Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, cytokine gene transfer into tumour cells has been shown to mediate tumour regression in animal models via immunomodulation. Consequently, a number of clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumour cells. Here, we report the results of a clinical phase I trial using for the first time autologous, interleukin 7 gene-modified tumour cells for vaccination of ten patients with disseminated malignant melanoma. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by a ballistic gene transfer technique and were then injected after in vitro irradiation s.c. at weekly intervals. Clinically, there was no major toxicity except for mild fever, and no major clinical response towards vaccination was observed. Eight of ten patients completed the initial three s.c. vaccinations and were eligible for immunological evaluation. Post vaccination, peripheral mononuclear cells (PBMCs) were found to contain an increased number of tumour-reactive proliferative as well as cytolytic cells, as determined by a limiting dilution analysis. In three of six patients, the frequencies of anti-melanoma cytolytic precursor cells increased between 2.6- and 28-fold. Two of these patients showed a minor clinical response. Analysis of the autologous tumour cell vaccines regarding IL-7 secretion after gene transfer, HLA class I and class II cell surface expression, secretion of immunosuppressive mediators (TGF-beta1, IL-10) and various melanoma-associated tumour antigens revealed a very diverse expression profile. In conclusion, vaccination using gene-modified autologous melanoma cells induced immunological changes in a group of advanced, terminally ill patients. These changes can be interpreted as an increased anti-tumour immune response. However, immunological modulation was most pronounced in patients in good physical condition. Therefore, patients with minimal tumour load or minimal residual disease might preferentially benefit from tumour cell vaccination in further studies. In order to evaluate the effects of the cytokine gene-modified tumour cell vaccines more precisely, an antigenically better defined vaccine is needed.
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PMID:Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study. 966 67

A B16 melanoma-specific CD8+ T cell line (AB1) was established from the spleen cells of C57BL/6 mice cured of B16 melanoma with interleukin (IL)-12 treatment. The AB1 line exclusively used T cell receptor Vbeta11. The AB1 cells exhibited a cytolytic activity against both syngeneic B16 melanoma and allogeneic P815 mastocytoma, whereas a cold inhibition assay revealed specificity of the AB1 cells against B16 melanoma. Their lostability to kill a class I loss variant of B16 melanoma was restored by the transfection of H-2Kb gene. In addition, their interferon (IFN)-gamma production was significantly suppressed by the addition of anti-H-2Kb monoclonal antibody, and RT-PCR analysis showed that the AB1 line expressed the mRNA encoding IFN-gamma, but not IL-4 or IL-10. The experiment using synthetic peptides of tyrosinase-related protein-2 (TRP-2) revealed that the AB1 cells could recognize TRP-2(181-188) peptide. Moreover, the AB1 cells showed an in vivo antitumor effect against established pulmonary metastases of B16 melanoma. Overall, these results indicate that the Tc1-type Vbeta11+ AB1 cells exert an antitumor activity against syngeneic B16 melanoma through recognition of TRP-2(181-188) peptide in an H-2Kb-restricted manner.
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PMID:Characterization of B16 melanoma-specific cytotoxic T lymphocytes. 987 72

It has been thought that natural killer (NK) cells appearing early in tumor lesions play a pivotal role in the innate immunity against tumor cells. Although NK cells serve as the first tumoricidal effector cells, they subsequently promote a shift in effectors from themselves to tumor-specific cytotoxic T lymphocytes (CTLs) that mediate the acquired immunity. The mechanism of this shift has not been fully elucidated, however, NK cell-derived T helper (Th) 1 cytokines such as interferon (IFN)-gamma seem to play a key role. Another NK-lineage, termed natural killer T (NK T) cells, may also participate in the innate period when they acquire the ability to secrete Th1 cytokines. Interleukin-4 (IL-4) and IL-10, belonging to Th2, and transforming growth factor-beta (TGF-beta), belonging to T regulatory (Tr) 1 cytokines, are known to suppress the development of NK, NK T cells, as well as CTLs and to block Th0 cell differentiation to Th1 cells, suggesting that tumor cells can evade the innate and acquired immunity by virtue of cells producing these inhibitory cytokines. In early tumor lesions of murine B16 melanoma, gammadelta T and alphabeta intermediate (int) T cells that co-infiltrate with NK and NK T cells can produce Th2 cytokines and inhibit the innate immunity. In MM2 mammary tumor-bearing mice, gammadelta T cells appearing both lesionally and systemically secrete Tr1-type cytokines and depress the acquired immunity. These Th2- or Tr1-type gammadelta T and alphabeta(int) T cells downregulate the tumoricidal cells by means of both their secreted cytokines and express major histocompatibility complex (MHC) class I molecules.
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PMID:Downregulation of innate and acquired antitumor immunity by bystander gammadelta and alphabeta T lymphocytes with Th2 or Tr1 cytokine profiles. 1043 55

The coexistence of tumor specific immunity with a progressing tumor remains a major paradox of tumor immunology. This enigma is most evident in partially regressing melanomas, where efficient eradication of tumor cells is closely linked to uncontrolled tumor growth. Mechanisms involved in this differential susceptibility of tumor cells to the host immune response may include altered production of immunosuppressive cytokines, i.e., transforming growth factor (TGF) beta or interleukin (IL) 10. Since only limited amounts of tissue samples are available from primary tumors, a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was established which allowed to estimate the amount of cytokine mRNA expressed in a small number of melanoma cells segregated by indirect immunomagnetic isolation. Thereby, we determined the expression of TGF-beta 1 and IL-10 mRNA in melanoma cells obtained from regressing and progressing areas of 9 primary tumors. TGF-beta 1 mRNA could be detected in all undiluted samples from progressing areas and in 7 samples from regression zones. Titration of the sample revealed that in 6 cases TGF-beta 1 mRNA could be detected at a significant higher titer in progressing than in regressing areas. IL-10 mRNA was present in 8 samples obtained from progressing and in 7 samples from regressing tumor areas. In 6 tumors IL-10 mRNA was detectable at a higher titer in the progression zones. Specificity of the PCR amplification was confirmed with a series of restriction enzyme digestions of the resulting PCR product. Based on these findings the hypothesis that immunosuppressive cytokines, such as TGF-beta 1 or IL-10, represent important factors for the melanoma cells to escape immune surveillance is supported.
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PMID:Differential expression of transforming growth factor beta 1 and interleukin 10 in progressing and regressing areas of primary melanoma. 1046 12

ImmTher, a liposome-encapsulated lipophilic disaccharide tripeptide derivative of muramyl dipeptide, previously showed activity against liver and lung colorectal metastases in a phase I trial. The purpose of the current studies was to investigate whether ImmTher could up-regulate specific cytokine gene expression and protein production, as well as activate the tumoricidal or cytostatic activity of human monocytes. ImmTher induced the expression and production of interleukin(IL)-1alpha IL-1beta, IL-6, IL-8, IL-12, macrophage chemotactic and activating factor, and tumor necrosis factor alpha but not IL-2 or IL-10. Cytostatic or cytotoxic monocyte activity was stimulated against human Ewing's sarcoma, osteosarcoma, and melanoma cells but not breast cancer cells. Production and secretion of these cytokine proteins may play a role in the antitumor activity of ImmTher.
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PMID:ImmTher, a lipophilic disaccharide derivative of muramyl dipeptide, up-regulates specific monocyte cytokine genes and activates monocyte-mediated tumoricidal activity. 1047 6

To target T-cells to the tumour area we created a recombinant protein of the bacterial superantigen (SAg) Staphylococcal enterotoxin A (SEA) and the Fab-fragment of a tumour-reactive antibody. This antibody-targeted SAg immunotherapy therapy has been shown to be highly efficient, eliminating > 95% of the pulmonary metastasis in mice carrying established melanoma micrometastases. Earlier studies demonstrated that elimination of the C215-expressing B16-melanoma lung metastasis was dependent on interferon (IFN)-gamma release and expression of perforin. In the present study, therapeutic effector functions were analysed both locally at the tumour site and systemically in the spleen. In order to elucidate the role of each T-cell subset during Fab-SEA therapy, CD4 knock-out (KO) and CD8 KO mice were used. Tumour size reduction was statistically significant in Fab-SEA-based tumour therapy in both types of T-cell-deficient mice compared to wild-type mice. CD4 KO mice displayed a drastic reduction in the number of tumour-infiltrating macrophages and CD8+ T-cells. Therapy-induced accumulation of perforin-containing cells at the tumour site was significantly impaired in CD8 KO mice, and marginally in CD4 KO mice. Moreover, CD4 KO mice failed to produce substantial amounts of the tumour suppressive cytokine IFN-gamma. This is in sharp contrast to normal mice where a massive local release was recorded. CD8 KO mice displayed a spontaneous production of interleukin (IL)-4 and IL-10 locally in the tumour. Neither normal nor CD4 KO mice produced detectable levels of these Th-2-associated cytokines. The high level of IL-10 was demonstrated to inhibit Fab-SEA tumour therapy, since the therapeutic efficacy was significantly higher in IL-10 KO mice. These results illustrate the importance of a finely tuned cellular collaboration to regulate the various phases of an efficient anti-tumour immune response.
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PMID:The distinct role of CD4+ and CD8+ T-cells during the anti-tumour effects of targeted superantigens. 1049 66

Hypotension caused by hypovolemic, hemorrhagic shock induces disturbances in the immune system that may contribute to an increased susceptibility to sepsis. The effect of chemically induced hypotension on circulating cytokines and adhesion molecules has not been investigated yet. In 21 patients scheduled for resection of malignant choroidal melanoma of the eye the perioperative serum levels of the cytokines IL-1beta, IL-6, IL-10, TNF-alpha, and the adhesion molecules sE-Selectin and sICAM-1 were investigated. Moderate hypothermia of 32 degrees C was induced in all patients. In 14 patients profound hypotension (mean arterial blood pressure 35-40 mmHg, hypotension group) was induced by enalapril and nitroglycerin for a mean duration of 71 min. In 7 patients the tumor was not resectable, and hypotension was not induced (controls). We did not detect significant differences in serum levels of cytokines or sE-Selectin perioperatively in patients with profound hypotension compared with controls. In both groups IL-6 serum levels increased significantly and reached a maximum after rewarming (17 +/- 6 and 16 +/- 5 pg/dL, respectively, P < 0.001). IL-1beta, IL-10, and TNF-alpha did not change perioperatively in both groups. On the first postoperative day sICAM-1 serum levels were significantly increased in both groups (mean increase of 96 and 54 ng/mL, respectively, P < 0.01 and P < 0.05). We conclude from this study that profound normovolemic arterial hypotension does not seem to have effects on serum levels of circulating IL-1beta, IL-6, IL-10, TNF-alpha, and sE-Selectin. Perioperative moderate hypothermia may be the reason for the postoperative increase in sICAM-1 levels independent of the blood pressure.
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PMID:Effect of profound normovolemic hypotension and moderate hypothermia on circulating cytokines and adhesion molecules. 1056 7

Melanoma-specific cytotoxic T lymphocytes (CTL) can be generated from peripheral blood lymphocytes (PBL) by mixed lymphocyte-tumour cell cultures. Analysis of CTL precursor frequencies in peripheral blood of melanoma patients is generally used for immunomonitoring purposes to evaluate vaccination efficacy. At present, it is unclear whether PBL-derived CTL generated in vitro are indicative of an anti-tumour immune response in vivo. Three tumour-specific human leucocyte antigen (HLA)-B/C-restricted CTL clones were derived from peripheral blood of a melanoma patient immunized with interleukin-7 (IL-7) gene-modified tumour cells. CTL clones differing in their T-cell receptor-gamma (TCRgamma) rearrangement produced interferon-gamma, IL-4 and/or IL-10. On the basis of their unique TCRgamma gene rearrangements clone-specific primers were generated for detection of clone-specific DNA by polymerase chain reaction. One CTL clone (E5) of the three was found to be selectively expanded in one of seven metastases obtained at autopsy, as determined by Southern blot hybridization. However, the presence of E5 in only one of seven metastases at death indicates that the in vivo accumulation of the specific CTL clone was not sufficient to contain tumour progression. Nevertheless, our data support the proposition that analysis of anti-tumour activity of PBL-derived CTLs may reflect an anti-tumour immune response in vivo.
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PMID:In vivo selective expansion of a tumour-specific cytotoxic T-cell clone derived from peripheral blood of a melanoma patient after vaccination with gene-modified autologous tumour cells. 1059 85

Dissemination of uveal melanomas is almost exclusively haematogenous, making angiogenesis of the tumour a prerequisite for the formation of metastases. Uveal melanomas must employ strategies to evade the immune system in order to escape immune surveillance. We therefore determined the expression of the following angiogenic and immunosuppressive factors in seven human uveal melanoma cell lines using reverse transcriptase-polymerase chain reaction (RT-PCR): secreted interleukin-1 receptor antagonist (sIL-1ra), interleukin (IL)-6, IL-8, IL-10, transforming growth factor (TGF)-alpha, TGFbeta, vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), angiopoietin-1 and angiopoietin-2. In addition, the secretion of sIL-1ra, IL-6, IL-8, IL-10, TGFbeta and VEGF was assayed by enzyme linked immunosorbent assay (ELISA). The potential of uveal melanoma cell lines to convert plasminogen to angiostatin was tested in an in vitro assay. All the factors except angiopoietin-1 were determined in one or more cell lines using RT-PCR, although these results were not necessarily confirmed by ELISA. Expression of VEGF and angiopoietin-2 was found in all seven cell lines. Production of angiostatin was observed in one cell line. All seven cell lines examined expressed angiogenic factors and most cell lines expressed immunosuppressive factors. The expression of VEGF and angiopoietin-2 in combination with a lack of angiopoietin-1 expression suggest high vascular remodelling capacity and could be of great relevance for the metastatic potential of uveal melanoma.
Melanoma Res 1999 Oct
PMID:Expression of angiogenic and immunosuppressive factors by uveal melanoma cell lines. 1059 10

The biological mechanisms of chemoimmunotherapy efficacy in vivo have not been fully clarified; furthermore, few data are available to predict its efficacy on the basis of clinical and immunological pretreatment factors. In this paper, pre- and post-treatment serum levels of cytokines (interleukin [IL]-6, IL-10, IL-12 and neopterin) and soluble IL-2 receptors (sIL-2R), as well as circulating levels of T-cell and NK subpopulations, were analysed according to clinical outcome in 66 advanced metastatic melanoma (MM) patients treated with subcutaneous IL-2 in association with interferon-alpha, cisplatin and tamoxifen. Our purpose was to correlate the immune modifications during treatment with the clinical response and to define pretreatment factors with predictive value for clinical outcome. The overall response rate was 35%, with a median overall survival of 11.3 months. During treatment, responding patients showed a common marked increase in IL-12 (mainly released by activated macrophages), sIL-2R and neopterin serum levels, associated with high levels of total lymphocytes and circulating natural killer lymphocytes; progressing patients were characterized by an increase in IL-6 serum levels (directly related to the increase in tumour burden). Multivariate analysis showed that high pretreatment IL-12 levels (P = 0.05) and, to a lesser extent, lactate dehydrogenase levels in the normal range (< or = 450 U/I; P = 0.061) are independent favourable prognostic factors for survival. Our results show that macrophage activation in an immunostimulating way either before or during treatment is associated with a better clinical response and improved survival in advanced MM patients treated with IL-2-based chemoimmunotherapy.
Melanoma Res 2000 Feb
PMID:Macrophage-mediated immunostimulation modulates therapeutic efficacy of interleukin-2 based chemoimmunotherapy in advanced metastatic melanoma patients. 1071 41


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