Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapeutic vaccination of tumor patients with cytokine gene-transfected tumor cells leads to tumor regression in animal models but has so far not resulted in significant clinical benefit. We and others demonstrated that tumor cells transfected to mediate overexpression of a cytokine gene activate immunologic effector cells for an improved proliferation rate and significantly higher antitumoral cytotoxic activity. Here, we performed a pilot study of therapeutic vaccination in patients with metastatic disease. Autologous tumor cells were simultaneously transfected with novel minimalistic, immunogenically defined, gene expression constructs (MIDGE) for overexpression of the two cytokines interleukin 7 (IL-7) and GM-CSF and newly designed double stem-loop immunomodulating oligodeoxyribonucleotides (d-SLIM) as a Th1-promoting and NK cell-stimulating adjuvant. Transfection was performed ex vivo by ballistomagnetic gene transfer. Patients received four subcutaneous injections of at least 1 x 10(6) of their expression-modulated and immunomodified autologous tumor cells. Ten patients have been enrolled in the study protocol. In all patients no adverse effects could be detected. IL-7 and interferon gamma levels were elevated in the serum of the patients after treatment. Interestingly, cytotoxicity of patient-derived PBLs increased significantly during treatment. All 10 patients had progressive disease when entering our protocol. One complete, one partial, and one mixed response with progression of abdominal metastases and regression of lung metastases were observed. Two patients showed a stable disease after treatment and five patients remained in progressive disease. Our observations confirm the capability of autologous expression-modified and immunomodulated tumor cell vaccines to stimulate a strong immune response in patients with metastatic cancer even in the presence of a large tumor burden.
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PMID:Therapeutic vaccination against metastatic carcinoma by expression-modulated and immunomodified autologous tumor cells: a first clinical phase I/II trial. 1117 63

Adenovirus (Ad) gene transfer vectors traffic to regional lymph nodes (RLNs) after footpad injections in mice, resulting in localized production of interferon gamma (IFN-gamma). With this background, we evaluated the hypothesis that Ad vector administration may inhibit RLN tumor metastasis independent of the transgene in the expression cassette. Tumors of MM48, a cell line with a propensity toward lymphogenous metastasis, were established in the footpads of syngeneic C3H mice, and E1(-)E3(-) Ad vectors encoding no transgene (AdNull) or encoding an irrelevant transgene (AdCD; Escherichia coli cytosine deaminase with no 5-fluorocytosine administration) were administered (10(10) particles) in a peritumoral location. Both vectors suppressed the growth of tumor in the regional (popliteal) lymph node. This effect was localized to the regional, but not distant, lymph nodes (p < 0.05). Heat inactivation of the vector or decreasing the dose of the vector to 10(9) particles did not suppress RLN growth of the tumor when compared with 10(10) particles of active AdNull (p < 0.05 and p < 0.01, respectively). The ability of an E1(-)E4(-) vector expressing beta-galactosidase (AdRSVbetagal.11) to suppress RLN tumor growth showed that the E4 region of the Ad vector was not responsible for the effect. Blocking either IFN-gamma or natural killer (NK) cells with systemic antibody treatment in immunocompetent mice allowed rapid growth of RLN metastases despite Ad vector administration, and Ad vector injection into the footpads of tumor-free mice induced the accumulation of NK cells in the RLN. These data demonstrate that, in a metastatic murine tumor model, a low dose (10(10) particles) of replication-deficient Ad vectors inhibits RLN metastases independent of a therapeutic transgene, an effect that is mediated, at least in part, by IFN-gamma and NK cells.
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PMID:Adenovirus gene transfer vectors inhibit growth of lymphatic tumor metastases independent of a therapeutic transgene. 1153 67

Skin melanoma, unlike other cancers, occurs on the body surface: it can be detected and treated before it reaches the stage where it can metastasise; the impact of surgery is unrivalled, but only while it is at this early stage. In melanomas more than 0.75-1.00 mm thick, an increasing proportion acquire metastatic properties. There is today evidence showing that wide excision does not help, and that the effect of surgery is limited to local control of the disease. According to randomised trials, the territory of early spread--without concomitant distant micrometastases--that can be eradicated by surgery is shrinking. It has been demonstrated that resection margins of 3-4 cm are no better in terms of recurrence and survival than margins of 1 or 2 cm. Most melanomas can now be adequately resected without skin grafting. Regional elective lymph node dissection for high-risk melanoma (1.5 mm thick or more) does not improve survival over that obtained with delayed lymph node dissection performed when clinical metastases appear. By analogy, prophylactic isolated limb perfusion with melphalan reduces the rate of in-transit metastases but does not improve survival. Sentinel node biopsy allows early detection of regional lymph node metastases with minimally invasive surgery. On-going randomised studies will show whether it can have any impact on survival. Considering the experience with elective lymph node dissection, it seems unlikely that selective--as opposed to elective--lymph node dissection, of positive sentinel nodes, will influence survival. The already extensive experience with sentinel node biopsy provides a death risk hierarchy: one N2 node (with clinical metastasis), one N1 node--or sentinel node--with micrometastasis and one N0 node with no histologically detectable micrometastasis but PCR positive give, respectively, 50%, 60% and 70% 5-year survival rates. In other words, the earlier the detection of metastasis, the longer the survival. In terms of growth kinetics, the earlier the detection of metastasis, the longer the time to death, with no evidence that surgery would have an impact. There is just one, as yet unpredictable, subset of pa- tients with lymph node-confined disease in whom surgery might have an impact. It is hoped that, in the future, gene expression profiles of primary melanoma will help to pick out these patients. Multivariate analysis has shown that the sentinel node status is the most powerful prognostic factor in primary melanoma. Sentinel node biopsy is a valuable tool for selecting patients for adjuvant treatments within the frame of clinical trials, in which micrometastatic and clinically involved lymph nodes are entered separately. In-transit metastases can be eradicated in 50% of cases by isolated limb perfusion with melphalan under mild hyperthermia. When in-transit metastases are recurrent, deep seated, or bulky, the combination of tumour necrosis factor (TNF) with melphalan and interferon gamma yields a complete response rate of around 80%. This is the first antiangiogenic treatment of cancer that is effective in clinical practice, but it has no effect on survival. Current better knowledge of melanoma biology indicates that local, limited surgery has an impact on local or regional spread only.
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PMID:The impact of surgery on the course of melanoma. 1207 9

Tumor cells are usually weakly immunogenic as they largely express self-antigens and can down-regulate major histocompatability complex/peptide molecules and critical costimulatory ligands. The challenge for immunotherapies has been to provide vigorous immune effector cells that circumvent these tumor escape mechanisms and eradicate established tumors. One promising approach is to engineer T cells with single-chain antibody receptors, and since T cells require 2 distinct signals for optimal activation, we have compared the therapeutic efficacy of erbB2-reactive chimeric receptors that contain either T-cell receptor zeta (TCR-zeta) or CD28/TCR-zeta signaling domains. We have demonstrated that primary mouse CD8(+) T lymphocytes expressing the single-chain Fv (scFv)-CD28-zeta receptor have a greater capacity to secrete Tc1 cytokines, induce T-cell proliferation, and inhibit established tumor growth and metastases in vivo. The suppression of established tumor burden by cytotoxic T cells expressing the CD28/TCR-zeta chimera was critically dependent upon their interferon gamma (IFN-gamma) secretion. Our study has illustrated the practical advantage of engineering a T-cell signaling complex that codelivers CD28 activation, dependent only upon the tumor's expression of the appropriate tumor associated antigen.
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PMID:Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. 1238 13

Death-associated protein (DAP) kinase is a gene that participates in apoptosis induced by interferon gamma. It appears to play a role in lung cancer metastasis in animal models, suggesting that DAP-kinase may function as a metastasis suppressor by inducing apoptosis. Expression silencing through CpG island methylation of DAP-kinase has been frequently found in connection with adverse survival, as cells lacking DAP-kinase appear to be more invasive and more metastatic in lung cancer. The purpose of this study was to analyze the promoter methylation status of DAP-kinase gene in brain metastases of solid tumors. Methylation-specific PCR was performed on ten brain metastasis samples derived from malignant melanoma (three cases), lung cancer (two), breast carcinoma (two), ovarian carcinoma (two) and colon carcinoma (one case), and in corresponding peripheral blood DNA samples. Two normal brain tissue samples were also analyzed, no promoter hypermethylation was observed in either case. DAP-kinase hypermethylated alleles were identified in nine metastases (90%), and in peripheral blood lymphocytes DNA from four cases. Our data suggest that silencing of DAP-kinase through promoter hypermethylation is a common event in the multistep process of tumor metastasis, including brain involvement.
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PMID:Frequent death-associated protein-kinase promoter hypermethylation in brain metastases of solid tumors. 1279 65

The extracellular domain of the receptor tyrosine kinase Tie2/TEK (exTEK) has been used as an angiopoietin decoy to study the role of angiopoietins in the tumor-host interactions, using a syngeneic model of experimental metastases and subcutaneous tumor. Soluble exTEK secreted by transfected tumor cells inhibited HUVECs from forming tubes in Matrigel. ExTEK-transfected C26 colon carcinoma and TS/A mammary tumor cells displayed reduced growth rate when injected subcutaneously, and reduced ability to form experimental metastases when injected intravenously. Immunohistochemical analysis of tumors and metastases showed increased leukocytes infiltration and signs of inflammation in exTEK-secreting compared to parental tumor, as well as impairment in neo-vessel growth and organization. However, while neoangiogenesis eventually rescued in the subcutis, it failed to organize in the experimental metastases of exTEK-secreting tumor, contributing to the hampering of metastatic growth and to increased mice survival. The reactive infiltrate of C26TEK contained a different percentage of leukocytes and was responsible for the tumor inhibition. In fact, leukopenia induced by gamma-irradiation of recipient mice or injection into interferon gamma (IFN-gamma) gene knockout (GKO) mice resulted in reduced mouse survival and an increased number of lung metastases. On the other hand, interleukin (IL)-12 treatment prolonged the survival of mice bearing subcutaneous C26TEK but not of those bearing lung metastases, suggesting that IL-12 could exert further antiangiogenic effects at the site where the tumor can restore neoangiogenesis. These results show in vivo that reduced angiopoietin availability at the tumor site induces a local inflammatory response and impairment of neoangiogenesis which act synergistically to limit tumor growth and metastasis.
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PMID:Angiopoietin decoy secreted at tumor site impairs tumor growth and metastases by inducing local inflammation and altering neoangiogenesis. 1498 59

The aim of this study was to evaluate the tolerability and activity of intratumoral administered human interleukin 12 encoded by a vector derived from the canarypox virus (ALVAC-IL-12). Nine patients with surgically incurable metastatic melanoma who had subcutaneous nodules available for injection were enrolled. ALVAC-IL-12 was administered by intratumoral injection on days 1, 4, 8, and 11. Tumor nodules greater than 2 cm in diameter were injected with 2 x 10(6) median tissue culture infectious doses (TCID(50)), and smaller tumors were injected with 1 x 10(6) TCID(50). The total dose per patient per time point ranged from 1 x 10(6) to 4 x 10(6) TCID(50). Toxicity was mild to moderate and consisted of inflammatory reactions at the injection site and fever associated with chills, myalgia, and fatigue. No dose-limiting toxicities occurred. Increases in IL-12 mRNA, and also increases in interferon gamma mRNA, were observed in ALVAC-IL-12-injected tumors compared with saline-injected control tumors in four of the nine patients. ALVAC-IL-12-injected tumors were also characterized by T cell infiltration. Three patients demonstrated increases in serum IL-12 and in interferon gamma levels. All patients developed neutralizing IgG antibody to the canarypox vector. One patient manifested a complete response of injected subcutaneous metastases and uninjected in-transit metastases. The intratumoral injection of ALVAC-IL-12 at these dose levels and according to this schedule was well tolerated and resulted in measurable biologic response in patients with metastatic melanoma.
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PMID:Intratumoral administration of a recombinant canarypox virus expressing interleukin 12 in patients with metastatic melanoma. 1570 92

MUC1 (mucin 1) is a transmembrane glycoprotein normally expressed on epithelia of the pancreas, breast, prostate, colon, and lung. However, this self-antigen is over-expressed and aberrantly glycosylated in adenocarcinomas, thereby making it a potential target for immunotherapy. Toward this goal, DNA plasmids encoding human MUC1 (pMUC1) and mouse interleukin-18 (pmuIL-18) were developed, and previous work demonstrated pMUC1/pmuIL18 vaccination protected MUC1 transgenic mice (MUC1.Tg) from subcutaneous tumor challenge. This report shows that pMUC1/pmuIL-18 is effective in preventing and treating pulmonary metastases in MUC1.Tg mice. Vaccination with pMUC1 or pmuIL-18 alone was insufficient to elicit measurable anti-tumor effects. However, co-administration of pMUC1 with pmuIL-18 reduced the incidence of lung tumors and prolonged survival. Furthermore, pMUC1/pmuIL-18 immunization protected mice from challenge with MUC1+ tumors, but not from MUC1- tumors, indicating that the anti-tumor effect is antigen-specific. More importantly, pMUC1/pmuIL-18 was effective in treating established tumors. Finally, in vivo antibody-mediated lymphocyte depletion and neutralization of interferon gamma (IFNgamma) revealed that CD8+ T cells and IFNgamma mediate the anti-tumor immunity. Collectively, these results demonstrate that pMUC1/pmuIL-18 breaks tolerance to MUC1, and induces antigen-specific immunity with protective and therapeutic benefit. This suggests that pMUC1/pmuIL-18 DNA vaccination may provide clinical benefit for patients with MUC1+ tumors.
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PMID:Intradermal vaccination of MUC1 transgenic mice with MUC1/IL-18 plasmid DNA suppresses experimental pulmonary metastases. 1729 19

Seventy-four (74) patients with metastatic melanoma were treated with patient-specific vaccines derived from autologous tumor cell lines. Cryopreserved irradiated tumor cells were injected weekly for 3 weeks, then monthly for 5 months. At a median follow up >6 years, the median event-free survival (EFS) was 4.5 months, with 13 patients alive and progression free 6-12 years later. Median overall survival (OS) was 20.5 months, with 29% 5-year OS. Tumor response rate was 9% among the 35 patients with evaluable disease who received at least 3 injections. Better survival was observed for patients who had minimal rather than clinically evident metastatic disease at the time vaccine therapy was initiated (5-yr OS 47% vs. 13%; p < 0.0001), received granulocyte-macrophage colony-stimulating factor and/or interferon gamma as an adjuvant (5-yr EFS 26% vs. 0%; p < 0.0001) or received an average of <7 million cells for each of the first 3 injections, compared to those who received 7-11.9 million or >12 million cells per injection (5-yr EFS OS 35% vs. 24%; p = 0.041 and p = 0.034). There was a trend toward better EFS for those who had a positive delayed type hypersensitivity (DTH) reaction to an intradermal injection of 1 million irradiated tumor cells at baseline, or converted to positive after 3 injections, compared to those whose DTH remained negative (5-yr EFS 39% vs. 18%; p = 0.159). This treatment approach is feasible, produces minimal toxicity, and is associated with longterm survival in a significant proportion of patients.
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PMID:Patient-specific vaccines derived from autologous tumor cell lines as active specific immunotherapy: results of exploratory phase I/II trials in patients with metastatic melanoma. 1765 Oct 37

Pancreatic adenocarcinoma is known for early aggressive local invasion, high metastatic potential, and a low 5-year survival rate. Matrix metalloproteinases (MMPs) play important roles in tumor growth and invasion. Earlier studies on pancreatic cancer have found increased expression of certain MMPs to correlate with poorer prognosis, short survival time or presence of metastases. We studied the expression of MMP-21, -26, and tissue inhibitor of matrix metalloproteinases (TIMP)-4 in 50 tissue samples, including 25 adenocarcinomas, seven other malignant pancreatic tumors, and 18 control samples of non-neoplastic pancreatic tissue with immunohistochemistry. The regulation of MMP-21, -26, and TIMP-4 mRNAs by cytokines was studied with RT-PCR in pancreatic cancer cell lines PANC-1, BxPC-3, and AsPC-1. MMP-21, -26, and TIMP-4 were detected in cancer cells in 64, 40, and 60% of tumors, respectively. MMP-21 expressed in well-differentiated cancer cells and occasional fibroblasts, like TIMP-4, tended to diminish in intensity from grade I to grade III tumors. Patients with metastatic lymph nodes had increased expression of MMP-26 in actual tumor samples. All cultured cancer cell lines expressed MMP-21 basally at low levels, and presence of the protein was confirmed immunohistochemically in cultured cells. MMP-21 expression was induced by epidermal growth factor (EGF) in PANC-1 cells. MMP-26 was neither expressed basally nor induced by tumor necrosis factor alpha, transforming growth factor beta-1 (TGFbeta1), EGF, or interferon gamma. Basal TIMP-4 expression was lowest in the poorly differentiated cancer cell line PANC-1 compared to better-differentiated BxPC-3 and AsPC-1 cells. TIMP-4 expression was induced by TGFbeta1 in PANC-1 cells and by EGF in BxPC-3 cells. Our findings suggest that MMP-21 is not a marker of invasiveness, but rather of differentiation, in pancreatic cancer and it may be upregulated by EGF. The putative role of MMP-26 as a marker of metastases warrants further studies. Unlike other TIMPs, TIMP-4 was not upregulated in relation to aggressiveness of pancreatic cancer.
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PMID:Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma. 1787 96


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