Vaccination with Allogeneic Dendritic Cells Fused to Carcinoma Cells Induces Antitumor Immunity in MUC1 Transgenic Mice

Tanaka, Yasuhiro; Koido, Shigeo; Chen, Dongshu; Gendler, Sandra J.; Küfe, Donald; Gong, Jianlin

doi:10.1006/clim.2001.5112

Cited by 64 publications

(31 citation statements)

References 39 publications

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“…Allogeneic DCs have been proposed as an alternative approach for cancer immunotherapy with an argument that the alloagression offers a generic tool to promote an effective T cell response to self MHC-restricted tumor peptides (51). Although recent clinical trials failed to demonstrate immunogenicity of allogeneic DCs loaded with tumor lysates (52), several investigations have shown the Ag presentation and induction of a potent tumor-specific immune response by allogeneic DCs fused with syngeneic or autologous cancer cells (53)(54)(55)(56)(57). Thus, generation of allogeneic hES cell-derived DC/autologous cancer cell hybrids could be seen as a feasible approach to the development of hES cell-based vaccines.…”

Section: Discussionmentioning

confidence: 99%

Directed Differentiation of Human Embryonic Stem Cells into Functional Dendritic Cells through the Myeloid Pathway

Slukvin

Vodyanik

Thomson

et al. 2006

The Journal of Immunology

113

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We have established a system for directed differentiation of human embryonic stem (hES) cells into myeloid dendritic cells (DCs). As a first step, we induced hemopoietic differentiation by coculture of hES cells with OP9 stromal cells, and then, expanded myeloid cells with GM-CSF using a feeder-free culture system. Myeloid cells had a CD4+CD11b+CD11c+CD16+CD123lowHLA-DR− phenotype, expressed myeloperoxidase, and included a population of M-CSFR+ monocyte-lineage committed cells. Further culture of myeloid cells in serum-free medium with GM-CSF and IL-4 generated cells that had typical dendritic morphology; expressed high levels of MHC class I and II molecules, CD1a, CD11c, CD80, CD86, DC-SIGN, and CD40; and were capable of Ag processing, triggering naive T cells in MLR, and presenting Ags to specific T cell clones through the MHC class I pathway. Incubation of DCs with A23187 calcium ionophore for 48 h induced an expression of mature DC markers CD83 and fascin. The combination of GM-CSF with IL-4 provided the best conditions for DC differentiation. DCs obtained with GM-CSF and TNF-α coexpressed a high level of CD14, and had low stimulatory capacity in MLR. These data clearly demonstrate that hES cells can be used as a novel and unique source of hemopoietic and DC precursors as well as DCs at different stages of maturation to address essential questions of DC development and biology. In addition, because ES cells can be expanded without limit, they can be seen as a potential scalable source of cells for DC vaccines or DC-mediated induction of immune tolerance.

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Section: Discussionmentioning

confidence: 99%

Directed Differentiation of Human Embryonic Stem Cells into Functional Dendritic Cells through the Myeloid Pathway

Slukvin

Vodyanik

Thomson

et al. 2006

The Journal of Immunology

113

View full text Add to dashboard Cite

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“…Tetrameric assay of soluble class I MHC-peptide complexes were used to detect antigenspecific CTL [6]. Tetramer of HLA-A*0201-MUC1 peptide (STAPPVHNV) and irrelevant tetramer were purchased from PROIMMUNE (Oxford, UK).…”

Section: Tetramer Assaymentioning

confidence: 99%

“…In this case, the tumor antigens, known or unidentified, can be fully presented in the context of self HLA class I and class II molecules to autologous T cells. Allogeneic DC have been used to fuse with syngeneic or autologous tumor cells [3,[6][7][8]. The advantage of this approach is that the fusion cells express both tumor-derived HLA class I molecules for the presentation of self MHC-restricted tumor peptide and allogeneic HLA class II molecules derived from the DC for direct stimulation of patient CD4 T cells [9].…”

Section: Introductionmentioning

confidence: 99%

Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells

Koido

Tanaka

Tajiri

et al. 2007

Vaccine

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We have reported that fusions of patient-derived dendritic cells (DC) and autologous breast cancer cells induce T-cell responses against autologous tumors. However, the preparation of fusion cells requires patient-derived tumor cells, and these are not always available in the clinical setting. In the present study, we explore an alternative approach to constructing DC-breast cancer fusion vaccine by using breast caner-cell lines. DC generated from HLA-A*0201-positive donor were fused to HLA-A*0201 + allogeneic MCF7 breast cancer cells. These fusion cells co-expressed tumor-associated antigens and DC-derived costimulatory and MHC molecules. Both CD4 and CD8 T cells were activated by the fusion cells as demonstrated by the production of IFN-γ. The fusion cells induced strong antigen-specific CTL activity against their parent cells. The lysis of targets was restricted by HLA-A*0201, since killing was blocked by the anti-HLA-A2 mAb. Similar CTL activity against HLA-A*0201-positive targets was induced when T cells were cocultured with fusions of DC and HLA-A*0201-negative allogeneic BT20 breast cancer cells. In addition, administration of T cells stimulated by DC-breast cancer fusion cells regressed seven-day-old tumors and rendered mice free of disease up to 90 days. These results suggest that tumor-cell lines can be used as a fusion partner in the construction of DC-tumor fusion vaccine. Such fusion cells hold promise since they can be used as a vaccine for active immunotherapy or as stimulators to activate and expand T cells for adoptive immunotherapy.

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“…Tetrameric assay Tetrameric assay of soluble class I MHC-peptide complexes were used to detect antigen-specific CTLs. 29 Complexes of PElabeled HLA-A2-MUC1 tetramer (950-958, STAPPVHNV), HLA-A2-CEA tetramer (571-579, YLSGANLNL) or HLA-A24-CEA tetramer (652-660, TYACFVSNL) were used (Proimmune, Oxford, UK). Tetrameric staining was performed according to the manufacturer's instructions.…”

Section: T-cell Proliferation Assaymentioning

confidence: 99%

Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells

et al. 2005

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Human metastatic colorectal carcinomas (CRCAs) express carcinoembryonic antigen (CEA) and/or MUC1 tumor-associated antigens as potential targets for the induction of active specific immunity. In the present study, freshly isolated metastatic CRCA cells were successfully fused with immature autologous human monocyte-derived dendritic cells (DCs). The created heterokaryons (DC/CRCA) coexpress the CRCA-derived CEA and MUC1 antigens and DC-derived MHC class II and costimulatory molecules. The fusion cells were functional in stimulating the proliferation of autologous T cells. In addition, both CD4 1 and CD81 T cells were activated by fusion cells, as demonstrated by the production of high levels of IFN-c. More importantly, coculture of fusion cells with patient-derived peripheral blood mononuclear cells (PBMCs) resulted in the induction of antigen-specific cytotoxic T lymphocytes (CTLs). CTLs were effective at lysis of not only autologous CRCA cells but also the CEA and/or MUC1-positive and HLA partially matched target cells. Antigen-specific CTL responses were confirmed by tetrameric analysis. Coculture of PBMCs with fusion cells resulted in increased frequency of CEAand MUC1-specific CTLs simultaneously. Taken together, these results indicate that freshly isolated human metastatic CRCA cells expressing the CEA and/or MUC1 may represent a potential partner for the creation of DC/tumor fusion cells targeting induction of antigen-specific CTL responses. Our report demonstrates the simultaneous induction of CRCA-specific CTL responses restricted by HLA-A2 and -A24. ' 2005 Wiley-Liss, Inc.Key words: dendritic cell; cytotoxic T lymphocyte; cytokine; MHC; tumor immunity CRCA is one of the most common malignancies and often metastasizes to the liver, lymph nodes and lung. At diagnosis, 15-20% of patients with CRCA have presented with metastatic liver disease. 1 Surgical resection is the treatment of choice for colorectal liver metastasis. However, tumor recurrence in the liver occurs in up to 60% of patients who undergo surgical resection.2 Therefore, therapy to prevent the recurrence of liver metastasis is needed. In this context, immunotherapy represents a potential approach for the prevention of recurrence of colorectal metastases. In support of the immunotherapy approach is the finding that CRCA cells overexpress the CEA, MUC1, Ep-CAM and Her-2/ neu antigens.3-8 CRCA cells also express mutated forms of the p53 and adenomatous polyposis coli 5,9 tumor-suppressor genes. In fact, there is increasing evidence that tumor-reactive and antigenspecific CTLs exist in patients with CRCA and have been expanded from tumor-infiltrating lymphocytes and PBMCs in CRCA patients. 7,8,10 These results indicate that active specific immunotherapy can be developed in patients with metastatic CRCA.DCs are potent professional APCs capable of priming naive T cells and inducing antigen-specific CTLs.11,12 DCs derive their potency from the expression of MHC class I and II, and costimulatory molecules that provide secondary signals for the acti...

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Vaccination with Allogeneic Dendritic Cells Fused to Carcinoma Cells Induces Antitumor Immunity in MUC1 Transgenic Mice

Cited by 64 publications

References 39 publications

Directed Differentiation of Human Embryonic Stem Cells into Functional Dendritic Cells through the Myeloid Pathway

Directed Differentiation of Human Embryonic Stem Cells into Functional Dendritic Cells through the Myeloid Pathway

Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells

Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells

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