Dendritic cell immunotherapy: mapping the way

Figdor, Carl G.; Vries, I. Jolanda M. de; Lesterhuis, W. Joost; Melief, Cornelis J.M.

doi:10.1038/nm1039

Cited by 886 publications

(753 citation statements)

References 44 publications

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“…38 In the clinical trial reported here, the DC viability immediately before injection was homogeneously high (Table 1). Regarding the DC phenotype, we noted considerable interpatient variation in the DC expression of maturation marker CD83 (Table 1).…”

Section: Discussionmentioning

confidence: 73%

Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

et al. 2006

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We have developed an individualized melanoma vaccine based on transfection of autologous dendritic cells (DCs) with autologous tumor-mRNA. Dendritic cells loaded with complete tumor-mRNA may generate an immune response against a broad repertoire of antigens, including unique patient-specific antigens. The purpose of the present phase I/II trial was to evaluate the feasibility and safety of the vaccine, and the ability of the DCs to elicit T-cell responses in melanoma patients. Further, we compared intradermal (i.d.) and intranodal (i.n.) vaccine administration. Twenty-two patients with advanced malignant melanoma were included, each receiving four weekly vaccines. Monocyte-derived DCs were transfected with tumor-mRNA by electroporation, matured and cryopreserved. We obtained successful vaccine production for all patients elected. No serious adverse effects were observed. A vaccine-specific immune response was demonstrated in 9/19 patients evaluable by T-cell assays (T-cell proliferation/interferon-g ELISPOT) and in 8/18 patients evaluable by delayed-type hypersensitivity (DTH) reaction. The response was demonstrated in 7/10 patients vaccinated intradermally and in 3/12 patients vaccinated intranodally. We conclude that immuno-gene-therapy with the described DC-vaccine is feasible and safe, and that the vaccine can elicit in vivo T-cell responses against antigens encoded by the transfected tumor-mRNA. The response rates do not suggest an advantage in applying i.n. vaccination. Cancer Gene Therapy (2006) 13, 905-918.

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Section: Discussionmentioning

confidence: 73%

Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

et al. 2006

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“…Inadequate DC characterization for each included patient has made interpretation and comparison of several previous DC trials difficult. 30 In our previous model systems for DC generation from healthy donors, a high component of CD14 þ cells was not observed. 16 The component of CD14 þ cells found in full-scale prepararations from melanoma patients could be due to a higher concentration of cells during culture.…”

Section: Discussionmentioning

confidence: 88%

“…In a vaccine trial, proper immunomonitoring will be essential, also for interpretation of clinical observations. 30 As responses in this vaccine approach could be directed to any of a broad array of unknown transfected antigens, testing with known melanoma antigens would be of limited value. We will accordingly test primarily for responses against the vaccine itself, using mockDCs as a negative control.…”

Section: Discussionmentioning

confidence: 99%

Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination

et al. 2005

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Most cancer vaccines to date have made use of common tumor antigens or allogenic cancer cell lines. The majority of tumor antigens may, however, be unique patient-specific antigens. Dendritic cells (DCs) are the most potent antigen-presenting cells known. The present report is a full-scale preclinical evaluation of autologous DCs transfected with autologous tumor-mRNA (tDCs) for vaccination in malignant melanoma. By using autologous tumor-mRNA, we intend to make the DCs present a broad spectrum of tumor-associated antigens relevant to each individual patient. Previously, we have described effective methods for mRNAtransfection into DCs by square-wave electroporation and for generating large numbers of DCs. Here, we demonstrate the ability of tDCs, made under full-scale vaccine conditions, to generate in vitro T-cell responses specific for antigens encoded by the transfected tumor-mRNA. T-cell proliferation assays demonstrated tDC-specific responses for all six patients tested. Responses were further studied by IFNg ELISPOT and Bioplex cytokine assays (two patients) and by experiments on isolated CD4 þ and CD8 þ T cells, including HLA-blockage (one patient). Moreover, we describe the results of extensive tumor-RNA analysis using Agilent Bioanalyser, a method that we have implemented in the clinical protocol. Based on this preclinical evaluation, a vaccine trial has been started.

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“…2 Several clinical studies exploit monocyte-derived DC (moDCs) vaccines to induce antigen-specific response in cancer patients. 3 Integrins are transmembrane a/b-heterodimers that regulate cell-cell and cell-extracellular matrix interactions. Lymphocyte function-associated antigen-1 (LFA-1, aLb2) is a leukocyte-specific integrin that mediates firm arrest on the endothelium and, within tissues, cell tethering and the formation of the immunological synapse.…”

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confidence: 99%

The lymphoid chemokine CCL21 triggers LFA‐1 adhesive properties on human dendritic cells

et al. 2010

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Dendritic cells (DCs) are the most potent APCs, involved in the induction of immunity and tolerance. Recently we showed that during differentiation of human DCs from monocyte precursors, Lymphocyte function-associated antigen-1 (LFA-1)-binding capacity is lost, although integrin expression levels were maintained constant, suggesting a different regulation mechanism of this integrin on different cell types. However, the exact role of LFA-1 in DC adhesion and migration remains obscure. Chemokines are potent regulators of integrin function, influencing migratory and adhesive properties of leukocytes. Here, we show that upon vaccination of cancer patients with human DCs, cells that have migrated in vivo into the lymph nodes upregulated the active form of LFA-1. We further show that exposure of human DCs to the lymphoid chemokine CCL21 specifically restores the high-affinity form of LFA-1 and induces binding to its ligand ICAM-1 under low shear stress. Our data indicate that on DCs LFA-1 may function as an inducible anchor during lymphatic transmigration or within the lymph nodes. A thorough understanding of the adhesive events during the DC life cycle will help to improve the outcome of DC-based antitumor clinical trials. Keywords: integrin; cell adhesion; affinity; migration; antigen-presenting cell Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), involved in the induction of immunity and tolerance. 1 DCs presenting foreign or self-antigen migrate to the lymph node, a spatially defined compartment that facilitates encounter of APCs with rare Ag-specific naive T and B cells. DCs originate from precursor cells in the blood (for example, monocytes) and are recruited to the tissues by transendothelial migration mediated by integrin-dependent arrest. 2 Several clinical studies exploit monocyte-derived DC (moDCs) vaccines to induce antigen-specific response in cancer patients. 3 Integrins are transmembrane a/b-heterodimers that regulate cell-cell and cell-extracellular matrix interactions. Lymphocyte function-associated antigen-1 (LFA-1, aLb2) is a leukocyte-specific integrin that mediates firm arrest on the endothelium and, within tissues, cell tethering and the formation of the immunological synapse. 4 LFA-1 shifts between bent, low-affinity and variable extended conformations with high affinity to its ligand intercellular adhesion molecule-1 (ICAM-1) and to a lesser extent also to ICAM-2 and ICAM-3. 5 Ligand binding can further be increased by dynamic redistribution of LFA-1 in the cell membrane, a phenomenon designated as avidity regulation. 6,7 In circulating leukocytes, LFA-1 remains largely inactive but becomes activated by endothelium-presented chemokines by signaling through G-protein-coupled receptors and application of shear stress, resulting in the extension of the molecule followed by immediate ligand binding. 8 The role of integrin activation in transendothelial migration has been widely studied. 9 Homing of DCs through the afferent lymphatics to the lymph nodes is still not comple...

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Dendritic cell immunotherapy: mapping the way

Cited by 886 publications

References 44 publications

Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA

Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination

The lymphoid chemokine CCL21 triggers LFA‐1 adhesive properties on human dendritic cells

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