated killer (LAK), antibody dependent cellular cytotoxic (ADCC) and non-MHC restricted T cells. These LGL subpopulations have all been associated with NK activity. In some species, enhanced NK activity is correlated with exposure to viral, bacterial and parasitic agents. Consequently, the host environment could serve as a modulatory factor of NK activity in laboratory animals. During our investigation of tumor regression in melanoma swine, we observed marked differences in the NK activity of peripheral blood lymphocytes collected from two separate groups of Sinclair melanoma miniature swine maintained under different conditions. Group A pigs were vaccinated and extensively treated for endo- and ectoparasites while group B swine were not. In addition, chronic exposure to infectious and parasitic diseases have been documented in the group B swine. Peripheral blood NK activity was assessed by standard in vitro 4-h chromium release assays. The NK activity of group B swine was markedly exaggerated when compared to group A swine. Thus, the significance of NK activity may be distorted as a result of the modulating effect of pathogen exposure.
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PMID:Host environment as a modulating factor of swine natural killer cell activity. 262 96

Twenty-five patients with disseminated cancer (nine with renal cell carcinoma, five with melanoma, three with Hodgkin's lymphoma and chronic myelocytic leukemia [CML], two with soft tissue sarcoma, one each with large-cell lymphoma, breast cancer, and colon cancer), 13 males and 12 females, aged 25 to 68, were treated with recombinant human interleukin-2 (rIL2) by continuous infusion and adoptive transfer of autologous lymphocytes activated in vitro with IL2. Patients underwent leukapheresis on days 1, 8, 15, and 22 of the treatment. Cells, bulk activated for 20 hours in serum-free culture medium with 1,000 U IL2/mL in transfusion transfer packs as culture vessels, were transfused the following day. The infusion of IL2 by continuous infusion for six days started immediately after each adoptive transfer for 4 weekly courses. The dose of IL2 was escalated weekly in each patient; starting doses of IL2 were also escalated in subsequent cohorts of patients until maximally tolerated doses were reached. Nine patients had objective tumor regressions (three with renal cell cancer, two with Hodgkin's lymphoma, and one each with melanoma, sarcoma, breast, and colon cancer). Six responses were partial, two were minor, and one was mixed. Responding patients were maintained with IL2 by continuous infusion for six days every 6 to 8 weeks, without adoptive cell transfer. The median duration of responses was 16 weeks (3 to 60 + weeks). Tumor regression was related to the dose of IL2 (greater than or equal to 3.4 x 10(6) U/m2/d for six days) and to the in vivo lymphoproliferative effects of the lymphokine, but not to the total number of cells adoptively transferred. Side effects of treatment were transient and quickly reversible. Renal, hepatic dysfunction, and dyspnea were directly related to the dose of IL2 and to lymphocytosis. Other toxicities were mild hypotension with mild fluid retention, oral mucositis, anemia, thrombocytopenia, fever, and fatigue.
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PMID:Recombinant interleukin-2 by continuous infusion and adoptive transfer of recombinant interleukin-2-activated cells in patients with advanced cancer. 266 33


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