Open AccessJournal Article
Autologous Human Monocyte-Derived Dendritic Cells Genetically Modified to Express Melanoma Antigens Elicit Primary Cytotoxic T Cell Responses In Vitro: Enhancement by Cotransfection of Genes Encoding the Th1-Biasing Cytokines IL-12 and IFN-α
Thomas Tüting,Cara C. Wilson,Dina M. Martin,Yvette L. Kasamon,Jennifer L. Rowles,Debora I. Ma,Craig L. Slingluff,Stephan Wagner,Pierre van der Bruggen,Joseph Baar,Michael T. Lotze,Walter J. Storkus +11 more
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TLDR
Results support the inherent strengths of gene-based vaccine approaches that do not require prior knowledge of responder MHC haplotypes or of relevant MHC-restricted peptide epitopes and may elicit a greater diversity of host therapeutic immunity, thereby enhancing the clinical utility and success of such approaches.Abstract:
DNA-based immunization strategies designed to elicit cellular antitumor immunity offer an attractive alternative to protein- or peptide-based approaches. In the present study we have evaluated the feasibility of DNA vaccination for the induction of CTL reactivity to five different melanoma Ags in vitro. Cultured, monocyte-derived dendritic cells (DC) were transiently transfected with plasmid DNA encoding human MART-1/Melan-A, pMel-17/gp100, tyrosinase, MAGE-1, or MAGE-3 by particle bombardment and used to stimulate autologous PBMC responder T cells. CTL reactivity to these previously identified melanoma Ags was reproducibly generated after two or three stimulations with genetically modified DC. Co-ordinate transfection of two melanoma Ag cDNAs into DC promoted CTL responders capable of recognizing epitopes from both gene products. Coinsertion of genes encoding the Th1-biasing cytokines IL-12 or IFN-alpha consistently enhanced the magnitude of the resulting Ag-specific CTL reactivity. Importantly, DC transfected with a single melanoma Ag cDNA were capable of stimulating Ag-specific CTL reactivity restricted by multiple host MHC alleles, some of which had not been previously identified. These results support the inherent strengths of gene-based vaccine approaches that do not require prior knowledge of responder MHC haplotypes or of relevant MHC-restricted peptide epitopes. Given previous observations of in situ tumor HLA allele-loss variants, DC gene vaccine strategies may elicit a greater diversity of host therapeutic immunity, thereby enhancing the clinical utility and success of such approaches.read more
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Dendritic Cells in Cancer Immunotherapy
Lawrence Fong,Edgar G. Engleman +1 more
TL;DR: Promising results from clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer suggest that immunotherapeutic strategies that take advantage of the antigen presenting properties of dendritic cells may ultimately prove both efficacious and widely applicable to human tumors.
Journal ArticleDOI
Dendritic Cell Vaccines for Cancer Immunotherapy
John M. Timmerman,Ronald Levy +1 more
TL;DR: Exploitation of the antigen-presenting properties of DCs offers promise for the development of effective cancer immunotherapies.
Journal ArticleDOI
Interferon-alpha in tumor immunity and immunotherapy.
TL;DR: Novel strategies for using these cytokines in cancer immunotherapy and in particular the use of IFN-alpha as an immune adjuvant for the development of cancer vaccines are suggested.
Journal ArticleDOI
Interferon-α and cancer : Mechanisms of action and new perspectives of clinical use
TL;DR: The advantage of using these cytokines as adjuvants of cancer vaccines and for the in vitro generation of highly active dendritic cells to be utilized for therapeutic vaccination of cancer patients is suggested.
Journal ArticleDOI
Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12.
Tetsuro Kikuchi,Yasuharu Akasaki,Toshiaki Abe,Takahiro Fukuda,Hideo Saotome,John L. Ryan,Donald Kufe,Tsuneya Ohno +7 more
TL;DR: Results show that administration of fusion cells and rhIL-12 safely induces clinical antitumor effects in some patients with malignant glioma.
References
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Journal ArticleDOI
The dendritic cell system and its role in immunogenicity
TL;DR: Dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells.
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A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma
P. van der Bruggen,Catia Traversari,Patrick Chomez,Christophe Lurquin,E De Plaen,B Van den Eynde,Alexander Knuth,Thierry Boon +7 more
TL;DR: In this paper, a gene was identified that directed the expression of antigen MZ2-E on a human melanoma cell line, which belongs to a family of at least three genes.
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Interleukin-12: A Proinflammatory Cytokine with Immunoregulatory Functions that Bridge Innate Resistance and Antigen-Specific Adaptive Immunity
TL;DR: IL-12 represents a functional bridge between the early nonspecific innate resistance and the subsequent antigen-specific adaptive immunity in the innate resistance/adaptive immune response to infection.
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Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation.
TL;DR: It is found that ligation of CD40 by CD40L triggers the production of extremely high levels of bioactive IL-12, which is the most potent stimulus in upregulating the expression of ICAM-1, CD80, and CD86 molecules on DCs.
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Proliferating dendritic cell progenitors in human blood.
Nikolaus Romani,S Gruner,D. Brang,Eckhart Kämpgen,Angela Lenz,B Trockenbacher,G Konwalinka,Peter O. Fritsch,Ralph M. Steinman,Gerold Schuler +9 more
TL;DR: Large numbers of DC progenitors are observed in cord blood and in adult blood from healthy donors, which should facilitate future studies of their Fc epsilon RI and CD4 receptors, and their use in stimulating T cell-mediated resistance to viruses and tumors.