UMLS:C0025202 - FACTA Search

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ganglioside GM2, expressed on the surface of some human cancers, is a promising target for immune therapy, since GM2 antibodies are cytotoxic, can be induced in humans by vaccination, and the presence of GM2 antibodies is associated with a better prognosis in melanoma patients. In our efforts to induce long-lived, cytotoxic GM2 antibodies, we investigated lipopolysaccharides (LPS) containing "GM2-like" oligosaccharides. LPS were prepared from Campylobacter jejuni serotypes O:1, O:23, or O:36 (all sharing the oligosaccharide structure GalNAcbeta1-4Gal(113NeuAc)-Hex with ganglioside GM2), and tested for their ability to induce GM2-reactive antibodies. Immunization of NZW rabbits (2 animals per vaccine) with LPS from C. jejuni serotype O:1 in Freund's adjuvant resulted in production of high-titer IgG antibodies reactive with purified bovine brain GM2 in ELISA, dot-blot immune strains and immune thin-layer chromatography, and with GM2 derived from various human tumors by immune thin-layer chromatography. These rabbit antibodies bound to cancer cell lines expressing GM2 on their cell surface, as determined by mixed hemadsorption assays, mediating strong antibody-dependent cellular cytotoxicity (ADCC) with tumor cells expressing cell-surface GM2. Antibodies induced by vaccination with C. jejuni serotype O:1 were higher-titer (IgG ELISA titer > 1:60,000) than antibodies induced by immunization with purified GM2 (IgG ELISA titer > 1:200). Immunization with LPS from C. jejuni serotype O:36 resulted in production of moderately high-titer IgM and low-titer IgG GM2 antibodies. Immunization with LPS from C. jejuni serotype O:23 did not elicit GM2-reactive antibodies. No clinical symptoms were observed in animals immunized with these LPS preparations, with purified GM2 ganglioside, or with LPS derived from C. jejuni serotype O:19 (containing a GM1-like oligosaccharide). Our results indicate that lipopolysaccharides sharing carbohydrate epitopes with gangliosides may be useful immunogens for inducing antibodies to ganglioside antigens.
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PMID:Induction of antibodies reactive with GM2 ganglioside after immunization with lipopolysaccharides from Camplyobacter jejuni. 860 9

Different approaches to generating human monoclonal antibodies (MAbs) against tumor-associated ganglioside antigens have been carried out in several laboratories. A specific goal addressed by our laboratory is to produce human MAbs to several ganglioside antigens of relevance as therapeutic targets, such as the GM2, GD2, GD3 and GM3 gangliosides in melanoma. In vitro immunization of human B lymphocytes from normal donors was performed using liposomes containing gangliosides as the immunizing antigen combined with either complete tetanus toxoid or a synthetic peptide corresponding to a T helper epitope to stimulate in vitro immunization. Specific human anti-ganglioside antibodies were obtained, indicating that the antibody response found in vitro was antigen-driven. To overcome the widely reported problems concerning stability of immunoglobulin production by the antibody-secreting cell lines, a method of positive selection using GM3-coated magnetic beads has been developed in order to rescue unstable clones. Development of new methods to reproducibly generate ganglioside-specific human MAbs will amplify the possibilities for diagnostic and therapeutic applications.
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PMID:Generation of human monoclonal antibodies against ganglioside antigens and their applications in the diagnosis and therapy of cancer. 867 58

In the 1970s a considerable amount of work was carried out in an attempt to identify an anti-tumor serological response in cancer patients. These analyses have not been very informative due to the complexity and heterogeneity of the response. More recently, the availability of recombinant molecules, synthetic peptides and analytic and semi-quantitative assays has enabled a better dissection of humoral immunity. Antibodies against intracellular antigens (c-myb, c-myc, p53 and p21 ras) have been found in a significant, albeit varying, proportion of patients bearing various tumors. Association with a poor prognosis is documented for anti-p53 antibodies in breast carcinoma patients. A number of cell surface antigens, including mucins, oncoproteins and carbohydrate antigens have been found to elicit a humoral immune response and, in some instances, circulating immune complexes were observed. A protective role for or, on the other hand, masking effects of such antibodies is still controversial. An indication that a serological response can be beneficial comes from vaccination studies. A significant association between the development of an anti-tumor antigen antibody response and prolonged survival was observed following vaccination of melanoma patients with GM2 or anti-idiotypic antibodies which molecularly mimic tumor-associated antigens. It is to be hoped that in the near future the numerous ongoing immunization trials and prognostic studies demonstrate whether antibody response can exert a protective role in vivo.
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PMID:1975-1995 revised anti-cancer serological response: biological significance and clinical implications. 874 Jul 84

Natural IgM antibodies against the melanoma cell-surface ganglioside GM2, and IgM antibodies induced by vaccination with GM2 adherent to bacillus Calmette-Guerin, have been correlated with increased disease-free and overall survival in melanoma patients in previous phase I and II clinical trials. A vaccine containing GM2 covalently attached to keyhole limpet hemocyanin (KLH) plus the immunological adjuvant QS-21 now induces higher-titer, longer-lasting IgM antibodies against GM2 and has recently entered phase III clinical trials. For the first time this new vaccine also induces IgG antibodies against GM2 in the majority of immunized patients. With regard to immunity against bacteria, IgM antibodies have been described to be 1000-fold more effective than IgG antibodies at opsonification, complement-mediated cytotoxicity and protection from bacterial challenge. Though IgG antibodies have the theoretical advantage of being able to mediate antibody-directed cell-mediated cytotoxicity (ADCC), they may inhibit complement mediated IgM effector mechanisms against melanoma cells. Our goal was to confirm the functional characteristics of the anti-GM2 IgM and IgG antibodies induced by vaccination and to determine the impact that IgG antibodies might have on IgM antibody reactivity with GM2-positive tumor cells. Post-immunization sera from seven immunized patients were separated by size-exclusion chromatography into IgM and IgG fractions and a variety of serological assays were performed with the individual fractions and their combinations. Assays identifying specific IgM or IgG reactivity demonstrated partial inhibition by the opposite fraction. However, when the endpoint was complement-mediated lysis or overall antibody binding, which may more faithfully predict in vivo complement-mediated opsonification and lysis, the combinations of IgM and IgG fractions consistently demonstrated higher reactivity than either fraction alone. In addition, ADCC was induced in all seven patients. The results were the same whether the sera were obtained after 2 months or 2 years of immunizations. These findings suggest that IgG antibodies induced by the GM2-KLH plus QS-21 vaccine will not inhibit and should further augment the clinical impact of induced IgM antibodies.
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PMID:Tumor cell reactivity mediated by IgM antibodies in sera from melanoma patients vaccinated with GM2 ganglioside covalently linked to KLH is increased by IgG antibodies. 906 3

Melanoma among Japanese is rare, and differs in its clinical and histological characteristics from that found in Caucasians. In this study, the ganglioside expression of melanoma specimens obtained from Japanese was determined and compared with previously published data on Caucasians. The ganglioside composition of 25 biopsy melanoma specimens, including 13 primary and 12 metastatic lesions, was studied using thin layer chromatography. Four gangliosides (GM3, GD3, GM2, GD2) were most commonly expressed in melanomas in Japanese. The expression of gangliosides was quite variable in both primary and metastatic melanomas as seen in previous reports. No significant differences were observed between gangliosides from primary and metastatic sites. A new type of ganglioside expression, in which GM3 was nearly the only ganglioside (> 95%), was found in metastatic tumors from two Japanese patients with acral lentiginous melanoma (ALM), which is the most common clinical and histopathological type of melanoma among Japanese but is very unusual among Caucasians. The patterns of expression were similar to those in Caucasians except for the detection of a "new" pattern.
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PMID:Ganglioside expression in melanomas from Japanese individuals: unusual pattern in two patients with metastatic lesions of acral lentiginous melanomas. 926 26

Understanding the distribution of tumor-associated antigens on cancers and normal tissues is essential for selection of targets for cancer immunotherapy. Seven carbohydrate antigens, potential targets for immunotherapy, were studied using a panel of well-characterized MAbs by immunohistochemistry on cryostat-cut tissue sections of 13 types of cancers and 18 normal tissues. GD2 and GD3 were present on most cancers of neuroectodermal origin and GD2 was also present on B cell lymphomas. 9-O-acetyl-GD3 was detected only on melanoma while fucosyl GM1 was detected only on small cell lung cancers (SCLC). Surprisingly, GM2 was strongly expressed on all tested tumors, including cancers of neuroectodermal origin and cancers of epithelial origin. Polysialic acid was primarily expressed on SCLC and neuroblastomas. Globo H was present on most cancers of epithelial origin. These antigens were also identified in normal tissues. Fucosyl GM1 was not expressed significantly on any of the normal tissues analyzed. GD3, GD2, GM2 and polysialic acid were detected in normal brain to varying degrees. GM2 and Globo H were expressed on the luminal surface of epithelia of a variety of organs. The unexpected expression of GM2 on a broad range of cancers and normal epithelial tissues was confirmed by loss after methanol fixation and by immune thin layer chromatography.
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PMID:Selection of tumor antigens as targets for immune attack using immunohistochemistry: I. Focus on gangliosides. 933 8

A better understanding of immune recognition of cells has led to identification of potential new targets on tumor cells. Noticeable successes in melanoma have been immunization with the GM2 ganglioside vaccine, and the identification of novel antigens such as MAGE, BAGE and GAGE recognized by T cells cloned from cancer patients with regressing disease. However, the unexpected finding that other antigens recognized by these T cells were overexpressed normal differentiation antigens such as tyrosinase. Pmel 17 and Melan A have led to vaccines developed against differentiation antigens expressed in other solid tumors. Monoclonal antibody, anti-idiotype and antigen based vaccines for colorectal target antigens 17-1A, CEA and 791Tgp72 are all in clinical development. Similarly HER2/neu and mucin overexpression in breast cancer represent promising targets. Mutations in tumor oncogenes or suppressor genes which lead to malignant transformation can also present tumor-specific antigens. The most effective vaccines against infectious disease are live viruses. The development of DNA vaccines which act like viruses in entering cells and show continuous production of antigens offers great potential for the future.
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PMID:Cancer vaccines. 939 16

Gangliosides GM2 [GalNAc beta 1-4(NeuAc alpha 2-3)Gal beta 1-4Glc beta 1-1Cer] and GD2 [GalNAc beta 1-4(NeuAc alpha 2-8NeuAc alpha 2-3)Gal beta 1-4Glc beta 1-1Cer] are cell surface tumor-associated antigens and have been demonstrated to be important markers of human malignant melanoma progression. Expression of these glycolipid antigens on melanoma tissues can be assessed by immunohistochemistry or biochemical analysis. These methodologies, however, are not logistically practical or sensitive for testing metastatic melanoma cells in blood or in tissue biopsies. In the present study, we hypothesized that the enzyme involved in GM2 and GD2 synthesis, beta 1-->4-N-acetylgalactosaminyltransferase (beta 1-->4GalNac-T), can be a useful marker for detection of occult metastatic melanoma. A reverse transcription PCR and Southern blot assay to detect beta 1-->4GalNac-T mRNA expression was developed. Beta 1-->4GalNac-T mRNA was detected in all 13 melanoma cell lines tested. Metastatic melanoma of lymph nodes and different organ sites expressed beta 1-->4GalNac-T mRNA at various levels. Detection sensitivity of the reverse transcription PCR assay was 1 ng of total RNA extracted from tumor specimens and approximately 5 melanoma cells in 20 million normal donor peripheral blood lymphocytes. In assessment of blood from 126 melanoma patients, beta 1-->4GalNac-T mRNA was more frequently found in advanced-stage melanomas and in patients showing more aggressive tumor progression. Normal donor blood samples (n = 37) were all negative for beta 1-->4GalNac-T mRNA expression. These results suggest that beta 1-->4GalNac-T mRNA is a promising molecular marker for detecting melanoma cells, characterizing antigen expression, and monitoring tumor progression.
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PMID:Assessment of messenger RNA of beta 1-->4-N-acetylgalactosaminyl-transferase as a molecular marker for metastatic melanoma. 951 30

Various adjuvant therapy trials in high risk melanoma are at present ongoing in the world. Interferon-alpha (IFN-alpha) and ganglioside vaccines are currently being evaluated on both sides of the Atlantic Ocean. In Europe, the two largest randomized trials are being carried out by the EORTC Melanoma Cooperative Group. In patients with a moderate risk (about 35%) of having micrometastatic disease, EORTC trial 18961 will investigate placebo versus vaccination with the ganglioside GM2 vaccine (GM2-KLH/QS-21) in 1000 patients with stage IIA melanoma (T3N0M0). This trial will be started during spring 1997. In stage IIB-IIIB (T4N0M0-TxN1-2M0) patients with a very high risk (about 80%) of having micrometastatic disease, EORTC trial 18952 (1000 patients) will investigate placebo versus adjuvant therapy with high or low intermediate doses of IFN-alpha2b (10 MU subcutaneously every day, 5 days per week for 4 weeks, followed by either 10 MU subcutaneously, three times weekly for 1 year, or 5 MU subcutaneously, three times weekly for 2 years). This review will discuss the trials and the philosophy of the programme, which allows more toxic treatments to be investigated in patients with a very high risk, and only treatments with little or no toxicity to be evaluated in patients with only a modest risk of disease. Other recently completed and ongoing trials are also discussed. From all programmes it is clear that in the case of medical efficacy, the toxicity, impact on quality of life, and costs of the treatment determine whether a treatment will be accepted and implemented.
Melanoma Res 1997 Aug
PMID:The current EORTC Melanoma Cooperative Group adjuvant trial programme on malignant melanoma: prognosis versus efficacy, toxicity and costs. 957 28

Patients with AJCC Stage IIB and III melanoma have a poor 5-year survival rate which has been the driving force behind attempts to find an effective adjuvant therapy for this stage of disease that would effectively reduce relapse and improve survival. Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum, and levamisole have not been successful in achieving this goal, nor have trials with chemotherapy in the adjuvant setting, including high-dose chemotherapy with autologous bone marrow transplantation. The recent Eastern Cooperative Oncology Group (ECOG) 1684 study showed significant improvement in relapse-free and overall survival with high doses of alpha interferon (IFNalpha) given for 1 year. Lower dosages of IFNalpha have to date been unsuccessful in impacting upon long-term survival. Recent data with vaccines have been encouraging, and the GM2-KLH vaccine is the focus of ongoing intergroup study comparing this treatment with IFNalpha in resected Stage IIB and III melanoma. The various regimens are reviewed in this article.
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PMID:Adjuvant therapy of melanoma. 958 23

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