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      Dendritic Cells Retrovirally Transduced with a Model Antigen Gene Are Therapeutically Effective against Established Pulmonary Metastases

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          Abstract

          Dendritic cells (DCs) are bone marrow–derived leukocytes that function as potent antigen presenting cells capable of initiating T cell–dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding β-galactosidase (β-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45–78% double positive for DC phenotypic cell surface markers by FACS ® analysis, and DC transduced with β-gal were 41–72% positive for β-gal expression by X-gal staining. In addition, coculture of β-gal transduced DC with a β-gal–specific T cell line (CTLx) resulted in the production of large amounts of interferon-γ, demonstrating that transduced DCs could process and present endogenously expressed β-gal. DC transduced with β-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, β-gal. Treatment with β-gal–transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with β-gal–transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the L d-restricted β-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.

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          Most cited references 25

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          Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells.

          In this pilot study, we investigated the ability of autologous dendritic cells pulsed ex vivo with tumor-specific idiotype protein to stimulate host antitumor immunity when infused as a vaccine. Four patients with follicular B-cell lymphoma received a series of three or four infusions of antigen-pulsed dendritic cells followed, in each instance, by subcutaneous injections of soluble antigen two weeks later. All patients developed measurable antitumor cellular immune responses. In addition, clinical responses have been measured with one patient experiencing complete tumor regression, a second patient having partial tumor regression, and a third patient resolving all evidence of disease as detected by a sensitive tumor-specific molecular analysis.
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            Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines

            Antigen presentation by host dendritic cells (DC) is critical for the initiation of adaptive immune responses. We have previously demonstrated in immunogenic murine tumor models that bone marrow (BM)- derived DC pulsed ex vivo with synthetic tumor-associated peptides, naturally expressed by tumor cells, serve as effective antitumor vaccines, protecting animals against an otherwise lethal tumor challenge (Mayordomo, J.I., T. Zorina, W.J. Storkus, C. Celluzzi, L.D. Falo, C.J. Melief, T. Ildstad, W.M. Kast, A.B. DeLeo, and M.T. Lotze. 1995. Nature Med. 1:1297-1302). However, T cell-defined epitopes have not been identified for most human cancers. To explore the utility of this approach in the treatment of tumors expressing as yet uncharacterized epitopes, syngeneic granulocyte/macrophage colony- stimulating factor-stimulated and BM-derived DC, pulsed with unfractionated acid-eluted tumor peptides (Storkus, W.J., H.J. Zeh III, R.D. Salter, and M.T. Lotze. 1993. J. Immunother. 14:94-103) were used to treat mice bearing spontaneous, established tumors. The adoptive transfer of 5 x 10(5) tumor peptide-pulsed DC dramatically suppressed the growth of weakly immunogenic tumors in day 4 to day 8 established MCA205 (H-2b) and TS/A (H-2d) tumor models, when applied in three biweekly intravenous injections. Using the immunogenic C3 (H-2b) tumor model in B6 mice, tumor peptide-pulsed DC therapy resulted in the erradication of established d14 tumors and long-term survival in 100% of treated animals. The DC-driven antitumor immune response was primarily cell mediated since the transfer of spleen cells, but not sera, from immunized mice efficiently protected sublethally irradiated naive mice against a subsequent tumor challenge. Furthermore, depletion of either CD4+ or CD8+ T cells from tumor-bearing mice before therapy totally suppressed the therapeutic efficacy of DC pulsed with tumor- derived peptides. Costimulation of the host cell-mediated antitumor immunity was critical since inoculation of the chimeric fusion protein CTLA4-Ig virtually abrogated the therapeutic effects of peptide-pulsed DC in vivo. The analysis of the cytokine pattern in the draining lymph nodes and spleens of tumor-bearing mice immunized with DC pulsed with tumor-eluted peptides revealed a marked upregulation of interleukin (IL) 4 and interferon (IFN) gamma production, as compared with mice immunized with DC alone or DC pulsed with irrelevant peptides. DC- induced antitumor effects were completely blocked by coadministration of neutralizing monoclonal antibody directed against T helper cell 1- associated cytokines (such as IL-12, tumor necrosis factor alpha, IFN- gamma), and eventually, but not initially, blocked by anti-mIL-4 mAb. Based on these results, we believe that DC pulsed with acid-eluted peptides derived from autologous tumors represents a novel approach to the treatment of established, weakly immunogenic tumors, and serves as a basis for designing clinical trials in cancer patients.
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              The biochemistry and cell biology of antigen processing and presentation.

              T lymphocytes with alpha beta receptors recognize antigen in association with the polymorphic products of the class I and class II loci of the major histocompatibility complex (MHC). This presentation of antigen results from the intracellular generation of protein fragments, and the binding and transport to the cell surface of these peptides in stable association with the MHC class I and class II molecules. Each class of MHC molecule appears specialized for capture of peptides present in a particular intracellular compartment. We describe here the structural basis of peptide-MHC molecule interaction, the differences in biochemical behavior that focus the two classes of MHC molecules on peptides of distinct size and location, and the cell biology of MHC molecule transport, peptide generation, and intracellular movement. The importance of conformational changes accompanying peptide binding that affect subunit stability of MHC molecules, and the relationship between these changes and the handling of proteins by intracellular chaperones, are emphasized as key features in the operation of the class I and class II presentation pathways.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                20 October 1997
                : 186
                : 8
                : 1213-1221
                Affiliations
                From the [* ]Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and the []Howard Hughes Medical Institute–National Institutes of Health Research Scholars Program, Bethesda, Maryland 20814
                Author notes

                Address correspondence to Patrick Hwu, Surgery Branch, National Cancer Institute, National Institutes of Health, Bldg. 10, Rm 2B42, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-402-1156; FAX: 301-435-5167; E-mail: pat@ 123456helix.nih.gov

                Article
                2199086
                9334360
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                Medicine

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