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

Past studies in animal models with gene-transfected tumour cells have suggested that GM-CSF may have a role in immunotherapy of tumours as a result of the effects it has on antigen-presenting cells. The present (phase I) studies were carried out to examine whether intralesional injections of GM-CSF induce regression of subcutaneous metastases in patients with melanoma and influence lymphoid infiltrates in and around the metastases. Thirteen patients had 15-50 mg doses of GM-CSF injected into two subcutaneous metastases. In each case one metastasis received only five injections before excision whereas the other received weekly injections up to 6 months. Partial regression of injected and/or non-injected metastases was seen in three patients. The metastases from the responding patients that were treated with intralesional GM-CSF had marked increases and high absolute numbers of T cell infiltrates into the tumour, particularly of the CD4 T cell subset. There was an increase in IL-2R expression on the T cells and an increase in the number of Langerhans' cells infiltrating the tumours. The best predictors of clinical responses therefore appeared to be high relative increases and high absolute numbers of CD4+ T cells and Langerhans' cells within the treated tumour. These results provide support for further exploration of the role of GM-CSF in immunotherapy of human melanoma.
Melanoma Res 1996 Jun
PMID:Clinical responses and lymphoid infiltrates in metastatic melanoma following treatment with intralesional GM-CSF. 881 28

Although the CD4 molecule is the major cellular receptor for human immunodeficiency virus (HIV), several lines of evidence suggest participation of additional molecules that are engaged after the binding of HIV to the CD4 receptor and that may facilitate viral entry into the target cell. Some of the post-CD4 binding, perfusion events involve the third hypervariable region (V3 loop) of the viral envelope protein gp120. To identify cellular proteins that interact with the V3 loop, we chose as a probe an antiidiotypic monoclonal antibody (MAb), anti-id2, which was prepared against the neutralizing MAb 110.4 that binds the V3 domain in the envelope glycoprotein gp120 of the LAI isolate of HIV-1. Anti-id2 reacted specifically with a 55- to 60-kDa protein in human T cell and monocytoid cell lines, and in a mouse melanoma cell line. This protein was identified immunologically and by protein sequence analysis as vimentin, an intermediate filament protein of lymphoid and other cells of mesodermal origin. Antiserum raised against vimentin inhibited nuclear translocation of HIV-1 DNA following infection of monocytes and CD4+ T cells with live virus, and reduced the amount of HIV-1 gag-specific RNA in the nuclei of monocytes following inoculation with HIV-1 pseudovirions. These data suggest that vimentin may participate in the early steps of HIV-1 replication, perhaps during the uptake of HIV-1 preintegration complexes into the nuclear compartment.
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PMID:Anti-idiotypic antibody to the V3 domain of gp120 binds to vimentin: a possible role of intermediate filaments in the early steps of HIV-1 infection cycle. 882 24

Adoptive transfer of tumor-sensitized T lymphocytes has demonstrated therapeutic efficacy in animal tumor models and in some patients with melanoma and renal cell cancers. In experimental settings, T lymphocytes derived from lymph nodes (LNs) draining progressively growing tumors can be activated ex vivo to generate tumor-reactive lymphocytes with therapeutic efficacy. Despite the theoretical concern regarding inaccessibility of the central nervous system to systemically transferred T cells, our recent experiments demonstrated that anti-CD3-activated tumor-draining LN cells are capable of mediating the regression of established intracerebral tumors. In this study, several staphylococcal enterotoxins (SEs), including SEA, SEC2, and SEE, and exfoliating toxin, known to be superantigens, were tested for their ability to stimulate tumor-draining LN cells to acquire antitumor reactivity for the treatment of intracerebral tumors. SEs bind to the MHC class II molecule and provide an activating signal to T cells bearing particular T-cell receptor Vbeta chains. Tumor-draining LN cells activated with SEs demonstrated selective Vbeta T-cell expansion. In adoptive immunotherapy of intracranial (IC) tumors, SEA-and SEC2-activated cells had the highest efficacy, whereas SEE-activated cells were not therapeutic. Despite the antigen independence of SE activation, the T cells retained immunological specificity for the tumor, which provided the initial in vivo sensitization of the LN. During the ex vivo stimulation with superantigens, both CD4+ and CD8+ T cells proliferated, and both subsets were required to mediate regression of IC tumors. In contrast to the adoptive immunotherapy of visceral tumors, the systemic administration of exogenous interleukin 2 failed to support the antitumor reactivity in mice depleted of CD4 cells, and, in fact, it inhibited the therapeutic efficacy. Furthermore, mice cured of intracerebral tumors by the adoptive transfer of T cells were resistant to an IC tumor rechallenge. However, in contrast to the immunological specificity demonstrated during the primary adoptive transfer, cured mice were able to reject challenge with several immunologically distinct fibrosarcomas but not a melanoma. These results indicate that superantigen-activated LN cells can circulate to and interact with intracerebral tumors mediating tumor regression in an immunologically specific manner. Although conditions that optimize the treatment of intracerebral tumors appear to be different from those for visceral tumors, analysis of T-cell receptor Vbeta expression among cells activated with several superantigens does not reflect a preferential usage of Vbeta gene segments in the immune response to autochthonous tumors.
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PMID:Treatment of intracranial tumors by systemic transfer of superantigen-activated tumor-draining lymph node T cells. 884 Sep 87

Interferon alpha (IFN-alpha) has a documented activity against malignant melanoma with a response rate of only approximately 20%. It would therefore be of considerable importance if patients likely to respond could be identified. The degree of mononuclear cell infiltration in primary tumours has been reported to correlate with a favourable prognosis. This investigation used monoclonal antibodies, anti-CD4, -CD8 and -CD11c, to identify subsets of tumour-infiltrating mononuclear cells in fine needle aspirates to study whether the presence of such cells correlates with the therapeutic effect of IFN-alpha. Twenty-one patients with systemic and 20 with regional metastatic malignant melanoma were studied before initiation of IFN-alpha treatment. A statistically significant correlation (P < 0.001) was found between the occurrence of CD4+ lymphocytes in fine needle aspirates and the therapeutic benefit of IFN-alpha in patients with systemic disease. Ten out of 11 with moderate to high numbers of infiltrating CD4+ lymphocytes achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, nine out of ten had progressive disease. Similar results were found in patients with regional disease.
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PMID:Tumour-infiltrating lymphocytes in metastatic malignant melanoma and response to interferon alpha treatment. 884 94

It has been postulated that IL-2 secreting cancer vaccines establish antitumor immunity because the cytokine acting in a paracrine fashion would deliver a helper signal directly to the T cells making contact with the modified tumor cells at the site of vaccination. However, patterns of lymphocyte recirculation cannot be reconciled with the above direct interaction model: only primed memory T cells rather than naive T lymphocytes patrol the periphery, while naive T cells travel to the peripheral lymph nodes, where priming occurs. We have found that in vivo treatment of mice with the antibody MEL-14 directed against L-selectin, which is a molecule expressed at high levels on naive T cells, can completely abrogate protection against a mouse melanoma conferred by an IL-2 secreting vaccine. Since mouse memory CD4 and CD8 T cells are L-selectin-low, only migration of naive T cells is perturbed by the in vivo antibody blockade. Thus, priming of naive T cells in the draining lymph node is a critical step for the successful vaccination by IL-2 secreting cancer vaccines. Such priming is performed most efficiently by professional antigen presenting cells; consequently, these data also imply that allogeneic origin of tumor vaccines may not exclude successful vaccination.
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PMID:Depletion of naive T cells of the peripheral lymph nodes abrogates systemic antitumor protection conferred by IL-2 secreting cancer vaccines. 887 31

Daudi Burkitt's lymphoma cells, unlike other tumor cell lines, stimulate human T cells coexpressing the variable (V) region genes TCRG-V9 and V TCRD-V2 to proliferate and secrete lymphokines. Hybrids, derived by the fusion of Daudi cells with the human melanoma cell line MZ2-MEL 2.2, retain the morphology of melanoma cells. Unlike the parental melanoma cell line, these Daudi x MZ2-MEL 2.2 hybrids stimulate secretion of tumor necrosis factor (TNF) and granulocyte/macrophage colony stimulating factor (GM-CSF) by CD4-positive Vgamma9/Vdelta2 T-cell clones. Whereas the stimulator phenotype of Daudi cells behaves as a dominant trait in Daudi x melanoma hybrids, the expression of B-cell differentiation markers is suppressed. Thus, the gamma/delta T-cell ligand expressed by Daudi cells behaves as a dominant tumor antigen in Daudi x melanoma hybrids and is unrelated to the differentiated B-cell phenotype. Dominant expression of the Daudi ligand for human Vgamma9/Vdelta2 T cells in these hybrids may provide a basis for defining the stimulatory principle at the molecular level.
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PMID:Recognition by human Vgamma9/Vdelta2 T cells of melanoma cells upon fusion with Daudi cells. 888 Oct 34

CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2 which interact with coreceptors on T-cells to regulate outcomes in terms of T-cell activation or specific non-responsiveness. Complementary studies at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential element in specific T-cell activation. The small xenobiotic Schiff base forming molecule tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T-cell surface amines provides a costimulatory signal to the T-cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The signalling pathway utilised by tucaresol converges with T-cell receptor signalling at the level of MAP kinase, promoting the tyrosyl phosphorylation of ERK2 by MEK (mitogen-activated protein kinase kinase). The Schiff base forming class of immunopotentiatory drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing. Tucaresol is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.
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PMID:Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential. 889 54

Selectively-bred Sinclair miniature swine exhibit a high incidence of congenital malignant melanoma which either proves fatal (10-15% of tumor-bearing piglets) or spontaneously regresses with a biphasic immunological phenomenon (85-90%) and no recurrence of malignancy. Mononuclear leukocytes were isolated from cutaneous melanomas and peripheral blood specimens collected from melanomatous (tumor-bearing) Sinclair swine during second-phase regression, and from peripheral blood specimens collected from non-melanomatous (tumor-free) Sinclair swine and control Hanford swine. Leukocyte identities were determined with single- and dual-parameter indirect immunofluorescence assays via flow cytometry. Assays for the specific surface antigens CD45, CD2, CD4, CD8, CD1, MHC class II, and N1 were employed to develop immunophenotypic profiles within the gated lymphocyte clusters from each TIL and PBL suspension. Significantly more CD8+ T-lymphocytes were identified in TIL suspensions than in peripheral blood leukocyte (PBL) suspensions (P < and = 0.05), regardless of breed or tumor status. Conversely, PBL suspensions contained significantly higher percentages of CD4+ T-lymphocytes than the levels found in TIL suspensions (P < and = 0.05). Virtually all TIL were MHC class II+, whereas the percentages of PBL expressing this antigen were markedly lower (P < and = 0.05). The percentages of T-lymphocytes co-expressing CD4 and CD8, a normal subset unique to swine, were generally consistent in all TIL and PBL suspensions examined. The results of this study have firmly established the immunophenotypic identities of cells associated with the second-phase regression phenomenon of this melanoma and have identified specific variations in the leukocyte profiles of the respective TIL and PBL suspensions.
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PMID:Immunophenotypic characterization of tumor infiltrating lymphocytes and peripheral blood lymphocytes isolated from melanomatous and non-melanomatous Sinclair miniature swine. 901 17

The mechanism by which murine tumour-infiltrating lymphocytes (TIL) decreased their anti-tumour activity during an in vitro culture with interleukin-2 (IL-2) was investigated. A phenotype analysis revealed that the TIL cultured for 7 days (TIL-d7) were exclusively NKI.1- CD4- CD8+ CD3+ cells and that this population was replaced by natural killer (NK)1.1+ CD4- CD8 CD3+ cells by day 27 (TIL-d27) during the culture of TIL. The TIL-d7 cells showed a cytolytic activity against B16 melanoma, whereas the TIL-d27 cells had lost this activity, suggesting that the decrease in the anti tumour effect of TIL during the culture with IL-2 was due to their populational change. Analysis on the characteristics of the TIL-d27 cells revealed that they expressed skewed T-cell receptor (TCR) V beta 5 and increased mRNA expression of V alpha 14. In addition, they expressed transforming growth factor beta (TGF-beta) mRNA. Interestingly, TGF-beta augmented the proliferation of TIL-d27 cells under the presence of IL-2, but suppressed that of TIL-d7 cells. Moreover, the proliferation of TIL-d27 cells was suppressed by anti-TGF-beta monoclonal antibody. Collectively, these results suggest that, in contrast to its suppressive effect on anti-tumour effector T cells. TGF-beta could be an autocrine growth factor for NKL1.1+ T cells and thereby induce non-cytolytic NK1.1+ T cells in the long-term culture of TIL.
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PMID:The emergence of non-cytolytic NK1.1+ T cells in the long-term culture of murine tumour-infiltrating lymphocytes: a possible role of transforming growth factor-beta. 901 32

Ly-6C+ cells constitute 13 +/- 3% of freshly isolated (CBA x C57BL/6)F1 mouse spleen leukocytes. Three distinct populations were identified: CD3 epsilon +NK-1.1- conventional T cells (6%), CD3 epsilon -NK-1.1- granulocytes (5%) and CD3 epsilon +NK-1.1+ T cells (approximately 2%). The CD3 epsilon +NK-1.1+ cells displayed a predominantly large granular leukocyte morphology and were the only Ly-6C+ cell subset identified by MAb 2B6-F2 to spontaneously lyse the NK-sensitive YAC-1 tumour in vitro. On further phenotypic analysis, these cells co-expressed high levels of TCRV beta 8.1/8.2 and CD11b, moderate levels of CD90 and low levels of CD4 or CD8. The removal of CD4+ and CD8+ cells prior to Ly-6C+ cell sorting showed that it was the CD4-CD8- double-negative (DN) CD3 epsilon +NK-1.1+ T-cell subset which was responsible for killing YAC-1. These results indicate that we have identified a DN Ly-6C+ subset of the recently designated NK-1.1+TCR alpha beta low natural T (NT) cells, which are capable of natural cell-mediated cytotoxicity (NCMC) against the NK-sensitive YAC-I tumour in vitro. Additionally, these cells mediated the in vitro killing of 2 further NK-sensitive tumours, murine B16 melanoma and human Jurkat T lymphoma. YAC-1 and Jurkat expressed Fas and were susceptible to anti-Fas MAb or rhuman Fas ligand (rhFasL)-induced lysis. Furthermore, anti-human Fas MAb M3 was shown to block sorted Ly-6C+ splenocyte in vitro killing of Jurkat. In contrast, B16 did not express cell-surface Fas and was resistant to anti-Fas MAb-induced lysis. Taken together, these results show that not only do Ly-6C+ NT cells kill NK-sensitive tumours in vitro but they mediate this activity via multiple cytotoxic mechanisms including Fas.
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PMID:Natural cell-mediated cytotoxicity (NCMC) against NK-sensitive tumours in vitro by murine spleen Ly-6C+ natural T cells. 903 54


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