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

T lymphocytes specifically recognizing autologous tumor cells in vitro can be generated from melanoma patients. Recognition of tumor cells by both CD4 and CD8 lymphocytes is mediated through the T-cell receptor and is restricted by HLA antigens. Although HLA-A2 has been identified as a restricting allele for many melanoma-specific cytotoxic T lymphocytes, T cells directed against antigens unique to each patient's tumor as well as antigens common to melanomas from unrelated individuals can be restricted by several different HLA alleles. A common melanoma antigen recognized in association with HLA-A1 has now been identified. The antigen is a nonapeptide derived from the gene MAGE1, a normal cellular gene preferentially expressed in a variety of solid tumors. Melanoma cells have been found to produce a soluble form of the intracellular adhesion molecule-1. Soluble intercellular adhesion molecule-1 effectively inhibits cell-mediated cytotoxicity in vitro, raising the possibility that its expression in vivo could promote escape of the tumor cells from immune effectors.
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PMID:Immunologic recognition of malignant melanoma by autologous T lymphocytes. 845 22

To study in vivo activated cytolytic T cells, CD8+ T cells clones were isolated from a melanoma patient (HLA A2, A11) treated with active specific immunotherapy for 5 years. CD8+ T lymphocytes, purified by fluorescence-activated cell sorting, were cloned directly from the peripheral blood without antigen-presenting cells in the presence of irradiated autologous melanoma cells and recombinant interleukin-2 (IL-2) and IL-4. These conditions were inhibitory to de novo in vitro immunization. Of the 28 cytolytic CD8+ T cell clones, 21 lysed the autologous melanoma cell line (M7) but not the autologous lymphoblastoid cell line (LCL-7) nor the two melanoma cell line, M1 (HLA A28) and M2 (HLA A28, A31), used to immunize the patient. The remaining 7 clones were also melanoma-specific, although their reactivities were broader, lysing several melanoma cell lines but not HLA-matched lymphoblastoid cells. Eight clones from the first group, ostensibly self-MHC-restricted, were expanded for further analysis. All expressed cluster determinants characteristic of mature, activated T cells, but not those of thymocytes, naive T cells, B cells or natural killer (NK) cells. They also expressed CD13, a myeloid marker. Of the 8 clones, 3 expressed both CD4 and CD8, but dual expression was not correlated with specificity of lysis. Two CD8+ and 2 CD4+ CD8+ clones were specific for the autologous melanoma cells, the other 4 were also reactive against other HLA-A2-positive melanomas. Cytotoxicity for both singly and doubly positive clones was restricted by HLA class I but not class II antigens. Analysis of the RNA expression of the T cell receptor (TCR) V alpha and V beta gene segments revealed heterogeneous usage by the A2-restricted clones and, perhaps, also by the broadly melanoma-specific clones. Apparent TCR-restricted usage was noted for the self-MHC-restricted clones; 2 of the 4 expressed the V alpha 17/V beta 7 dimer. Since the T cell clones were derived from separate precursors of circulating cytotoxic T lymphocytes (CTL), the V alpha 17/V beta 7 TCR was well represented in the peripheral blood lymphocytes of this patient. In summary, we show that melanoma cells presented their own antigens to stimulate the proliferation of melanoma-reactive CD8+ CTL. CTL with a range of melanoma specificities and different TCR alpha beta dimers were encountered in this patient, perhaps as a result of hyperimmunization.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Clonal analysis of in vivo activated CD8+ cytotoxic T lymphocytes from a melanoma patient responsive to active specific immunotherapy. 851 49

We performed immunohistochemistry on tumor infiltrating lymphocytes (TILs) in a 78-year-old man with choroidal malignant melanoma. Cell suspensions of TILs from fresh specimens and peripheral blood lymphocytes (PBLs) were stained with anti-CD3, anti-CD4, anti-CD8, anti-CD29, anti-CD45RA, and anti-human leukocyte antigen (HLA)-DR monoclonal antibodies and analyzed using three-color flow cytometry. In light microscopy, the number of infiltrating lymphocytes around the tumor was very small. Immunohistochemically, T lymphocytes were more numerous than B lymphocytes. Flow cytometric analysis showed that CD8+ cells were more numerous than CD4+ cells in CD3+ cells in TILs, and most of these cells also expressed HLA-DR antigen. CD29+ (memory) cells were increased and CD45RA+ (naive) cells were decreased in CD4+ cells in TILs as compared with PBLs. We concluded that the increase in the percentage of activated memory T lymphocytes and the decrease of naive T lymphocytes may reflect a localized antigen-specific immunological response in choroidal malignant melanoma.
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PMID:[Analysis of infiltrating lymphocytes in choroidal melanoma]. 853 59

The therapeutic potential of adoptive therapy using tumour-infiltrating lymphocytes (TIL) has been demonstrated in a number of clinical trials. However, freshly isolated tumour-infiltrating lymphocytes (TIL) are often impaired in their proliferative and cytotoxic responses, which limits their use in immunotherapy. Several hypotheses with regard to the poor effector function of TIL have been postulated, including the production of immunosuppressive factors by tumour cells. In a previous paper we reported the efficient expansion of immunoreactive TIL from a variety of solid tumours by stimulation with a combination of monoclonal antibodies (mAbs) against CD3 and CD28. In the present study we analysed whether this protocol would be improved by the removal of tumour cells at the start of the culture. We tested a highly immunogenic tumour, melanoma, and a poorly immunogenic tumour, colon carcinoma. Removal of tumour cells highly improved anti-CD3/CD28 stimulated expansion of TIL from colon carcinoma, resulting in a significantly higher percentage of potentially tumour-specific CD8-positive T-cells and a reduced CD4/CD8 ratio compared to expansion in the presence of tumour cells. In contrast, expansion and CD4/CD8 ratio of melanoma-derived TIL was not significantly influenced by the removal of autologous tumour cells. CD3/CD28-stimulated melanoma TIL cultured in the absence of tumour cells showed specific lysis of autologous tumour cells comparable to melanoma TIL cultured in high-dose IL2. However, no cytotoxicity could be detected in colon TIL irrespective of the culture conditions used. On the other hand, 3/8 colon carcinoma TIL cultures and 9/12 melanoma-derived TIL cultures showed IFN gamma secretion upon stimulation with autologous tumour cells. We conclude that stimulation of TIL with a combination of mAbs to CD3 and CD28 in the absence of tumour cells induces efficient expansion of potentially tumour-specific cells from a highly and a poorly immunogenic tumour. Removal of tumour cells does not have a negative influence on the generation of tumour-specific T cells, while cell yield improves. Therefore, for large-scale cultures this protocol can efficiently induce the outgrowth of tumour-specific TIL, at the same time providing a useful source of autologous tumour cells that can be stored and used to direct or test antitumour specificity.
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PMID:Culture of tumour-infiltrating lymphocytes from melanoma and colon carcinoma: removal of tumour cells does not affect tumour-specificity. 853 75

Peripheral mononuclear cells (PMNC) from 18 melanoma were monitored for vaccine-related changes in their immune responses by measuring functional activity and phenotypic expression of PMNC prior to- and following 4-6 vaccinations. Assays included: cytolytic responses directed against melanoma cell lines included in the vaccine (M20, M14, HM54 and SKMel28), control melanoma (SKMel23) and non-melanoma (SKCo1, K562 and Daudi) cell lines. Direct lytic responses were significantly enhanced following vaccine treatment, mainly against M20 cell line and was further augmented following In Vitro Stimulation (IVS) by Mit-C-treated M20 or M14 cells. No evidence was found of augmentation of NK or LAK activity by vaccine treatment. Significantly enhanced proliferative responses to of vaccine-treated patients' PMNC to melanoma cell lines were also observed. The human melanoma cell lines used for vaccine preparation (M14, M20 and SKMel28) are high expressors of HLA class I, while high expression of HLA-DR only on M20 cells. Cell surface markers' study indicate a shift in CD4/CD8 ratio from 1.1 to 2.1 and increase in CD25 and HLA-DR positive cells. In M20-stimulated cultures of post-vaccine patients' PMNC the predominant phenotype was CD3+/CD4+. In conclusion, we have demonstrated that treatment with polyvalent allogeneic melanoma vaccine significantly augments T-cell mediated CD3+/CD4+), anti-melanoma lytic and proliferative responses, non-MHC-restricted.
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PMID:In vitro cell-mediated immune responses induced by a polyvalent allogeneic melanoma vaccine. 854 60

The use of immunomodulating gene therapy in the treatment of malignant disease is under intensive investigation. In this study, we examined the potential of melanoma-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) to inhibit melanoma progression in a murine model. The HGH18 murine melanoma cell line was transfected with the murine GM-CSF gene in a SV40 expression vector that resulted in melanoma clones that produced varying amounts of GM-CSF. Syngeneic mice inoculated s.c. with HFH18 parental melanoma cells or HFH18 cells transfected with the GM-CSF gene n the noncoding 3'-5' orientation [HFH18/GM-CSF(-) cells] develop large tumors that reach a mean tumor volume of 3300 mm3 by day 30. In contrast, animals inoculated with two melanoma clones producing high levels of GM-CSF [HFH18/GM-CSF(++) and HFH18/GM-CSF(+ + +)] either completely reject the tumor cells or develop tumors with a mean volume of only 40 mm3. In comparison, animals inoculated with a melanoma clone producing low levels of GM-CSF [HFH18/GM-CSF(+)] develop large tumors averaging 2000 mm3, thus demonstrating a dose-response effect of tumor inhibition by melanoma-derived GM-CSF. Additionally, vaccination with irradiated GM-CSF-producing melanoma cells conferred optimal immunogenicity against a subsequent challenge with HFH18 cells. Tissue sections from excised GM-CSF-producing tumor cell inoculation sites but not from HFH18 parental or HFH18/GM-CSF(-) inoculation sites demonstrate a dense inflammatory infiltrate composed of neutrophils, tissue macrophages, and numerous CD4- and CD8-positive lymphocytes but few melanoma cells. Large numbers of dendritic cells and cells expressing the B7-2 costimulatory molecule are detected only within HFH18/GM-CSF(+ + +) melanoma inoculation sites. Our results lend further support to clinical trials of GM-CSF gene therapy in the treatment of advanced malignant melanoma, possibly by the recruitment of dendritic antigen-presenting cells.
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PMID:Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells. 861 71

We previously showed that anti-idiotypic mAb (mAb2) F16-16D7 (16D7) to the paratope (or paratope-related idiotope) of the anti-CD4 mAb HP2/6 induces anti-CD4 Abs in BALB/c mice. In view of the potential ability of 16D7 to induce anti-CD4 Ab in humans and the potential benefits of anti-CD4 Abs in the treatment of autoimmune diseases, we evaluated the immunologic response to and assessed the safety of four 2-mg 16D7 s.c. injections in one patient with systemic lupus erythematosus (SLE) and one with rheumatoid arthritis (RA). 16D7 induced anti-isotypic and anti-anti-idiotypic Abs (Ab3), which were almost exclusively of the IgG isotype. Ab3 specifically reacted with 16D7 as they inhibited its binding to mAb HP2/6. Although Ab3 did not react with cellular or recombinant CD4 (rCD4), single-cell enzyme-linked immunospot assays of anti-CD4 Ab production revealed many more spot-forming cells in rCD4- and 16D7-coated wells than in wells coated with BSA or 16D7 isotype-matched MK2-23. Spot-forming anti-CD4 Abs were specifically induced by 16D7, since rCD4-dependent spot formation 1) was not observed with PBL from one patient with SLE, one with mixed connective tissue disease, and one with melanoma immunized with MK2-23; and 2) was inhibited by 16D7 and not by MK2-23. Spot-forming anti-CD4 Abs recognize a CD4 epitope identical (or closely related) to that seen by HP2/6, since this specifically inhibited spot formation. A substantial, although transient, CD4+ T cell depletion was only observed in the RA patient. Local and/or general toxicity and laboratory and/or clinical signs indicative of immunodepression or diseases relapse were not observed during an 18-month follow-up.
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PMID:Human CD4-internal antigen anti-idiotypic monoclonal antibody: induction of a CD4-specific response in humans. 861 87

We have reported that medium containing recombinant human IL-1 (rIL-1), rIL-2, rIL-4, and rIL-6 (MB-1,2,4,6 medium) efficiently expanded autologous tumor specific CTLs in vitro. For further examination of the CTLs cultured in MB-1,2,4,6, the therapeutic activity on tumor growth inhibition in vivo and established CTL clones were studied. In vivo therapy with the CTLs in combination with rIL-2 was highly effective. To investigate CTL clones, 19 CD8+ T cell clones were obtained by limiting dilution method, each clone retained autologous-melanoma-specific, HLA-class I-restricted cytolytic activity. Four T cell clones were analyzed in detail. These T cell clones displayed a CD3+, CD4-, CD8+, CD11b-, CD16-, CD56-, CD45RA-, TcR alpha/beta + phenotype and monoclonal antibodies to HLA class I, CD3, and CD8 antigens inhibited their cytolytic activity. Moreover, these CTL clones recognize one of common melanoma antigens associated with HLA-B (B49). Analysis of the effect of different cytokines on the proliferation and cytotoxicity of cloned CTL revealed the highest growth rate in MB-1,2,4,6 but no dependence on particular cytokine combinations for autologous tumor-specific cytolytic activity. These results suggest (1) the usefulness of MB-1,2,4,6 medium in expanding autologous tumor-specific CTLs, which can be used in adoptive immunotherapy, (2) HLA-B molecules can present one of common melanoma antigens, and (3) the independence of CTLs from any cytokine combination once they become target-specific.
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PMID:HLA-B-restricted, CD8+ cytolytic human T cell clones derived from a melanoma-invaded lymph node. 874 95

The natural history of thyroid tumours and the hyper-reactivity of the immune system in patients with thyroid cancer suggest that immune surveillance may play a role in the control of this disease. A study was therefore undertaken to analyse the phenotypic and functional features of tumour-infiltrating lymphocytes (TILs) derived from thyroid tumours. In a series of experiments, it was found that, in contrast to TILs derived from patients with melanoma or renal cell carcinoma, thyroid TILs could be efficiently expanded in vitro only in the presence of allogeneic EBV transformed B (B. EBV) cells. Indeed, only one of the seven thyroid-derived TILs grew in vitro without feeder cells, whereas all 16 thyroid-derived TILs could be expanded in the presence of allogeneic B. EBV feeder cells. Phenotypic analysis of these TILs revealed a frequent in vitro expansion of an unusual T cell population that expressed both the CD4 and CD8 markers. Indeed, it was demonstrated that in five of 14 TILs in short-term culture (< day 23) and four of 11 TILs in long-term culture (> day 40), a lymphocyte population that coexpressed CD4 and CD8 antigen accounted for more than 15% of the total TIL population. This double-positive T cell population was not observed in TILs derived from melanoma or renal cell carcinoma. Thyroid-derived TILs also displayed an intense cytolytic activity against NK-sensitive tumour targets with 10 of 11 TILs exhibiting significant cytotoxicity towards the NK-sensitive K562 cell line. Six of 11 TILs were also cytotoxic towards autologous tumour, but when cold target inhibition with K562 was performed with three cultures, unlabelled K562 completely inhibited lysis of autologous tumour cells. A significant expansion of CD3+CD56+ T cells in the different TIL populations may explain this high level of NK-like cytotoxicity. In conclusion, TILs derived from thyroid tumours could be efficiently expanded in vitro under certain culture conditions. Different strategies must be explored to enhance their specific tumour autologous specificity, however, before they can be used in immunotherapy protocols.
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PMID:Phenotypic and functional characterisation of tumour-infiltrating lymphocytes derived from thyroid tumours. 875 59

The co-expression of B7.1 (CD80) and intercellular adhesion molecule (ICAM)-1 (CD54) on tumor cells can induce tumor immunity and immunological memory. We show here that the non-immunogenic tumor lines Lewis lung carcinoma and B16F10 melanoma, co-transfected with B7.1 and ICAM-1, induced cytotoxic levels of membrane tumor necrosis factor (TNF) on naive syngeneic T cells within 24 h. Membrane TNF expression, primarily on CD4 cells, was responsible for tumor cell lysis by naive spleen cells and could be completely abolished by anti-TNF antiserum. It is suggested that the strong induction of TNF cytotoxicity may be important in the establishment of tumor immunity.
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PMID:Rapid induction of tumor necrosis factor cytotoxicity in naive splenic T cells by simultaneous CD80 (B7.1) and CD54 (ICAM-1) co-stimulation. 881 62


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