Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human melanoma antigens and their epitopes recognized by T cells have been identified using a variety of methods. These antigens are classified as 1) melanocyte specific melanosomal proteins (MART-1, gp100, tyrosinase and TRP-1), 2) proteins expressed in testis and a variety of cancers (MAGE-1, MAGE-3, BAGE and GAGE), 3) tumor specific mutated proteins (beta-catenin, MUM-1 and CDK4), and 4) others (p15). Some of the HLA-A2 binding non-mutated melanoma epitopes contained non-dominant anchor amino acids and have relatively low HLA-A2 binding affinity, suggesting that these epitopes were likely to be subdominant or cryptic self determinants. The significant correlation observed between vitiligo development and IL2 based immunotherapy suggested that autoreactive T cells specific for these self peptides were involved in melanoma regression in vivo. In addition, since adoptive transfer into patients of CTL recognizing these epitopes resulted in tumor regression, these epitopes may be tumor rejection antigens. Melanoma reactive CTL were efficiently induced from PBL of patients by in vitro stimulation with PBMC pulsed with these melanoma epitopes and may be useful in adoptive transfer protocols for the treatment of patients with metastatic melanoma. An immunization trial using the MART-1 and gp100 peptides in conjunction with incomplete Freund's adjuvant is in progress. These identified antigens may be useful for the development of new immunotherapies for the treatment of melanoma patients as well as for understanding the mechanisms of anti-tumor immune responses and autoimmune disorders against melanocytes.
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PMID:Human melanoma antigens recognized by T lymphocytes. 868 99

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

Mutations have been identified in the beta2-microglobulin gene of tumor cells of two metastatic melanoma patients who received immunizations with MAGE peptides. One mutation abolishes the start codon whereas the other introduces a premature stop codon. The second beta2-microglobulin allele of both tumors appears to be lost on the basis of sequence data and loss of microsatellite heterozygosity. The lack of beta2-microglobulin gene product results in the absence of HLA class I antigens on the surface of the tumor cells. This may explain why the tumors of both patients progressed despite the immunization treatment and shows the necessity of analyzing in depth the antigen presentation capability of the tumor cells for the interpretation of clinical trials involving anti-tumor vaccination.
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PMID:Mutations of the beta2-microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptides. 989 50

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

A total of 17 patients with metastatic melanoma were treated with intratumoral interferon-gamma (IFN-gamma) retroviral vector in a phase I clinical trial. A cycle of treatment consisted of five daily injections every 2 weeks. Patients were divided into two treatment arms that involved a single course (one cycle) of treatment (group I; n = 9) and multiple cycles (six cycles) of treatment (group II; n = 8). Patients received intratumoral injections of IFN-gamma (10(7) plaque-forming units/mL administered at 0.3, 0.5, and 1.0 mL per cohort of patients). All patients receiving multiple injections either maintained stable disease (n = 5) or achieved a partial or complete response (n = 3) of the injected lesion, whereas in patients receiving a single cycle of treatment, only one of nine patients had a response. Patients were assessed for immunoglobulin G antibody (Ab) responses to the melanoma-associated antigens (MAA) tyrosinase, gp100, TRP-2, and MAGE-A1 by affinity enzyme-linked immunosorbent assay. Anti-MAGE-A1 and tyrosinase Ab were significantly elevated from baseline (day 0) to week 16 during treatment (P = .005; P = .002, respectively) in patients who received multiple injections. Patients undergoing treatment who had a clinical response (stable disease or better) also had significantly more elevated Ab responses to a greater number of MAA (P = .0004). The induction of systemic Ab responses to multiple MAA also correlated with systemic clinical responses. These studies suggest that multiple anti-MAA Ab responses are associated with clinical responses to IFN-gamma retroviral treatment and may be used as surrogate response markers.
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PMID:Induction of melanoma-associated antigen systemic immunity upon intratumoral delivery of interferon-gamma retroviral vector in melanoma patients. 1102 94

Cancer-testis antigens expressed by different-histotype transformed cells are suitable targets for tumor immunotherapy. However, their heterogeneous expression in neoplastic lesions limits the eligibility of patients for cancer-testis antigen-directed vaccination, and low levels of cancer-testis antigens' expression may impair immune recognition of malignant cells. Because of the primary clinical relevance of cancer-testis antigens' expression in neoplastic tissues, 68 unrelated or sequential metastatic lesions from 56 patients were used to characterize the molecular mechanisms regulating the presence and levels of expression of different cancer-testis antigens of the MAGE family (i.e., MAGE2, 3 and 4) in cutaneous melanoma. Polymerase chain reaction-based methylation analyses showed that methylation status of specific cytosine-guanine dinucleotides in the promoters of investigated cancer-testis antigens correlated with their heterogeneous expression within unrelated metastatic melanoma lesions, and with their homogeneous expression among sequential metastases from three patients with melanoma. Unlike methylated promoters, unmethylated promoters of MAGE2, 3 and 4 genes drove the expression of reporter gene-enhanced green fluorescent protein after transient transfection of cancer-testis antigen-positive Mel 142 melanoma cells. Furthermore, de novo expression of MAGE3 gene induced by the treatment of Mel 195 melanoma cells with the DNA hypomethylating agent 5-aza-2'-deoxycytidine was associated with a 6%-12% demethylation of selected cytosine-guanine dinucleotides in its promoter. Finally, 5-aza-2'-deoxycytidine induced a 16-fold increase of MAGE3 expression in Mel 313 melanoma cells expressing constitutively low levels of the antigen, but did not affect that of Mel 275 melanoma cells expressing high baseline levels of MAGE3. Overall, these findings identify promoter methylation as a shared mechanism directly regulating the expression of therapeutic cancer-testis antigens in metastatic melanomas, and foresee the clinical use of 5-aza-2'-deoxycytidine to design new chemoimmunotherapeutic strategies in patients with melanoma.
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PMID:Promoter methylation controls the expression of MAGE2, 3 and 4 genes in human cutaneous melanoma. 1192 7

'Cancer-germline' genes such as the MAGE gene family are expressed in many tumors and in male germline cells but not in normal tissues. They encode shared tumor-specific antigens, which have been used in therapeutic vaccination trials of metastatic melanoma patients. To establish whether there is a correlation between tumoral regressions and T-cell responses against the vaccine antigen, we evaluated the responses of patients vaccinated with a MAGE-3 antigenic peptide or a recombinant virus coding for the peptide. Blood lymphocytes were stimulated with antigenic peptide followed by detection with tetramer, T-cell cloning, and TCR analysis. In 4/9 regressor patients and in 1/14 progressors we found a low level, usually monoclonal cytolytic T lymphocyte response against the MAGE-3 peptide.
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PMID:Cytolytic T-cell responses of cancer patients vaccinated with a MAGE antigen. 1244 79

Patients with metastatic melanoma who expressed HLA-Cw*0702 and whose tumors had demonstrable MAGE-A12 expression were immunized with the peptide MAGE-A12:170-178 administered subcutaneously in incomplete Freund's adjuvant (IFA). The peptide was administered either every week or every 3 weeks for 4 cycles. Patients were evaluated for toxicity and for immunologic and clinical response to peptide immunization. Pre-treatment fine needle aspirates were obtained to document MAGE-A12 expression for enrollment. MAGE-A12 mRNA was identified in 62% of specimens. Nine patients were selected for vaccination based on MAGE-A12 expression and the presence of HLA-Cw*0702. The immune response was monitored both by tetrameric HLA-Cw*0702/MAGE-A12:170-178 complexes and by analysis of interferon-gamma mRNA transcription using a quantitative real-time polymerase chain reaction assay after peptide-specific stimulation. The samples consisted of circulating lymphocytes analyzed ex vivo or after 10 to 14 days of in vitro sensitization. One of 9 patients sustained an ongoing partial clinical response. No convincing evidence of enhancement of the systemic immune response against MAGE-A12:170-178 could be documented. Because of the modest immunological and clinical results, the present protocol has been discontinued as new routes of administration are being considered.
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PMID:Clinical and immunological evaluation of patients with metastatic melanoma undergoing immunization with the HLA-Cw*0702-associated epitope MAGE-A12:170-178. 1267 81

"Cancer-germline" genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific Ags, which have been used in therapeutic vaccination trials of cancer patients. MAGE-3 is expressed in 74% of metastatic melanoma and in 50% of carcinomas of esophagus, head and neck, bladder, and lung. We report here the identification of a new MAGE-3 peptide, which is recognized by three different CD4(+) T cell clones isolated from a melanoma patient vaccinated with a MAGE-3 protein. These clones, which express different TCRs, recognize an HLA-DR1 peptide ACYEFLWGPRALVETS, which corresponds to the MAGE-3(267-282) and the MAGE-12(267-282) protein sequences. One of the T cell clones, which expresses LFA-1 at a high level, lysed tumor cells expressing DR1 and MAGE-3. Another of these DR1-restricted CD4(+) clones recognized not only the MAGE-3/12 peptide but also homologous peptides encoded by genes MAGE-1, 2, 4, 6, 10, and 11.
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PMID:A MAGE-3 peptide presented by HLA-DR1 to CD4+ T cells that were isolated from a melanoma patient vaccinated with a MAGE-3 protein. 1281 1

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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