Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peptide specificity of cultured tumor-infiltrating lymphocytes (TIL) was systematically investigated in a group of HLA-A2.1+ metastatic melanoma patients consecutively referred to our department for surgical treatment. Seven samples from 6 patients were studied. All surgical specimens showed evidence of gp 100, MART-1/Melan-A and Tyrosinase gene expression as detectable by reverse PCR (rPCR). Cultured TIL from 2 patients displayed cytotoxic activity against autologous or HLA-matched EBV-transformed cells previously pulsed with MART-1/Melan-A27-35 peptide. In contrast, no CTL activity against gp100(280-288) or tyrosinase1-9 peptides could be observed. TIL were then repeatedly stimulated in vitro with the same peptides. After 6 restimulation courses at weekly intervals, specific recognition of gp100(280-288) and MART-1/Melan-A peptides was detectable in 3 and 5 TIL populations, respectively. In one case Tyrosinase1-9-specific CTL could be demonstrated. Two TIL populations from metastases resected from a melanoma patient at 6 months' distance showed a different peptide specificity pattern, and no specific CTL could be generated from simultaneously sampled peripheral blood mononuclear cells (PBMC). All peptide-specific CTL populations also displayed significant cytotoxic activity against HLA-A2.1 matched melanoma cell lines expressing the antigens under investigation. Our data indicate that CTL specific for MART-Melan-A27-35, gp100(280-288) or Tyrosinase1-9 peptides could be expanded with varying frequency from TIL derived from 4 out of 6 HLA-A2.1+ patients whose tumors expressed the genes encoding these tumor-associated antigens (TAA).
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PMID:Peptide-specific CTL in tumor infiltrating lymphocytes from metastatic melanomas expressing MART-1/Melan-A, gp100 and Tyrosinase genes: a study in an unselected group of HLA-A2.1-positive patients. 759 2

We applied an enzyme-linked immunospot (ELISPOT) assay for the detection and quantification of blood-derived CD8+ T cells recognizing peptide antigens presented by HLA-A2.1. CD8+ T lymphocytes were isolated from peripheral blood and were stimulated for 40 h with peptide-loaded A2.1-positive 0.174 x CEM.T2 cells. Tumor necrosis factor alpha (TNF-alpha) secreted by single T cells in response to antigen contact was trapped on nitrocellulose membranes precoated with anti-TNF-alpha antibodies and was then immunochemically visualized as spots. With this assay, up to 25% of cloned cytolytic T lymphocytes (CTL) were detected during the test period that recognized defined melanoma antigens in association with HLA-A2.1. CD8+ lymphocytes responsive to a known immunogenic HLA-A2.1-binding peptide from reverse transcriptase of the human immunodeficiency virus (HIV) were only detectable in HIV-infected patients, but not in anti-HIV-negative donors. T cells reacting with a peptide derived from a mutated cyclin-dependent kinase 4 (CDK4-R24C) were exclusively detected among CD8+ lymphocytes isolated from blood of the patient, whose melanoma had previously been found to carry the CDK4-R24C allele. T cells responding to HLA-A2.1-associated peptides of normal melanocyte differentiation antigens tyrosinase and Melan-A/MART-1 were found at low frequencies in almost all donors tested, which might reflect a natural autoimmunity to these antigens. However, in a melanoma patient we found a few days after surgery of melanoma metastases high frequencies of T cells against Melan-A/MART-1 and tyrosinase peptides (up to 38 per 10(5) CD8+ T cells), which gradually decreased during the following months. In an HIV-infected patient with progressive disease we observed a loss of T cells reactive with the HIV reverse transcriptase peptide. These observations provide evidence that peptide-dependent TNF-alpha spot formation in vitro resulted from previous antigen exposure in vivo. Therefore, the TNF-alpha ELISPOT assay might be useful in monitoring antigen-specific T lymphocyte responses during the natural course of diseases as well as during therapeutic interventions aiming at the induction of protective T cell immunity. In addition, it might help to identify immunodominant T cell epitopes.
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PMID:Detection and quantification of blood-derived CD8+ T lymphocytes secreting tumor necrosis factor alpha in response to HLA-A2.1-binding melanoma and viral peptide antigens. 866 32

Incidence and mortality of human malignant melanoma has risen rapidly over recent decades. Although the notorious resistance to treatment is characteristic for metastatic malignant melanoma, only a few experimental models have been established to study the metastatic cascade or to test new alternative treatment modalities. Thus, new human models are wanted. Here, we describe the metastatic behaviour of seven human melanoma cell lines derived from two primary cutaneous melanomas (WM 98-1, WM 1341) and five metastases established from liver (UKRV-Mel-4), skin (M7, M13), pleural effusion (UKRV-Mel-2) and lymph node (MV3). All cell lines were analysed for their capacity to grow in nude mice after s.c. and i.v. administration. M13 cells developed liver metastases spontaneously after s.c. injection, and subsequent passages of M13 and M7 melanoma cells caused liver metastases after i.v. injection, whereas MV3 and WM98-1 gave rise to lung metastases, using the same inoculation route. In contrast, WM 1341, UKRV-Mel-2 and UKRV-Mel-4 grew only very slowly in nude mice after s.c. injection and did not cause any metastases after i.v. or s.c. administration. The pattern of metastases or growth kinetics did not correlate with the interleukin 8 or tumour necrosis factor secretion of cell lines. Adhesion molecules and growth factor receptor expression on the cell lines differed widely, as determined by flow cytometry, with the low metastatic cell lines (UKRV-Mel-2, UKRV-Mel-4 and WM 1341) demonstrating a marked reduction in VLA-1 and VLA-5 expression compared with the metastatic lines (M7, M13, MV3 and WM 98-1). Expression of pigment-related proteins such as tyrosinase, TRP-1, TRP-2, Melan-A/MART-1, gp100, MAGE1 or MAGE-3 was not associated with growth and metastatic characteristics of the melanoma cell lines analysed. In conclusion, the established human melanoma cell lines exhibited diverse growth behaviour in nude mice in congruence with some early established prognostic markers such as VLA-1 and VLA-5. The xenografts provide good models for further study of metastatic processes as well as for evaluation of alternative treatment modalities including new pharmaceutical drugs and gene therapeutic targeting using tissue-specific gene regulatory elements for gene targeting.
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PMID:Metastatic potential of human melanoma cells in nude mice--characterisation of phenotype, cytokine secretion and tumour-associated antigens. 868 21

The human immune repertoire appears to be capable of recognizing normal antigens expressed by tumor cells. Among these antigens, those of differentiation, characterized by a restricted tissue expression, could be of clinical interest since they may represent a target for immunotherapeutic protocols. In this context we have evaluated, in benign and malignant lesions of the melanocytic lineage, the expression of the Melan-A/MART-1 antigen, which has been shown to be recognized by T cells, of HLA-A2 melanoma patients. The immunohistochemical analysis conducted with a Melan-A/MART-1 monoclonal antibody demonstrated that the antigen expression does not correlate with transformation or tumor progression. At variable levels Melan-A/MART-1, differently from other differentiation antigens, is homogeneously expressed by multiple autologous metastases and by melanoma metastases at different body sites. This tissue distribution adds further biological support to the ongoing use of Melan-A/MART-1-related peptides in active immunotherapy.
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PMID:Melan-A/MART-1 antigen expression in cutaneous and ocular melanomas. 940 52

Human melanoma cells express several antigens which are recognized by autologous and specific CTL clones in association with HLA-class-I molecules. Many of these antigens represent suitable targets for tumor immunotherapy, since their expression in human melanoma cells is common and highly specific. In order to achieve real clinical success with therapeutic vaccination strategies, one important requirement is the expression of the target antigen by all the tumor lesions of a patient. We have studied this issue by assessing, through an RT-PCR approach, the expression of MAGE-1, MAGE-2, MAGE-3, BAGE, GAGE-1/2, Tyrosinase and Melan-A/MART-1 genes in 17 clusters of simultaneous in-transit or regional lymph-node metastases collected from 15 stage-III and 1 stage-IV (AJCC/UICC pTNM system) melanoma patients. In 14 out of 17 clusters of simultaneous metastatic lesions (82%), the homogeneity in the pattern of gene expression within the cluster was complete. Heterogeneity within the same cluster was observed in only 3 out of 17 clusters (18%) and represented only minor features. Our data reveal that, in AJCC-stage-III melanoma patients, different but simultaneous metastatic lesions express the same pattern of antigen-coding genes. These observations have 2 main clinical implications: (i) the antigenic characterization of one single and easily accessible lesion allows identification of optimal targets for an active antigen-specific immunotherapy treatment; (ii) almost all the metastatic lesions are expected to be hit by the immune response eventually induced against the tumor antigen. Moreover, these data suggest that active specific immunotherapy directed against MAGE-1, MAGE-3, BAGE, GAGE-1/2, Melan-A/MART-1 and Tyrosinase antigens could be exploited as an adjuvant treatment to surgery in high-risk AJCC-stage-III-melanoma patients.
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PMID:High homogeneity of MAGE, BAGE, GAGE, tyrosinase and Melan-A/MART-1 gene expression in clusters of multiple simultaneous metastases of human melanoma: implications for protocol design of therapeutic antigen-specific vaccination strategies. 965 May 52

It has recently been shown that tumor-associated antigens (TAAs) can evoke tumor-specific T-cell-defined immune responses in cancer patients, thereby offering the possibility of treating patients with such antigens. To develop T-cell-based immunotherapeutic approaches for renal cell carcinoma (RCC), we studied the mRNA expression profile of the TAAs RAGE-1, tyrosinase, MAGE-1, MAGE-2, NY-ESO-1, Melan-A/MART-1, glycoprotein (gp) 75, gp100, beta-catenin, PRAME, and MUM-1 in 14 human RCC cell lines and in tissue specimens of 37 primary RCCs, 2 related metastases, and 33 specimens of normal renal epithelium. Reverse transcription-PCR was performed with TAA-reactive primers, and the specificity of the PCR products was confirmed by Southern blot and/or direct sequencing. PRAME (10 of 14 cell lines), RAGE-1 (7 of 14 cell lines), and gp75 (4 of 14 cell lines) antigens were expressed in a high percentage of RCC cell lines, although the level of TAA expression varied among the different RCC cell lines. However, low levels of TAA expression in RCC cells are sufficient for recognition by TAA-specific CTLs. Transcription of tyrosinase, Melan-A/MART-1, MAGE-1, MAGE-2, NY-ESO-1, gp100, beta-catenin, and MUM-1 was not detected in any RCC cell line. Approximately 50% of surgically removed neoplasias expressed at least one TAA. RAGE-1 mRNA expression was found in 8 of 39 (21%) RCC samples, PRAME mRNA expression was found in 15 of 39 (40%) RCC samples, and gp75 mRNA expression was found in 4 of 39 (11%) RCC samples, but the expression levels of these TAAs were heterogeneous in the different RCC lesions. One RCC specimen expressed MAGE-2, whereas transcription was not detected in any RCC specimen for MAGE-1, NY-ESO-1, tyrosinase, Melan-A/MART-1, gp100, beta-catenin, and MUM-1. The normal kidney epithelium samples were negative for any TAA tested. Thus, RAGE-1, PRAME, and gp75 expression is found with a different frequency in surgically removed lesions and in RCC cell lines, suggesting that a subgroup of RCC patients could be selected for immunotherapeutic strategies that may benefit from immunization against the RAGE-1, gp75, and/or PRAME antigens. However, additional targets for T-cell-based immunotherapy of RCC have yet to be identified.
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PMID:Heterogeneous expression of the tumor-associated antigens RAGE-1, PRAME, and glycoprotein 75 in human renal cell carcinoma: candidates for T-cell-based immunotherapies? 975 17

Recent insights in antigen presentation, the identification of human tumor antigens, and the demonstration of MHC class-I-restricted cytotoxic T lymphocyte (CTL) recognition of peptides encoded by tumor antigen have renewed the interest and enthusiasm for the development of cancer vaccines. Melanoma serves as a paradigm of an immunogenic human tumor, and several tumor antigens, including MAGE, MART-1/Melan-A and gp100, recognized by CTLs, have now been isolated. Candidate antigens for novel vaccine trials may include HLA class-I-binding tumor peptides that serve as CTL epitopes, whole tumor protein, or DNA-based vaccines. Requirements for the use of peptides are that the patient's tumor presents the relevant CTL epitopes as used in the vaccine and expresses the appropriate MHC class-I-restricting molecule. Immunological monitoring may be facilitated when using peptide-based vaccines. Because optimal presentation of tumor antigens may depend on provision of appropriate costimulatory signals, it may be more advantageous to administer professional antigen-presenting cells (APCs), such as dendritic cells (DCs) pulsed with tumor peptide or protein, to cancer patients. Developments in molecular genetics have led to a new approach in vaccines consisting of cancer cells genetically engineered to express immunomodulatory molecules. This may result in increased antitumor responses to both gene-modified as well as unmodified tumor cells. The therapeutic approach is extended to vaccination trials with recombinant viruses containing the genes encoding tumor antigens, minigenes containing multiple CTL epitopes, or double recombinant vectors engineered to express both the tumor antigen and immunostimulatory molecules. Clinical peptide, protein and DNA-based vaccine trials have recently been initiated. Thus far, exciting clinical remissions were obtained in melanoma patients following vaccination with HLA-A1-binding MAGE-3 peptide and in B-cell lymphoma patients immunized with autologous DCs pulsed with anti-idiotype protein, i.e., the individual patient's unique tumor antigen. Also, following injection of foreign HLA-B7 DNA into cutaneous melanoma metastases, T-cell migration into treated lesions and enhanced cellular immunity at the site of the tumor were shown in some patients. These encouraging results suggest that effective new vaccines in cancer will be identified.
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PMID:Vaccine Trials for the Clinician: Prospects for Tumor Antigens. 1038 61

Melanoma-reactive human cytotoxic T lymphocytes (CTLs) mediate tumor regression in vivo through specific recognition of MHC-associated peptide epitopes, many of which are encoded by the melanocytic tissue differentiation proteins gp100/Pme117 and MART-1/Melan-A. Vaccines using these peptides may induce protective or therapeutic immunity against melanoma. Rational design of such approaches is aided by a clear understanding of the identity of these antigenic peptides; however, most CTL epitopes described to date were identified indirectly. Especially where these peptides may be used in human clinical trials for the treatment or prevention of cancer, there is substantial need for direct evaluation of HLA-A*0201-associated peptides from MART-1 and gp100 that are naturally processed and presented. To that end, we have isolated peptides directly from HLA-A*0201 molecules of human melanoma cells and have determined that naturally processed epitopes for HLA-A*0201-restricted, melanoma-reactive CTLs include the nonamers MART-1(27-35) (AAGIGILTV), gp100(154-162) (KTWGQYWQV), gp100(209-217) (ITDQVPFSV) and gp100(280-288) (YLEPGPVTA) and the decamer gp100(476-485) (VLYRYGSFSV). Among these, the one that appears to be most abundant at the cell surface is gp100(154-162) (KTWGQYWQV). The others are among the less abundant peptides. HLA-A*0201-restricted CTLs from one melanoma patient who has survived metastatic disease recognized MART-1(27-35) (AAGIGILTV), gp100(280-288) (YLEPGPVTA) and gp100(154-162) (KTWGQYWQV) and were cross-reactive on longer peptides that contained these nonamer sequences. These peptides, identified by both an indirect genetic approach and by a direct peptide approach, can be used for tumor vaccine strategies with confidence that they are identical to the naturally processed peptide epitopes presented at the surface of melanoma cells in association with HLA-A*0201 molecules.
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PMID:Mass-spectrometric evaluation of HLA-A*0201-associated peptides identifies dominant naturally processed forms of CTL epitopes from MART-1 and gp100. 1041 64

The identification of circulating tumor cells in the peripheral blood of patients with malignant melanoma by detection of melanoma associated protein transcripts using the reverse transcriptase polymerase chain reaction (RT-PCR) technique has been introduced as a noninvasive and sensitive technique for early detection of tumor progression and metastatic disease. An alternative approach is the analysis of S-100 protein in the serum of melanoma patients by a luminoimmunometric assay (LIA). In this study, the sensitivities of RT-PCR and LIA were compared. Seventy-seven blood samples of 59 melanoma patients were analyzed for tyrosinase, Melan-A/MART-1, MAGE-3, gp100, and p97 expression by multimarker RT-PCR; 540 serum samples of 352 melanoma patients were analyzed for S-100 protein concentration by LIA. In stage III 23.8% and in stage IV 37.5% of the samples were positive for at least one marker in multimarker RT-PCR, versus 8.1% and 48.1% of elevated S-100 levels analyzed by LIA, respectively. In a direct comparison, 31 identical samples were analyzed by multimarker RT-PCR and by S-100 LIA. In stage III 18.2% and in stage IV 45% of the samples were positive by multimarker RT-PCR versus 45.5% and 80% by S-100 LIA, respectively. S-100 LIA was more sensitive in detection of metastatic disease in melanoma patients than multimarker RT-PCR and should be evaluated in further studies. RT-PCR might be more useful in the analysis of micrometastases in anatomic compartments other than peripheral blood.
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PMID:Tumor markers in peripheral blood of patients with malignant melanoma: multimarker RT-PCR versus a luminoimmunometric assay for S-100. 1054 77

Systemic effects on T-cell-mediated antitumor immunity, on expression of T-cell adhesion/homing receptors, and on the promotion of T-cell infiltration of neoplastic tissue may represent key steps for the efficacy of immunological therapies of cancer. In this study, we investigated whether these processes can be promoted by s.c. administration of low-dose (0.5 microg/kg) recombinant human interleukin-12 (rHuIL-12) to metastatic melanoma patients. A striking burst of HLA-restricted CTL precursors (CTLp) directed to autologous tumor was documented in peripheral blood by a high-efficiency limiting dilution analysis technique within a few days after rHuIL-12 injection. A similar burst in peripheral CTLp frequency was observed even when looking at response to a single tumor-derived peptide, as documented by an increase in Melan-A/Mart-1(27-35)-specific CTLp in two HLA-A*0201+ patients by limiting dilution analysis and by staining peripheral blood lymphocytes (PBLs) with HLA-A*0201-melanoma antigen-A/melanoma antigen recognized by T cells (Melan-A/Mart)-1 tetrameric complexes. The CTLp burst was associated, in PBLs, with enhanced expression of T-cell adhesion/homing receptors CD11a/CD18, CD49d, CD44, and with increased proportion of cutaneous lymphocyte antigen (CLA)-positive T cells. This was matched by a marked increase, in serum, of soluble forms of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecules (VCAM)-1 and intercellular adhesion molecules (ICAM)-1. Infiltration of neoplastic tissue by CDS+ T cells with a memory and cytolytic phenotype was found by immunohistochemistry in eight of eight posttreatment metastatic lesions but not in five of five pretreatment metastatic lesions from three patients. Increased tumor necrosis and/or fibrosis were also found in several posttherapy lesions of two of three patients in comparison with pretherapy metastases. These results provide the first evidence that rHuIL-12 can boost the frequency of circulating antitumor CTLp in tumor patients, enhances expression of ligand receptor pairs contributing to the lymphocyte function-associated antigen-1/ICAM-1, very late antigen-4/VCAM-1, and CLA/E-selectin adhesion pathways, and promotes infiltration of neoplastic lesions by CD8+ memory T cells in a clinical setting.
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PMID:Peripheral burst of tumor-specific cytotoxic T lymphocytes and infiltration of metastatic lesions by memory CD8+ T cells in melanoma patients receiving interleukin 12. 1091 69


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