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

Dendritic cells (DCs) are the most effective APCs and are being studied as natural adjuvants or Ag delivery vehicles to elicit T cell-mediated antitumor immunity. This study examined whether inoculation of DCs fused with poorly immunogenic tumor cells elicited tumor-reactive T cells for adoptive immunotherapy. DCs derived from bone marrow of C57BL/6 (B6) mice were fused with syngeneic B16 melanoma or RMA-S lymphoma cells by polyethylene glycol. The B16/DC and RMA-S/DC fusion hybrids expressed MHC class I, class II Ags, costimulatory molecules, as well as DC-specific and tumor-derived surface markers. The tumor/DC hybrids were capable of processing and presenting tumor-derived Ags, and immunization of B6 mice with irradiated B16/DC or RMA-S/DC vaccine elicited tumor-specific CTL activities. Vaccination of B6 mice with irradiated B16/DC fusion preparations induced partial host protective immunity against B16 tumor challenge. Reduced tumor incidence and prolonged survival time were observed. Adoptive transfer of T cells derived from B16/DC vaccine-primed lymph nodes into B16 tumor-bearing mice greatly reduced the number of established pulmonary metastases with or without in vivo administration of IL-2. Moreover, adoptive transfer of RMA-S/DC vaccine-primed, cultured lymph node T cells eradicated disseminated FBL-3 tumor. The results demonstrate that tumor/DC fusion products are effective cellular vaccines for eliciting T cell-mediated antitumor immunity.
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PMID:Eliciting T cell immunity against poorly immunogenic tumors by immunization with dendritic cell-tumor fusion vaccines. 982 May 28

This study demonstrates that systemic interleukin 2 (IL-2) can decrease the homing of syngeneic immune T cells to the target organ of metastases and accelerate unwanted side effects of allogeneic immune T cells. As a tumor system, we used the well-characterized highly aggressive DBA/2 mouse leukemia ESb and its less aggressive adhesion variant, ESb-MP. Systemic IL-2 treatment was performed with recombinant human interleukin-2 (Proleukin), which was slowly released via an implanted osmotic pump or was modified with polyethylene glycol (PEG-IL-2) to achieve constant plasma levels. Allogeneic B10.D2 antitumor immune spleen cells (ISPL cells) exerted strong graft-versus-leukemia (GvL) reactivity after adoptive transfer into late-stage ESb-MP tumor-bearing DBA/2 mice. Mls(a) superantigen-reactive vbeta6 donor T cells were not eliminated or tolerized by in vivo priming with the tumor cells and were present in active proliferation in liver infiltrates. When exogenous PEG-IL-2 or Proleukin was applied in addition to ISPL cells in such mice, the strong GvL-mediated protective immunity was converted into a fatal graft-versus-host disease. IL-2 treatment alone had no toxic effect and caused a moderate protection effect in the absence of an effect on local tumor growth. Potentiation of GvH reactivity of B10.D2 ISPL by PEG-IL-2 was proven in non-tumor-bearing DBA/2 mice, in which graft-versus-host disease was characterized by: (a) heavy hepatic lymphocytic infiltration, (b) irreversible increase of serum glutamate-oxalacetate-transaminase and glutamate-pyruvate-transaminase levels, (c) weight loss, and (d) death. Antagonistic effects of systemic IL-2 on GvL were observed with syngeneic DBA/2 anti-ESb immune peritoneal effector cells (PECs). There was a detrimental effect of systemic IL-2 on liver target organ infiltration by immune T cells causing, at day 6 after transfer, a drop from 20-30 CD4 or CD8 T cells per liver lobule in the PEC group to <5 in the PEC plus IL-2 group. The results emphasize the importance of a better understanding of IL-2 function in vivo and of its interaction with immune cell function to improve protocols for optimal application in the clinic to achieve maximal GvL effects.
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PMID:Antagonistic effects of systemic interleukin 2 on immune Tcell-mediated graft-versus-leukemia reactivity. 982 26

Interferons are used in the therapy of multiple sclerosis, Kaposi's sarcoma, hepatitis and melanoma. Their short half-life that requires frequent injections can be increased by polyethylene glycol (PEG) modification. A 50-year-old patient was diagnosed as having an acrolentiginous melanoma (Breslow >5 mm, Clark level IV) and inguinal lymph node metastases. After surgical excision and lymphadenectomy, immune therapy with 6.0 microg pegylated interferon alpha(2b)/kg body weight, s.c., was started. Cutaneous ulcerations at the injection sites developed 9 months after treatment initiation. The patient also developed blurred vision and presented with binasal scotomas and pathological visually evoked potentials and electroretinogram. The cutaneous ulcerations slowly healed under local therapy and reduction of the concentration of the PEG-modified interferon from 0.86 to 0.43 mg/ml. The dosage was maintained. Two months later, the therapy was stopped due to disease progression. Vision subsequently recovered. Cutaneous reactions evolved at the sites of subcutaneous injections of PEG-modified interferon alpha(2b). Changes in vision can probably be attributed to immunotherapy.
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PMID:Cutaneous ulceration after injection of polyethylene-glycol-modified interferon alpha associated with visual disturbances in a melanoma patient. 1105 21

The potent immunomodulatory, antiproliferative and antiviral properties of interferons (IFNs), together with their availability in large amounts thanks to the recombinant DNA technique, have resulted in their widespread clinical use in a variety of viral and nonviral proliferative disorders. In dermato-oncology, IFNs have been used primarily in melanoma, but also in nonmelanoma skin cancer, such as squamous and basal cell carcinomas, Kaposi sarcomas and lymphomas. Trials with IFNs have been performed in patients with melanoma in an adjuvant setting (stage II and III) and in metastatic disease (stage IV). While the response rates with IFNs as single agents in stage IV disease usually do not exceed 15%, the use of adjuvant IFNs has been claimed to increase disease-free survival (stage II), or even overall survival (stage III), in low- or high-dose regimens, respectively; the latter, however, involved numerous side-effects and were beset with lack of compliance and acceptance, as well as being very costly. Pegylated IFN (PEG-IFN) is a form of recombinant human IFN that has been chemically modified by the covalent attachment of a branched metoxpolyethylene glycol moiety. Pharmacogenetic and pharmacodynamic data obtained in animal and in phase I studies have indicated that PEG-IFN injected once a week has the potential to be superior in efficacy to human IFN injected three times a week. The safety profiles of PEG-IFN and IFN are comparable in healthy volunteers and in chronic hepatitis C (CHC) patients. PEG-IFN is currently being evaluated for the treatment of CHC, renal cell carcinoma, chronic myelogenous leukaemia, and malignant melanoma, the last in both stage IV and stage III disease.
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PMID:Perspectives of pegylated interferon use in dermatological oncology. 1207 10

Malignant melanoma has been shown to be susceptible to T cell-mediated immunity and, therefore, is a candidate for vaccination approaches. Clinical trials using dendritic cells (DC) loaded with peptides corresponding to tumor antigens are ongoing in several institutions, and some promising results have already been published. However, every single peptide-based vaccine can only be used in a patient with a given single HLA type, and this strategy is not appropriate for patients with rare HLA types or with tumors without defined antigens. A clinical pilot study in patients with disseminated melanoma refractory to standard therapy was initiated using a different approach. The authors generated autologous monocyte-derived DC and fused these DC with gamma-irradiated primary autologous tumor cells by incubation in polyethylene glycol. In previous experiments, the authors had shown that these fused cell products are potent inducers of a T-cell response in a mixed lymphocyte tumor cell culture. Seventeen patients were immunized with the cell product by s.c. injection in monthly intervals without any serious side effects. Of these patients, one had a partial response with decrease in size of all evaluable tumor manifestations. In one patient, some of the metastases were regressing despite an overall progressive disease, and one patient achieved disease stabilization for six months. In the responding patient, in parallel to tumor regression, circumscript hair depigmentation occurred. These data show, that a hybrid vaccine of DC and tumor cells can be safely applied and can induce tumor regressions, however, the clinical efficacy of the approach in its present form is insufficient.
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PMID:The treatment of patients with disseminated malignant melanoma by vaccination with autologous cell hybrids of tumor cells and dendritic cells. 1221 80

We have shown previously that i.v. injection of interleukin-2-(IL-2) activated natural killer (A-NK) cells together with IL-2 leads to a substantial localization of the A-NK cells into most, but not all, well-established B16 lung metastases in C57BL/6 mice within 12-24 hr. We demonstrate that the morphology of the lung metastases, (loose or more compact in appearance), and their location in the lungs (on the surface or deep in the lung parenchyma) are closely tied to the infiltration-permissiveness of the metastases as well as their sensitivity to treatment with A-NK cells. Although more than 1100 A-NK cells/mm(2) were found in deep metastases with a "loose" morphology (D-L), only 534, 90 and 89 cells/mm(2) were found in surface-loose (S-L), surface-compact (S-C) and deep-compact (D-C) metastases, respectively. The best infiltrated metastases responded best to the A-NK cell therapy. Thus, metastases of the D-L phenotype became reduced by 65-90% after treatment with 2 x 10(6) A-NK cells and IL-2 (120000 IU Peg-IL-2 every 12 hr for 3 days) compared to similar lesions in animals treated with PEG-IL-2 alone. In contrast, poorly infiltrated metastases, that is lesions of the compact phenotype (D-C and S-C) as well as loose metastases on the lung surface (S-L), did not react significantly to this treatment. We conclude that adoptively transferred A-NK cells are able to eliminate even well-established metastases. The existence of metastases that are resistant to infiltration by the transferred effector cells at time of treatment might reduce the efficacy of cell-based immuno-therapeutic ventures.
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PMID:Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases. 1271 43

Systemic gene delivery systems are needed for therapeutic applications; in some situations, target cells might be spread throughout the organism, as in the case of cancer metastases, which can be reached only via the systemic route. Within the class of nonviral vectors, polymer-based transfection particles named DNA polyplexes and lipid-based systems named DNA lipoplexes are being developed for this purpose. For systemic circulation, masking the surface charge of DNA complexes has to be accomplished to avoid interactions with plasma components, erythrocytes, and the reticuloendothelial system. Among other vector formulations, polyplexes based on polyethylenimine (PEI), shielded with polyethylene glycol (PEG), and linked to the receptor binding ligands transferrin (Tf) or epidermal growth factor (EGF) have been developed. Complexes were found to mediate efficient gene transfer into tumor cell lines in a receptor-dependent and cell-cycle-dependent manner. Systemic administration of surface-shielded Tf-PEI polyplexes into the tail vein of mice resulted in preferential gene delivery into distantly growing subcutaneous tumors. In contrast, application of positively charged PEI polyplexes directed gene transfer primarily to the lung.
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PMID:Tumor-targeted gene transfer with DNA polyplexes. 1277 43

There is increasing incidence of adenocarcinoma of the esophagastric junction (EGJ) especially in young white men (+35% in 30 years). The reasons for this are not yet well known, however one of the main causes is gastro-esophageal-reflux disease (GERD). The differentiation of a EGT carcinoma in three subtypes is important for therapy: adenocarcinoma of the distal esophagus (type I), cardia carcinoma (type II) and subcardial gastric carcinoma (type III). The most important risk-factor for type I-cancers is "barrett's metaplasia" resulting from GERD over years. The risks for the type II- and type III-carcinomas may be obesity and high caloric and fat intake. The role of Helicobacter pylori infection and adenocarcinoma of the subcardia is unproven. Preoperative tumor staging is difficult and tumor-stage is most often underestimated (esp. in the case of a high-grade dysplasia where in 43% carcinomas one already established). Therapy for all three types of EGJ tumors is surgical. Transhiatal (rarely transthoracic) esophagectomy with lymphadenectomy and proximal gastrectomy is performed for type-I-tumors, type-II and III-tumors are treated like a gastric cancer with total gastrectomy, lymphadenectomy and distal esophagectomy. Lymph-node metastases and advanced tumor-stage are bad prognostic factors, complete tumor resection (R0 resection) with extended lymphadenectomy will improve prognosis. The results of a preoperative combined-modality therapy are encouraging, but have not yet shown a definitive benefit. In case of distant metastases, radio-chemotherapy combined with gastroenterologic treatments (e.g. esophageal prostheses, PEG, etc.) will be used as a palliative treatment option.
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PMID:[Carcinomas of the esophago-gastric junction: surgical strategies]. 1281 32

Fusion of tumor cells with antigen-presenting cells (APCs) has been proposed for the preparation of cancer vaccines. However, generation of these hybrids, using physical or chemical methods such as electrofusion or polyethylene glycol (PEG), has been difficult to standardize. Characterization of cell fusion has also been problematic because of difficulties in differentiating fusion from cell aggregation, leakage of cellular dyes and dendritic-cell (DC) phagocytosis of tumor material. In this report, we describe a new method to generate hybrid cell vaccines, based on gene transfer of a viral fusogenic membrane glycoprotein (FMG) into tumor cells, and incorporate a genetic method by which true hybrid formation can be unambiguously detected. We describe a new class of tumor cell-DC hybrid that can be rapidly isolated after cell fusion. These hybrids are highly potent in in vitro antigen presentation assays, target lymph nodes in vivo and are powerful immunogens against established metastatic disease.
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PMID:A new genetic method to generate and isolate small, short-lived but highly potent dendritic cell-tumor cell hybrid vaccines. 1292 49

Systemic adjuvant chemotherapy achieves unsatisfactory results for inoperable liver tumors and metastases. Various clinical studies have shown that locoregional chemotherapy increased the survival rate by a few months. The aim of this study was to investigate tumor targeting of the most frequently used cytostatic 5-fluouracil by modifying systemic and locoregional therapy by liposome encapsulation. The tumor concentration of 5-FU encapsulated in SUV-PEG liposomes increases by a factor of 27 in systemic therapy and a factor of 90 in locoregional therapy. The tumor concentration of 5-FU increases by a factor of 8000, if the blood flow is additionally slowed by starch microspheres (Spherex) during locoregional therapy with liposome-encapsulated 5-FU.
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PMID:[Liposome encapsulation of cystostatic drugs and starch microspheres improve tumor targeting in locoregional therapy. An animal experiment study of CC 531 liver tumor]. 1451 43


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