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

In a previous randomized Phase III trial (P. O. Livingston et al, J. Clin. Oncol., 12: 1036-1044, 1994), we demonstrated that immunization with GM2 and bacille Calmette-Guerin reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-GM2 antibodies. That vaccine formulation induced IgM anti-GM2 antibodies in 74% but induced IgG anti-GM2 antibodies in only 10% of the patients. To optimize the immune response against GM2, a reformulated vaccine was produced conjugating GM2 to keyhole limpet hemocyanin (KLH) and using the adjuvant QS21 (GM2-KLH/QS21). In pilot studies, 70 microg of vaccine induced IgG anti-GM2 antibodies in 76% of the patients. We wished to define the lowest vaccine dose that induced consistent, high-titer IgM and IgG antibodies against GM2. Fifty-two melanoma patients who were free of disease after resection but at high risk for relapse were immunized with GM2-KLH/QS21 vaccine at GM2 doses of 1, 3, 10, 30, or 70 ILg on weeks 1, 2, 3, 4, 12, 24, and 36. Serum collected at frequent and defined intervals was tested for anti-GM2 antibodies. Overall, 88% of the patients developed IgM anti-GM2 antibodies; 71% also developed IgG anti-GM2 antibodies. GM2-KLH doses of 3-70 microg seemed to be equivalent in terms of peak titers and induction of anti-GM2 antibodies. At the 30-microg dose level, 50% of the patients developed complement fixing anti-GM2 antibodies detectable at a serum dilution of 1:10. We conclude that the GM2-KLH/QS21 formulation is more immunogenic than our previous formulation and that 3 microg is the lowest dose that induces consistent, high-titer IgM and IgG antibodies against GM2.
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PMID:Induction of antibodies against GM2 ganglioside by immunizing melanoma patients using GM2-keyhole limpet hemocyanin + QS21 vaccine: a dose-response study. 1074 10

Gangliosides have been thought to be tumor markers of various neuroectoderm-derived cancers. However, their roles in malignant phenotypes of cancer cells are not well understood. We have performed the remodeling of ganglioside profiles of mouse melanoma B16 (B78 subline) by introducing GM2/GD2 synthase cDNA, and analyzed the phenotypic changes such as cell morphology, growth, adhesion and c-fos gene expression. Although newly expressed GM2 was clearly detected, GM2-positive transfectant cells showed rather reduced growth rates in vivo and in vitro, lower expression levels of c-fos gene and increased levels of cell adhesion to extracellular matrices compared to control cells. These results suggested that GM2 is involved in the regulation of cell-cell or cell-extracellular matrix interaction, and negatively control cell proliferation.
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PMID:Alteration of tumor phenotypes of B16 melanoma after genetic remodeling of the ganglioside profile. 1085 34

Several gangliosides such as GM2, GD2, and GD3 have been thought of as target molecules for active or passive immunotherapy of human cancers because of their dominant expression on the tumor cell surface, especially in tumors of neuroectodermal origin. We established a number of mouse or rat monoclonal antibodies (mAbs) to a series of gangliosides to investigate the nature of the molecules on the cell surface. Some of those mAbs were converted to chimeric or humanized mAbs with the aim of developing immunotherapy for human cancer. It is desirable for mAbs to remain on the cell surface for a long time so that they can exert effector functions such as complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). We found that mAbs to GM2, GD2, and GD3 remain on the cell surface for > or =60 min after binding, while mAbs to other types of carbohydrate such as sialy Le(a) are quickly internalized. A chimeric mAb to GD3, KM871, was generated by linking cDNA sequences encoding light- and heavy-chain variable regions of mouse mAb KM641 with cDNAs encoding the constant region of human immunoglobulin gamma1 (IgG-1). KM871 bound to a variety of tumor cell lines, especially melanoma cells, including some cell lines to which R24 failed to bind. In a preclinical study, intravenous injection of KM871 markedly suppressed tumor growth and radiolabeled KM871 efficiently targeted the tumor site in a nude mouse model. This chimeric mAb is being evaluated in a phase I clinical trial in melanoma patients. The chimeric mAb KM966 and humanized mAb KM8969 to GM2 originated from a mouse IgM mAb. When human serum and human peripheral blood mononuclear cells were used as effectors in CDC and ADCC, respectively, KM966 and KM8969 killed GM2-expressing tumor cells effectively. In addition, these mAbs may induce apoptosis of a small cell lung cancer cell line cultured under conditions mimicking physiological tumor conditions.
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PMID:Recombinant antibodies against ganglioside expressed on tumor cells. 1095 Jan 41

The clinical experience that spontaneous anti-melanoma immune reactivity can occur has stimulated the search for methods to induce this in patients diagnosed with melanoma. Non-specific approaches using a variety of immune stimulants such as BCG or cytokines have met with limited success, as have vaccines derived from tumour cells. More recently, melanoma antigens have been identified that can act as specific targets for immune recognition. Cell surface glycolipids such as the gangliosides GM2 and GD3, can be targeted by antibodies. This has provided the basis for clinical trials with ganglioside vaccines and monoclonal antibody infusions. Antigens recognized by cytotoxic lymphocytes have also been described in the last 5 years. These are peptide antigens derived from intracellular proteins which are present on the cell surface in association with HLA molecules. These antigens include MAGE 1 and 3, tyrosinase, MelanA/MART-1 and gp100. Clinical trials with these have commenced and novel treatment strategies are being developed. Since tumours can be typed for specific antigens and specific immune responses can be measured, the reasons for treatment success or failure can be analysed more effectively than in the past. For example, the emergence of antigen-negative tumour variants can be assessed. This should enable a more systematic approach for developing new immunotherapies for melanoma.
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PMID:Immunotherapy of melanoma: targeting defined antigens. 1099 77

Last year the Melanoma Group of the European Organization for Research and Treatment of Cancer (EORTC-MG) completed accrual (1418 patients) for trial EORTC 18952, a three-arm phase III trial evaluating adjuvant therapy with two different intermediate doses of interferon (IFN) alfa-2b versus observation for stage IIB-III melanoma. About 25% of the patients entered the trial with tumor-positive sentinel nodes (SNs). Prognosis was significantly better in SN-positive patients than in patients with palpable regional node involvement (P < .00001). Subsequently the EORTC-MG embarked on two large phase III trials of adjuvant therapy based on the tumor status of the SN. In trial EORTC 18961 for stage II melanoma, GM2-KLH/QS-21 vaccination is compared with observation (1300 patients); in trial EORTC 18991 for stage III melanoma, 5-year treatment with pegylated interferon alfa-2b (PEG-Intron) is compared with observation (900 patients). Translational research projects will compare SN assessment by hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and reverse transcriptase-polymerase chain reaction (RT-PCR) to determine the relative accuracy of each method and its correlation to relapse and survival of patients with stage II melanoma. In stage III patients, a similar workup of the most proximal nonsentinel node in the full lymph-node dissection specimen will indicate the accuracy of each methodology to detect nodal metastasis beyond the SN and the prognostic significance thereof. These findings will be correlated to the results of sequential blood testing by RT-PCR and by tumor marker assays for S100, TA90, and angiostatin. In addition, tumor-positive and tumor-negative SNs will be assessed for activated cytotoxic T lymphocytes and downregulation of dendritic cell functions.
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PMID:The EORTC melanoma group translational research program on prognostic factors and ultrastaging in association with the adjuvant therapy trials in stage II and stage III melanoma. European Organization for Research and Treatment of Cancer. 1159 96

Gangliosides such as GD3, GM2, and GD2 are abundantly expressed on the cell surfaces of various malignant cells, suggesting the potential for anti-ganglioside antibody therapy for tumors. Anti-ganglioside GD2 antibody treatment is currently undergoing clinical trials for melanoma and neuroblastoma. We previously reported high in vivo antitumor effects of anti-GM2 ganglioside antibody against lung cancer. To determine whether anti-GM2 antibody may be clinically indicated for gastrointestinal cancers, we evaluated the mRNA expression of alpha2,8 sialyltransferase, a GD3 synthase, and beta1,4 N-acetylgalactosaminyltransferase (beta1,4 GalNAc-T), a GM2/GD2 synthase, in gastrointestinal cancers. We performed modified semi-quantitative RT-PCR, which reduces complexity incidental to radiolabeling on samples taken from small surgically removed clinical specimens. Stomach (19/22) and colorectal (21/30) cancers showed decreased expression of alpha2,8 sialyltransferase as compared with respective normal tissues (P < 0.05). In contrast, increased expression of beta1,4 GalNAc-T was detected in both types of tumors. Clinicopathological analysis revealed significantly higher expression level of alpha2,8 sialyltransferase in the poorly differentiated than in the well-differentiated stomach cancer group (P < 0.05). Furthermore, the expression level of alpha2,8 sialyltransferase was significantly decreased in male as compared with female colorectal cancer patients (P < 0.05). These results suggest that expression level of GM2 ganglioside is elevated in gastrointestinal cancer, and that anti-GM2 antibody may be applicable to its treatment.
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PMID:Decreased expression of alpha2,8 sialyltransferase and increased expression of beta1,4 N-acetylgalactosaminyltransferase in gastrointestinal cancers. 1185 18

Progenics Pharmaceuticals is developing GMK vaccine (a ganglioside conjugate vaccine coupled to keyhole limpet hemocyanin and formulated with the adjuvant QS-21), licensed from the Memorial Sloan-Kettering Cancer Center, for the potential treatment of melanoma and other cancers [194258], [325284]. It was previously under co-development with Bristol-Myers Squibb, but in May 2001, all rights to the GMK vaccine were returned to Progenics [409168]. It was the first of a new class of ganglioside conjugate vaccine evaluated by Progenics [194258]. GMK vaccination induces antibodies against GM2 ganglioside capable of specifically killing melanoma cells. Melanoma patients with antibodies against GM2 ganglioside have significantly improved disease-free and overall survival compared to antibody-negative subjects. The vaccine is undergoing two phase III trials, the first comparing GMK to high-dose IFNalpha in melanoma patients with more serious disease and at a high risk of relapse, and the second, in collaboration with the European Organization for Research and Treatment of Cancer, comparing GMK (14 doses of GMK over three years) to no treatment other than close monitoring of malignant melanoma patients at immediate risk of relapse [409168]. In February 1999, Lehman Brothers predicted that the vaccine had a 50% probability of reaching market, with an estimated first launch date in 2002. The analysts predicted potential peak sales in 2008 of $150 million in the US and $100 million in the rest of the world at that time [319225]. In January 2000, Lehman Brothers expected that an NDA filing would take place in 2002, with possible launch of the vaccine in 2003. In addition, Lehman Brothers estimated potential peak sales at $500 million [357788]. In August 2000, Punk, Ziegel & Company predicted that Progenics Pharmaceuticals will become sustainably profitable in 2003 following the launch of GMK and PRO-542 in 2002 [390063]. In July 2001, Ladenburg Thalmann predicted a $257 million market potential for GMK in the US, with the non-US market equivalent to the US market. A launch date of 2005 in the US, with a worldwide launch in 2006, was estimated [433347].
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PMID:GMK (Progenics Pharmaceuticals). 1205 67

Dendritic cell (DC) development and function is critical in the initiation phase of any antigen-specific immune response against tumours. Impaired function of DC is one explanation as to how tumours escape immunosurveillance. In the presence of various soluble tumour-related factors DC precursors lose their ability to differentiate into mature DC and to activate T cells. Gangliosides are glycosphingolipids shed by tumours of neuroectodermal origin such as melanoma and neuroblastoma. In this investigation we address the question of whether gangliosides suppress the development and function of monocyte-derived DC in vitro. In the presence of gangliosides, the monocytic DC precursors showed increased adherence, cell spreading and a reduced number of dendrites. The expression of MHC class II molecules, co-stimulatory molecules and the GM-CSF receptor (CD116) on the ganglioside-treated DC was significantly reduced. Furthermore, the function of ganglioside-treated DC was impaired as observed in endocytosis, chemotactic and T cell proliferation assays. In contrast to monocytic DC precursors, mature DC were unaffected even when higher doses of gangliosides were added to the culture. With regard to their carbohydrate structure, five different gangliosides (GM2, GM3, GD2, GD3, GT1b), which are typically shed by melanoma and neuroblastoma, were tested for their ability to suppress DC development and function. Suppression was induced by GM2, but not by the other gangliosides. These data suggest that certain gangliosides impair DC precursors, implying a possible mechanism for tumour escape.
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PMID:Gangliosides inhibit the development from monocytes to dendritic cells. 1245 34

A 68 year old woman developed oculomotor paresis shortly after metastatic progression of her melanoma was discovered. She was then immunised with the tumour antigen MAGE-3 in combination with an immunological adjuvant. During immunisation her symptoms worsened and she developed severe, predominantly proximal axonal motor neuropathy and became bedridden. IgM antibodies against gangliosides GM2, GD3, and GQ1b were detected in serum obtained two weeks before and nine weeks after the onset of symptoms. Immunohistochemically, the patient's IgM reacted with the tumour and co-localised with GQ1b. She improved neurologically following steroid treatment and became ambulatory.
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PMID:Paraneoplastic ophthalmoplegia and subacute motor axonal neuropathy associated with anti-GQ1b antibodies in a patient with malignant melanoma. 1264 75

Ten B16 mouse melanoma cell lines with increasing metastatic potential to lungs (B16LuF1 to B16LuF10) were generated by in-vitro & in-vivo selection technique starting with B16F1 melanoma cell line. The number of metastatic tumor nodules in lungs rose with increasing metastatic potential. Tumor cell gangliosides of B16LuF1 to B16LuF10 cell lines, analysed and compared with TLC, showed eight major ganglioside bands. Band1 to band6 corresponded with standard gangliosides GT1b, GD1b, GD1a, GM1, GM2 and GM3 respectively. Band7 and Band8 could not be identified. The concentration of total as well as individual ganglioside bands of B16LuF1 to B16LuF10 cells appeared to rise with increasing metastatic potential. Gangliosides from the plasma of these cell lines (B16LuF1 to B16LuF10) maintained in-vivo in C57BL/6 mice on TLC analysis gave eight major ganglioside bands, similar to those of cells. Plasma gangliosides appeared to rise with increasing metastatic potential. However, it was interesting to see that only band5 and band6 gangliosides in plasma increased almost linearly with increasing metastatic potential. The remaining six ganglioside bands in the plasma did not show such correlation. Band5 and Band6 gangliosides corresponded with standard gangliosides GM2 and GM3 respectively. Gangliosides of the spent culture media, secreted by these cell lines in-vitro in tissue culture also gave eight major ganglioside bands, similar to that of cells. Spent culture media gangliosides appeared to increase with increasing metastatic potential. However, concentration of only band5 and band6 gangliosides of spent culture media increased almost linearly with increasing metastatic potential, thus further confirming the role of band5(GM2) and Band6(GM3) gangliosides in regulating metastatic potential of B16-melanoma cells to lung.
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PMID:Correlation of gangliosides GM2 and GM3 with metastatic potential to lungs of mouse B16 melanoma. 1272 32


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