UMLS:C0278883 - FACTA Search

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Query: UMLS:C0278883 (metastatic melanoma)
6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumour-infiltrating lymphocytes (TIL) in four different primary human malignant melanomas and their corresponding metastatic lesions was characterized using a recently developed method based on the reverse-transcription-coupled polymerase chain reaction (RT-PCR). All patients were typed for HLA-A1 and -A2, either serologically or by a newly developed RT-PCR method. Two of these patients expressed HLA-A2, one the HLA-A1 haplotype and one further patient was heterozygous HLA-A1/-A2. The prognostic parameters for all four patients indicated that rapid progression of the disease was to be expected. However, only two of the patients showed rapid progression, while the remaining two patients are still alive after more than 3 years. In TIL in primary melanomas, a possible correlation was suggested between HLA-A2 and the preferential usage of the TCR V gene families V alpha 4, V alpha 5, V alpha 22 and V beta 8, whereas the V beta 3 gene family appeared to be expressed together with HLA-A1. Other highly expressed V gene families, apparently not restricted to either HLA-A1 or -A2, were V alpha 1 (expressed in three of four primary tumours) and V alpha 21 (expressed in two of four tumours). We found no evidence suggesting any correlations between the haplotypes HLA-A1 and -A2 and preferential V gene family expression in the metastatic lesions, and the only common feature was V alpha 8, which was found to be highly expressed in two out of three subcutaneous metastases. The V gene families, which were highly expressed in the primary tumour were generally not, or only very weakly, expressed in metastases and vice versa, possibly reflecting a change in the phenotype of the metastatic melanoma target cells. With regards to patient 0368, it was possible to obtain and study material from two subcutaneous metastases. The first metastasis was excised more than a year after the primary tumour, showing a completely different V region repertoire. The second metastasis was excised at surgery 2 years after primary surgery and likewise showed a dramatic shift in comparison to the first subcutaneous metastasis. Although the present study only included a small number of patients, it suggests that the estimation of V gene expression, if applied to a larger amount of patient material, might make it possible to substantiate further the suggested correlations between the T cell response against the tumour, HLA and antigen expression.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Analysis of T cell receptor alpha beta variability in lymphocytes infiltrating melanoma primary tumours and metastatic lesions. 795 26

The T cell receptor (TCR) alpha beta variable (V) gene family usage of tumor-infiltrating lymphocytes (TIL) in different primary human malignant melanomas and corresponding metastatic lesions were characterized using a recently developed method using the reverse transcription coupled polymerase chain reaction (RT-PCR). This semiquantitative RT-PCR method could be adapted to analysis of formalin-fixed, paraffin-embedded histopathological samples of primary tumor material and demonstrated to be reproducible and to be useful for the assessment of V alpha- and V beta-gene family usage in tumor samples. The TIL in primary tumors were observed to preferentially express certain TCR V alpha- and V beta-gene families: V alpha 4, and V beta 8 were highly expressed in several of the primary tumors analyzed using this method. With respect to V alpha 22 and V beta 8, the preferential expression of these V-gene families was demonstrated to be due in situ clonal expansion of T cells by means of cloning and sequencing of the CDR3 regions (V-J or V-D-J, respectively) corresponding to the RT-PCR products from one of the primary tumors. The observed preferential usage of certain TCR V alpha and V beta-genes strongly suggest the in situ clonal expansion of specific populations of T cells in accordance with recent results from others. These clonal T cell populations probably react with certain melanoma-associated peptides presented by specific HLA molecules. The preferential usage of certain V alpha- and V beta-gene families observed in several tumors further supports the involvement of a limited number of shared melanocyte or melanoma-associated peptides. Since the HLA status of the patients is obviously important to interpret these results, some of the patients were typed for HLA-A1 and -A2, the two most well-characterized restriction elements for melanoma-associated antigens, either serologically or by a newly developed RT-PCR method which similarly could by applied directly to the tumor material. In TIL in primary melanomas, a possible correlation was suggested between HLA-A2 and the preferential usage of the TCR V-gene families V alpha 4, V alpha 5, V alpha 22 and V beta 8, whereas the V beta 3-gene family appeared to be expressed together with HLA-A1. The V-gene families which were highly expressed in the primary tumors were generally not, or only very weakly, expressed in the corresponding metastases and vice versa, possibly reflecting a substantial change in the phenotype of the metastatic melanoma target cells. Continued studies of larger patient materials will be necessary to extend and validate these conclusions and of obvious interest for the further analysis of the T cell response in melanoma.
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PMID:Analysis of T cell receptor alpha beta variability in tumor-infiltrating lymphocytes in primary and metastatic melanoma. 874 27

The MAGE-3 gene is a member of a multigene family that is selectively expressed by subsets of different human tumor types, including malignant melanoma, but not by normal tissues except for testis and placenta. A cytolytic T lymphocyte (CTL)-defined MAGE-3 antigen, corresponding to the MAGE-3 peptide 271-279 associated with the human leukocyte antigen (HLA)-A2 molecule, has been recently identified using T lymphocytes from a normal individual stimulated in vitro with peptide-pulsed autologous antigen-presenting cells. Because MAGE-3 is expressed in 76% of metastatic melanomas, the HLA-A2-restricted MAGE-3 antigen should be expressed by approximately 37% of Caucasians bearing a metastatic melanoma tumor, thus representing an attractive candidate for the elicitation of specific CTL immune responses in vivo. In this study, we determined the proportion of HLA-A2+ melanoma patients displaying detectable MAGE-3 peptide 271-279-specific CTL precursors in peripheral blood. Peptide-specific CTL populations were obtained from at least 4 of 11 HLA-A2+ patients. Peptide-specific CTL lines derived from these populations readily lysed HLA-A2-positive target cells that were pulsed with MAGE-3 peptide 271-279 at nanomolar concentrations yet were unable to recognize (as assessed by cytolysis and cytokine production) MAGE-3-expressing autologous or allogeneic HLA-A2-positive melanoma lines. Similarly, the CTL lines failed to recognize MAGE-3-negative HLA-A2-positive tumor lines after transfection with the MAGE-3 gene, although they were able to recognize COS-7 cells transfected with MAGE-3. In contrast, HLA-A1-positive melanoma lines transfected with MAGE-3 were efficiently recognized by CTL lines directed against the MAGE-3 peptide 168-176, a known HLA-A1-restricted CTL epitope. These results suggest that the expression level of the MAGE-3 peptide 271-279, unlike that of MAGE-3 peptide 168-176, in melanomas may be too low to allow efficient recognition by specific CTLs. Thus, it appears that despite the presence of CTL precursors against MAGE-3 peptide 271-279 in some HLA-A2+ melanoma patients, the usefulness of this peptide for specific immunotherapy of melanoma may be limited.
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PMID:Analysis of MAGE-3-specific cytolytic T lymphocytes in human leukocyte antigen-A2 melanoma patients. 904 53

We have established a sensitive ELISPOT assay measuring interferon gamma (IFN gamma) release on a single-cell basis to detect influenza peptide-specific CD8+ T cells in uncultured peripheral blood mononuclear cells (PBMC). Using this method, we studied the T cell response to HLA-A1 and HLA-A2.1 binding peptide epitopes derived from the MAGE-1 and MAGE-3 proteins, from the melanoma-associated antigens tyrosinase, Melan-A/MART-1 and gp100, and from influenza proteins in stage IV melanoma patients and healthy controls. In 18 of 24 HLA-A2-positive donors (75%), but only in 9 of 25 HLA-A2-positive melanoma patients (36%) T cells reactive with the influenza matrix peptide were demonstrated (p = 0.007). T cells responding to one or several of the melanoma-associated peptides were detected in 5 of 25 HLA-A2-positive patients with metastatic melanoma. Four of these 5 patients had been treated with interleukin-2- and IFN alpha-containing therapy. Two of the 24 healthy donors had T cells reactive with the MART-1 27-35 peptide. No reactivity with the HLA-A1-binding peptides from MAGE-1 or MAGE-3 was detected in any of the HLA-A1-positive healthy controls or melanoma patients. These results show that the IFN gamma-ELISPOT assay is suitable to determine quantitatively T cells reactive with melanoma-associated and influenza peptide epitopes in uncultured PBMC. The failure to detect T cells responding to influenza in many melanoma patients with progressive disease may indicate an impairment of their T cell function.
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PMID:Analysis of the T cell response to tumor and viral peptide antigens by an IFNgamma-ELISPOT assay. 918 91

An enzyme-linked immunospot (ELISPOT) assay was adapted to detect peptide-specific CD8+ T lymphocytes in peripheral blood mononuclear cells (PBMCs). In HLA-A1-, HLA-A2-, and/or HLA-A3-positive individuals, we determined the release of IFN-gamma on a single cell level in response to three different peptide epitopes derived from the influenza matrix protein and nuclear protein containing the HLA-A2.1- and HLA-A1- or HLA-A3-binding motif, respectively. Comparison of the ELISPOT assay with the standard chromium release assay revealed a close correlation between the number of peptide-specific IFN-gamma-releasing T cells in PBMCs and the level of specific cytotoxicity after 14 days of in vitro expansion. The ELISPOT assay detected T cells with specificity for the HLA-A2. 1-binding epitope derived from the matrix protein in 76% of HLA-A2-positive healthy individuals (n = 25); the median frequency was 41 in 10(6) PBMCs. We also detected peptide-specific T cells in 10 of 12 HLA-A2-positive patients with metastatic melanoma with a median frequency of 20.5 in 10(6) PBMCs. In 10 of 24 HLA-A3-positive individuals and in 2 of 14 HLA-A1-positive individuals, peptide-specific T cells for a HLA-A3- and a HLA-A1-binding epitope derived from the nucleoprotein, respectively, were present. In conclusion, the ELISPOT assay may be suitable to monitor a peptide-specific T-cell response in vaccination protocols using peptides derived from tumor or viral antigens.
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PMID:A sensitive ELISPOT assay for detection of CD8+ T lymphocytes specific for HLA class I-binding peptide epitopes derived from influenza proteins in the blood of healthy donors and melanoma patients. 981 76

A total of 123 tumor-infiltrating T lymphocyte (TIL) cultures established from patients with HLA-A1, -A2, -A3, -A24, or -A31 metastatic melanoma in the Surgery Branch, National Cancer Institute, were screened for recognition of shared melanoma antigens including five melanosomal proteins (tyrosinase, MART-1/melan-A, gp100, TRP1, TRP2) as well as peptides derived from MAGE-1 and MAGE-3. Examination of the specificity of these T cells indicated that 16% of HLA-A1 TIL, 57% of HLA-A2 TIL, 7% of HLA-A3 TIL, 13% of HLA-A24 TIL, and 27% of HLA-A31 TIL recognized shared melanoma antigens restricted by major histocompatibility complex class I. Melanosomal proteins were frequently recognized by these TIL, and MART-1(27-35), gp100(154-162), gp100(209-217), and gp100(280-288) represent highly immunogenic epitopes that were recognized by a high percentage of HLA-A2 restricted melanoma reactive TIL. Recognition of gp100 by HLA-A2 restricted TIL significantly correlated with clinical response to adoptive immunotherapy with TIL in 21 HLA-A2 melanoma patients (p = 0.024). Four HLA-A1, two HLA-A2, two HLA-A3, one HLA-A24, and two HLA-A31 restricted shared antigen-specific TIL did not recognize the previously identified antigens tested in this study, and may be useful for the identification of new melanoma antigens. The observation that TILs isolated from patients with metastatic melanoma recognized melanosomal proteins in the context of predominant HLA-A alleles implies that it may be possible to develop immunotherapies for patients with melanoma expressing diverse HLA types.
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PMID:Recognition of shared melanoma antigens in association with major HLA-A alleles by tumor infiltrating T lymphocytes from 123 patients with melanoma. 1068 34

Thirty-three metastatic melanoma patients were vaccinated according to a phase I-II study with an allogeneic melanoma cell line that was genetically modified by transfection with a plasmid containing the gene encoding human interleukin 2 (IL-2). The cell line expresses the major melanoma-associated antigens and the HLA class I alleles HLA-A1, -A2, -B8, and Cw7. All patients shared one or more HLA class I alleles with this cell line vaccine. Patients were immunized by three vaccinations, each consisting of 60 x 106 irradiated (100 Gy) melanoma cells (secreting 120 ng of IL-2/10(6) cells/24 hr) administered subcutaneously at weekly intervals for 3 consecutive weeks. Side effects of treatment consisted of swelling of locoregional lymph nodes and induration at the site of injection, i.e., a delayed-type hypersensitivity (DTH) reaction. In three patients, vaccination induced inflammatory responses in distant metastases containing necrosis or apoptosis along with T cell infiltration. Apoptosis occurred only in Bcl-2-negative areas, not in Bcl-2-expressing parts of the metastases. Two other patients experienced complete or partial regression of subcutaneous metastases. Seven patients had protracted stabilization (4 to >46 months) of soft tissue metastases, including one patient who developed vitiligo after vaccination. Immune responses to the vaccine could be detected in 67% of the 27 patients measured. Vaccination was shown to induce a variable change in the number of anti-vaccine cytotoxic T lymphocytes (CTLs) in peripheral blood, which did not correlate with response to treatment. However, in two of five patients the frequency of anti-autologous tumor CTLs measured was significantly higher than before vaccination. This study demonstrates the feasibility, safety, and therapeutic potential of vaccination of humans with allogeneic, gene-modified tumor cells, and that frequencies of vaccine-specific CTLs among patient lymphocytes can be determined by using a modified limited dilution analysis (LDA).
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PMID:Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line. 1075 53

To determine whether circulating tumor-reactive T cells are present in melanoma patients, unstimulated T cells from peripheral blood were tested for recognition of HLA-A2- or HLA-A1-matched melanoma cell lines using the ELISPOT assay. Eleven out of 19 patients with metastatic melanoma had a T-cell response with up to 0.81%, 0.78%, 0. 53%, 0.12%, 0.10%, 0.09%, 0.07%, 0.06%, 0.06%, 0.04%, and 0.04% of peripheral blood mononuclear cells (PBMC) secreting IFNgamma upon exposure to various HLA-A2- or HLA-A1-matched melanoma cell lines. These T-cell responses were mediated by CD8+ T cells and could specifically be blocked by an anti-HLA-A2 antibody in HLA-A2-positive patients. Separation experiments performed in one melanoma patient showed tumor-reactive T cells in both the CD8+ effector T cell (CD45RA+/IFNgamma+) as well as the CD8+ memory T-cell compartment (CD45RO+/IFNgamma+). In 3 out of 5 patients, in whom autologous cell lines were available, similar frequencies of T cells in response to HLA-A1- or HLA-A2-matched allogeneic and autologous tumor cells were observed, while 2 patients had a T-cell response restricted to either the autologous or the allogeneic cell lines. These results give evidence for the presence of tumor-reactive CD8+ T cells in more than half of melanoma patients tested. Although some of these patients have clinical evidence for an immunological-mediated tumor control, several patients have growing tumors suggesting presence of escape mechanisms.
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PMID:High frequencies of circulating melanoma-reactive CD8+ T cells in patients with advanced melanoma. 1092 59

The major goal of therapeutic cancer vaccine trials is to mediate tumor regression. However, it is critically important to devise in vitro immunological assays that correlate with clinical outcome, for use as surrogate markers of vaccine efficacy. To date, clinical emphasis has been placed on peptide vaccines, but trends towards the use of more complex immunogens such as whole proteins require the development of efficient and sensitive methods for monitoring their immunological effects. In the context of a vaccination trial using full-length tyrosinase (Ty) to immunize patients with metastatic melanoma, a monitoring technique was developed in which autologous dendritic cells (DC) infected with a recombinant adenovirus encoding the Ty protein were used to assess the Ty-specific reactivity of fresh peripheral blood lymphocytes (PBL) collected from patients at different intervals during therapy. Quantitative real-time RT-PCR (qRT-PCR) was used to measure the production of cytokine mRNA by T cells following a 2.5-h incubation with Ty-expressing DC. Two out of ten patients studied demonstrated Ty protein-specific reactivity that increased during and after the period of vaccination. While one of these patients also reacted to an HLA-A1-compatible Ty peptide, the second did not recognize any of the known Ty epitopes, highlighting the importance of this technique for monitoring the effects of complex vaccines.
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PMID:Quantitative real-time RT-PCR as a method for monitoring T lymphocyte reactivity to full-length tyrosinase protein in vaccinated melanoma patients. 1213 25

We have analyzed the T cell responses of HLA-A1 metastatic melanoma patients with detectable disease, following vaccination with a recombinant ALVAC virus, which bears short MAGE-1 and MAGE-3 sequences coding for antigenic peptides presented by HLA-A1. To evaluate the anti-MAGE CTL responses, we resorted to antigenic stimulation of blood lymphocytes under limiting dilution conditions, followed by tetramer analysis and cloning of the tetramer-positive cells. The clones were tested for their specific lytic ability and their TCR sequences were obtained. Four patients who showed tumor regression were analyzed, and an anti-MAGE-3.A1 CTL response was observed in three of these patients. Postvaccination frequencies of anti-MAGE-3.A1 CTL were 3 x 10(-6), 3 x 10(-3), and 3 x 10(-7) of the blood CD8 T cells, respectively. These three responses were monoclonal. No anti-MAGE-1.A1 CTL response was observed. These results indicate that, like peptide immunization, ALVAC immunization produces monoclonal responses. They also suggest that low-level antivaccine CTL responses can initiate a tumor regression process. Taken together, our analysis of anti-MAGE-3.A1 T cell responses following peptide or ALVAC vaccination shows a degree of correlation between CTL response and tumor regression, but firm conclusions will require larger numbers.
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PMID:Monoclonal anti-MAGE-3 CTL responses in melanoma patients displaying tumor regression after vaccination with a recombinant canarypox virus. 1456 71

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