IgM Anti-Ganglioside Antibodies Induced by Melanoma Cell Vaccine Correlate with Survival of Melanoma Patients

Takahashi, Takenori; Johnson, Timothy D.; Nishinaka, Yumiko; Morton, Donald L.; Irie, Reiko F.

doi:10.1046/j.1523-1747.1999.00493.x

Cited by 75 publications

(43 citation statements)

References 20 publications

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“…Tumor-associated gangliosides are highly immunogenic in humans (10). In studies of active immunotherapy, patients who received a melanoma cell vaccine for treatment of metastatic melanoma had survival rates that correlated with serum concentrations of IgM but not IgG anti-ganglioside antibody (11,12). In studies of passive immunotherapy, i.t.…”

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confidence: 99%

Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma

Azuma¹,

Ishikawa²,

Kawai³

et al. 2007

Clinical Cancer Research

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Purpose: L612, a human IgM monoclonal antibody produced by an EBV-transformed human B-cell line, binds to ganglioside GM3 and kills GM3-positive human melanoma cells in the presence of complement. It has been shown to be effective in some patients with late-stage melanoma. L612 consists of hexameric IgM (about 20%), pentameric IgM (about 74%), and other minor IgM molecules. Because hexameric IgM activates complement more effectively than pentameric IgM, we developed and evaluated a hexamer-dominant recombinant IgM for clinical applications. Experimental Design: Chinese hamster ovary (CHO) cells were transfected with heavy-and light-chain genes of L612, with or without the joining-chain gene. Antitumor effects of the recombinant IgM secreted from CHO cells were evaluated in vitro and in vivo. Results: Recombinant IgM secreted from CHO cells without the joining chain (designated CA19) was f80% hexameric, whereas recombinant IgM from CHO cells transfected with heavy-, light-, and joining-chain genes (designated CJ45) was about 90% pentameric. Both CA19 and CJ45 recombinant IgMs caused complement-dependent cytotoxicity against human and mouse melanoma cell lines, but the amount of CA19 required for 50% specific cytotoxicity was 5 to 10 times smaller. I.v. injection of CA19 compared with CJ45 or native L612 elicited more profound antitumor activity in nude rats bearing a GM3-positive mouse melanoma xenograft. Conclusions: A hexamer-dominant human IgM against GM3 may provide a more potent treatment option for patients with GM3-positive melanoma.

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confidence: 99%

Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma

Azuma¹,

Ishikawa²,

Kawai³

et al. 2007

Clinical Cancer Research

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“…[12][13][14] In addition, CD1 molecules have been shown to be involved in immune responses directed against tumors which express neuraminic acid containing glycolipids called gangliosides. [15][16][17][18] Immunotherapy approaches using ganglioside vaccines were therefore used in several cancers, including melanoma. mising glycolipid presentation to CD1-restricted T cells.…”

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confidence: 99%

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

Gerlini

Tun-Kyi

Dudli

et al. 2004

The American Journal of Pathology

130

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CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n ‫؍‬ 10) but not in primary melanoma lesions (n ‫؍‬ 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor. CD1 molecules are cell surface glycoproteins and represent a non-classical, non-polymorphic antigen-presenting system which is distantly related to major histocompatibility complex (MHC) class I and class II molecules. While MHC molecules form complexes with peptides, the CD1 system presents lipids and glycolipids of self and foreign origin.

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“…It is particularly difficult to predict relevant responses, and traditional methods for profiling antiglycan responses lack the necessary throughput for comprehensive evaluations. Although relatively few studies of humoral responses to glycans have been published, several associations between clinical outcome and antiglycan antibody responses have been reported (17)(18)(19). These studies analyzed only a few glycans in a small number of patients; more in-depth studies could uncover other important antiglycan responses.…”

Section: Significancementioning

confidence: 99%

Humoral response to a viral glycan correlates with survival on PROSTVAC-VF

Campbell

Gulley

Oyelaran

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Because individual cancer patients differ considerably in their clinical benefits from immunotherapies, early indicators of response could help physicians personalize treatments. Unfortunately, conventional clinical response criteria can be misleading for cancer vaccines. Herein, we show that early humoral responses to xenogenic Forssman disaccharide displayed on PROSTVAC-VF’s viral vectors correlate with long-term survival of vaccinated prostate cancer patients. The survival correlation for anti-Forssman responses was observed consistently when PROSTVAC-VF was used either as monotherapy or combined with the radiopharmaceutical Quadramet. Monitoring postvaccination anti-Forssman humoral responses could offer a simple indicator of response many months before conventional clinical response criteria become reliable. Finally, this study suggests that modifying glycans may improve poxvirus-based vaccines even when not specifically designed to target glycans.

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IgM Anti-Ganglioside Antibodies Induced by Melanoma Cell Vaccine Correlate with Survival of Melanoma Patients

Cited by 75 publications

References 20 publications

Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma

Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

Humoral response to a viral glycan correlates with survival on PROSTVAC-VF

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